Food Prevention Age Related

Evidence-based
Functional Foods
for Prevention
of Age-related Diseases
Surajit Pathak
Antara Banerjee
Asim K. Duttaroy
Editors
123
Evidence-based Functional Foods for Prevention of
Age-related Diseases
Surajit Pathak • Antara Banerjee
Asim K. Duttaroy
Editors
Evidence-based
Functional Foods for
Prevention of Age-related
Diseases
Editors
Surajit Pathak Antara Banerjee
Faculty of Allied Health Sciences Faculty of Allied Health Sciences
Chettinad Hospital & Research Institute, Chettinad Hospital & Research Institute,
Chettinad Academy of Research and Chettinad Academy of Research and
Education Education
Chennai, Tamil Nadu, India Chennai, Tamil Nadu, India
Asim K. Duttaroy
Department of Nutrition, Faculty of
Medicine
Institute of Basic Medical Sciences
University of Oslo
Oslo, Norway
ISBN 978-981-99-0533-1 ISBN 978-981-99-0534-8 (eBook)

https://doi.org/10.1007/978-981-99-0534-8
© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore
Pte Ltd. 2023
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Preface
This book, Evidence-Based Functional Foods for Prevention of Age-Related

Disorders, deals with the beneficial impacts of functional foods on the health and
well-being of older people. Many chronic diseases such as CVD, brain disorders,
immune disorders, and cancers are more frequent in the aged population.
Nutrient requirements for optimum health and function of old physiological sys-
tems are often quite distinct from those for young people. Therefore, the unique
nutrition problems of the elderly are being intensively investigated. The growing
demand for healthy food has stimulated a rapid increase in research on functional
foods to prevent or address nutrient deficiencies and improve the health of the aging
population. Functional foods have been shown to modulate gene expression, cellu-
lar redox system, brain function, gut health, and immune function. Functional foods
include omega-3 fatty acids, polyamines, minerals, probiotics, prebiotics, polyphe-
nols, dietary fiber, etc. This book aims to provide an overview of recent develop-
ments in the role of functional foods in promoting healthy and active aging, with a
specific focus on their effects on the nutritional status of older adults.
The primary objective is to describe the latest development as to how food com-
ponents or supplements can help treat the aged population. This book has 20 chap-
ters that aim to describe the roles of functional foods in preventing age-related
disorders with the latest scientific developments in this area. The chapters describe
the roles of diet-gene interactions, macronutrients, polyamines, omega-3 fats, min-
erals, and several other nutrients, including antioxidants and energy restriction in
aging. This book provides current information on functional food components,
including antioxidants, omega-3 fats, prebiotics, bioactive flavonoids, minerals,
macronutrients, and many other bioactive food components. Each chapter details
the roles of functional foods in aging challenges and offers innovative and impactful
insights into those challenges and possible mechanisms. This book also presents
innovative functional food ideas for managing healthy aging and the processes and
investigation of aged people.
The chapters are written by recognized functional food specialists, medical sci-
entists, and nutritionists and cover the basics of functional food science. Despite
their busy schedules, these authors wrote chapters for this book. This book provides
v
vi Preface
the latest developments to food scientists, biochemists, medical doctors, nutrition-

ists, food technologists, students majoring in food science, and public health
professionals.
We hope that the book will be a valuable resource for older adult care providers
and government entities worldwide who are seeking ways to improve elder care and
may inspire collaborative opportunities to enhance the well-being of the aged
population.
We sincerely thank Springer Nature for assistance in publishing this book.
Chennai, Tamil Nadu, India Surajit Pathak

Chennai, Tamil Nadu, India Antara Banerjee
Oslo, Norway Asim K. Duttaroy
Contents
1 Cellular Aging: An Introduction, Principle, Hallmarks,

and Aging-Associated Diseases �� 1
Meenu Bhatiya, Asim K. Duttaroy, Surajit Pathak,
and Antara Banerjee
2 Anti-oxidant and Anti-ageing Mechanism of Bioactive
Compounds in Modulating the Ageing-Related Epigenetic Factors �� 19
Diptimayee Das, Amit Dey, Asim K. Duttaroy, Antara Banerjee,
and Surajit Pathak
3 iet-Gene Interactions that Regulate Longevity and Diseases�� 37
D
Tripti Nair, Sonia Verma, and Arnab Mukhopadhyay
4 Antioxidants and Ageing �� 61
Sayantan Chakraborty
5 utrition and the Ageing Brain�� 81
N
Emily Connell, Matthew Pontifex, and David Vauzour
6 mega-3 Fatty Acids and Ageing Brain�� 101
O
Navya Sree Boga and Sanjay Basak
7 raditional Foods and Ageing�� 129
T
Damal Chandrasekar Mathangi and
Arambakkam Janardhanam Hemamalini
8 acronutrients and Their Roles in Aging �� 137
M
Ahamed Basha Abdul Bari and Prince Johnson Samuel
9 Micronutrient Status Among Adults in the Asia Pacific
and Potential Impact on Age-Related Diseases �� 155
Stephen French, Taichi Inui, and Akiko Kuwabara
10 ut Microbiome and Its Metabolites in Ageing�� 183
G
Soumam Dutta and Asim K. Duttaroy
vii
viii Contents
11 Importance of Functional Foods Against Aging of Adult

Stem Cells �� 205
Jayanta Kumar Das, Theodore Lemuel Mathuram, Andres
Dominguez Solano, and Madhumita Das
12 Advantages of Functional Foods in Supporting and Maintaining
Hair and Skin Health�� 223
Vijayalakshmi Muraleedharan, Gayathri S Kamath,
Greeshma Sasikumar, and Sreejith Parameswara Panicker
13 elineating the Role of Phytochemicals in Targeting Age-Related
D
Cardiovascular Diseases Through the Lens of Network Medicine�� 245
Monojit Kamilya, Asim K. Duttaroy, and Subhajit Dutta
14 lant-Derived Natural Products Targeting Multiple Pathways as
P
Potential Therapeutics in the Treatment of Parkinson’s Disease�� 263
Amulya Vijay and Anandan Balakrishnan
15 ging in Indian Women: Health Status �� 281
A
Nirmalasaravanan Narayanasamy, Audinarayana N,
and Arindam Das
16 Energy Restriction on Cellular and Molecular Mechanisms
in Aging �� 297
Leila Haghshenas, Mohsen Nabi-Afjadi, Hamidreza Zalpoor,
Maryam Bakhtiyari, and Francesco Marotta
17 ge-Related Neurodegenerative Diseases�� 325
A
Narmadhaa Sivagurunathan and Latchoumycandane Calivarathan
18 reventive Role of Nutraceutical Agents Against Aging�� 345
P
R. Jayasree, C. Thangam, Langeswaran Kulanthaivel,
and Gowtham Kumar Subbaraj
About the Editors
Surajit Pathak Ph.D., is currently working as a Professor at the Chettinad Academy of Research
and Education, Kelambakkam, Chennai. He has received his Ph.D. in Zoology from the University
of Kalyani, West Bengal, India, in 2007, and completed his postdoctoral training at the University
of Alabama, USA, University of Padova, Italy, and University of Linkoping, Sweden. His current
research focuses on inflammatory bowel disease, colon cancer, and microRNA. He has published
more than 80 research articles in peer-reviewed international journals of repute. He is an editorial
board member of various renowned international high-impact journals. He is a member of multiple
professional research bodies in India and abroad.
Antara Banerjee is working as Associate Professor at the Chettinad Academy of Research and
Education, Chennai. She completed her Ph.D. in 2008 and pursued her postdoctoral research at the
University of Padova, Italy, till 2012. Later, she joined as a Senior Research Associate at the
University of Linkoping, Sweden, till 2015 and worked in collaboration with Karolinska Institute,
Sweden. She has published more than 70 high-impact peer-reviewed articles in international and
national journals. She is serving as an editorial board member and reviewer for several interna-
tional and national journals. Her core expertise is in stem cell biology and regenerative medicine,
and oncology and alternative medicine.
Asim K. Duttaroy is a professor at the Faculty of Medicine, University of Oslo, Norway. His
research programs focus on the roles of food components in growth and development and the
prevention of diseases such as diabetes and cardiovascular disease. He is also investigating the
roles of the antiplatelet and antihypertensive properties of fruits and vegetables. His discoveries of
antithrombotic factors in tomatoes and kiwifruits are patented internationally, and three companies
(Provexis Limited in the United Kingdom, IDIA AS in Norway, and Genimen Pharmacon in India)
are working to commercialize these discoveries. He has published over 300 research articles and
reviews, 7 books, and several book chapters and editorials. In addition, he is the Editor-in-Chief of
the journal Food & Nutrition Research and a guest editor of several journals such as Nutrients and
Frontiers in Physiology.
ix
Contributors
Audinarayana N Department of Sociology and Population Studies, Bharathiar

University, Coimbatore, Tamil Nadu, India
Maryam Bakhtiyari Department of Medical Laboratory Sciences, Qazvin
University of Medical Sciences, Qazvin, Iran
Anandan Balakrishnan Department of Genetics, Dr. ALM PG IBMS, University
of Madras, Chennai, Tamil Nadu, India
Antara Banerjee Faculty of Allied Health Sciences, Chettinad Hospital &
Research Institute, Chettinad Academy of Research and Education, Chennai, Tamil
Nadu, India
Ahamed Basha Abdul Bari Physiology, Chettinad Hospital and Research
Institute, Chettinad Academy of Research and Education, Chengalpattu, Tamil
Nadu, India
Sanjay Basak, PhD Molecular Biology Division, National Institute of Nutrition,
Indian Council of Medical Research, Hyderabad, India
Meenu Bhatiya Faculty of Allied Health Sciences, Chettinad Hospital & Research
Institute, Chettinad Academy of Research and Education, Chennai, Tamil
Nadu, India
Navya Sree Boga, Msc Molecular Biology Division, National Institute of
Nutrition, Indian Council of Medical Research, Hyderabad, India
Latchoumycandane Calivarathan Molecular Pharmacology and Toxicology
Laboratory, Department of Biotechnology, School of Integrative Biology, Central
University of Tamil Nadu, Thiruvarur, Tamil Nadu, India
Sayantan Chakraborty Department of Public Health, Amity Medical School,
Amity University Haryana, Gurgaon (Manesar), Haryana, India
Department of Public Health, Delhi Pharmaceutical Sciences and Research
University, Government of NCT of Delhi, New Delhi, Delhi, India
xi
xii Contributors
Emily Connell Norwich Medical School, Faculty of Medicine and Health Sciences,
University of East Anglia, Norwich, UK
Arindam Das Research, IIHMR, Jaipur, Rajasthan, India
Diptimayee Das Faculty of Allied Health Sciences, Chettinad Hospital & Research
Nadu, India
Jayanta Kumar Das Florida Memorial University, Miami Gardens, FL, USA
Miami Dade College, Miami, FL, USA
Palm Beach State College, Lake Worth, FL, USA
Madhumita Das Miami Dade College, Miami, FL, USA
Amit Dey Faculty of Allied Health Sciences, Chettinad Hospital & Research
Nadu, India
Asim K. Duttaroy Department of Nutrition, Faculty of Medicine, Institute of
Basic Medical Sciences, University of Oslo, Oslo, Norway
Soumam Dutta Food and Nutrition Division, University of Calcutta, Kolkata, India
Subhajit Dutta Department of Biotechnology, National Institute of Technology,
Durgapur, West Bengal, India
Functional Genomics and Metabolism Research Unit, Department of Biochemistry
and Molecular Biology, University of Southern Denmark, Odense M, Denmark
Stephen French Applied Health Sciences, School of Public Health, Indiana
University, Bloomington, USA
Leila Haghshenas Postdoc Association Member of Harvard Medical School,
Boston, MA, USA
Arambakkam Janardhanam Hemamalini Department of Clinical Nutrition, Sri
Ramachandra Faculty of Allied Health Sciences, Sri Ramachandra Institute of
Higher Education and Research, Chennai, Tamil Nadu, India
Taichi Inui DSM Nutritional Products, Tokyo, Japan
R. Jayasree Department of Pharmacology, Sri Venkateswaraa Medical College
Hospital and Research Institute, Chennai, Tamil Nadu, India
Monojit Kamilya Department of Biotechnology, National Institute of Technology,
College of Medicine and Health Sciences, University of UAE, Al Ain, Abu
Dhabi, UAE
Langeswaran Kulanthaivel Department of Biotechnology, Alagappa University,
Science Campus, Karaikudi, Tamil Nadu, India
Contributors xiii
Akiko Kuwabara Osaka Metropolitan University, Osaka, Japan

Francesco Marotta ReGenera R&D International for Aging Intervention and
Vitality and Longevity in Medical Science Commission, FEMTEC World
Federation, Milano, Italy
Damal Chandrasekar Mathangi Department of Mind Body Medicine and
Lifestyle Sciences, Sri Ramachandra Faculty of Allied Health Sciences, Sri
Ramachandra Institute of Higher Education and Research, Chennai, Tamil
Nadu, India
Theodore Lemuel Mathuram Department of Biochemistry, University at Buffalo,
Buffalo, NY, USA
Arnab Mukhopadhyay Molecular Aging Laboratory, National Institute of
Immunology, New Delhi, India
Vijayalakshmi Muraleedharan Department of Zoology, University of Kerala,
Thiruvananthapuram, Kerala, India
Mohsen Nabi-Afjadi Department of Biochemistry, Faculty of Biological Sciences,
Tarbiat Modares University, Tehran, Iran
Tripti Nair Molecular Aging Laboratory, National Institute of Immunology, New
Delhi, India
Nirmalasaravanan Narayanasamy Faculty of Mother Teresa Post Graduate and
Health Sciences, Puducherry, India
Sreejith Parameswara Panicker Advanced Centre for Regenerative Medicine
and Stem Cell Research in Cutaneous Biology (AcREM-Stem), University of
Kerala, Thiruvananthapuram, Kerala, India
Surajit Pathak Faculty of Allied Health Sciences, Chettinad Hospital & Research
Nadu, India
Matthew Pontifex Norwich Medical School, Faculty of Medicine and Health
Sciences, University of East Anglia, Norwich, UK
Prince Johnson Samuel Physiology, Vels Medical College and Hospital (under
VISTAS), Tiruvallur, Tamil Nadu, India
Greeshma Sasikumar Department of Zoology, University of Kerala,
Narmadhaa Sivagurunathan Molecular Pharmacology and Toxicology
Laboratory, Department of Biotechnology, School of Integrative Biology, Central
University of Tamil Nadu, Thiruvarur, Tamil Nadu, India
Andres Dominguez Solano Miami Dade College, Miami, FL, USA
xiv Contributors
Gowtham Kumar Subbaraj Faculty of Allied Health Sciences, Chettinad

Academy of Research and Education (Deemed to be University), Kelambakkam,
Tamil Nadu, India
C. Thangam Department of Pharmacology, KSR Institute of Dental Science and
Research, Tiruchengode, Tamil Nadu, India
David Vauzour Norwich Medical School, Faculty of Medicine and Health
Sciences, University of East Anglia, Norwich, UK
Sonia Verma Division of Neuroscience and Ageing Biology, CSIR-Central Drug
Research Institute, Lucknow, Uttar Pradesh, India
Amulya Vijay Department of Genetics, Dr. ALM PG IBMS, University of Madras,
Chennai, Tamil Nadu, India
Gayathri S Kamath Department of Zoology, University of Kerala,
Hamidreza Zalpoor American Association of Kidney Patients, Tampa, FL, USA
Chapter 1
Cellular Aging: An Introduction, Principle,
Hallmarks, and Aging-Associated Diseases
Meenu Bhatiya, Asim K. Duttaroy, Surajit Pathak, and Antara Banerjee
Abstract Aging is a complex natural biological process that shows progressive

decline or deterioration in physiological function with age. It is a series of processes
that rely on time. Cellular aging can be generally conceptualized by aging hallmarks
that lead to aging processes as well as determining the phenotypic and molecular
changes throughout the age. Aging is an impact of time, which shows changes in func-
tion at multiple levels, such as physiological (organ, tissue), cellular, molecular, phys-
iochemical (enzymatic, hormonal), and metabolic levels. Aging is an accumulation of
damage. Several research articles confirm that cellular senescence, oxidative stress,
and reactive oxygen species play a crucial role in aging and age-related disease devel-
opment. An imbalance among pro- and antioxidant species leads to oxidative stress,
that damages cells at the molecular level. Overproduction and accumulation of ROS
damage cellular macromolecules and influence lifespan. Here, we examine the funda-
mentals of aging and the hallmark of aging to explain the cellular and molecular-level
alterations related to aging. For understanding the mechanism of cellular aging, we
explain apoptosis, autophagy, and inflammation. Many diseases such as cardiovascu-
lar disease, cancer, diabetes, arthritis, and Alzheimer’s disease is associated with
aging. Here, we discuss the role of several natural bioactive compounds and flavo-
noids such as vitamin C in the treatment of supplementation in aging-related diseases.
Keywords Cellular senescence · Epigenetics · Telomeres · Hallmarks of aging

Plant extract
M. Bhatiya · S. Pathak · A. Banerjee (*)

Faculty of Allied Health Sciences, Chettinad Hospital & Research Institute,
Chettinad Academy of Research and Education, Chennai, Tamil Nadu, India
e-mail: antarabanerjee@care.edu.in
A. K. Duttaroy
Department of Nutrition, Faculty of Medicine, Institute of Basic Medical Sciences, University
of Oslo, Oslo, Norway
© The Author(s), under exclusive license to Springer Nature Singapore Pte 1

Ltd. 2023
S. Pathak et al. (eds.), Evidence-based Functional Foods for Prevention of
Age-related Diseases, https://doi.org/10.1007/978-981-99-0534-8_1
2 M. Bhatiya et al.
1.1 Introduction
1.1.1 Aging
Aging is a complicated biological process that, eventually leads to a time-depen-

dent deterioration in the function of the physiological organs, tissues, and cells.
The aging phenomenon is associated with a gradual deterioration of the systemic
and physiological functions of the different cellular, molecular, and tissue ele-
ments, and can be affected by both environmental and genetic factors (Rozing
et al. 2020). To sustain tissue homeostasis and function, a multicellular organism
must achieve a balance between cell mortality rate and cell propagation rate. A
variety of theories have been suggested to understand aging, such as the shorten-
ing of telomere, cellular senescence, accumulation of DNA damage in cells, and
degradation of several cellular organelles, such as mitochondria and ER. There is
no direct evidence supporting cellular senescence, but some evidence is available
that suggests that telomere shortening happens in aged tissues and cells (Di
Micco et al. 2021). Aging is the route for various risk factors such as cancer,
diabetes, cardiovascular disorders, and neurodegenerative diseases (de Pablos
et al. 2019).
1.2 Principles of Aging
Bio-gerontology is the branch of science that deals with the biological basis of
aging, aging-related disease, and age-related changes in organisms, the progres-
sion, and rate of aging vary from organism to organism, even in organs and tis-
sues within an organism also it varying (Harper and Holmes 2021). Thus, aging
can be defined at a broad, macro, and micro-molecule levels. Furthermore, bio-
gerontologists concluded that aging is programmed, stochastic, and individualis-
tic based on these observations. Aging is a biosocial issue, underlying the basis
of most of the major human diseases, such as cancer, cardiovascular diseases,
diabetes, dementia, neurodegeneration, and osteoporosis (Agraharam et al. 2022).
Whereas the effective diagnosis of every disease, despite age, is a social and
moral requirement, the best approach for improving the quality of human life in
old age is to minimize the risk of age-related diseases by interfering in the funda-
mental aging process. Accumulation of molecular damage is the major character-
istic of aging. The main cause of age- related damage accumulation is the
inefficiency and degradation, failure of the DNA repair system, and turnover of
signaling pathways (Ogrodnik et al. 2019). The progressive failure in mainte-
nance and repair mechanisms is the universal biochemical cause of aging and
age-related diseases. In other words, aging is the impact of time on the human
body. Aging shows variation at multiple levels such as enzymatic, hormonal, and
biochemical levels.
1 Cellular Aging: An Introduction, Principle, Hallmarks, and Aging-Associated… 3
1.2.1 Cellular and Metabolic Aging
Cellular aging is the limited number of times a cell can divide and after a particular
number of divisions, cells will lose their division capacity. The cell division poten-
tial of a cell is based on telomere length. Normally, the cell can divide almost 50
times until the telomere is not able to replicate due to telomere shortening. The cell
with more genetic damage, more free radicals, and other factors, would continue to
replicate due to alteration in cellular functioning (Bernitz et al. 2016). Hormones
have a tremendous role in aging. Hormone levels fluctuate throughout life, from
fetus development to teenage maturity and age. At the time of puberty, the hormonal
level carries acne and larger pores and at an older phase of life, hormones change
leading to dry, saggy, and loose wrinkled skin and menopause (Affrald and Narayan
2023). The cells, as per our daily routine, utilize food. The cell converts macro bio-
molecules into absorptive micro biomolecules and produces energy and by-
products. The alteration in the mechanism of metabolizing and producing energy
enables the individual to accumulate damage over the lifespan with time. According
to researchers, the alteration, slow and improper functioning of the metabolic func-
tion such as calorie restriction is the cause of delay in human aging (Katsyuba
et al. 2020).
1.3 Hallmarks of Aging
Aging is affected by the multi-factorial biological process and the hallmark of aging
provides a framework to study the primary or secondary cause of aging and explains
the mechanism in a systematic manner (Kaushik et al. 2021) (Fig. 1.1).
1.3.1 Primary Hallmarks
1.3.1.1 Genomic Instability
DNA stability and integrity are continually challenged by endogenous risks, includ-
ing defective DNA replication, accumulated (ROS) reactive oxygen species, and
spontaneous hydrolytic reactions as well as exogenous risks such as physical agents,
and chemical and biological agents (Kahroba et al. 2020). Genetic lesions are com-
plex due to extrinsic or intrinsic damage, including spontaneous mutation, point
mutations, gene destruction, chromosome translocations, chromosome addition and
deletion, and telomeric shortening due to virus or transposon incorporation. The
cellular system of organisms established a sophisticated system network known as
a DNA repair system is the potential to repair any kind of nuclear DNA damage
(Golato and Wilson III 2020). In addition, these specific nuclear DNA can even
cause genome instability, resulting in premature aging syndromes or aging-related
4 M. Bhatiya et al.
Fig. 1.1 Hallmarks of aging
diseases. This accumulated genetic damage during lifespan act as the basic denomi-
nator in aging (Ashapkin et al. 2019).
1.3.1.2 Telomere Attribution
Accumulated DNA damage during age directly affects the genome, although some
specific chromosomal zones, such as the telemetric regions, are specifically prone to
age-related diseases (Hu et al. 2022). A telomere at each end of a chromosome is a
region of repeated nucleotide sequences. The telomere shields the chromosomal end
from degradation and fusion with adjacent chromosomes. Specialized DNA poly-
merase called telomerase has the potential to synthesize the terminal ends of liner
DNA known as a telomere. Sometimes, the telomerase loses its replication capacity.
The exhaustion of telomere represents the limit of cell proliferative potential, so-
called replicative senescence or Hayflick limit (Hall et al. 2017).
1.3.1.3 Epigenetic Alteration
Epigenetic alterations such as DNA methylation, alterations in Histone protein,

Chromatin remodeling, Transcriptional alterations, and Inversion epigenetic altera-
tions, affect all cells and tissues throughout their lifespan. Multiple enzymatic sys-
tems such as DNA methyl transferases, acetylases, histone deacetylases, histone
methylases, and demethylases, as well as complexes of a protein involved in chro-
matin remodeling. A histone modification is a post-transcriptional modification
such as histone methylation, acetylation, phosphorylation, and ubiquitination. These
post-transcription changes in histone can affect the expression of genes by altering
the structure of chromatin. The epi-genome understanding and manipulation hold

promise to strengthen age-related treatment and increase healthy lifespan (Ilango
et al. 2020).
1.3.1.4 Loss of Proteostasis
Proteostasis is linked to aging and aging-related diseases (Lu and Guo 2020). All
the cells have various advanced systems to sustain their proteomes stable and func-
tional. Proteostasis mechanisms involve in stabilization and maintenance of folded
proteins such as the heat-shock protein family, and the degradation of misfolded
proteins by the proteasome or lysosome mechanisms. In the cellular systems, these
mechanisms function in an ideal coordinated manner to restore protein and elimi-
nate and degrade misfolded protein to prevent damaged protein accumulation and
continuous renewal and folding of cellular proteins. According to many research
studies, proteostasis can alter with aging. In addition, the accumulation and expres-
sion of misfolded proteins can develop many age-related diseases, including
Alzheimer’s disease, Parkinson’s disease, and cataracts (Anirudhan et al. 2021).
1.3.2 Antagonistic Hallmarks
1.3.2.1 Deregulated Nutrient Sensing
Deregulated nutrient sensing is an important hallmark of aging. Nutrient sensing is

the unique ability of cells to find out and respond to the fuel metabolic substrate,
such as glucose. The nutrient-sensing mechanism involves the IGF-1 intracellular
signaling pathway, which is the one triggered by insulin, which stimulates the cells
and informs the availability of glucose. IGF-1 and insulin signaling are also known
as the “insulin and IGF-1 signaling (IIS) pathway” which participates in glucose
sensing (Smith et al. 2018). The other interconnected nutrient-sensing systems are
mTOR, which senses high amino acid concentration, AMPK, which detects high
AMP levels and senses low energy, and Sirtuin which detects high NAD+ levels and
thereby senses low energy.
1.3.2.2 Mitochondrial Dysfunction
Mitochondrial activity has a major effect on aging and Mitochondrial dysfunction

can accelerate mammalian aging (Zia et al. 2022). when the efficacy of the respira-
tory chain decreases then, the electron leakage starts increasing and the generation
of ATP is reduced, in the aged cell. So, the mitochondrial dysfunction and aging
relationship have been a major challenge suspected for research in aging. According
to mitochondrial free radical theory, reactive oxygen species (ROS) production rate
6 M. Bhatiya et al.
rises because of the aging-related increasing mitochondrial malfunction, which fur-

thers mitochondrial decline and damages cells (Giorgi et al. 2018).
1.3.2.3 Cellular Senescence
Cellular senescence was first described by Hayflick and his colleagues when they
were working on cell culture. They noticed that normal human embryonic fibroblasts
would differentiate only for several limited times and after a sequential passage cell
undergo a permanent growth arrest state called proliferative or cellular senescence
(Marotta et al. 2021). Cellular senescence is the process caused by the cells that have
reached irreversible growth arrest which contributes to phenotypic aging. Cellular
senescence is the beneficiary action to the damage when the tissues exhaust their
proliferation potential. This eventually becomes deleterious for aging. Commonly,
cellular senescence is an outcome of a variety of stresses, these cells accumulate and
promote age-related disease which leads to the loss of tissue regeneration through
the exhaustion of stem cells and progenitor cells (Di Micco et al. 2021). There are
two general cellular senescence models which explain the contribution of cellular
senescence with aging. First, senescent cells can multiply to the point where tissue
strength and functional ability are impaired in tissues. A second model indicates that
stem cell senescence limits their regenerative capacity, leading to a gradual loss of
tissue strength and functional potential. Several mechanisms such as telomere short-
ening and DNA damage can trigger by cellular senescence (Borghesan et al. 2020).
The senescence of the cell is indicated by an increase in the size of the cell, lyso-
somal content, and the senescence-associated β -galactosidase [SA-β-gal] activity. It
is induced by multi-factorial reasons such as oxidative damage oncogene activation,
telomere attrition, and irradiation. It may cause the perturbation of homeostasis in
mitochondria which may accelerate age-related phenotypes. The defect in the mito-
chondria can generate ROS, which can be solely responsible for cellular senescence;
the supporting factor is a free radical aging theory (Bhatiya et al. 2021). In many cells
types hydrogen peroxide act as a potent inducer of cellular senescence. Exogenous
hydrogen peroxide treatment can promote cellular senescence even while endoge-
nous ROS is involved in establishing and maintaining irreversible growth arrest.
Excessive production leads to replicative senescence and oncogene-induced senes-
cence. The cells accumulated due to senescence in tissues that are aged can be inferred
using the markers that are surrogates such as DNA damage (Di Micco et al. 2021).
1.3.3 Integrative Hallmarks
1.3.3.1 Stem Cell Exhaustion
The cumulative effect of many aging-related damaging factors is stem cell exhaus-
tion. Stem cell rejuvenation may be able to reverse the aging phenotype at the
organismal level, according to recent promising findings (Sriramulu et al. 2018).
Reducing the tissue regenerative capacity becomes the most evident in aging char-
acteristics when hematopoiesis decreases with age, leading to a decline in the devel-
opment of adaptive immune cells called immune-senescence, and an increased
occurrence of anemia and myeloid malignancies.
1.3.3.2 Altered Intercellular Communication
Aging is involved both cell-autonomic as well as intercellular communication

changes such as endocrine and neuronal communication. Aging is not a biological
phenomenon exclusively for cells. Cell with some growing intercellular communi-
cation alteration, providing the opportunity to modulate aging at this stage. Thus,
neuro-hormonal signaling such as renin-angiotensin, and insulin-IGF1 signaling,
appear to downregulate aging by increasing inflammatory reactions, Immune sur-
veillance of pathogens, decreasing premalignant cells, and all tissue’s functional
and mechanical properties are impacted by changes in the peripheral and extracel-
lular environment’s composition (Mallick et al. 2019).
1.4 Oxidative Stress
Oxidative stress can be defined as a modification or imbalance of pro-oxidants and

antioxidants which results in possible damage. Oxidant stress occurs as reactive
oxygen species production overwhelms the endogenous antioxidant defenses. In
many age-related disorders, oxidative stress plays a vital role (Reshma et al. 2022).
The reactivity of oxygen allows it to participate in transfers of the high-energy elec-
tron, thus enabling the production of mass quantities of adenosine-5-triphosphate
(ATP) by oxidative phosphorylation. Oxidative stress research has become an
increasingly growing and evolving topic of study, particularly in the field of studies
on aging. The oxidative stress aging theory is based on the principle of structural
damage concept with age-related functional changes to the accumulation of oxida-
tive damage to macromolecules (Zavadskiy et al. 2022).
1.5 Reactive Oxygen Species (ROS)
Free radicals can be defined as species containing more than one unpaired electron.
The incomplete electron shell which providing high reactivity to these free radi-
cals. Normally, reactive oxygen species (ROS) act as an intracellular signaling
molecule at normal (Costa et al. 2021). Higher ROS levels disrupt cellular signal-
ing processes by acting as an attacking molecule and start attacking protein, lipid,
and nucleic acid (Phull et al. 2018) (Fig. 1.2). Under physiological conditions,
superoxide anion (O2•−) is the most abundant oxygen-free radical, and
8 M. Bhatiya et al.
Fig. 1.2 Impact of reactive

oxygen species
Fig. 1.3 Role of ROS in normal, cancer, and senescent cells
mitochondria are considered the primary source. Superoxide dismutase, an enzyme

that changes superoxide into hydrogen peroxide, detoxifies free radicals such as
superoxide (Costa et al. 2021). Despite not being a free radical, hydrogen peroxide
falls under ROS due to its crucial function in the production and detoxification of
free radicals. ROS affect cellular activity in a variety of ways at the homeostatic
level, including via activating protein kinases and redox-sensitive transcription fac-
tors (Fig. 1.3).
1.6 Molecular Mechanism of Cellular Aging
As the burden of aging-associated disorders is increasing, our understanding of cel-

lular changes that occur during aging also should increase. Molecular knowledge
has important medical and social implications as it has the potential of being
Fig. 1.4 Mechanism of aging and age-associated diseases
exploited to delay aging and the onset of aging-associated disorders. Current under-
standing of aging at the molecular level, and how targeting these aging-associated
changes might increase health span and lifespan (Fig. 1.4).
1.6.1 Apoptosis
Apoptosis, a programmed cell death, is a life-long regulated cycle that helps to

eliminate required or defective cells. Apoptosis plays a vital role in embryonic
development during limb formation and eliminates damaged cells (Opferman and
Kothari 2018). Alzheimer’s and Parkinson’s diseases were associated with an
increase in apoptosis. Several pathways and proteins regulate apoptosis. The signal-
ing protein p53 is capable of sensing damage. In the cell, catabolic processes start
when the cell gets an apoptosis-induced molecular signal, and apoptosis-specific
enzymes continue to degrade the cellular components and fragmentation of nuclear
DNA. During apoptosis, chromatin condensates, shrinking of the cell due to a break
in the integrity of the cell and irregular bulge in plasma membrane occur, finally the
cell breakdown into smaller apoptotic bodies which contains cell organelles and
nuclear components (Wallig and Janovitz 2022). These apoptotic bodies are then
eliminated by macrophages.
10 M. Bhatiya et al.
1.6.2 Autophagy
Autophagy is another process that can induce cell death. Like apoptosis, this
mechanism is strongly regulated and plays a normal role in the production,
development, and homeostasis of cells (Basak et al. 2020). Autophagy enables
a starving cell to reallocate nutrients from wasteful pathways to more essential
ones, and it also plays an important role in housekeeping by extracting mis-
folded or aggregated proteins, sorting out degraded organelles such as mito-
chondria and endoplasmic reticulum, and eliminating intracellular pathogens
(Wu et al. 2020). Some researchers suggest that mitochondrial dysfunction,
which is believed to lead to cellular aging, exists in part due to cells’ inability to
extract their defective mitochondria. Moreover, autophagy degrades proteins so
that they can be replaced and also degrades defective proteins that are no longer
functional.
1.6.3 Inflammation
“Inflammation” is a notable intercellular connection modification linked to aging.

Inflammation occurs due to the accumulation of pro-inflammatory tissue damage
and the deterioration of a progressively compromised immune system. Secretion of
pro-inflammatory cytokines promotion activation of the NF-πB transcription and
development of defective autophagy resistance is the tendency of senescent cells
(Lynch et al. 2020). Besides inflammation, emerging research suggests that aging-
related alterations in tissue may result in aging-specific deterioration to the other
tissues, due to inter-organ synchronization.
1.7 Aging-Associated Diseases
1.7.1 Cardiovascular Disease
Cardiovascular disease is still the most prevalent cause of death for older people.
Cardiovascular disease includes chronic ischemic heart disease, congestive heart
failure, and arrhythmia. Ischemic heart disease can be diagnosed at an early age
whereas vascular remodeling and vascular stiffness develop in normal aging.
Inflammation due to atherosclerosis and more vascular changes results in the risk of
cardiac attacks, stroke, and promoting peripheral artery disease, and neurological
dysfunction (Agraharam et al. 2022).
1.7.2 Cancer
Aging is an irreversible time-dependent deterioration in functional organ activity,

which is the main risk factor for one of human morbidity mortality’s most important
factors, including cancer (Figuer et al. 2021). According to the Surveillance
Epidemiology and End Results (SEER) Database of the US National Cancer
Institute, 43% of men and 38% of women will develop a lifetime invasive cancer.
Among these, 23% of men and 19% of women will die from cancer. More than half
of cancers arise in people aged 70 years. In most developed countries life expec-
tancy now exceeds 80 years, according to the World Health Organization (WHO).
Cancer is becoming an increasingly critical health problem worldwide as the popu-
lation ages. The underlying mechanism in both cancer and aging is the time-
dependent accumulation of cellular damage (Deka et al. 2021).
1.7.3 Osteoarthritis
Osteoarthritis is the second most prevalent chronic disease in senior citizens and a
major source of chronic pain and disability. In one survey, 52% of 85-year-olds had
an osteoarthritis diagnosis. Osteoarthritis tends to have a higher prevalence in
females than males and the chances of knee and hip arthritis increase with the age.
Another risk factor for osteoarthritis is Obesity. The treatments for osteoarthritis
often require extensive joint replacement surgery.
1.7.4 Diabetes Mellitus
Diabetes rates have increased and become more overweight as populations age.
Diabetes incidence in older adults in the United States could increase 2050 by more
than 400%. At age 85 (32), diabetes is a major risk factor for cardiovascular disease.
Diabetes and peripheral arterial disease are associated which contributes to diabetic
foot ulcers (Azhar et al. 2021). The approaches to treating diabetes should be individu-
alized. a major risk of hypoglycemia is having Sulfonylureas and insulin, so the use of
more prone older adults should be cautiously weighed up. For patients diagnosed with
hypoglycemia, post-acute treatment is provided during problematic periods.
1.7.5 Osteoporosis
Osteoporosis is a natural reduction of bone mass with aging. Older age, have osteo-
porosis, which is a more extreme loss of bone mass. Osteoporosis disease is associ-
ated weakness of bone and with increased bone fracture rates with age. Bone density
in women starts decreasing with the age for that bone density test recommended
over 65 ages. While the incidence of fractures decreases with the age of men over
age 85. To increase bone density and reduce the rate of bone fracture supplements
of calcium and vitamin D are recommended, however, the effectiveness of these
supplements is still controversial.
1.7.6 Dementia
Cognitive deterioration is a common problem of age-related brain changes

whereas dementia, is not a result of natural aging. The term Dementia is the col-
lection of all conditions triggered by disabilities that affect the capacity of mem-
ory profoundly it impairs the ability to perform regular activities such as feeding.
Loss of memory is a common symptom of dementia, but memory loss alone is
not dementia. Patients having dementia are having increasingly serious issues
with activities such as memory, vocabulary, and loss of problem-solving capac-
ity. It can also trigger changes in personality and difficulties in regulating
emotions.
1.7.7 Alzheimer’s Disease
The most prevalent form of dementia is Alzheimer’s disease. it affects approxi-

mately 5.2 million people in the US, according to the National Institute of Aging.
Alzheimer’s disease is a chronic, systemic brain disorder that is gradually affecting
memory, vocabulary, cognitive skills, and planning capacity (Rajagopal et al.
2022). The ability to perform the basic activities of everyday life is reduced over
time. Symptoms first appear in most Alzheimer’s patients after age 60. A protein
called amyloid precursor protein (APP) is usually found in brain tissue. The
enzymes cut off into fragments referred to as beta-amyloid as part of the recovery
of this protein and are usually discarded. Nevertheless, these sticky protein frag-
ments bind to each other in Alzheimer’s disease and build up spaces between two
neurons. Neurofibrillary tangles are defects in the brain cells within the microtu-
bules. During the early stages of Alzheimer’s symptoms will not appear till or up to
10 years but the plaques and the neurofibrillary tangles are accumulating and kill-
ing damaging most of the brain cells. As the number of neurons dies rises, the
affected part of the brain starts to shrink. The deterioration is common in the final
stages of Alzheimer’s disease, and brain tissue has been significantly diminishing.
Individuals in the end stage of Alzheimer’s disease cannot carry on communication
or react to their environment.
1.8 Alternative Treatment Strategies for Aging

Associated Diseases
Many natural compounds were proposed for supplementation treatments. Among

them, more attention has been given to a few specific molecules and bioactive com-
pounds such as Vitamin C, Quercetin, Rutin, Curcumin, and Resveratrol.
1.8.1 Vitamin C
The primary source of vitamin C is ascorbic acid. Vitamin C acts as both a reducing
and antioxidant agent. Ascorbate can also react with reactive oxygen species and
inactivate ROS. Various cellular functions are mediated by vitamin C for enhancing
the bioavailability of nitric oxide needed to maintain homeostasis in endothelial
cells. However, the role of vitamin C associated with aging-related diseases is not
investigated extensively since this antioxidant has always been used in association
with other molecules (Barbosa et al. 2020).
1.8.2 Quercetin
Quercetin has shown tremendous ability not only to minimize inflammation caused
by dysfunctional senescent cells but also to prevent healthy cells from senescent
cells. Treatment with quercetin also promotes natural cell activity and delays the
cycle of cell aging. Quercetin, as an antioxidant, can neutralize harmful free radi-
cals, and unstable molecules that damage high concentrations of cells. Free radicals
play a major role in chronic disease growth, such as cardiovascular disease, diabe-
tes, cancer, and other age-related diseases (Akbari et al. 2022). Today, further
research going on its biological activity has revealed how it can also delay or pre-
vent cellular aging, and even induce cell death in cancer cells.
1.8.3 Rutin
Rutin, a quercetin glycoside is a member of a class of bioflavonoids believed to pos-

sess antioxidant properties. Rutin, a glycoside of quercetins, is a member of the
bioflavonoid family. Previous research established Rutin as an anti-aging, anti-
inflammatory, and anti-carcinogenic antioxidant capable of scavenging radicals of
superoxide (Pandey et al. 2021). It has also been demonstrated that rutin is capable
of inhibiting collagen-stimulated human platelet aggregation, reducing capillary

fragility, prolonging the activated partial thromboplastin duration, and exerting anti-
thrombotic activity. The present research indicates that rutin decreases skin aging
by increasing dermal density and elasticity by controlling the enzyme.
1.8.4 Curcumin
Curcumin is phenol derived lipophilic bioactive compound extracted from the

Curcuma longa rhizome (Borghesan et al. 2020). Oral administration of curcumin
is absorbed by the body as an active metabolite from tetrahydrocurcumin, which is
converted by an enzyme found in the intestinal epithelium called reductase.
Extensive research has been suggesting that curcumin has highly therapeutic and
pharmacological potential as an anti-oxidant, anti-aging, anti-mutagenic, and anti-
bacterial agent (Zia et al. 2021). The medicinal properties of curcumin are high with
anti-cancer and neuroprotective effects.
1.8.5 Resveratrol
Phytoalexin compound, resveratrol is a bioactive compound belonging to the stil-

bene family, extracted from plants, such as nuts, berries, and grapes, mostly in the
glycosylated form. It is synthesized by plants in response to environmental stress
such as temperature, ozone, ultraviolet irradiation, and fungal infection (Bhatiya
et al. 2020). Resveratrol targeting and controls various signaling enzymes such as
AMPK and NAD-dependent Sirt-1 deacetylase to modulate various aging-related
cell signaling pathways. Resveratrol is a strong antioxidant and also inhibits LDL
degradation in vitro, which is related to coronary heart disease (Kaur et al. 2021).
Resveratrol’s anti-inflammatory characteristics raise the possibility that it has neu-
roprotective effects on neurodegenerative diseases, which are studied in cellular
models of age-related illnesses including Alzheimer’s disease.
1.9 Discussion
Aging is a complex biological phenomenon. Aging is a multifactorial process com-

posed of both genetic and environmental components. Every physiological process
within an organism system, every tissue within a system, and every type of cell
within a tissue has its aging direction. The aging process must therefore be studied
as part of a whole and understood as the sum of its parts. Cellular and molecular
basis study of aging is the best way to understand the study of aging-related dis-
ease. Cellular level changes of aging can be studied, as changes in cellular
components, cellular dynamics, cellular communication, and progressive deterio-

ration of functional integrity with time. There are several hallmarks of aging which
provides a framework for the study of aging in a linear form. These hallmarks also
contribute to understanding the aging mechanisms at the cellular and molecular
levels and to determining their phenotypic changes. In aged people, endogenous
antioxidant systems decline in effectiveness which makes them more susceptible to
oxidative stress. As we know, oxidative stress indirectly promotes age-related dis-
eases such as diabetes, aging, cardiovascular disease, and osteoporosis. Oxidative
stress forms in cells due to the overproduction and accumulation of ROS and the
imbalance between antioxidants and ROS (Moraes et al. 2020). According to previ-
ous research, clinical trials focusing on the treatment of bioactive compounds rich
in antioxidants analyze the positive or negative effects of aging and aging-associ-
ated diseases. A linear relationship of dose-response between overproduction of
ROS and biological damage, culminating potentially in disease and mortality.
Oxidative stress would also be the primary cause of aging and a significant deter-
minant of lifespan.
1.10 Conclusion
The aging process is universal, multiplex biological process. Cellular and molecular
biology are powerful tools in the research field now being applied by scientists for
the study of the mechanism of aging and aging-related disease. The results of these
studies should serve to advance our understanding of aging and to focus future
research efforts. As antioxidant play a protective role in the pathogenesis of age-
related diseases. Hence, the bioactive compound enriches antioxidant and can be
proving a useful approach for lifespan extension and therapeutic approach for
aging-related disease.
Acknowledgments The authors are thankful to Chettinad Academy of Research and Education
(CARE) for providing infrastructural and financial support to complete this piece of work.
Conflict of Interest The authors declare no conflict of interest, financial or otherwise.
Availability of Data Not applicable.
Funding This work was supported by the grants sanctioned to Dr. Antara Banerjee
(PI) grant number: Ref.No.004/Regr/AR-Research/2022–05 from the Chettinad
Academy of Research and Education.
Ethical Approval and Consent to Participate Not applicable.
Consent for Publication All authors have given their consent for the publication
of the manuscript.
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Chapter 2
Anti-oxidant and Anti-ageing Mechanism
of Bioactive Compounds in Modulating
the Ageing-Related Epigenetic Factors
Diptimayee Das, Amit Dey, Asim K. Duttaroy, Antara Banerjee,

and Surajit Pathak
Abstract Ageing is the multifaceted reduction in physiological function of all living

organisms. Several characteristics of ageing have been identified, including epigen-
etic dysregulation. Epigenetic dysregulation is receiving a lot of attention right now
as a key component in ageing and age-related neurodegenerative diseases including
Alzheimer’s, Parkinson’s and Huntington’s disease, where it may influence interac-
tions between genetic and environmental risk factors. Life expectancy diversity is
influenced by epigenetic factors such as DNA methylation and histone modifica-
tions. Histone variations, changes in chromatin accessibility, histone and heterochro-
matin loss, aberrant histone modifications and unregulated miRNA expression are all
epigenetic alterations that contribute to ageing and ageing-related diseases. Oxidative
stress, which is caused by the build-up of reactive oxygen species (ROS), can cause
lipid, protein, nucleic acid and organelle damage, resulting in an unbalanced homeo-
stasis and the induction of cellular senescence, which is one of the key processes
driving ageing. The senescent-associated phenotype includes chronic, pro-inflamma-
tory signals which cause risk in developing ageing-related disorders (ARDs).
Researchers have discovered that anti-ageing bioactive components have promising
anti-ageing properties in vitro, in animals and in humans. Recent research has
revealed that bioactive compounds have distinct modes of action, enhanced effective-
ness and reduced toxicity. Hence, this bioactive compound has the ability to suppress
the ROS formation and can be investigated as therapeutics interventions in ARDs.
D. Das · A. Dey · A. Banerjee · S. Pathak (*)

Faculty of Allied Health Sciences, Chettinad Hospital & Research Institute,
Chettinad Academy of Research and Education, Chennai, Tamil Nadu, India
e-mail: drsurajitpathak@care.edu.in
A. K. Duttaroy
Department of Nutrition, Faculty of Medicine, Institute of Basic Medical Sciences,
University of Oslo, Oslo, Norway

Ltd. 2023
20 D. Das et al.
Keywords Ageing · Epigenetic dysregulation · Oxidative stress · Ageing-related

disorders · Bioactive compounds
2.1 Introduction
Ageing is a natural process defined by increasing degradation of physiological

function, with chronic illnesses and poor health being the primary risk factors.
According to prominent evolutionary scientist Ernst Mayrl, there are primarily
two distinctions between living and non-living organisms. First, organisms repro-
duce themselves, and subsequently, they evolve over time. The two differences
are the indirect products of the biological hierarchy which gives rise to the fea-
tures such as phenotypic plasticity, ageing, adaptability and death (Macedo
et al. 2017).
A sudden loss of weight and a slow contraction of muscles are signs of the deg-
radation of the cells’ physiological integrity during the ageing process. There are
several risks associated with ageing, including reduced bone density, changes to
the cardiovascular system, cognitive decline and a pro-inflammatory state in the
organism, which leads to various cancer, diabetes, cardiovascular disorders and
neurodegenerative diseases as well as increases the possibility of death
(Campisi 2012).
Towards the end of one’s life, cellular damage accumulates and causes ageing. It
is primarily the nine hallmarks that contribute to cellular ageing and determine its
phenotypic characteristics that may be used as a means of defining cellular ageing.
Epigenetic changes, genomic instability, torn telomeres, stem cell fatigue and
impaired nutrition sensing are some examples of these changes.
Individually hallmark ideally highlights the requirements that (1) it should age
naturally; (2) ageing should not be accelerated by experimental aggravation; (3)
ageing should not be increased by experimental aggravation; and (4) the ageing
process should be normally retarded by experimental amelioration and increase
healthy lifespan (Gems and Partridge 2013). For the long duration of period, age-
ing was considered as the passive process which occurs randomly and was not
subjected to any kind of gene regulation or stress response. The ageing of the
organism can be delayed or altered using active constituents isolated from the natu-
ral bioactive components which have a potent ability to reduce inflammation.
Ageing is affected by the multi-factorial biological process which affects the entire
process. The hallmark provides a framework to study the primary or secondary
cause of ageing and explains the mechanism in a systematic manner (Pitt and
Kaeberlein 2015). To find possible therapeutic targets to halt the ageing process,
numerous research studies have been conducted to decipher ageing’s signs. All
these factors indicate ageing, such as stem cell fatigue, impaired intercellular com-
munication, senescence, genomic instability and epigenetic dysregulation (López-
Otín et al. 2013).
2 Anti-oxidant and Anti-ageing Mechanism of Bioactive Compounds in Modulating… 21
2.1.1 Cellular Senescence
Cellular senescence is the process caused by the cells that have reached the irrevers-
ible growth arrest which contributes to the phenotypic ageing. It is the beneficiary
response to damage that eventually becomes the deleterious and accelerates ageing
when the tissues exhaust their capacity for regeneration.
The cellular senescence an outcome of a variety of stresses, these cells accumu-
late and promote age-related disease which leads to the loss of tissue regeneration
through exhaustion of stem cells and progenitor cells. They secrete different kinds
of growth factors, cytokines and proteases which are collectively called as
senescence-associated secretory phenotype (SASP). These SASP factors due to its
paracrine and autocrine activities are capable to alter the tissue homeostasis. Hence,
cellular senescence is the after effect of the numerous pathological conditions
affected in an organism in the association with the ageing (Zivanovic 2012).
The senescence of the cell is indicated by an increase in the size of the cell, lyso-
somal content and the senescence-associated b-galactosidase (SA-β-gal) activity. It
is induced by multi-factorial reasons such as oxidative damage oncogene activation,
telomere attrition and irradiation. It may cause the perturbation of homeostasis in
mitochondria which may accelerate age-related phenotypes. The defect in the mito-
chondria can generate ROS, which can be solely responsible for the cellular senes-
cence; the supporting factor is a free radical ageing theory (Hu et al. 2012).
The free radical theory of ageing explains the study of cellular senescence. The
hydrogen peroxide is a potent inducer of cellular senescence in many cells types.
The exogenous treatment of hydrogen peroxide can promote cellular senescence
while endogenous ROS is implicated on the establishment and maintenance of irre-
versible arrest of growth. Excessive production leads to replicative senescence and
oncogene-induced senescence.
2.1.2 Epigenetics and Ageing
A reversible heritable mechanism called epigenetics changes gene expression

through modifications of chromatin rather than underlying DNA sequences.
Nucleosomes, which are repeated structural components of eukaryotic chromatin,
are highly condensed structures. The N-terminal histone tails and core histones
interact via the histone-fold domains. It has been found that post-translational modi-
fications to these tails influence gene expression frequently. In addition to acetyla-
tion and methylation, histones are also phosphorylated and ubiquitinated (Torres
and Fujimori 2015). A new paradigm in ageing epigenetics is developing, which
promises exciting discoveries in the near future, including a DNA methylome and
histone modification map that will help identify a ‘young’ cell from an ‘old’ one,
and identify all the chromatin modifier enzymes involved. Figure 2.1 illustrates this
process.
22 D. Das et al.
Fig. 2.1 The role of epigenetic factors in the maintenance of telomeres in ageing
2.1.2.1 DNA Methylation and Ageing
DNA methylation occurs, predominantly in CG dinucleotides. DNA methyltrans-

ferases are enzymes that add methyl groups to DNA (DNMTs). DNMT3A and
DNMT3B initiate DNA methylation, but DNMT1 maintains DNA methylation dur-
ing DNA replication. In DNA replication, DNMT1 maintenance methyltransferase
activity can be reduced passively or actively, resulting in DNA demethylation. The
methylation of DNA changes both globally and locus-specifically with ageing,
according to several studies. Methylation levels were positively connected to ageing
among the age-associated sites, and these sites were mostly found in CpG islands.
These worldwide methylation changes may result in genomic instability and telo-
mere integrity degeneration, both of which may contribute to the ageing cellular
phenotype (Florath et al. 2014). As humans age, changes in the expression and/or
activity of DNMTs or other epigenetic modifiers involved in DNA demethylation
may explain this ageing-related methylation. Ageing-related DNA hypermethyl-
ation, on the other hand, is produced by an increase in the expression of DNMT3,
which is known to be involved in de novo DNA methylation (Casillas et al. 2003).
Furthermore, a recent research (Mcclay et al. 2014) revealed that ageing-related
hypomethylation is associated to a variety of histone markers detected utilising
whole blood DNA on ageing-related differentially methylated regions (DMRs)
from people ranging in age from 25 to 92. Hypomethylated areas in DMRs are
related with histone changes such as acetylation and methylation (McClay et al.
2014). These findings imply that the coordination of DNA methylation and histone
modifications during the ageing process may influence age-related epigenetic alter-
ations and chromatin structure.
2.1.2.2 Histone Modifications and Ageing
The occurrence of various types or combinations of histone modifications across the

lifespan is also characterised by a gradual decrease in histone levels, which has a
significant influence on chromatin structure. Trimethylation of H4K20 rises with
age, as it does phosphorylation of H3S10, although trimethylation of H3K9 and
H3K27 decreases and acetylation of tH3K9 increases (Bártová et al. 2008). Both
histone levels and post-translational modifications alter during the replicative age of
Saccharomyces cerevisiae cells. Indeed, overall protein levels of H3, H4, and H2A
were decreased in aged cells, as was the expression of acetylated H3K56 (Feser and
Tyler 2011). Furthermore, Caenorhabditis elegans study revealed that ASH-2 tritho-
rax complex components, ASH-2 itself, WDR-5, and the H3K4 methyltransferase
SET-2 were harmful to longevity, and that H4K5 acetylation, but not total H4 pro-
tein levels, decreased with age (Feser et al. 2010). H4K12 acetylation changes in
mice have been linked to age-related cognitive decline (Greer et al. 2010).
Furthermore, as seen in Fig. 2.2, loss of SIRT6, an H3K9 deacetylase implicated in
telomere function, ageing-associated gene expression, and recruitment of the
DNA-PK catalytic subunit to chromatin in response to DNA damage, may result in
a premature ageing-like phenotype (Peleg et al. 2010). Histone-modifying enzymes
also play an essential role in ageing. The Sirtuin family, a class of evolutionary
conserved NAD-dependent histone deacetylases (HDACs) involved in a variety of
intracellular processes such as chromatin remodelling, apoptosis, transcriptional
silencing, and lifespan, is responsible for the regulation of two critical histone post-
translational modifications, namely the acetylation of H3 and H4 at lysine 9 and 16,
Fig. 2.2 Telomerase-mediated stress response in ageing

24 D. Das et al.
respectively (Burgess and Zhang 2010). In replicatively aged yeast cells, Sir2 pro-
tein levels decreased with age, which was connected to an increase in H4K16 acety-
lation and histone loss at certain subtelomeric locations (McGuinness et al. 2011).
2.1.2.3 Non-coding RNA and Ageing
According to studies, non-coding RNAs (ncRNAs) are produced by the majority of

eukaryotic genomes and are involved in a number of intracellular processes as well
as being part of the epigenetic machinery. MicroRNAs (miRNAs) are small noncod-
ing single-stranded RNAs (19–22 nucleotides) that have recently emerged as an
important research topic in the field of ageing. MiRNAs can impede translation or
induce mRNA degradation by binding to their gene targets in a sequence-specific
way (Kinser and Pincus 2020). As a result, they control a wide range of biological
functions, such as cell proliferation, differentiation, and death (Lai et al. 2019). In
humans, around 2000 miRNAs have been found, and they appear to be involved in
the regulation of approximately 60% of all human genes (Kozomara and Griffiths-
Jones 2014). One of the first ncRNAs to be linked to the ageing process was miRNA
lin-4, which targeted the transcription factor lin-14 and was revealed to influence
longevity in C. elegans (Kinser and Pincus 2020). A Drosophila research found that
deleting mir-125 (a lin-4 homolog) reduced male fly longevity (Chawla et al. 2016).
However, the function of this miRNA in humans is unknown. While little is known
about the roles of miRNAs in animal ageing, a recent research examined whole-
blood samples from 5000 people and discovered 127 miRNAs that were expressed.
2.2 Oxidative Stress-Induced Ageing
The imbalance in the oxidative and anti-oxidative systems in cells is known as oxi-
dative stress. The anti-oxidative system contains enzymes such as SOD and GSH-Px,
while the oxidative system comprises reactive oxygen and nitrogen species (ROS
and RNS). Irreversible growth arrest occurs in cells as a result of time-dependent
damage accumulated during numerous culture passes, also known as replicative
senescence. They are resistant to apoptosis and undergo malignant growth by induc-
tion and maintenance of cell senescence, cytostasis. Senescent cells are continually
changing but cannot grow like cancer cells. In in-vivo experiments, senescent cells
had a broad and flat form with abundant cytoplasmic and vacuolar granularity, as
well as high levels of lysosomal-galactosidase activity (SA-gal), p16, p21, and IL-6
(Rossiello et al. 2022).
Cell senescence can be caused by oxidative stress, mitochondrial dysfunction,
oncogene expression, DNA damage, and the loss of tumour suppressor genes such
as INPP4, NF1, PTEN, and RB1. Provocation of endogenous cues causes a phe-
nomenon known as replicative senescence, which differs from stress-induced pre-
mature senescence. The two processes have functional and molecular characteristics,
although the extrinsic and intrinsic events apoptosis and cell senescence differ
depending on the degree of cell homeostasis disruption (Ziegler et al. 2015).
The autocrine and the paracrine activities in the senescent cells are highly main-
tained by the tissues secreting molecules and they act at multiple levels such as
metabolic control, epigenome, gene expression and protein processing. The senes-
cence process which contributes to the specific mitochondrial pathway through
which there is an alteration in the mitochondrial redox state. The chemicals released
by senescent cells have a role in pathological and physiological events such as
wound healing, tissue remodelling during embryogenesis, and the onset of ageing
as well as age-related disorders in diverse animals.
The secretome produces essential cytokines for cancer cell development, encour-
aging carcinogenesis, which is connected to cellular metabolic status. Mitochondrial
DNA damage (mtDNA), signalling pathways via p53, Ras, p21, and p16, and
autophagy can all be implicated in the cause-effect link between cell senescence and
cellular ROS generation.
2.3 Ageing-Related Diseases (ARDs)
Many age-related problems are caused by ageing, and it has a significant influence
on social and economic stability. The ageing-associated diseases are the complica-
tions arising from the senescence. Ageing involves risk in developing cardiovascu-
lar disease (CVD), osteoarthritis, diabetes, cancer and numerous neurodegenerative
diseases. The main reason for the ageing- related disease is disturbed metabolism
with the mitochondrial damage. The increase in the frequency of ageing-associated
diseases found to increase with the senescence. Cell senescence is recognised as an
ageing signature for two reasons: (1) the buildup of senescent-related cells in organ-
ism tissue parallel to age progression; and (2) stem and progenitor cell depletion
occurs when senescent cells accelerate the age-related reduction in tissue regenera-
tion (Sarikhani and Firouzamandi 2022).
2.3.1 Neurodegenerative Diseases
The most common risk factor for the development of neurological diseases is ageing.
Alzheimer’s disease (AD) is the most common neurological disorder worldwide, and
its prevalence increases with age (Trevisan et al. 2019). Alzheimer’s disease is char-
acterised by extracellular amyloid plaques, intracellular neurofibrillary tangles
(NFTs), and Tau protein hyper-phosphorylation (Harini et al. 2022). Parkinson’s dis-
ease (PD) is another neurological disorder and almost doubles between the ages of 50
and 80 (Pringsheim et al. 2014). Parkinson’s disease (PD) is defined by the loss of
dopaminergic neurons in the substantia nigra (SN) (Kanaan et al. 2007). Several stud-
ies have shown that Parkinson’s disease has the same cell function decline as ageing.
26 D. Das et al.
Ageing has a substantial impact on the cardiovascular and arterial systems, increas-
ing the prevalence of cardiovascular disorders (CVD) such as stroke, atherosclero-
sis, myocardial infarction and hypertension (Donato et al. 2018). Increased arterial
stiffness, altered diastolic performance, decreased LV systolic reserve capacity,
Hypertrophy, and decreased endothelial function are all pathological alterations in
ageing cardiovascular tissues (Metkar and Girigoswami 2019). Telomere shortening
has been associated to vascular cell ageing, cardiovascular illness, arterial throm-
botic events, cardiovascular risk factors (including obesity, hypertension, smoking
and type-2 diabetes) and aortic valve stenosis.
2.3.3 Musculoskeletal Disorders
The elderly are more prone to injury and degenerative musculoskeletal disorders.
Sarcopenia and osteoarthritis (OA) are two of the most prevalent musculoskeletal
illnesses associated with ageing, and they both have considerable economic conse-
quences (Grote et al. 2019). Sarcopenia is characterised as a decline in muscle mass
and function as people age. Increased inflammation causes an increase in ROS gen-
eration in the skeletal muscles, resulting in cell death and impacting skeletal muscle
catabolism (Musci et al. 2020). Impaired mitochondrial activity and antioxidant
defences have also been related to the development of sarcopenia. Inconsistently,
some individuals reach advanced age in the good clinical conditions demonstrating
the fact that healthy ageing can be achieved. The research and the observations are
trying to find a treatment which can intercept to prevent and delay ageing-related
disease development, to increase health span and compressing the morbidity. Most
of the research work conducted recently mainly focuses on hypertension and cho-
lesterol, the levels of triglyceride and cancer. However, evidence for the most effec-
tive strategy would be the target the molecular mechanisms shared by all the
age-related disease (Crimmins 2015).
2.4 Modern Therapies Related to Ageing
There is no proven methodology to stop or delay, human ageing process. Much

valid scientific data is not available in the field of anti-science and longevity. It is
possible to delay some ageing process by avoiding unprotected exposure to the sun,
balanced diet can lower the cardio-vascular diseases; however, a single age-related
disease cannot be scientifically considered as delaying ageing. Ageing refers to the
changes that occur during an organism’s life span, with the pace at which the
changes occurs varying (Tungmunnithum et al. 2022). Many widely accepted
hypotheses explain why ageing occurs, although it is typically seen as planned

development. The ageing is the attributed through the free radical-induced damages,
molecular cross-linking, telomere shortening, presences in the genes of senescence
in the DNA and changes in the immulogical functions. The theories of the ageing
are categorised into three such as Programmed theory, Combined theory and
Damage theory (Cohen et al. 2022).
The technological advancement aims at explicit purpose of curing the ageing
which would prolong a healthy life. There is multi-factorial process in the ageing.
Following therapies were suggested to delay the ageing such as Caloric restriction,
Hormonal therapies, Antioxidants, Stem cells, telomere-based therapies and
ALT-711.
The stem cell was the other therapy used for ageing-related issues. It demon-
strated that the stem cell had the potency to cure the health issues ranging from
blindness, liver restoration and nerve regeneration as well as potent therapy for the
autoimmune diseases and other age-related diseases namely skin carcinogenesis,
wound healing and muscular dystrophies. The stem cells have been used for treating
various diseases of ageing and rejuvenation. It has been postulated that mitochon-
drial metabolism is an essential regulator in ageing in somatic stem cells. The dif-
ference in the embryonic stem cell can affect both therapeutic potential as well as
research application. Further studies and potential application is required to investi-
gate the variation in the signaling pathways and mechanism which may yield to the
delay in ageing process.
The hormones are used for the therapy of anti-ageing, the patients with the defi-
ciencies of GH and IGH-1 exhibit early signs of ageing. On the study conducted,
growth hormone was used as an anti-ageing medication, GH has been demonstrated
to have extremely favourable benefits on the elderly, and hGH pills have showed an
increase in muscular mass and libido, as well as an improvement in the immune
system. There are also some worries that hGH might promote cancer, particularly in
individuals who already have malignant or pre-malignant tumours. The general
view is that it can be employed as an anti-ageing therapeutic agent, but additional
study is needed to analyse potential side effects and assure therapeutic agent safety
(Burke 2022).
Antioxidants are employed in anti-ageing treatment to combat ROS and their
effects on lipids, proteins, and nucleic acids, which display an array of endogenous
anti-oxidant system, which is increased by input from co-factors and ingestions of
exogenous anti-oxidants. The most popular anti-oxidants include vitamins A, E, and
C, as well as coenzyme Q10, which was widely utilised. Few studies have found
that antioxidants do not slow down the ageing process, but rather lead to increased
longevity. Antioxidants are often utilised as anti-ageing treatments and can be found
in dietary supplements. Few studies found that marketed products had no effect on
mortality, either favourably or adversely, but in certain mice, it has been demon-
strated to increase cancer growth. High-dose antioxidant supplements can do more
harm than benefit, although low-dose antioxidant combinations can occasionally
have a positive impact, depending on food and lifestyle (Lim et al. 2022).
28 D. Das et al.
Telomere-based therapeutics has the potential to slow the ageing process by

increasing cell proliferative capacity in vitro and reversing tissue degeneration in
mice. The fundamental idea behind the commercialisation of telomerase kits is to
estimate an individual’s biological age and, for some, the risk of telomerase shorten-
ing linked diseases such as liver cirrhosis, coronary heart disease, and
arthrosclerosis.
2.5 Currently Proposed Treatments Involving Bioactive

Compounds in Age-Related Disorders
The bioactive compound which is naturally present in the food is known as

‘nutraceuticals’. The studies have been conducted to identify the nutraceuticals
to prevent the pathological conditions especially ageing-related diseases (ARDs)
or that mimic the anti-ageing action. Plants are a rich source of biologically
active natural products known as secondary metabolites, the most notable of
which are phenolic and polyphenolic compounds (Oroian and Escriche 2015).
Diet is an important part of everyday living, and dietary patterns and specialised
nutritional supplements may play an important role in boosting human health
and extending life. According to current research, adopting a Mediterranean diet
and supplementing with particular vitamins may reduce morbidity and death.
Rhodiola, Curcumin, Quercetin and Gallic acid has the most relevant anti-age-
ing property.
2.5.1 Rhodiola rosea
The Rhodiola rosea is widely distributed in higher altitudes in the Arctic and moun-
tainous region throughout Europe and Asia. It is the plant popularly found in the
regions of Eastern Europe and Asia, with the capability of enhancing performance,
eliminating fatigue enhancing work and preventing high altitude sickness. The
Rhodiola rosea has six distinct groups of chemical compounds such as
Phenylpropanoids, Flavonoids, Phenyl ethanol derivatives, Monoterpenes,
Triterpenes and Phenolic acids. The extract from the root solely contains about 140
bioactive compounds mainly rhodioloside or salidroside which has capability to
protect cells from pre-mature ageing when exposed to the oxidative-stress
(Polumackanycz et al. 2022). The extract of the Rhodiola rosea has proven to show
the protective effect and increasing immunity and can fight against age-related
immune deficiency issues known as immune-senescence (Amintas et al. 2022) and
has anti-ageing, neuroprotective activities, anti-cancer, possess adaptogenic proper-
ties and anti-oxidative as well (Sun et al. 2022).
2.5.1.1 Effects of Rhodiola on Ageing-Related Diseases
Rhodiola rosea contains bioactive substances such as salidroside, which has the
capacity to reduce the effects of neurodegenerative illnesses such as Alzheimer’s. It
is an age-related neurodegeneration that causes memory and learning problems in
the early stages. Salidroside protects neurons from oxidative stress by activating
anti-oxidant enzymes such as hemeoxygenase 1 (HO-1), thioredoxin (TRX), and
peroxiredoxin 1 (PRX1). Salidroside also enhances the amount of the anti-apoptotic
protein BCL-XL while decreasing the level of the pro-apoptotic protein BAX
(Ajdert et al. 2022). Salidroside protects against both myocardial hypoxia and
ischemia-reperfusion damage. The cardioprotective properties of salidroside were
demonstrated in studies showing salidroside dramatically lowered levels of lactate
dehydrogenase, CK, and CK-MB caused by strenuous swimming. Salidroside
reduces MDA concentration while increasing GSH-Px and SOD activities, indicat-
ing that it can protect the heart from repetitive strenuous damage (Xiong et al. 2022).
2.5.2 Curcumin
The hydrophobic yellow polyphenol CUR is a bioactive chemical ingredient of the

Curcuma longa Linn rhizome that is often used in cooking as a food colouring and
preservation. CUR is the primary active component in turmeric, accounting for
about 2–5% of the plant (Kapakos et al. 2012). Curcumin’s antioxidant benefits may
be achieved via the stimulation of anti-inflammatory responses. Its ability to
decrease inflammatory enzymes such inducible cyclooxygenase-2 (COX-2) and
nitric oxide synthase (iNOS) and lipoxygenase (LOX) is most likely responsible for
its anti-inflammatory properties (Menon and Sudheer 2007). Furthermore, curcum-
in’s anti-inflammatory activities are linked to its capacity to block NF-κB activity
and lower TNF-α levels, which is a known NF-κB pathway activator (He et al.
2015). Curcumin has the ability to modify the low-grade chronic inflammatory state
(inflamm-ageing) that is widespread in the ageing process and is thought to be a
common driving factor in various age-related disorders (Furman et al. 2019).
2.5.2.1 Effects of Curcumin on Ageing-Related Diseases
Curcumin’s varied actions provide a sound theoretical foundation for considering it

as a prospective option for the treatment of age-related diseases (Abrahams et al.
2019). Curcumin has been demonstrated in various in vitro and in vivo studies to
have antioxidant, anti-inflammatory, anti-microbial, immunomodulatory, cardio-
protective, hepatoprotective, nephroprotective, anti-neoplastic, hypoglycaemic and
anti-rheumatic properties (Balaji et al. 2022). Curcumin can be used to treat a vari-
ety of clinical problems, including age-related renal and eye diseases, rheumatoid
arthritis, atherosclerosis, cardiovascular, type 2 diabetes, neurological illnesses,
30 D. Das et al.
cancer, and osteoporosis (Sundar Dhilip Kumar et al. 2018). Curcumin supplemen-
tation, according to Derosa et al. (2016), can significantly lower circulating interleu-
kin 6 (IL-6) concentrations, which are known to be a crucial role in inflammatory
reactions; astonishingly, the most profound impacts were reported in individuals
with greater levels of systemic inflammation.
Curcumin is without a doubt one of the most promising phytobioactive sub-
stances in terms of metabolic effects. It has been demonstrated to aid in the preven-
tion and treatment of type-2 diabetes in adults (Zhang et al. 2013). Curcumin has
been proven in animal models to reduce hyperglycemia, improve β-cell function,
prevent β-cell death, lower insulin resistance, and delay the establishment of type-2
diabetes (Zhang et al. 2013). A variety of experimental and clinical investigations
have completely proven curcumin’s usefulness in the prevention and treatment of
cardiovascular disease (Wongcharoen and Phrommintikul 2009). A number of
in vitro studies have shown that curcumin has anti-atherogenic properties. A reduc-
tion in cholesterol build-up has been shown to mediate this impact (Zhao et al.
2012). The relevance of micro-RNAs such as miR-126 in investigating the molecu-
lar processes behind such effects has been demonstrated (Li et al. 2019). Long-term
treatment of curcumin to mice resulted in decreased plasma and hepatic cholesterol
levels as well as suppression of early atherosclerotic lesions (Jayakumar et al.
2016). Changes in immune gene expression were responsible for these effects.
Curcumin also prevented atherogenesis in an atherosclerosis animal model, such as
apoE/LDLR-double knockout mice given a fat-rich Western diet (Olszanecki
et al. 2005).
Curcumin has been shown to have neuroprotective properties in both in vitro and
in vivo Alzheimer’s disease models. In the human neuroblastoma cell type SH-SY5Y,
it was shown to protect against mitochondrial and synaptic damage (Reddy et al.
2016). Curcumin’s anti-AD effect in animal models is due to its ability to penetrate
the BBB, which reduces aggregation and protects neurons from toxic insults (Reddy
et al. 2018). Curcumin has been shown to improve synaptic function, cognitive
decline, and tau clearance in Alzheimer’s disease mice models.
Curcumin has been shown to have therapeutic promise for age-related musculo-
skeletal problems such as osteoporosis (Peddada et al. 2015). Curcumin’s therapeu-
tic potential in osteoporosis is supported by recent in vitro and in vivo data. It was
proven in animal models of this condition to enhance several aspects of bone health
by influencing multiple processes in differentiation and osteoclast activation, as
well as mineral density and bone mechanical characteristics. NO generation, recep-
tor activator of NF-κB ligand (RANKL) repression, cytokine synthesis, nuclear fac-
tor kappa B (NF-κB), and ROS creation are most likely involved activities (Peddada
et al. 2015). Curcumin, for example, was discovered to prevent bone structure dete-
rioration and to promote favourable changes in bone turnover when taken orally; the
likely involvement of pro-inflammatory cytokines such as IL-6 and TNF-α in these
effects was revealed (Girigoswami et al. 2020).
Curcumin’s anti-cancer potential has been investigated in a number of human
Phase I and II clinical studies. Its therapeutic potential has been studied most thor-
oughly in patients with pancreatic cancer, one of the world’s deadliest cancers
(Bimonte et al. 2016). In a Phase II research, Dhillon et al. (2008) discovered that
oral curcumin was well tolerated and, despite modest absorption, exhibited strong
anti-inflammatory and anti-neoplastic effects in a large number of patients with
advanced pancreatic cancer. This medicine lowered the expression of inflammation-
related proteins such as NF-kB, COX-2, and phosphorylated signal transducer and
activator of transcription 3 (p-STAT3) in these patients’ peripheral blood mononu-
clear cells when provided orally. Curcumin’s therapeutic effectiveness in colorectal
cancer patients was also proven in a Phase IIa clinical trial, including the reduction
of aberrant crypt foci (Carroll et al. 2011).
2.5.3 Quercetin
Quercetin has been used to treat inflammation, cancer, arthritis, allergic responses,
and cardiovascular disease. The flavonoid also has a crucial function in platelet
aggregation, lipid peroxidation, and mitochondrial biogenesis (Batiha et al. 2020).
Quercetin is a powerful chemical that may be utilised to treat a variety of health
problems. In vivo and in vitro, quercetin has antioxidant effects. The antioxidant
activity of quercetin protects against a variety of age-related diseases (Ulusoy and
Sanlier 2020). A diet high in quercetin provides a number of health advantages. It
works to reduce inflammation, coagulation, hypertension, and hyperglycemia.
Several clinical studies indicate that quercetin supplementation is used to prevent
and treat a wide range of chronic illnesses, including cardiovascular disease (Huang
et al. 2020).
2.5.3.1 Effects of Quercetin on Ageing-Related Diseases
Flavonoids have been shown to be effective in the prevention of neurodegenerative

illnesses and may even postpone the progress of neurodegeneration. Quercetin has
been shown in studies to have neuroprotective properties. Quercetin inhibits the
neuroinflammatory process by downregulating pro-inflammatory cytokines such as
iNOS and NF-kB, hence stimulating neuron regeneration. Quercetin inhibits lipid
peroxidation and hence protects neurons from oxidative injury. Neuronal cells serve
as antioxidants at lower doses of 5 M and 10 M quercetin, but become toxic at
greater concentrations of 20 M and 40 M (Khan et al. 2019).
Quercetin treatment improved dyslipidaemia, decreased serum blood glucose
levels, increased insulin levels, and reduced oxidative stress in diabetic rats. Oral
administration of quercetin to rats decreased sexual activity, sperm count and
motility, and diabetes-induced testicular damage. Quercetin reduced blood pres-
sure in hypersensitive rats when given intravenously (Shabbir et al. 2021).
Quercetin mitigates the effects of oxidative stress and protects pancreatic cells
from β-cell damage. It has been demonstrated that the chemical reduces hepatic
cell oxidative stress and increases antioxidant enzymes such as catalase and heme
oxygenase.
32 D. Das et al.
Quercetin is a potent flavonoid with chemo-protective activities in a range of

in vivo and in vitro studies. Its anti-cancer properties, such as decreased prolifera-
tion, the ability to cause apoptosis, mitotic inhibition, and cell cycle arrest, make it
a reliable chemical in cancer therapy (Reyes-Farias and Carrasco-Pozo 2019). In the
case of human leukaemia, quercetin was demonstrated to stop the cell cycle at G2.
Quercetin has also been linked to changes in p53-related pathways in cancer cells.
It inhibits the activity of cyclins A, B, and CDK2, maintaining MCF-7 breast cancer
cells in the S phase of the cell cycle. Quercetin inhibits malignant cell apoptotic
pathways, causing cancer cells to die.
2.6 Conclusions and Perspectives
With an ageing population, healthy ageing has emerged as a critical public health
priority. Genetics and environmental factors have been linked to ageing for decades.
Furthermore, epigenetic modifications influence the ageing process. Hence, epigen-
etic indicators such as histone alterations and DNA methylation are linked to age-
ing. Several studies have found epigenetic biomarkers, most notably DNA
methylation, that can predict the biological age of specific tissues. These findings
imply that epigenetic techniques might be exploited to develop effective anti-ageing
medications. Nutrients and their metabolites play critical roles in epigenetic control
as well as antioxidant substrates. Nutritional availability modifications, such as cal-
orie restriction and direct supplementation with bioactive substances, have been
related to ageing via epigenetic mark alterations and ROS generation. The physio-
logical alterations generated by dietary intervention in rhodiola and trachurus
extract may be responsible for epigenetic modifications and the suppression of ROS
generation. R-L bioactive substances often contain anti-oxidant and anti-ageing
qualities that can protect cells from damage caused by intrinsic and extrinsic causes,
and oxidative stress created by the cells may prevent cellular senescence. This bio-
active compound might open the path for researchers to target and understand the
therapeutic impacts of ageing-related diseases. However, more research into the
anti-ageing and anti-oxidant properties of the R-L bioactive component therapy will
help to verify this finding. As a result, it is critical to establish direct proof of nutri-
tional benefits of R-L bioactive chemicals in the future, as well as to research epi-
genetic markers that can predict individual responses and whether it can effectively
regulate the anti-ageing process and ageing-related disorders.
Acknowledgments The authors thank the Chettinad Academy of Research and Education
(CARE) for providing infrastructural and financial support and the University of Oslo, Norway, for
completing this work.
Consent for Publication Not applicable.
Funding This work was supported by the grants sanctioned to Dr. Surajit Pathak
(PI) by the Chettinad Academy of Research and Education (CARE).
Conflict of Interest The authors report no conflict of interest.
Author’s Contributions AB and SP was involved in the conception of the study

and design, while DD and AB wrote the manuscript. AB, AD, and DD were involved
in designing the images. ADR, AB, and SP critically reviewed the manuscript. All
authors read, reviewed, and approved the final manuscript.
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Chapter 3
Diet-Gene Interactions that Regulate
Longevity and Diseases
Tripti Nair, Sonia Verma, and Arnab Mukhopadhyay
Abstract Aging, an almost universal phenomenon, encompasses a gradual yet con-

stant deterioration of the metabolic functions of the body. Aging is characterized by
an increased homeostatic imbalance and an elevated risk of systemic metabolic fail-
ures leading to diseases, with the ultimate outcome being death. Age-related meta-
bolic disorders, such as cardiovascular diseases and type-2 diabetes, are among the
major causes of mortality worldwide. A plethora of research has established that
aging is regulated by genes functioning in important metabolic pathways. Thus
quite expectedly, the nutrient content of a diet has been found to modulate the lifes-
pan of an organism and define the severity or course of several age-related or other
illnesses. Under normal conditions, an organism can modulate its gene expression
to adapt to these diet-induced metabolic changes to display normal health and lifes-
pan. However, in the presence of an altered allele, the effects of diet or one of its
components may become apparent in terms of health, disease, or longevity effects.
Identifying such diet-gene pairs and the associated molecular mechanisms is neces-
sary for developing dietary and therapeutic interventions that would prevent or treat
diseases and promote healthy aging.
Keywords Diet-gene pairs · Aging · Metabolism · Age-associated disorders ·

Gene polymorphism · Diet supplementation · Disease susceptibility
T. Nair · A. Mukhopadhyay (*)

Molecular Aging Laboratory, National Institute of Immunology, New Delhi, India
e-mail: arnab@nii.ac.in
S. Verma
Division of Neuroscience and Ageing Biology, CSIR-Central Drug Research Institute,
Lucknow, Uttar Pradesh, India
e-mail: sonia.verma1@cdri.res.in

Ltd. 2023
38 T. Nair et al.
Abbreviations
AD Alzheimer’s disease
ALH-6 ALdehyde Dehydrogenase
AMD Age-related macular degeneration
APOA5 APOlipoprotein A-V
APOE APOlipoprotein E
ATP7B ATPase copper transporting 7 Beta
ATPsynD ATP synthase subunit D
BCAA Branched-chain amino acids
BRS-3 Bombesin Receptor Subtype 3
CCHa2R CCHamide-2 Receptor
CVD Cardiovascular diseases
DGRP Drosophila genetic reference panel
DTT Dithiothreitol
ech-6 Enoyl-CoA hydratase
FLR-4 FLuoRide resistant 4
FTO FaT mass and Obesity
GLUT GLUcose Transporter
GSTM1 Glutathione S-Transferase Mu
HC High caloric
HDL High-density lipoprotein
HMGCR 3-Hydroxy-3-MethylGlutaryl-Coenzyme A Reductase
HNF4 Hepatocyte Nuclear Factor 4
HP-LS High protein and low sugar
HS-LP High sugar and low protein
IRS1 Insulin Receptor Substrate 1
LD Lipid droplets
LDL Low-density lipoprotein
LPS LipoPolySaccharide
MAPK Mitogen activated protein kinase
MEF2 Myocyte Enhancer Factor 2
MRPL-2 Mitochondrial Ribosomal Protein Like 2
MTHFR MethylTetraHydroFolate Reductase
MUFA Monounsaturated fatty acids
NAD(P)H Nicotinamide adenine dinucleotide phosphate reduced
NHR-114 Nuclear Hormone Receptor 114
NMUR-1 NeuroMedin U Receptor 1
NRF2 NF-E2-Related transcription factor
OSM-3 OSMotic avoidance abnormal
P5C 1-Pyrroline-5-carboxylate
P-80 Polysorbate 80
PLP PyridoxaL 5’-phosphate
PMT-2 Phosphatidylethanolamine MethylTransferase 2
PNPO Pyridox(am)iNe 5-Phosphate Oxidase
3 Diet-Gene Interactions that Regulate Longevity and Diseases 39
PUFA PolyUnsaturated fatty acids

RANKL Receptor Activator of Nuclear factor-Kappa-Β Ligand
RICT-1 Rapamycin-Insensitive Companion of TOR
RIPS-1 Rhy-1-Interacting Protein in Sulfide
RPE Retinal pigmented epithelium
SAM S-adenosyl methionine
SIRT-6 NAD+-dependent deacetylase (SIRTuin-6)
SKN-1 SKiNhead 1
SNP Single nucleotide polymorphism
SOD2 SuperOxide Dismutase 2
Spen Split ends
T2DM Type-2 diabetes mellitus
TCF7L2 TransCription Factor 7-Like 2
TG Triglyceride
TNFα Tumor Necrosis Factor-alpha
UPRmt Mitochondrial unfolded protein response
ZPR1 Zinc finger PRotein-1
3.1 Introduction
Aging is the major risk factor for chronic diseases that are more prevalent in the
elderly. The gradual decline in the activity of various biological processes with age
increases the risk of individuals developing age-associated pathologies. Impaired
mitochondrial function, DNA repair system dysfunction, dysregulated immunity,
hormonal imbalance, proteostasis collapse, and altered metabolic signaling are a
few biomarkers of aging. These hallmarks of aging are also the driving factors
involved in the initiation as well as the advancement of age-associated disorders.
Few instances of such diseases include cardiovascular diseases (CVD), neurodegen-
erative disorders, arthritis, and type-2 diabetes (T2DM). The frequency of these
diseases increases exponentially with age. An individual’s genetic predisposition
also substantially influences aging and age-associated or other disorders. For exam-
ple, variations in the genes coding for APOlipoprotein E (APOE), Receptor Activator
of Nuclear factor-Kappa-Β Ligand (RANKL), TransCription Factor 7Llike 2
(TCF7L2) have been associated with Alzheimer’s disease (AD), osteoporosis, and
T2DM, respectively (Cluett and Melzer 2009). In the coming decades, with advance-
ments in wellness programs, the population with age above 65 is predicted to dou-
ble. Therefore, to meet the healthcare needs of the growing aging population,
identifying strategies that can improve the conditions of individuals predisposed to
age-associated or related disorders is crucial.
To support growth and cellular functions, food is critical for all organisms. Most
organisms have a wide variety of dietary choices. These vary in nutrient composi-
tion, which can affect life-history traits such as development, survival, and health by
altering the metabolic status of an organism. Therefore, deficiency or excess of
40 T. Nair et al.
nutrients has been found to affect aging and influence the progression and/or sever-
ity of various age-associated disorders. Diet can have immediate as well as long-
lasting effects on animal physiology and that of its future generations (Pang and
Curran 2012). Importantly, the genetic make-up of an individual also plays a crucial
role in determining the outcome of dietary choices. Genes modulate metabolism
depending upon the nutrient availability to maintain physiological homeostasis so
that the organism can display normal life-history traits. The metabolic flexibility
brought about by gene interactions, when an organism is exposed to different nutri-
ent source and composition, help it adapt to a diverse nutritional environment, pro-
viding evolutionary advantages. With aging, this metabolic flexibility progressively
declines and may thus increase susceptibility to age-dependent metabolic disorders.
Additionally, mutations in such genes disrupt the adaptive capacity to the diet lead-
ing to an altered rate of aging in a diet-specific manner. Studies in Caenorhabditis
elegans, Drosophila melanogaster, and mice have uncovered several such instances
of diet-gene pairs, where the outcome of mutations in a particular gene is evident
only on a specific diet. Similarly, in humans, we are aware of multiple polymor-
phisms in metabolic genes that cause diseases treatable with a modified diet or diet
supplementations.
Mechanistic studies in elucidating the nature of diet-gene interactions are few
and primarily driven by research in model organisms. In this chapter, we highlight
some instances of diet-gene interactions that regulate aging. We also provide some
examples of human age-associated or other diseases caused by gene mutations that
can be treated with dietary interventions. We posit that more studies providing
mechanistic insights into diet-gene interactions are required as they can be capital-
ized to prevent/treat diseases and promote a healthy lifespan.
3.2 Dietary Composition and Aging (for More Details, Refer

to Chaps. 10 and 12)
The nutritious component of a diet primarily consists of carbohydrates, proteins,

and fats as essential macronutrients as well as vitamins and minerals as micronutri-
ents. The quantity and quality of any of these factors in each diet have been demon-
strated to alter the rate of aging in different model organisms and, importantly,
promote/prevent disease incidences in humans.
3.2.1 Carbohydrates
Carbohydrate metabolism plays a key role in maintaining homeostasis of cellular

energy levels, synthesis of cellular components, and development and reproduction
of an organism (Mattila and Hietakangas 2017). Dysregulation in carbohydrate flux
may cause increased incidences of chronic inflammatory diseases as well as
multiple metabolic disorders such as obesity, diabetes, diabetic nephropathy,

increased triglyceride (TG) storage, and cancer (Mattila and Hietakangas 2017;
Parkhitko et al. 2020), negatively affecting life span.
3.2.2 Lipids
Lipids aid in energy storage, membrane synthesis, and cellular signaling.

Supplementation of fatty acids such as arachidonic, linoleic, oleic, palmitoleic, and
eicosapentaenoic acid improves lifespan and stress tolerance and decreases
α-synuclein aggregation, and delays onset of amyloid-β toxicity, along with other
health-span benefits. Aberrant lipid metabolism is the cause of obesity, insulin resis-
tance, diabetes, Alzheimer’s disease (AD), atherosclerosis, and other geronto-
metabolic disorders (Johnson and Stolzing 2019).
3.2.3 Amino Acids
Maintaining a balanced dietary quotient of protein is essential for multiple aspects

of cellular homeostasis, systemic immune response, and stress response as they are
modulated by amino acids, peptides, and proteins (Timmerman and Volpi 2008).
Protein restriction in Drosophila and mice significantly extends lifespan. Methionine
restriction and manipulation of methionine metabolism increase lifespan in yeast,
worms, flies, and mice (Parkhitko et al. 2019). On the other hand, supplementation
of branched-chain amino acids (BCAA) leucine, valine, and isoleucine increases
chronological lifespan in yeast and worms (Alvers et al. 2009; Edwards et al. 2015;
Mansfeld et al. 2015). BCAA supplementation to middle-aged mice improves mito-
chondrial biogenesis and enhances cardiac and skeletal muscle functions (D’Antona
et al. 2010). Therefore, amino acids play a multifaceted role in regulating an organ-
ism’s health span and longevity.
3.2.4 Vitamins
Vitamins, required in small quantities, significantly regulate multiple aspects

of organism physiology and health. They are cofactors to enzymes that play
important roles in maintaining metabolic and epigenetic homeostasis (Vitamin
B1-B12 and A), neuro-cognitive functions (Vitamin B6-B12 and K), behavioral
responses (Vitamin B1 and B12), mitochondrial respiration (Vitamin B2, B5,
B7, and B12), cellular growth and differentiation (Vitamin B1, B2, B5, B9, C,
A, D, E, and K), cellular detoxification and stress responses (Vitamin B3, B9,
C, A, D, and E), embryonic morphogenesis, tissue morphology and functioning
42 T. Nair et al.
(Vitamin B1, B5, B9, B12, and A), and immune response and inflammation
(Vitamin B5, B7, B9, B12, C, A, D, E, and K) (Thomas 2006). Deficiency of
Vitamins, as well as hypervitaminosis (specifically Vitamin A), can adversely
affect health.
3.2.5 Minerals
Minerals are classified into two major classes, macro-minerals and micro-
minerals. Minerals play diverse roles, ranging from skeletal development to
transmission of nerve impulses. They also regulate the production of different
hormones and play an important role in heart functionality. Macro- and micro-
elements are found in the dentitions (Ca, F and P) and bones (Ca, Mg, P, B, Mn,
and F), while most micro-elements (Cu, Fe, Mg, Mn, Se, and Zn) function as
structural components of various enzymes. Macro-minerals (Ca, P, Na, K, and
Mg) function in nerve cell signaling and transmission. Micro-minerals regulate
erythrocyte formation (Co, I, and Fe) and activate antioxidant enzymes (Mo).
Minerals also regulate immune responses (Ca, Se, Cu, Mg, and Zn) and neuro-
nal functioning (Cr and Mn). Thus, minerals affect a vast range of molecular,
cellular, and physiological processes required for life and well-being
(Gharibzahedi and Jafari 2017).
3.3 Diet-Gene Interactions Modulating Aging and Disease

in Model Organisms
Research on longevity and healthy aging requires model organisms that have a short
lifespan, inexpensive maintenance, and an easily manipulable genome. Invertebrates
like Drosophila, C. elegans, and mammalian models such as mice have contributed
immensely to our understanding of the aging processes and disease mechanisms.
The feasibility of performing dietary and genetic interventions in these species has
been useful in identifying diet-gene pairs required for maintaining normal aging
patterns or ameliorating disease pathologies. This section discusses a few such pairs
studied using C. elegans, Drosophila, or mice that regulate aging, metabolism,
stress response, and disease phenotypes (Table 3.1).
Considering the word limitation, the chapter could not include all the published
reports of diet-gene interactions and their effects on organismal lifespan, health, and
disease.
Table 3.1 Summary of diet-gene pairs modulating aging and disease in model organisms
Genes
S. Dietary maintaining
no. modifications Effects homeostasis References
Caenorhabditis elegans
1 ↑↑↑ vitamin B12 • Lifespan extension flr-4 Verma et al.
• Lower (2018), Nair et al.
phosphatidylcholine levels (2022)
• p38 MAPK pathway
activation
• Elevated cytoprotective
gene expression
• Heightened stress
tolerance
2 ↓↓↓ tryptophan • Sterility nhr-114 Gracida and

• Germline defects Eckmann (2013)
• Lower detoxification
gene expression
3 ↓↓↓ vitamin B12 • DTT-induced rips-1 Gokul and Singh
– Developmental toxicity (2022)
– Depleted SAM levels
– Intensified ER
proteotoxic stress
4 ↓↓↓ • Lifespan extension nmur-1 Maier et al.

lipopolysaccharide osm-3 (2010)
5 ↓↓↓ feeding on • Lifespan extension rict-1 Soukas et al.
HB101 skn-1 (2009)
6 ↑↑↑ proline • 1-pyrroline-5- alh-6 Pang and Curran
catabolism carboxylate build-up nmur-1 (2014)
• Reduced mitochondrial
function
• Increased ROS
• Lifespan suppression
• Reduced fecundity and
fertility
7 ↑↑↑ fat • Energy homeostasis ech-6 Liu et al. (2022)
disruption
8 ↓↓↓ vitamin B12 • Low methionine mrpl-2 Amin et al. (2020)
synthase activity
• Methionine restriction
• Lifespan extension
• UPRmt activation
• Enhanced mitochondrial
function
Drosophila melanogaster
1 ↑↑↑ protein • Lifespan extension Sirt6 Shukla and
Kolthur-
Seetharam (2022)
(continued)
44 T. Nair et al.
Table 3.1 (continued)

Genes
S. Dietary maintaining
no. modifications Effects homeostasis References
2 ↑↑↑ sugar • Lifespan extension Mef2 Zhao et al. (2020)
↓↓↓ protein • Heightened stress
tolerance in muscles
3 ↑↑↑ carbohydrate • Lethality CG4607 Francis et al.
(2021)
4 ↑↑↑ protein • Heightened stress ATPsyn-d Sun et al. (2014)
↓↓↓ carbohydrate resistance
• Lifespan extension
5 ↑↑↑ sugar • Lifespan extension in Spen Gillette et al.
mated females (2020)
Mice
1 ↑↑↑ zeaxanthin • Inducing antioxidant Sod2 Biswal et al.
response (2018)
• Preserved RPE structure
and function
2 ↑↑↑ n-3 fatty acids • Lowered pro- Ccl2 and Cx3cr1 Tuo et al. (2009)
inflammatory cytokines
• Increase anti-
inflammatory response
• Delayed progression or
reversion of retinal
lesions
3.3.1 Serine Threonine Kinase Gene (flr-4)
FLR-4 is involved in moderating vitamin B12-mediated effects on cellular metabo-

lism and, thus, longevity. The flr-4 gene was initially identified in a forward genetic
screen for genes required for fluoride resistance in C. elegans (Katsura et al. 1994).
Later, it was found that the kinase-dead allele, n2259, possesses a longer lifespan
on the E. coli HT115 compared to E. coli OP50 (Verma et al. 2018). OP50 and
HT115 have been reported to differ in nutrient and metabolite contents, thus affect-
ing the expressions of various genes in the worm and their normal physiology
(Soukas et al. 2009; Pang and Curran 2014). The OP50 strain was also found to
possess lower vitamin B12 levels compared to HT115. The elevated dietary vitamin
B12 level in E. coli HT115 was shown to activate the p38 MAPK pathway, induce
cytoprotective gene expression, and increase stress tolerance and lifespan in the
flr-4 mutant (Verma et al. 2018; Nair et al. 2022). Mechanistically, the higher vita-
min B12 levels increase the flux through the one-carbon cycle in the mutant, thereby
transcriptionally downregulating the phosphatidylethanolamine methyltransferase
2 (pmt-2) gene, leading to lower phosphatidylcholine levels that activate the p38
MAPK pathway (Nair et al. 2022). Thus, flr-4 prevents ectopic activation of the p38
MAPK pathway on food with different vitamin B12 levels to maintain a normal
life span.
3.3.2 Nuclear Hormone Receptor Gene (nhr-114)
The mammalian HNF4 is a nuclear factor that functions in the hepatocytes, regulat-
ing lipid and glucose metabolism, thereby maintaining metabolic homeostasis
(Hayhurst et al. 2001; Van Gilst et al. 2005). In C. elegans, the HNF4 ortholog
NHR-114 regulates germline development. Interestingly, the nhr-114 depletion
results in sterility when fed E. coli OP50 but not HT115 (Gracida and Eckmann
2013). On downregulating nhr-114, germline defects such as nuclear aberrations,
irregularly differentiated oocytes, and condensed germline are visible on OP50 but
not on the HT115 diet (Gracida and Eckmann 2013). Interestingly, supplementing
tryptophan to E. coli OP50 significantly diminishes the nhr-114 knock-down-
associated sterility and upregulates the expression of detoxification genes (Gracida
and Eckmann 2013). Meanwhile, the wild-type worms do not exhibit any dietary
tryptophan-dependent germline defects and sterility. Thus, NHR-114/HNF4 assures
germline health, regardless of dietary inputs, by compensating for dietary variations
in tryptophan levels between the E. coli diets and mounting a variety of stress
responses to protect the developing germ line. Therefore, a mutation in the gene
seems to accelerate germline aging on a diet lacking enough of the amino acid.
3.3.3 S-Adenosyl Methionine (SAM)-Dependent

Methyltransferase Gene (rips-1)
RIPS-1, a protein with a putative SAM-dependent methyltransferase domain, is

involved in developmental toxicity caused by the presence of dithiothreitol (DTT).
Interestingly, wild-type worms develop normally when DTT is added to E. coli
HT115 feed but display toxicity on E. coli OP50 containing DTT. DTT causes devel-
opmental defects by inducing the expression of rips-1 gene, depleting SAM levels,
and intensifying endoplasmic reticulum proteotoxic stress. The loss of function allele
of rips-1 improves worm development on E. coli OP50 containing DTT. Since
RIPS-1 functions in the one-carbon metabolism by transferring a methyl group from
SAM to a substrate, supplementing vitamin B12 to E. coli OP50 containing DTT can
also alleviate and reverse the toxicity of DTT by restoring SAM levels (Gokul and
Singh 2022). The upregulation of RIPS-1 in E. coli OP50 or low vitamin B-12 condi-
tions suggests a defense response elicited by organisms against reagents such as DTT.
3.3.4 Kinesin Motor Protein (osm-3) and Neuromedin U

Receptor (nmur-1) Genes
The C. elegans osm-3 gene is essential for cilia formation in the sensory neurons
(Snow et al. 2004), while the nmur-1 is the worm ortholog of mammalian NMUR
expressed in neurons. Compared to wild-type, the osm-3 and nmur-1 mutants
46 T. Nair et al.
display lifespan extension on the E. coli OP50 but not on HT115 (Maier et al. 2010).
Interestingly, a double mutant of osm-3 and nmur-1 does not display an additive
effect, suggesting that both the genes regulate lifespan via similar mechanisms. The
sensory neurons expressing osm-3 and nmur-1 aid in perceiving dietary cues by dif-
ferentiating between the lipopolysaccharide (LPS) structure of the two E. coli
strains. The outer core of the LPS of the E. coli HT115 (a K-12 strain) is longer than
the E. coli OP50, a B strain (Klena et al. 2005). The effect of nmur-1 on lifespan is
indeed LPS-dependent as the mutant worms live longer on the LPS-truncated K-12
strain but not on the parent strain (Maier et al. 2010).
3.3.5 Mechanistic Target of Rapamycin Complex 2 Subunit

(RICTOR) Gene (rict-1)
Mutants of the conserved RICTOR gene ortholog, rict-1 in C. elegans, exhibit varia-
tions in life-history traits on different bacterial diets. Rict-1 functions as a critical
sensor of organismal energy status and appropriately guides calories into crucial
metabolic processes such as energy storage, growth, lifespan maintenance, and
reproduction. The rict-1 mutants are short-lived on E. coli OP50 and long-lived on
E. coli HB101 as well as HT115 (Soukas et al. 2009). The HB101 (and HT115) and
OP50 diet have similar protein and fat content; however, HB101 (and HT115) have
many folds higher carbohydrate content, qualifying them as high-quality worm food
(Brooks et al. 2009). The reduced lifespan of the mutants on OP50 is due to exces-
sive feeding. On HB101, the consumption of bacteria is reduced, thereby extending
lifespan. This extended lifespan is suppressed if the transcription factor skn-1 gene
is knocked down. Since SKN-1, a mammalian Nrf2 ortholog, is required for dietary
restriction-induced longevity (Bishop and Guarente 2007), the short lifespan of
rict-1;skn-1 on HB101 suggests the role of RICT-1 in regulating the rate of feeding
on different diets. The absence of the functional protein disrupts this feeding behav-
ior, reducing HB101 consumption, inducing dietary restriction, and extending
longevity.
3.3.6 Aldehyde Dehydrogenase Gene (alh-6)
Another gene required by C. elegans adaptive response to diet is alh-6, an ortholog

of the human aldehyde dehydrogenase. This enzyme catalyzes the two-step break-
down of proline by converting 1-pyrroline-5-carboxylate (P5C) into glutamate. The
alh-6 mutant worms show lifespan suppression, reduced fecundity, and fertility
only when fed on OP50, but not HT115, as they accumulate toxic levels of P5C that
affect mitochondrial function, producing reactive oxygen species. Antioxidants
such as ascorbate and N-acetylcysteine rescue the lifespan defects of alh-6 mutants
on the OP50 diet (Pang and Curran 2014). This suggests that proline catabolism is
activated in worms when fed OP50. Active ALH-6 efficiently metabolizes P5C to
sustain mitochondrial homeostasis that is otherwise disrupted by toxic levels of P5C
build-up in the absence of the functional protein. This, however, does not occur in
HT115. Interestingly, without functional NMUR-1, alh-6 mutants no longer present
mitochondrial defects and live a normal lifespan on an OP50 diet (Pang and Curran
2014). Thus, in addition to providing energy, diet can also impose physiological
challenges like mitochondrial dysfunction on an organism and negatively affects the
rate of animal aging; however, neuronal and metabolic tissues function together to
promote mitochondrial adaptation and maintain physiological homeostasis.
3.3.7 Enoyl-CoA Hydratase Gene (ech-6)
Excessive dietary fat disrupts energy homeostasis, leading to a shorter lifespan in

C. elegans. However, a mutation in the ech-6 gene that is suggested to function in
the branched-chain amino acid (BCAA) catabolic pathways prevents lifespan short-
ening when the worms are grown on media supplemented with oleic acid-rich
dietary fat polysorbate 80 (P-80). Knocking down ech-6 under normal conditions
shortens lifespan, possibly suppressing mitochondrial metabolic functions and
aberrant amino acid catabolism. However, in P-80 treated ech-6 mutants, fat-
enriched diets had little effect on lipid levels, possibly because the fuel may be burnt
by beta-oxidation to produce energy, contrary to storage as triglyceride (TG) seen in
wild-type. During ech-6 deficiency, supplementing P-80 upregulates biological pro-
cesses involved in the production of energy and lysosome-related processes that
contrasts with the broader metabolic effects seen in wild-type worms. Thus, the
gene ech-6 represents a factor that can fine-tune metabolic flexibility in response to
excessive dietary fat intake to modulate lifespan (Liu et al. 2022).
3.3.8 Mitochondrial Ribosomal Protein Gene (mrpl-2)
Mitochondrial unfolded protein response (UPRmt) is a cellular defense response

stimulated by multiple types of mitochondrial dysfunction and regulated by a coor-
dinated mito-nuclear cross-talk that recovers normal mitochondrial function. The
mrpl-2 gene helps maintain mito-nuclear balance, negatively regulating UPRmt in
C. elegans. Compared to the wild-type strain, the mrpl-2 loss-of-function mutation
activates UPRmt, in a diet-dependent manner, increases mitochondrial function,
extends lifespan, and boosts resistance towards infection only when fed low vitamin
B12 diet E. coli OP50. This is because on the low vitamin B12 diet, a reduction in
the activity of methionine synthase, which converts homocysteine to methionine in
the SAM/methionine cycle, activates UPRmt-induced longevity. In wild-type worms
on low B12 diet OP50, functional MRPL-2 prevents this aberrant stimulation of
UPRmt and maintains the normal rate of aging. However, on E. coli HT115, the
48 T. Nair et al.
higher vitamin B12 levels lead to an increased supply of methionine and the mito-
nuclear imbalance in mrpl-2 mutant is insufficient to induce the UPRmt resulting in
normal aging rates (Amin et al. 2020).
3.3.9 NAD+ -Dependent Deacetylase Gene (Sirt6)
Nutrient inputs regulate physiological fitness during development and adulthood.

Developmental dietary inputs have often been shown to determine lifespan and
health span in adults, but the mechanisms are poorly characterized. In this regard, the
study by Shukla et al. has illustrated how differential carbohydrate and protein ratios
during development lead to the programming of adult physiological measures from
aging to metabolic homeostasis. Moreover, the study identified SIRT6 as one of the
key components necessary to control plasticity and memory of responses later in life
because of varied diets during development. Interestingly, while loss of SIRT6 led to
accelerated developmental progression, it also resulted in a detrimental impact on
physiological fitness in adults. Besides clearly establishing the tunable adaptation of
life history changes, the study also proposed epigenetic mechanisms and metabolic
sensing as possible mediators of such memory (Shukla and Kolthur-Seetharam 2022).
3.3.10 Myocyte Enhancer Factor Gene (Mef2)
An evolutionarily conserved transcription factor, MEF2 controls biological pro-

cesses such as lipid metabolism and mitochondrial function. Muscle-specific atten-
uation of MEF2 activity in Drosophila leads to the accumulation of large
intramuscular lipid droplets (LD) in a diet-specific manner. LD are cellular organ-
elles that store neutral lipid and provide energy substrates for mitochondrial beta-
oxidation. Diet and nutrient availability are factors that shape lipid droplet
diversification. High sugar and low protein (HS-LP) or high protein and low sugar
(HP-LS) diets increase LD size compared to a high calorie (HC) diet in wild-type
flies. When Mef2 is non-functional, large intramuscular lipid droplets with higher
cholesterol ester and low TG are accumulated in response to HS-LP and HC diets,
but not in the HP-LS diet. The accumulation of intramuscular lipid droplets also
enhances organismal lifespan and stress protection of muscles. This Mef2-diet
mediated accumulation of lipid and lifespan extension depends on cyclin E func-
tion; however, the exact mechanism is not yet known (Zhao et al. 2020).
3.3.11 Putative Glucose Transporter Gene (CG4607)
Not all individuals respond similarly to the same diet due to the diverse genetic
variations. The effects of different dietary exposures to starvation resistance were
compared using 178 inbred strains from the Drosophila genetic reference panel
(DGRP) that covers various genetic polymorphisms. DGRP consists of fully

sequenced inbred lines derived from a natural population; therefore, it is a powerful
tool for understanding genetically-driven metabolic responses. Adult male flies
show variable resistance to starvation-induced death when fed a diet with different
macronutrient combinations (high carbohydrate or high-fat). A majority of the sin-
gle nucleotide polymorphism (SNP) that contributed to this diet-gene effects are
located in the noncoding regions of genes; for example, a SNP >500 bp upstream of
the start site of gene CG4607, a homolog of the human glucose transporters GLUT6
and GLUT8, may affect transcription, splicing or post-transcriptional processing of
RNA. By reducing glucose utilization, silencing of CG4607 produced lethality in
flies on high carbohydrate but not on high protein or high-fat diet. The CG4607
knock-down flies also exhibited higher levels of glycogen post-starvation and broke
down more TG under starvation conditions (Francis et al. 2021). Thus, genetic vari-
ations play a determining role in the response of an organism to different diets,
thereby affecting life history traits.
3.3.12 Neuropeptide CCHamide-2 Receptor Gene (CCHa2R)
Diet restriction has been demonstrated to have pro-longevity effects in most model
organisms. Importantly, natural genetic variations found among the wild population
of organisms can affect diet-dependent longevity. One such example is a SNP in
CCHa2R gene (2R_1939249_SNP) that reduces the levels of metabolites such as
pipecolate, valine, serine, and methionine. Neuron-specific attenuation of CCHa2R
leads to a longer lifespan under dietary restriction but not on an ad libitum diet.
CCHa2-R is a neuron-enriched G-protein coupled receptor that exclusively binds to
the neuropeptide CCHa2 that expresses mostly in the fat body, and at low levels in
the gut and neurons. This axis is involved in the regulation of insulin signaling and
satiety in response to nutritional status. The human homolog of CCHa2R is bombe-
sin receptor subtype 3 (BRS3), expressed in the central nervous system and gastro-
intestinal tract, similar to the expression pattern of CCHa2R peptide in Drosophila.
Since BRS3 is also involved in mammalian gut-brain axis signaling, it is tempting
to speculate that the mechanisms may be conserved between flies and mammals (Jin
et al. 2020).
3.3.13 ATP Synthase Subunit Gene (ATPsynD)
ATPsynD is a component of the mitochondrial electron transport chain complex

V. Silencing of D. melanogaster ATPsynD reduces TOR signaling, enhances protein
homeostasis, and activates antioxidant defences in a sex and diet-specific manner.
The ATPsynD knock-down mediated stress resistance, and longevity occurs only
when the flies are fed a diet low in a carbohydrate-to-protein ratio (Sun et al. 2014).
Interestingly, knocking down the gene in C. elegans also increases life span; how-
ever, it is not known whether diet has any effect on this phenotype (Hansen et al. 2005).
50 T. Nair et al.
3.3.14 RNA-Binding Protein Split Ends Gene (Spen)
Genetics plays a critical role in the development of obesity and metabolic syndrome.
The Spen is a transcriptional regulator of fat catabolism. The fat body-specific
knock-down or mutation in Spen leads to blockade of fat catabolism, higher levels
of stored TG, decreased lipase expression, and increased adiposity. These are also
accompanied by a compensatory increase in glycolytic flux and protein catabolism.
Interestingly, diets supplemented with yeast early during development partially res-
cues these metabolic dysfunctions and developmental defects in the Spen mutant.
On the other hand, high sugar moderately improves the longevity of mated females
(Gillette et al. 2020). Interestingly, diet supplementation was heavily dependent on
the developmental timings, with yeast supplementation in adulthood being detri-
mental. Since Spen is a conserved gene, such studies point at the possible use of
dietary interventions in humans to improve metabolic dysfunction associated with
certain genetic factors.
3.3.15 Pyridox(am)ine 5-Phosphate Oxidase Gene (PNPO)
The brain-localized PNPO enzyme catalyzes the rate-limiting step in the synthesis
of the active form of vitamin B6, known as pyridoxal 5′-phosphate (PLP). SNPs in
PNPO have been associated with neonatal epileptic encephalopathy and early-onset
epilepsy. The PNPO variants can cause mild to complete inactivation of this enzyme.
The R116Q, D33V, and R95H are a few of the PNPO mutations reported in patients
with neonatal epileptic encephalopathy. The Drosophila transgenic lines expressing
the human PNPO mutant alleles demonstrate allele-dependent variation in seizure
onsets and seizure types. These alleles also display a variable reduction in PNPO
level and different degrees of lifespan shortening effect. Interestingly, these mutants
show more diversified phenotypes upon dietary treatments. For example, on a sugar-
only diet, the R116Q but not D333V homozygotes become hyperactive (Chi et al.
2022). This suggests that allele-diet interactions contribute to the ultimate pheno-
typic manifestations of these polymorphisms.
3.3.16 Genes Associated with Age-Related

Macular Degeneration
Age-related macular degeneration (AMD) is one of the leading causes of irrevers-

ible blindness among the population > 50 years of age. Diet-gene interactions have
been found to alleviate AMD-associated pathologies in mice models. Retinal pig-
ment epithelium-specific deletion of Sod2, the mitochondrial Superoxide Dismutase
2, results in the development of AMD-like pathologies in mice due to massive
oxidative stress. Daily zeaxanthin, a carotenoid, supplementation to Sod2flox/flox

VMD2-cre mice increased retinal pigmented epithelium (RPE) expression of NRF2-
regulated enzymes, such as catalase, NAD(P)H quinone dehydrogenase 1 and heme
oxygenase 1, thus inducing an antioxidant response (Biswal et al. 2018). Zeaxanthin
supplementation also reduced RPE thinning and preserved RPE structure and func-
tion. It would be interesting to study whether zeaxanthin supplementation slows
disease progression once retinal and/or RPE degeneration has initiated.
In another AMD model, Ccl2−/−/Cx3cr1−/− mice treated with a high n-3 fatty acid
diet showed a delayed progression, or even reversion of retinal lesions, compared to
the low n-3 fatty acids group. The ocular transcript levels of pro-inflammatory cyto-
kines, TNFα and IL6, were lowered while anti-inflammatory eicosanoids, prosta-
glandin D2, and leukotriene B4 were increased in the mice fed on high n-3 fatty
acids (Tuo et al. 2009). The study supports the epidemiological retrospective studies
on the protective relationship between n-3 fatty acids intake and advanced AMD
(Lawrenson and Evans 2015).
3.4 Diet-Gene Interactions in Human Aging

and Associated Diseases
Aging is a critical risk factor for a variety of human pathologies, including neurode-
generative diseases, cancer, and metabolic diseases. Diet-gene pairings also have
crucial implications for human physiology and disease progression. In randomized
clinical trials focusing on the effects of dietary interventions on weight mainte-
nance, insulin resistance, and lipid profile, individuals’ genotype was found to be an
important determinant (Qi 2014). In multiple nutrigenetic and nutrigenomic studies,
the effect of genetic background in response to diet interventions in multiple cohorts
with diverse genetic predispositions has begun to explicate. Few such examples
have been detailed below (also see Fig. 3.1).
3.4.1 TCF7L2 and IRS1 in Type-2 Diabetes Mellitus
The interplay between genetics and environmental factors results in variable sever-
ity of T2DM. At least 200 genetic variants have been identified as T2DM-related
alleles. The polymorphism is present in genes regulating pancreatic β-cell function,
insulin secretion pathway, and insulin signaling. Some of these variants would
increase susceptibility to T2DM and dietary factors can interact with these genetic
variants to modulate the risk of T2DM development. Genetic polymorphisms in the
gene TCF7L2 are associated with an increased risk of T2DM. A high fiber intake
increases the T2DM risk in carriers of allele rs12255372 or rs7903146 while non-
carriers display a reduced risk of T2DM (Hindy et al. 2016; Ortega et al. 2017).
52 T. Nair et al.
Fig. 3.1 Gene-diet interactions in age-associated diseases. Diet interventions have crucial impli-
cations on the effect of genetic background in human physiology and disease progression. For
instance, consumption of raw vegetables reduces incidence of carcinoma among individuals with
the GSTM1-deletion genotype. High carbohydrate intake lowers plasma triglyceride levels in indi-
viduals carrying APOA5 (rs662799) allele. Replacing saturated fatty acids by MUFAs and carbo-
hydrates improves insulin sensitivity in the carriers and reduces T2DM susceptibility in individuals
homozygous for FABP2 (rs1799883) allele. Cognition and plasma AD biomarkers in aged APOEε4
carriers is improved when fed a high-fat diet. Consuming more fibre proves beneficial to HMGCR
(rs17238540) carriers at high risk of coronary heart diseases. Mediterranean diet interacts with the
TNF-α (rs1800629) allele and reduces risk of obesity, CVD, and multiple sclerosis. SNP- Single
Nucleotide Polymorphism; MUFA- Monounsaturated Fatty Acids; GSTM1- Glutathione
S-transferase Mu; APOA5- Apolipoprotein A-V; FAB2- Fatty Acid-Binding protein 2; HMGCR-3-
Hydroxy-3-Methylglutaryl-Coenzyme A Reductase; TNF-α-Tumor Necrosis Factor-alpha
Genetic variants near the gene encoding insulin receptor substrate 1 (IRS1) have
been associated with T2DM. The variant rs2943641 T allele lowers the risk of insu-
lin resistance which is further modulated by dietary factors like monounsaturated
fatty acids (MUFAs), and carbohydrate quantity. Low consumption of MUFAs and
low total fat consumption decrease resistance to insulin. Carriers of Ala54Thr poly-
morphism (rs1799883) in intestinal fatty acid-binding protein 2 are more suscepti-
ble to T2DM than homozygous individuals (Qiu et al. 2014). Replacement of
saturated fatty acids by MUFAs and carbohydrates improves insulin sensitivity in
the carriers. Thus, individuals with higher genetic predisposition should change
their dietetic patterns depending on the effect of diet on the variation-specific T2DM
phenotypes (Ortega et al. 2017).
3.4.2 APOE and ATP7B in Alzheimer’s Disease
The most significant genetic risk factor for AD is the ε4 allele of the APOE gene,
increasing the risk for AD up to ∼tenfold in homozygous persons. APOE ε4 is asso-
ciated with weakening neuronal repair, overwhelming amyloid plaque formation,
and heightened oxidative stress. When aged APOE ε4 carriers with cognitive
impairment or non-carriers with normal cognition were fed a high-fat diet, cogni-
tion and plasma AD biomarkers in ε4 carriers improved but worsened in ε4 non-
carriers (Hanson et al. 2015). Interestingly, APOE ε4 carriers also demonstrate
resistance to improvement on a ketogenic diet (Henderson et al. 2009).
The defects in copper homeostasis caused by variations in genes like ATP7B are
associated with a significant increase in AD risk. ATP7B encodes a plasma mem-
brane copper-transport protein, and carriers of a loss-of-function ATP7B variant
(ATP7BK832R) have higher levels of free copper in serum than non-carriers. This cop-
per overload leads to the intoxication of various organs, including the brain, where
it enhances the A-β deposition and increases oxidative stress, while a low copper
diet lowers the risk of AD in ATP7BK832R carriers (Squitti et al. 2014).
3.4.3 APOA5 and ZPR1 in Cardiovascular Diseases
CVDs, a group of disorders of the heart and blood vessels, include coronary artery
disease, hypertensive heart disease, rheumatic heart disease, etc. The major risk fac-
tors associated with CVD include elevated TG and low-density lipoprotein (LDL)
cholesterol levels in serum and reduced activity of lipoprotein-lipase. Apolipoprotein
A-V (APOA5) rs662799 and rs2266788 minor alleles elevate the risk of increased
TG and decreased high-density lipoprotein (HDL) cholesterol concentrations in the
bloodstream. APOA5 is predominantly expressed in the liver and is an important
determinant of plasma TG levels. Interestingly, low fat intake increases plasma TG
levels while high carbohydrate intake lowers plasma TG concentration in individu-
als carrying the minor alleles. Individuals who are carriers of rs662799 and have
low calcium intake display higher plasma TG concentrations than those with mod-
erate calcium intake (Jiang et al. 2010). Further studies on such diet-gene interac-
tions may promote genotype-based personalized nutrition to manage the risk of
age-related disorders.
The zinc finger protein-1 ZPR1 is an essential gene in mice and is required for
transcription and cell proliferation. The rs964184 C > G variation in the gene has
been associated with elevated levels of fasting and postprandial TG, thus increasing
the risk of myocardial infarction in patients with CVD. The G-carriers on
Mediterranean Diet have higher fasting and postprandial TG, while their levels are
reduced to that of non-carriers when on a low-fat diet (Alcala-Diaz et al. 2022).
Such evidence supports the notion of precision nutrition, based on diet-gene interac-
tions, to benefit the health of genetically predisposed individuals.
54 T. Nair et al.
3.4.4 Methyltetrahydrofolate Reductase Gene (MTHFR)
One-carbon metabolism gene MTHFR plays an essential role in the folate-

methionine cycle. MTHFR helps convert 5,10-methylenetetrahydrofolate to
5-methyltetrahydrofolate, thus facilitating crucial cellular processes such as DNA,
RNA, and protein methylation. The MTHFR 677TT genotype reduces the activity
of the reductase and results in suboptimal plasma folate and elevated plasma homo-
cysteine levels. Polymorphism of MTHFR is associated with an increased risk of
CVD (Liew and Gupta 2015). Supplementing the diet with folate has been found to
effectively increase folate and normalize homocysteine levels in TT homozygotes
(Ashfield-Watt et al. 2002). It would be interesting to carry out detailed studies on
the effect of folate supplementation on the incidence and severity of CVD in indi-
viduals homozygous for the MTHFR 677TT allele.
3.4.5 Tumor Necrosis Factor-Alpha (TNFA)
Tumor necrosis factor-alpha is a pro-inflammatory cytokine and plays a vital role in

the inflammatory responses in obesity, insulin resistance, dyslipidemia, and cardio-
metabolic disease. Individuals with the -308G → A rs1800629 promoter polymor-
phism in the TNFA gene exhibit higher BMI, higher leptin levels, and
disproportionately higher levels of soluble TNFR2, making them genetically predis-
posed to increased risk of obesity, CVD, and multiple sclerosis (Dalziel et al. 2002;
Babu et al. 2012). A 12-month regime of a Mediterranean diet was found to interact
with the rs1800629 allele and reduce TG levels as well as inflammation status, qual-
ifying it as a potential treatment of the metabolic syndrome (Gomez-Delgado
et al. 2014).
3.4.6 Fat Mass and Obesity-Associated Gene (FTO)
FTO or alpha-ketoglutarate-dependent dioxygenase enzyme regulates energy

homeostasis, and it is expressed highly in brain regions involved in controlling
nutrition and energy expenditure. The A allele of FTO (rs9939609) leads to high
adiposity and increased BMI, alterations in appetite, altered ghrelin synthesis and
secretion, as well as type 2 diabetes. Individuals carrying FTO polymorphism have
been found to benefit more from consumption of a Mediterranean diet or Eastern
European diet, again highlighting the important of considering diet-gene interac-
tions in designing treatment options for metabolic syndrome (Xiang et al. 2016; Di
Renzo et al. 2018; Chmurzynska et al. 2019).
3.4.7 Glutathione S-Transferase Mu Gene (GSTM1)
GSTM1 catalyzes the phase II detoxification of toxins, carcinogens, drugs, and

products of oxidative stress, by conjugation to the tripeptide glutathione.
Polymorphisms in GSTM1 lead to null activity of the enzyme, which causes
increased incidences of squamous cell carcinoma of the head and neck (Geisler and
Olshan 2001). Weekly consumption of raw but not cooked vegetables has been
associated with reduced incidence of carcinoma among individuals with the
GSTM1-deletion genotype (Gaudet et al. 2004).
3.4.8 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase
Gene (HMGCR)
HMGCR is a critical enzyme in cholesterol biosynthesis. The HMGCR polymor-

phism like T > G SNP (rs17238540) causes hypercholesterolemia and hypertriacyl-
glycerolemia and thus, increases susceptibility toward coronary heart diseases
(Freitas et al. 2010a, b). The type of allele present in an individual influences serum
lipid and TG response to dietary supplements. For example, with a higher intake of
saturated fatty acids, the G allele carriers present lower HDL levels than TT indi-
viduals. In response to dietary fibre intake, the G allele carriers present lower serum
TG compared with TT individuals (Freitas et al. 2010a, b). Therefore, consuming
more fibre and less saturated fat would benefit individuals at high risk of coronary
heart diseases.
3.5 Conclusion
Both environmental and intrinsic cues, such as diets and genes, respectively, have
been independently identified as significant regulators of organismal aging and dis-
ease. Studies on model organisms have discovered various aging-regulating genes
and advanced our understanding of the biological processes that modulate the rate
of aging. The type of dietary intake has pro- or anti-longevity effects, but these are
counterbalanced mainly by organismal metabolic responses, controlled by a com-
plex genetic network, to maintain homeostasis. Nevertheless, no two individuals are
genetically similar. Owing to the mutations that accumulate during development,
minor genetic differences are also present even in monozygotic twins. Based on the
host’s genotype, the same diet may exert distinct effects on the life history traits of
different individuals. Thus, diet and genetic background can interact to maintain the
normal rate of aging, and animals that can adapt to different food sources are in an
evolutionary advantageous state as their survival would not solely depend on the
availability of a specific diet.
56 T. Nair et al.
During aging, the gradual loss of metabolic plasticity increases susceptibility to

age-related disorders. Several alleles have been identified that predispose individu-
als to various age-associated disorders and modulate the severity of diseases.
Interactions between an individual’s genotype and diet further dictate the incidence
of the diseases and phenotypic variations among patients, amplifying the heteroge-
neity of the disease among individuals. This may have significant implications in
developing treatment strategies. Therefore, dietary intervention based on an indi-
vidual’s genetic makeup may provide a novel therapeutic strategy for better man-
agement of age-associated or other debilitating diseases.
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Chapter 4
Antioxidants and Ageing
Sayantan Chakraborty
Abstract Antioxidants are compounds which react with free radicals and neutral-
ise them. Various metabolic processes in the body produce free radicals as their
by-products. Free radicals can damage DNA, lipids and proteins of cell membranes.
They can peroxidise several lipids, including low-density lipoproteins, which accu-
mulate in the wall of blood vessels and disrupt blood circulation throughout the
body. Free radicals are also involved in Alzheimer’s disease, acute and chronic kid-
ney disease, atherosclerosis, myocardial infarction. Antioxidants break down free
radicals, remove them from the site, and delay ageing. Telomere shortening by free
radicals is directly linked with ageing and age-related diseases. Various antioxidants
are present in our body as water-soluble, fat-soluble, enzymatic, non-enzymatic,
small, and large molecular antioxidants. Enzymatic antioxidants are mainly present
in mitochondria and cytosol, and non-enzymatic antioxidants are present in blood
plasma. To avoid oxidative damages, consumption of antioxidant-rich foods are
suggested. Foods are divided depending on the amounts of antioxidants. Guava, red
grapes, spinach, carrots, raisins, turmeric, ginger, cumin, and green tea are rich
sources of antioxidants. Antioxidants in coloured vegetables and fruits boost immu-
nity, prevent age-related diseases, delay ageing and reduce mortality.
Keywords Antioxidants · Ageing · Age-related diseases · Free radicals ·

Oxidative stress
S. Chakraborty (*)
Department of Public Health, Amity Medical School, Amity University Haryana,
Gurgaon (Manesar), Haryana, India
Department of Public Health, Delhi Pharmaceutical Sciences and Research University,
Government of NCT of Delhi, New Delhi, Delhi, India
e-mail: schakraborty@ggn.amity.edu

Ltd. 2023
62 S. Chakraborty
4.1 Introduction
Ageing is a complex biological process; in humans, it has a multifactorial origin.

Ageing results from long-term cellular and molecular damages, with which free
radicals are inherently involved. Ageing leads to an increasing number of diseases
and disorders and a gradual decrease in physical and mental capacity. Biological
changes, environmental conditions, and life transitions such as loss of loved ones,
death of parents, friends, siblings, separation from children, and retirement acceler-
ate the ageing process (Olshansky and Carnes 2010).
Besides the genetic factors, several factors such as diet, exercise, pollution, and
lifestyles also assume great importance. Social isolation, lack of mobility, dental
problems, food faddism, and inadequate nutrition are major problems of old age.
Reactive oxygen species (ROS) and reactive nitrogen species (RNS), such as super-
oxide, hydroxyl, and nitric oxide radicals damage the DNA and lead to the oxida-
tion of lipid and proteins in cells (Metodiewa and Kośka 1999). Oxidation-Reduction
reaction is the primary source of energy. Dehydrogenation is the most common
form of biological oxidation (Xu et al. 2017).
Immunity decreases with age, called immunosenescence. Disease prevalence
increases due to reduced cellular and humoral immune responses. Both the humoral
and cellular adaptive immune systems protect cells by destroying microbes.
Primarily it is regulated by antibody response, then by cytotoxic T-cell mediated
immune response.
Oxygen-derived free radicals are responsible for cellular damage, leading to sev-
eral diseases, including cancer, retinopathy, cataracts, etc. In addition, antioxidants
have a strong influence on the immune system of the elderly.
Any substance impedes cell oxidation by free radicals or prooxidant radicals is
an antioxidant. According to the Free radical theory in 1956 Denham Harman, free
radicals are produced during aerobic respiration because cumulative oxidative dam-
age is the cause of ageing and death (Blumberg 2000). Free radicals have unpaired
electrons. These highly reactive unpaired electrons react with molecules and dam-
age proteins, lipids, carbohydrates, cell membranes, peptide bonds, and nucleic
acids (Phaniendra et al. 2015). Several experimental evidence favouring the free
radical theory of ageing comes from invertebrates (Viña et al. 2013). In a study by
Schriner et al., mice that have extra catalase in their mitochondria live 18% longer
and were less likely to develop cataracts, but they did not appear to age slower
(Schriner et al. 2005). Free radical theory is one of the most promising explanations
for the process of ageing (Jayanthi et al. 2010).
Since antioxidants can neutralise free radicals by electron donation, the most
logical approach was to use them as supplements to prevent ageing. Free radicals
are atoms or molecules with unpaired electrons that damage our tissue. Antioxidants
combine with free radicals in the body and neutralise their damaging effects.
Therefore, the use of medicinal plants as a source of bioactive compounds, particu-
larly natural antioxidants, has increased substantially worldwide. Beta-Carotene,
lycopene (abundant in tomatoes), lutein (found in green vegetables), zeaxanthin,
cryptoxanthin, and polyphenols found in some fruits, olive oil, tea, grapes, and
oranges have antioxidant effects.
4 Antioxidants and Ageing 63
This chapter describes the relationship between free radicals, ageing-related

physiological changes, antioxidants’ impacts, and defence mechanisms.
4.2 The Physiological Process of Ageing
Aging involves various physiological changes:
4.2.1 Gastrointestinal Tract
From gum disease to tooth decay and other pathophysiological factors, adequate
dietary intake is reduced. Loose, painful teeth and ill-fitting dentures cause difficul-
ties in mastication. Lips, tongue, salivary glands and teeth play a role in chewing,
breaking down and swallowing food. Swallowing food without proper chewing
results in digestive problems. In the case of the tongue, due to the decreasing num-
ber of taste buds, taste sensitivity is reduced, and food may seem less appetising.
People over 70 years old have a common problem of xerostomia. Decreased secre-
tion of saliva leads to xerostomia (dryness of the mouth) which makes swallowing
difficult. After swallowing, the bolus reaches the posterior pharyngeal wall, where
the musculature contracts around it, but the intestine’s motility decreases, leading to
impaired absorption of nutrients. The absorptive capacity of the small intestine is
reduced by 30%. Gastric emptying diminishes progressively with age, and the acid-
ity and pepsin content in gastric juice also decreases. Food stays in the stomach for
a longer period, which gives a feeling of fullness. Fat and carbohydrate absorption
decreases to a lesser extent with age. Fat tolerance decreases because of inadequate
secretion of fat-digestive enzyme lipase (Nigam and Knight 2017).
4.2.2 Telomere Shortening
A telomere is a region of repetitive DNA sequences at the end of a chromosome

(Blackburn et al. 2006). Telomeres perform many vital roles; the three main roles of
telomeres are: (a) it protects the end of chromosomes. Without their protection cap
DNA gets damaged. It also protects chromosome ends from degradation and ille-
gitimate recombination; (b) they ensure the replication of chromosomes during cell
division; and (c) they help in arranging each of the 46 chromosomes. Telomere
function is inextricably linked with cell age (Shammas 2011). With each cell divi-
sion, chromosomes become shorter. In cells without telomeres, DNA becomes bro-
ken and damaged, which causes cells to stop dividing, cell fate and ageing. Telomere
density is higher in rapidly dividing cells such as eggs, sperm, and stem cells. It’s
concentration is less in somatic cells. The number of telomeres decreases by 20 to
40 per year. Ageing is not the only cause of telomere shortening. Factors such as
64 S. Chakraborty
lifestyle, diet, smoking, obesity, etc. are responsible for telomere shortening.
Maintaining a healthy diet can prevent telomere shortening and protect against vari-
ous chronic diseases (Jennings et al. 2000).
4.2.3 Changes in Cardiovascular System
The risk of cardiovascular disease also increases with age. The progressive accumu-
lation of atheromatous plaques on veins, arteries wall or vascular walls leads to
narrowing of the lumen of blood vessels and decreased blood flow. Not only does it
alter the mechanical and structural properties of the vascular wall, but it also
decreases arterial elasticity. The decline in cardiac output reduces the efficiency of
other organs. Due to reduced blood flow, the digestion, absorption and distribution
of nutrients are less efficient. We should take care of our hearts from childhood.
Fatty material, fats, and collagen accumulate in the artery and form plaque; as a
result, there is difficulty in blood flow in the arteries. As the age increases, a thick
layer of fat falls in the artery, in which case the size of the lumen of the artery
decreases, because of which blood cannot flow smoothly. This plaque reduces blood
flow or completely stops blood flow and causing heart diseases.
4.2.4 Renal Changes
With increasing age, chronic and acute kidney diseases are possible. Blood flow
decreases with age, and the number of functioning nephrons also decreases. The
smaller number of functioning nephrons lessens the glomerular filtration and tubu-
lar reabsorption of essential nutrients. Thus, the excretion of wastes and return of
nutrients to the circulation is less efficient. According to research from Johns
Hopkins University researchers, more than 50% of seniors over the age of 75 are
believed to have kidney disease. The National Kidney Foundation (NKF) urges
everyone over the age of 60 to be screened for kidney disease. NKF also recom-
mends that people with diabetes, hypertension, and kidney failure in their families
are a high-risk group. Swelling of the face and feet, frequent urination (especially at
night), urinary sensation and presence of blood or pus in the urine, difficulty urina-
tion, and dribbling urine are symptoms of kidney diseases (Kolman 2019).
4.2.5 Change in BMR
The basal metabolism decreases by about 2% for each decade from 25 years of age
due to increased body fat and lesser muscle tension. Age is the most important fac-
tor that changes basal metabolic rate. Physical activity and energy consumption
decrease with age. Energy requirements decrease in the elderly. As a result, the
uptake of vitamins, minerals, and antioxidants gradually decreases. Walking, doing
heavy work, and going to the office decrease with age. As a result, older adults usu-
ally lead a sedentary lifestyle. And if energy consumption increases during this
time, fat accumulates in the body. Body fat tends to accumulate in the abdominal
cavity in the elderly. According to the Food and Nutrition Board/ Institute of
Medicine, the USA average decreases of 2.9% and 2% per decade, respectively, for
men and women of average body weight (Basal metabolic rate of 18.5–25.0 kg/m2).
Healthy lifestyle and physical activity decrease BMI. The ability to maintain a nor-
mal body temperature is also lessened, this condition is called Hypothermia, which
is deadly for elderly people (Shimokata and Kuzuya 1993).
4.2.6 Carbohydrates and Fat Metabolism
With age, the level of bad cholesterol (LDL, VLDL) and triglycerides in the blood
also gradually increases (Roberts and Rosenberg 2006) (Fig. 4.1).
Fig. 4.1 Process of ageing. (Source: https://erj.ersjournals.com/content/44/5/1332)

66 S. Chakraborty
4.3 Antioxidants
Components that combine with free radicals in the body and neutralise their damag-
ing effects are called antioxidants. All antioxidants work together to protect our
cells from damage and keep our body healthy. Although antioxidants have many
definitions. According to chemical definition, a substance that opposes oxidation or
inhibits reactions promoted by oxygen or peroxidase is called an antioxidant. The
biological definition of antioxidant is: antioxidants are synthetic or natural sub-
stances that prevent or delay the deterioration of a product or are capable of coun-
teracting the damaging effects of oxidation in animal tissues. The Institute of
Medicine defines an antioxidant as a substance that significantly decreases the
adverse effects of reactive species such as ROS or RNS on normal physiological
function in humans. ROS and RNS mean reactive oxygen species and reactive
nitrogen species, respectively.
4.4 Classifications, Locations and Functions
Antioxidants can be classified in different ways. Based on their activities, they are
classified as: enzymatic antioxidants and non-enzymatic antioxidants (Moussa
et al. 2020).
Depending on the solubility, antioxidants can be differentiated into two types, as
water-soluble and lipid-soluble antioxidants (Azat Aziz et al. 2019). Few examples
of water-soluble antioxidants are ascorbic acid, glutathione, uric acid, etc. Few
examples of lipid-soluble vitamin E, carotenoids, etc.
The antioxidants can also be classified according to their size, the small-molecule
antioxidants and large-molecule antioxidants (Nimse and Pal 2015). Ascorbic acid,
retinol, β-carotene, tocopherol and polyphenolic compounds are small molecule
antioxidants. Vitamin C, vitamin E, carotenoids, and glutathione peroxidase are
large molecule antioxidants (Fig. 4.2).
Fig. 4.2 Classification of antioxidants. (Source: https://images.app.goo.gl/2DduSh99Rt4s14rA9)
4.5 Enzymatic Antioxidants
Enzymatic antioxidants break down free radicals, such as superoxide radicals and
hydrogen peroxide and remove them from the site. Some enzymatic antioxidants
are: superoxide dismutase (SOD), glutathione peroxidase (GSH), catalase (CAT),
glutathione reductase, etc. (Jeeva et al. 2015). These antioxidants react chemically
in the presence of various cofactors (zinc, copper, manganese, iron) to convert free
radicals first into hydrogen peroxide and then into the water.
4.6 Superoxide Dismutase (SOD)
Superoxide dismutase is located in mitochondria and cytosol. This antioxidant

destroys superoxide radicals and helps the conduit in transmitting the injury caused
by free radicals. Copper-zinc containing enzymes are found in the cytoplasm, and
manganese SOD is located in the mitochondria.
4.7 GSH and Glutathione Reductase
The oxidative form of glutathione is not protective, but the reduced form is defen-
sive in nature. Three main reduced forms of glutathione which play as enzymatic
antioxidants are Glutathione reductase, Glutathione peroxidase and Glutathione
68 S. Chakraborty
transferase, located at mitochondria and cytosol. Glutathione peroxidase reduces

lipid hydrogen peroxides to their corresponding alcohol to remove hydrogen perox-
ide and organic peroxide (Lubos et al. 2011). Some studies suggest that glutathione
peroxidase and superoxide dismutase play an essential role in celiac disease.
Glutathione peroxidase and glutathione reductase play a key role in preventing
increased levels of oxidative stress. Type 2 diabetes with microalbuminuria, diabetic
nephropathy—all these patients have low levels of glutathione peroxidase in serum
or blood.
4.8 Catalase
One of the most important enzymatic antioxidants present in cytosol and mitochon-
dria is Catalase. In a two-step reaction, Catalase breaks down two hydrogen perox-
ide molecules into one molecule of oxygen and two molecules of water and then
removes hydrogen peroxide (Nandi et al. 2019). In 1948, the first prokaryotic cata-
lase was purified from the organism of an aerobic bacterium Micrococcus lysodeik-
ticus. Catalase malfunctioning or deficiency is associated with many diseases such
as anemia, Alzheimer’s disease, cardiovascular disease, Wilson disease, bipolar dis-
order, etc. Low catalase activities have been reported in schizophrenic patients.
4.9 Non-enzymatic Antioxidants
In addition to enzymatic antioxidants, human blood plasma has highly efficient

small molecular weight compounds which act as antioxidants called non-enzymatic
antioxidants. Few non-enzymatic antioxidants are vitamin E, vitamin C, uric acid,
carotenoids, bilirubin, ubiquinones, nitric oxide, etc.
4.9.1 Vitamin E
Vitamin E is a group of eight fat-soluble compounds with potent antioxidant effects.

Alpha-tocopherol is the most biologically active form of vitamin E (Ref) Dutta-Roy,
A.K., Gordon, M.J., Campbell, F.M., Duthie, G.J., James, W.P.T: Vitamin E require-
ments, transport, and metabolism: Role of α-tocopherol-binding proteins. Journal of
Nutritional Biochemistry, 5, 562-570, 1994. Plant oils such as rapeseed (vegetable
oil), sunflower, soya, corn and olive oil, nuts, and seeds are good sources of vitamin
E (Miller 2006). In the human body, vitamin E is mainly present in the cell mem-
brane. Vitamin E breaks antioxidants in cell membranes and helps proper immune
function and cellular signalling. Vitamin E supplements significantly reduced sys-
tolic and diastolic blood pressure and triglycerides, low-density lipoproteins (refs).
4.9.2 Uric Acid
Uric acid inhibits lipid peroxidation and scavenges free radicals. The major limita-
tion of uric acid is it acts only in the hydrophilic environment (Sautin and Johnson
2008). Urate is a very efficient scavenger of highly reactive oxygen species (hydroxyl
radicals, singlet oxygen, etc.). Uric acid is the product of purine metabolism.
4.9.3 Carotenoids and Flavonoids
The two primary antioxidants available from plants are carotenoids and flavonoids.
They are very potent natural and lipid-soluble antioxidants. Both of them are located
in membrane tissues. Flavonoids scavenge hydroxyl and superoxide radicals from
cells. According to the World Health Organization, cancer is a primary cause of
death and accounted for around 13% of all deaths in 2008. Carotenoids and flavo-
noids protect against many diseases related to ageing, such as neurological disor-
ders, various types of information, diabetes, cardiovascular disease, cancer, etc.
Cantaloupe, carrot, papaya, and kale are good sources of carotenoids. Berries, red
cabbage, tea, and onion are good sources of flavonoids.
4.9.4 Vitamin C
Water soluble vitamin C is the most effective antioxidant in plasma. It is protective

against ageing-related problems and neurological disorders. Few clinical studies
suggest that vitamin C (ascorbic acid) reduces wrinkles and improves skin texture
and appearance. It is essential for the growth, development and repair of all tissues
in the body. It is indispensable in many vital body functions, including collagen
formation, iron absorption, immune system strengthening, wound healing, etc.
Parkinson’s disease and arthritis are significant problems in the elderly; daily vita-
min C intake can reduce these problems. All sour fruits such as lemons, oranges,
tamarinds, tomatoes, grapes, and bitter gourds are good sources of vitamin C (Nimse
and Pal 2015; Jeeva et al. 2015).
4.10 Foods Containing Antioxidants
Antioxidants from dietary sources can protect from various diseases, such as cardio-
vascular disease and cancers, and it is also very effective as antiaging agent.
Fruits, vegetables, nuts, and seeds are good sources of antioxidants. Scientists at
NIH (National Institute of Health and Aging) develop ORAC scores to measure
70 S. Chakraborty
antioxidant capacity in different foods. Foods with higher ORAC values can neu-
tralise more harmful free radicals. Free radicals damage cells and cause many age-
related degenerative diseases. According to researchers, 3000-5000 antioxidant or
ORAC units are able to meet the body’s daily requirements. Many times, due to
eating higher antioxidant-containing foods (apple, cherry, cloves, turmeric, peaches,
broccoli, etc.), the antioxidant in the body increased by 15–20%. But antioxidant
capacity in the blood is tightly regulated. Excess antioxidants are simply excreted
by the kidneys. Five serving varieties of fruits and vegetables give an approximate
ORAC score of 3500, according to UK FSA and FDA (Carlsen et al. 2010).
4.11 Antioxidants and Their Sources
USDA researches 100 foods from each food category and gives a list of the top 20
foods. Among them, small red beans, blackberries, wild blueberries, strawberries,
black beans, sweet cherries, plums, and red delicious apples are quite significant.
American Dietetic Association gave an authoritative list of the highest antioxidants
containing the top 20 foods (Reilly 2015).
Food group Highest antioxidants containing foods

Fruits Guava, red grapes, cherries, peaches, oranges, strawberries,
etc.
Vegetables Spinach, broccoli, carrots, potatoes, cabbage, avocados,
pumpkin, etc.
Dried fruits Dried pears, apples, raisins, dates, etc.
Spices and herbs Turmeric, parsley, curry powder, basil, ginger, cumin, etc.
Cereals and nuts Walnuts, almonds, cashews, etc.
Beverages Green tea, pink grapefruit juice, apple juice, pomegranate
juice, etc.
4.11.1 Guava
Guava is one of the antioxidant-rich fruits. The first highest vitamin C content fruit
is amla, and the second highest vitamin C content fruit is guava. Not only in guava
fruit but the leaf, root and bark of this tree are also very useful. Guava leaves also
have a high content of antioxidants. We get a few important antioxidants from
guava; they are quercetin, ascorbic acid, ferulic acid, caffeic, and gallic acid.
Quercetin has high reducing power, it breaks down hydrogen peroxide to form
water. Elderly people often suffer from arthritis, brain dysfunction, and arterioscle-
rosis. Antioxidants present in guava are beneficial in many degenerative diseases
including arthritis, cancer, heart disease, arteriosclerosis and brain dysfunction
(Naseer et al. 2018).
4.11.2 Spinach
Spinach contains many active antioxidants. Both glucuronic acid derivatives of fla-
vonoids and coumaric acid derivatives are present in aqueous extract of spinach
leaves. Spinach leaves also contain two phyto-pigments xanthine and lutein. It also
contains carotenoids. We find that the tendency to develop cataracts increases with
age. Xanthine, lutein, beta carotenoids prevent cataracts. Vitamin A present in spin-
ach, which protects the mucous membrane of the eye and increases eyesight.
Besides these, carotenoids are also very good for the eyes. Spinach is very useful in
reducing blood pressure, weight loss, constipation, etc. Spinach is also very effec-
tive in removing various skin problems such as wrinkles, acne, etc. (Bergman
et al. 2001).
4.11.3 Dates
Dates are rich in phenolic antioxidants, such as sinapic acid, p-coumaric, ferulic,
flavonoids and procyanidis. It also contains vitamin B1, B2, B3, B5, vitamin A and
vitamin C. Dried dates have more sugar content (sucrose). Due to its high antioxi-
dant content, it is included in functional food. Traditional use of dates can be seen
in several diseases such as bronchitis, wound healing, fever, intestinal disorder, etc.
Sinapic acid, p-coumaric, ferulic, and flavonoids have antibacterial and anti-
inflammatory activity. Dates are also a good source of carotenoids. 100gm dates
contain 3942 mg phenolic compounds and carotenoids. Dates cure anemia, improve
brain function and increase the body’s immune system (Rahmani et al. 2014).
4.11.4 Turmeric
Turmeric contains a very powerful antioxidant called curcumin. Curcumin reduces

blood pressure and blood sugar, enhances immunity power, protects neurons and
postpone the onset of age-related disease such as Alzheimer’s disease, rheumatoid
arthritis, metabolic syndrome, cancer, etc. As a result of oxidative stress, the amount
of pro-inflammatory cytokines such as 1L-6 and 1L-1 increases in tissue and causes
low-grade inflammation (inflame-ageing). It has been confirmed through various
in vitro experiments that curcumin is an anti-cancer agent. So, curcumin antioxi-
dants in turmeric can also prevent terrible diseases such as cancer. It triggers the
Nrf2/ARE signalling pathway, which activates a few antioxidative enzymes such as
heme oxygenase and thioredoxin reductase, which play vital roles in oxidative
stress-related diseases. Turmeric is also called a natural antibiotic. For a long time,
we have seen that turmeric is applied to the wound. Turmeric oil helps to stop bleed-
ing and protects that area from infection. Curcumin is a highly lipophilic compound
72 S. Chakraborty
which crosses the blood-brain barrier (BBB) and reaches the brain to protect the
brain against ageing, and neurodegenerative disorders. Curcumin also reduces mel-
anin production and makes our skin fair and glowing (Sikora et al. 2010).
4.11.5 Walnuts
When you hear about nuts, the first thing that comes to mind is its fat content. But
nuts contain many useful antioxidants. Vinson analysed antioxidants in nine types
of nuts such as walnuts, peanuts, hazelnuts, pistachios, almonds, Brazil nuts, pecans,
macadamias, and cashews. He said that walnuts have the highest level of antioxi-
dant content. Useful antioxidants in walnuts are ellagic acid, ellagitannins, catechin,
melatonin, and vitamin E (32). Deposition of fatty materials on the inner walls of
arteries increases with age, causing atherosclerosis. Melatonin and vitamin E reduce
low-density lipoproteins (bad cholesterol) and prevent atherosclerosis. Ellagic acid
decreases the levels of inflammation and melanin production (Chen et al. 2018).
4.11.6 Green Tea
The antioxidant presents in green tea is epigallocatechin-3-gallate (EGCG). This

natural antioxidant, catechin, reduces the formation of free radicals and protects
cells from damage. Catechin plays a leading role in shedding belly fat (Gunnars 2020).
4.11.7 Antioxidant Activity of Fresh Fruits
Antioxidant activity DPPHa (Trolox equivalent)

Name mg/100 g
Guava 891
Apple 330
Grapes (green) 137
Indian plum 500
Papaya 46
Orange 167
Mango 211
Pomegranate 149
Water melon 32
Sweet lime 149
Chiku 141
Banana 41
2, 2′-Diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity. (Source:

a
Nutrition News NIN, 31 or book source: Food Science, B Srilakshmi)
4.12 Mechanism of Antioxidants and Ageing
Antioxidants have immense importance in keeping the body healthy and disease-
free. Free radicals are typical by-products of various physiological processes that
continue throughout the day in our bodies. These free radicals damage our cells and
tissues. Antioxidants neutralise these free radicals and protect the body from dam-
age (Lobo et al. 2010). Free radicals cause oxidative stress, accelerating the ageing
process. Antioxidants reduce several age-related diseases such as arthritis, glau-
coma, cardiovascular disease, neurological diseases, etc. (Fig. 4.3).
Fig. 4.3 Free radicals, gene expression, telomere and antioxidant as a model figure. (Source:
https://ars.els-cdn.com/content/image/1-s2.0-S0024320520310936-ga1_lrg.jpg)
74 S. Chakraborty
4.13 Antioxidant Defence System
A variety of antioxidants exist to control enzymatic and non-enzymatic damage by

reactive oxygen species (ROS).
The enzymatic defence system includes Glutathione peroxidase, Glutathione
reductase, Glutathione transferase, Catalase, and Superoxide dismutase.
The non-enzymatic system includes:
(a) Ascorbic acid, Selenium, Glutathione, Alpha-tocopherol, Beta Carotene.
(b) Ceruloplasmin, Uric acid, Anserine, Transferrin, Carnosine.
Superoxide dismutase, Glutathione peroxidase, and Catalase these enzymatic
antioxidants and non-enzymatic antioxidants such as albumin and bilirubin are
endogenous antioxidants. When the concentration of ROS in tissue increases,
endogenous antioxidants cannot neutralise all free radicals. So, endogenous antioxi-
dants fail to give complete protection to our bodies. That is why exogenous antioxi-
dants are needed. These exogenous antioxidants are available in foods, nutritional
supplements, and pharmaceuticals. There are several metals containing enzymes
which scavenge and destroy free radicals. Various essential nutrients act as cofac-
tors for all these enzymes. Some examples are given below.
4.14 Selenium
The amount of free radicals in the body increases due to various reasons. Consuming
certain drugs, various radiations, and being exposed to heavy metals such as cad-
mium, lead, etc. increases the body’s free radicals (Jaishankar et al. 2014). When the
concentration of ROS exceeds the concentration of antioxidants, this extra ROS
causes lipid peroxidation and damages the lipid layer of the cell membrane.
Polyunsaturated fatty acids (PUFA) are very useful in maintaining membrane per-
meability. But polyunsaturated fatty acids are more susceptible to peroxidation
(Catalá 2013). As a result of the damage to the cell membrane, nutrient absorption
decreases in the cell, which results in a deficiency of various essential elements,
vitamins, and minerals.
Not only the cell membrane but also the ROS extensively damage the DNA. At
first, reactive oxygen species break the double strand of DNA and then damage the
base and DNA protein, creating lesions in chromatin and sugars. This process is
done by oxidation, methylation, deamination and depurination. Natural or dietary
antioxidants help living organisms to live healthy in an oxygen-rich environment.
Free radicals also cause protein oxidation. Protein peroxidation, damage in the
amino acid chain and loss of parent amino acid is linked with ageing. Selenium is a
component of a wide range of antioxidants such as glutathione peroxidase, thiore-
doxin reductase, selenophosphate synthetase, selenoprotein H, selenoprotein K,
methionine sulfoxide reductase B1, etc. These antioxidants protect tissues from
damage caused by protein oxidation and lipid oxidation. Selenium-containing anti-

oxidants decrease free radicals production and convert peroxidised lipids to stable
and harmless products. Low dietary intake of selenium leads to Kashin-Beck dis-
ease, Keshan disease, male infertility, etc. (Zoidis et al. 2018).
Zinc and copper are components of redox-inert metal of copper/zinc superoxide
dismutase. According to some studies, zinc, copper, and their dependent enzymatic
antioxidants are responsible for age-related variations. Low or high zinc concentra-
tion causes cellular oxidative stress, which is very harmful to cells. Zinc-containing
antioxidants Superoxide dismutase converts superoxide radicals to hydrogen perox-
ide to oxygen. Zinc increases immunity power, making our skin healthy. Zinc is also
important for neural functions (Sfar et al. 2009; Lee 2018).
Iron-containing enzymatic antioxidant Catalase alters hydrogen peroxide to
water and oxygen.
4.15 The Mechanism for Disposal of Free Radicals
• Zinc containing superoxide dismutase converts superoxide radicals to hydrogen

peroxide (H2O2).
• Selenium-containing glutathione peroxidase converts hydrogen peroxide (H2O2)
to water (H2O).
• Glutathione reductase regenerates reduced glutathione.
• Iron-containing enzyme catalase alters two molecules of hydrogen peroxide into
two molecules of water and oxygen.
• Vitamin E reacts with free radicals and is oxidised, and forms water.
• Vitamin E also reacts with lipid peroxyl radical, oxidises itself, and forms stable
hydroperoxide.
• In the presence of vitamin C, vitamin E can be regenerated from oxidised vita-
min E (Nimse and Pal 2015) (Fig. 4.4).
Colourful fruits and vegetables are the richest sources of antioxidants. Other
major plant pigments besides chlorophyll are carotenoids, lycopene, lutein, flavo-
noids, etc. Plant pigments such as anthocyanin are present in pink, red, and
Fig. 4.4 Role of dietary

antioxidants. (Source:
https://images.app.goo.gl/
PXF32L1CqD1SkyjbA)
76 S. Chakraborty
blue-coloured fruits and vegetables such as berries, red cabbage, etc. Anthocyanin
is a water-soluble pigment belonging to the flavonoid group. Currently, 500 types of
anthocyanin have been discovered. ‘Anthos’ means flower, and ‘cyanine’ means
blue. Anthocyanin is normally present in the cytoplasm of a cell. It protects cells
from ultraviolet rays. This pigment reduces the risk of cardiovascular disease, can-
cer, neurological disorders, and age-related diseases (Sudhakar et al. 2016).
Carotenoids give plants and fruits yellow, orange and bright red colours. Various
health benefits are available from carotenoids. Few sources of carotenoids are car-
rots, watermelon, cantaloupe, papaya, spinach, mangos, kale, etc. About 600 types
of carotenoids have been found in plants, bacteria, and algae. Beta carotenoid is
notable among them. Xanthophyll contains fruits and vegetables, primarily red and
orange Oxygen. Containing molecules are found in dark green leafy vegetables
such as spinach, kale, and broccoli. Few forms of carotenoids, such as beta-
carotenoids, convert into vitamin A, which is crucial for vision (Anthony 2018).
Foods rich in carotenoids can prevent the growth of cancer cells and keep the eyes
healthy (Sudhakar et al. 2016).
Lycopene is a tetraterpene compound belonging to the family of carotenoids.
Tomato is a rich source of lycopene. Lycopene hinders the onset of several diseases,
including diabetes, oxidative stress-mediated malfunctions, skin and bone disease,
neural and reproductive disorders, liver disease, etc. (Imran et al. 2020). Lycopene
is responsible for the red and orange colour of fruits and vegetables. The bioavail-
ability of lycopene in the body also decreases with age. Lycopene can remove more
singlet oxygen than beta-carotene and alpha-tocopherol. A higher intake of lyco-
pene reduces the risk of prostate cancer. Lycopene is one of the most potent anti-
inflammatory nutraceuticals. Increasing the amount of lycopene in the blood reduces
the risk of cancer.
Lycopene has anticarcinogenic effects, reducing the risk of several cancers such
as lung cancer, stomach cancer, ovary cancer, breast cancer, and prostate cancer.
Research suggests that a proper dose of lycopene reduces the number and size of
ovarian tumours. It protects cells from cell damage caused by free radicals and cell
necrosis. Lycopene supplementation protects the liver and lung by hindering nico-
tinic acetylcholine receptors expressed in the lung and CYP2E1 in the liver.
Lycopene also acts as an antidiabetic by increasing insulin secretion.
Lycopene is also helpful in pancreas injury and urination problems caused by
diabetes. Cardioprotective compound lycopene decreases very low-density lipopro-
teins (VLDL), low-density lipoproteins (LDL), triglycerides (TG) and total choles-
terol and increases the level of high-density lipoproteins (HDL) (Dullaart et al.
1987). Thus, lycopene reduces blood pressure and protects the heart from various
types of fatal heart diseases such as atherosclerosis, myocardial infarction, etc.
(Imran et al. 2020).
As age increases, the ability of the intestine to absorb vitamins also decreases.
Then we have to take more vitamins or vitamin supplements from outside. Vitamin
E is essential for muscle health. Fat-soluble vitamin E reacts with loose electrons,
oxidises itself and protects cells from oxidative damage. Alpha-tocopherol is the
most active and abundant vitamin E. Sedentary lifestyle and malabsorption of
vitamin E cause several chronic age-related diseases, so vitamin E is involved in

reaching longevity. The moisturising power of vitamin E makes our skin healthy
and protects our skin from oxidative damage sunburn (2014).
Vitamin C decreases the formation of wrinkles, fine lines, age spots. It fights
against harmful toxins or free radicals and improves skin texture and appearance. It
also protect cells from sunburn. It increases immunity power and helps eliminate
diabetes, hypertension, cardiovascular disease, and Alzheimer’s disease. It acceler-
ates the production of collagen and elastin and regenerates cells, delaying the skin’s
ageing process (Monacelli et al. 2017; Oregon State University 2021).
Oxidative stress is the result of an imbalance between prooxidants and antioxi-
dants. The chemiluminescence process is used a lot to study oxidative stress in liv-
ing organisms in vitro. In vivo, this process has been proposed as a non-invasive
method to assess free radical skin damage. Tropical application of vitamin C or
ascorbic acid before exposure to UVA decreases the UVA-induced chemilumines-
cence signal. This is very effective process to assess oxidative damage by UVA in
the skin and how vitamin c protects our skin from UVA. According to American
Dietetic Association spokeswoman Dee Sandquist, vitamin C obtained directly
from fruits and vegetables is better than a supplement. Vitamin C nourishes the cell
well from the inside to the outside. A study about this has been published in the
American Journal of Clinical Nutrition, where the nutrient intake and skin ageing of
4025 people aged 40–75 years were observed. It has been seen here that people who
have taken more vitamin C have less tendency to dry skin and fewer wrinkles on the
skin (Ou-Yang et al. 2004; Zelman 2020).
4.16 Conclusions
Ageing is the result of long-term cell damage, molecular damage by free radicals
produced as a result of various chemical reactions occurring in the body for a long
time. Ageing is a biological process which depends on environmental factors, men-
tal factors, etc. Free radicals such as ROS and RNS cause extensive damage to the
cell membrane, protein, lipid, DNA and accelerate the ageing process. The unpaired
electron in free radicals is the cause of ageing and death. Oxidative damage leads to
several age-related diseases, including retinopathy, cataract, hypertension, diabetes,
atherosclerosis, etc. Antioxidants neutralise free radicals by combining with
unpaired electrons. Antioxidants are of different types depending on activities, solu-
bility, and size. The mitochondria and cytosol of the cell usually contain enzymatic
antioxidants. SOD, GSH, CAT destroys superoxide radicals and remove hydrogen
peroxide and organic hydrogen peroxide. Human blood plasma also contains highly
effective small molecular weight non-enzymatic antioxidants. Among them, vita-
min E, uric acid, and vitamin C are quite significant. High triglyceride levels and
hypertension are common problems for every elderly person. Vitamin E supple-
ments reduce systolic, and diastolic blood pressure and total cholesterol. Urate
reacts with highly reactive free radicals like singlet oxygen, and hydroxyl radicals
78 S. Chakraborty
and neutralises them. Water soluble vitamin C reduces wrinkles and improves skin
condition. It has a vital role in collagen production, wound healing and iron absorp-
tion. As we get older, some changes happen in our bodies. Gum diseases, tooth
decay, loose, painful teeth, and reduced saliva causes mastication and swallowing
difficulties. Telomere is also crucial for cell division and replication. Smoking, obe-
sity, and alcohol consumption are responsible for telomere shortening. The risk of
atherosclerosis, myocardial infarction, and Alzheimer’s disease also increases with
age. Progressive accumulation of fats on blood vessels leads to narrowing of the
lumen. As a result, blood cannot flow properly in all organs such as the kidney,
brain, etc. Thus, most elderly people suffer from chronic and acute kidney and neu-
rological diseases. The number and the capacity of nephrons also decrease. The
antioxidant defence system is made with different antioxidants, including glutathi-
one peroxidase, glutathione reductase, ceruloplasmin, transferrin, etc. The amount
of free radicals increases due to various drug consumption, pollution, etc. The risk
of several chronic diseases decreases with diets rich in colourful vegetables and
fruits. Because colourful vegetables and fruits contain many powerful antioxidants
such as carotenoids, lutein, lycopene, etc., higher intake of these antioxidant-rich
foods reduce the risk of diseases, delay ageing and lower the risk of mortality.
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Chapter 5
Nutrition and the Ageing Brain
Emily Connell, Matthew Pontifex, and David Vauzour
Abstract As the detrimental impacts of the ageing process accumulate, individuals

become increasingly susceptible to cognitive dysfunction and neurological disor-
ders. Diet has emerged as a key ‘modifiable factor’ that over a life course can have
considerable implications upon cognitive function. This stems from its ability to
modulate multiple processes such as neuroinflammation, endogenous antioxidant
defence system and gut microbiota structure and function, which have an integral
role in memory, learning and cognitive function. This chapter aims to highlight
some of the key dietary nutrients, as well as whole diet approaches which may pro-
mote healthy neurological function, particularly during ageing. The emergence of
novel pathways by which diet may influence healthy ageing (e.g., gut microbiome),
and the advancement of new methodological approaches (neuroimaging, metabolo-
mics, biomarkers) has enabled researchers to uncover novel mechanisms that may
underpin this relationship. Despite this, the translation of these findings into a clini-
cal setting remains challenging, marred by inconsistent and often contradictory
results, suggesting further research using more standardised approaches is needed.
Keywords Ageing brain · Cognitive function · Polyphenols · Polyunsaturated

fatty acids · Vitamins · Mediterranean diet
E. Connell · M. Pontifex · D. Vauzour (*)

Norwich Medical School, Faculty of Medicine and Health Sciences, University of East
Anglia, Norwich, UK
e-mail: D.Vauzour@uea.ac.uk

Ltd. 2023
82 E. Connell et al.
5.1 Introduction
The global population is ageing. In 2015, the elderly proportion of society (e.g.,
60 years or over) comprised of 901 million people accounting for 12.3% of the
global population. By 2050, this number is expected to reach 2.1 billion, or 21.3%
of the population (United Nations Department of Economic and Social Affairs,
Population Division 2019). Given that age is the primary risk factor for cognitive
decline; age-related neurological diseases such as dementia will undoubtably
become increasingly prevalent over the coming decades. While some decline in
cognition is to be expected as an inevitable part of the ageing process, approxi-
mately 15% and 11% of the population over 65 years develop more extensive cogni-
tive impairment, namely mild cognitive impairment (MCI) and age-related
dementias such as Alzheimer’s disease (AD) respectively. Although more complex
in reality, MCI generally describes a decline in mental abilities which exceeds nor-
mal ageing, without functional impairment and dementia (Petersen et al. 1999).
Dementia (of which AD is the most common form), often follows MCI, and pres-
ents when the degree of cognitive decline reaches a level in which an individual’s
ability to carry out everyday tasks and activities becomes impaired. Debilitating
conditions such as AD and dementia have a profound societal and economic impact,
which are projected to intensify to overwhelming proportions over the forthcoming
years. To address this global challenge, strategies to mitigate disease burden are
urgently required. In the case of AD, it has been estimated that delaying disease
onset by as little as 2–5 years could result in a 20–35% reduction in predicted AD
prevalence by 2050 (Lewis et al. 2014), highlighting how preventative measures
could be used to significantly lessen overall disease burden. Targeting lifestyle fac-
tors is an attractive option in the prevention of neurodegenerative disease given their
modifiable nature. Therapeutic interventions/strategies targeting these lifestyle fac-
tors (e.g., diet and exercise) can be used to shift an individual to a more favourable
status which promotes healthy brain ageing, while resisting aberrant changes
(Fig. 5.1).
Nutrition is a key influencer of cognitive function. Indeed, current evidence
indicates that nutritional strategies can delay or ameliorate neurodegenerative
disease progression (Trichopoulou et al. 2003; Dangour et al. 2010). Individual
dietary components, such as vitamin B, selenium and omega-3-fatty acids have
been associated with protective roles during brain ageing (Trichopoulou et al.
2003; Dangour et al. 2010). However, long-term exposure and individuals with
low baseline exposure are often required to observe a meaningful effect.
Therefore, synergistic dietary patterns which encompass numerous bioactive
compounds, such as the Mediterranean diet, DASH (Dietary Approaches to Stop
Hypertension) diet and the hybrid MIND (Mediterranean-DASH Intervention for
5 Nutrition and the Ageing Brain 83
Fig. 5.1 Lifestyle factors associated with healthy and pathological ageing. (Figure created with
BioRender)
Neurodegenerative Delay) diet, have become increasingly popular (Trichopoulou

et al. 2003). This is supported by the World Health Organization and Public
Health England, who are now promoting whole diet approaches to delay or pre-
vent cognitive decline (Scientific Advisory Committee on Nutrition 2018; World
Health Organisation 2019). The mechanistic basis by which diet exerts its neuro-
protective actions is diverse and nutrient dependent. Dietary factors modulate a
wide range of processes and pathways including neuroinflammation, endogenous
antioxidant defence systems and gut microbiota structure and function, which
will in turn affect learning/memory and ultimately cognitive function. Given the
complexity of these interactions, the exact biological effects of many single nutri-
ents remain unclear. This chapter aims to summarise current evidence and future
directions of both single nutrient and combination dietary approaches in the con-
text of healthy brain ageing (Table 5.1).
Table 5.1 Impact of the Mediterranean, MIND and DASH dietary patterns on health and cognitive
function
Study Dietary pattern Participants Findings
Gkotzamanis Mediterranean The HELIAD study: 1226 Higher adherence to the
et al. (2022) adults over 65 years Mediterranean dietary
pattern was associated with
more favourable trajectories
in ageing
Tsivgoulis Mediterranean REGARDS study: 17,478 Higher adherence to the
et al. (2013) participants 45 years and over Mediterranean diet
with no history of cognitive correlated with lower
impairment at baseline incidences of cognitive
impairment
Trichopoulou Mediterranean 22,043 adults from Greece 44-month follow-up showed
et al. (2003) higher adherence to the
Mediterranean diet was
significantly associated with
a reduction in mortality
Féart et al. Mediterranean 1410 participants 65 years and Higher Mediterranean diet
(2009) older adherence was linked with
slower cognitive decline on
the mini-mental state
examination test only and
was not associated with
dementia
Wu and Sun Mediterranean Systematic review and A linear relationship was
(2017) meta-analysis of 9 cohorts with found between
34,168 participants Mediterranean diet score and
incidence of cognitive
decline
Rodríguez- Mediterranean PREDIMED trial: 2866 A Mediterranean diet
Rejón et al. non-diabetic participants supplemented with extra
(2014) virgin olive oil or nuts lowers
glycaemic load and
glycaemic index
Berti et al. Mediterranean 70 participants (30–60 years Lower Mediterranean diet
(2018) old) adherence was associated
with progressive AD brain
biomarker abnormalities
Gu et al. Mediterranean 674 elderly adults without Mediterranean diet
(2015) dementia adherence was associated
with less brain atrophy,
equivalent to 5 years of
ageing
Zbeida et al. Mediterranean Analysis of the US National Mediterranean diet
(2014) Health and nutrition survey adherence was associated
(NHANES) 1999-2002 and with better health outcomes
from the Israeli National and cognitive functioning
Health and nutrition survey
(MABAT ZAHAV) 2005–2006
(continued)

Study Dietary pattern Participants Findings
Mosconi et al. Mediterranean 52 cognitively healthy adults Lower adherence to the
(2014) (mean age 54 years) Mediterranean diet was
associated with cortical
thinning in similar regions to
AD patients
Shannon et al. Mediterranean EPIC-Norfolk study: 8009 The Mediterranean diet
(2019) adults from the UK improved global cognitive
function equivalent to 1.7
fewer years of cognitive
ageing
Wengreen DASH and 3831 adults over 65 years Greater adherence to both
et al. (2013) Mediterranean the DASH and
Mediterranean dietary
patterns was linked with
higher cognitive function
over 11 years
Tangney et al. DASH and 826 memory and aging project Both the DASH and
(2014) Mediterranean participants Mediterranean diet patterns
were linked with slower rates
of cognitive decline
Haring et al. DASH and 6425 postmenopausal women Adherence to the dietary
(2016) Mediterranean between the ages of 65–79 patterns did not modify the
risk of cognitive decline in a
9-year follow-up
Morris et al. MIND 960 participants from the The MIND diet was found to
(2015) memory and aging project significantly slow cognitive
decline (both global
cognitive score and each of
the five cognitive domains)
with age
Melo van Lent MIND 2092 participants (mean age of Greater MIND diet
et al. (2021) 61 years) adherence is linked with
better cognitive performance
and larger total brain
volume, but not with
cognitive decline
Arjmand et al. MIND 50 healthy obese women The MIND diet was
(2022) associated with the reversal
of the destructive effects of
obesity on cognition and
brain structure
5.2 The Gut Microbiota-Brain Axis, Nutrition and Ageing
The involvement of the gut microbiota in health and disease dramatically emerged
over the last decade. It is becoming increasingly apparent that this involvement
extends to cognitive function and neurodegenerative disease development. The gut
microbiota, a dense population of 1014 microorganisms living in a mutualistic
relationship with their host, plays many important roles: shaping immune system
development, metabolising dietary nutrients, forming vital bioactive compounds,
digesting complex polysaccharides and synthesising essential vitamins. The intesti-
nal microbiome is dynamic and rapidly responds to various intrinsic (e.g., genetics,
immune response, metabolites) and extrinsic factors (e.g., diet, lifestyle, antibiotic
intake). Diet can account for up to 57% of changes in gut microbiota composition
(Clark and Mach 2016) and therefore is one of the most influential factors. Long-
term dietary consumption modulates the structure and activity of the gut microbiota
population, while the short-term intake of animal or plant products can overcome
inter-individual variances in microbial gene expression and modify microbial com-
munity structure. Hence, an individual’s microbial community is significantly
impacted by their dietary intake, this community in turn shapes the individual’s
development and health, suggesting that diet can be used as a valuable therapeutic
tool to promote human health, including cognitive disorders.
Dietary compounds can elicit a substantial influence upon cognition by commu-
nicating through a gut microbiota-brain axis. The gut microbiota-brain axis is a
bidirectional communication system connecting the gut, liver, and central nervous
system (CNS) that is modulated by the microbiome. The gut sends signals to the
brain via numerous neurocrine, endocrine and neuroimmune mediated pathways,
while the brain controls the secretory and sensory function of the gut. Once dietary
components reach the gut, they are broken down by the gut microbiota to form key
microbial-derived metabolites. These bioactive compounds exit the gut and enter
the systemic circulation where they can induce direct effects by crossing into the
brain or indirect effects by activating the vagus nerve.
As we age, gut microbiota composition and function changes. In humans, this
has been correlated with a reduction in species diversity, a decline in Clostridiales
and Bifidobacterium and an increase in Proteobacteria and pathobionts such as
Enterobacteriaceae. While most of these changes are harmless, major shifts in com-
position, known as ‘dysbiosis’, can trigger harmful local and systemic inflamma-
tion, which are associated with shifts in gut-derived metabolites. For example, the
abundance of Bifidobacterium, a commensal species that produces the important
short-chain fatty acid metabolite from dietary fibres, is inversely related to inflam-
mageing in the elderly population (Ragonnaud and Biragyn 2021). Older age is
associated with an increase in dysbiosis, with pro-inflammatory gut microbiota
populations increased, replacing more beneficial microbes. Together, these changes
can have detrimental consequences and therefore identifying nutritional approaches
to modulate the gut composition could assist with longevity.
5.3 Inflammation, Nutrition and Ageing
Inflammation is an essential process of innate (non-specific) immunity. Generally,

inflammation is the local response reaction to injury, pathogens, irritants or oxida-
tive stress, which stimulates increased blood flow, capillary dilation, leucocyte
infiltration and the production of host chemical mediators to remove toxic agents
and restore damaged tissue. Importantly, the termination of inflammation requires
both the production of cytokines and other anti-inflammatory mediators, as well as
the elimination of pro-inflammatory pathways. Despite the essential role of inflam-
mation in host immunity, when inflammation is prolonged (known as chronic low-
grade inflammation) it becomes detrimental and is present in many chronic
conditions such as type-2 diabetes, cardiovascular disease and even neurological
disorders such as dementia. However, although the relationship between chronic
conditions and inflammation is well recognised, the extent to which inflammation
plays a role and its causation remains unclear.
Ageing is associated with the development of low-level systemic, chronic inflam-
mation, known as ‘inflammageing’, a term coined by Claudio Franceschi in 2000.
Inflammageing has been highlighted as a key factor that may promote and worsen
cognitive decline in older adults, as baseline levels of inflammatory biomarkers
have been found to increase with age (Sartori et al. 2012). Therefore, although
inflammation with age may be a natural effect of immune senescence, it also
increases the susceptibility of the host to pathogenesis, including in the brain.
Studies also suggest modulatory factors of the immune response may become less
effective as we age, decreasing the regulation of the immune response. This process
may explain why we observe changes in cytokine profiles in elderly individuals
(Kim et al. 2011), particularly proinflammatory cytokines such as interleukin-1 beta
(IL-1β), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6), which pres-
ent in higher concentrations in brain regions such as the hippocampus and cortex.
In the mammalian brain, neuroinflammation activates microglia, macrophages
and inflammatory mediators such as cytokines, chemokines and complement pro-
teins, which in turn generate a significant number of pro-inflammatory factors that
are detrimental to neuronal cells. Limbic and related neuronal structures, including
the hippocampi and basal ganglia (brain regions that modulate key cognitive pro-
cesses such as memory, attention, emotion, and perception) are comprised of a
larger number of enzymes associated with the inflammatory response and conse-
quently, are more at risk to progressive damage (Raz and Rodrigue 2006).
Accumulating evidence also implicates low-grade chronic inflammation in the
pathogenesis of neurodegenerative disorders. Amyloid plaque depositions and neu-
rofibrillary tangles, two key pathological features of AD, are correlated with mark-
ers of inflammation. Ownby and colleagues also suggest AD patients may have
increased body temperature, further associating the inflammatory processes
(Ownby 2010).
Dietary compounds can modulate the neuroinflammatory process. Polyphenols,
unsaturated fats and antioxidant vitamins have been found to inhibit oxidative
stress and neuroinflammation, while saturated fats can promote inflammation, par-
ticularly in the hypothalamus. Westernised dietary patterns, including high fat and
fibre deficiency, have been associated with neuroinflammation and neurodegenera-
tion. As mentioned in the previous section, dietary patterns can significantly influ-
ence gut microbiota composition and as such can modulate brain function through
the microbiota-gut-brain axis. For example, high-fat diet-induced gut microbiota
alterations can decrease cognitive function in mice. Furthermore, the transplanta-

tion of obese-type microbiota into healthy mice leads to intestinal barrier disrup-
tions and increased cognitive dysfunction (Bruce-Keller et al. 2015). Gut microbiota
can influence inflammatory responses in the brain by influencing microglia matu-
ration and function, and therefore changes to the gut microbiota caused by diet can
be a major modulator of the initiation of neuroinflammatory processes and subse-
quent dysfunction caused by this. Identifying a safe, cheap and easily imple-
mentable nutritional approach to regulate microbiota could therefore be of great
importance to improve harmful aspects of the microbiota-gut-brain axis dysregula-
tion, subsequently reducing neuroinflammation and cognitive impairment that
arises with age. For example, in mice, microbiota-accessible carbohydrates pre-
vented high-fat diet-induced cognitive impairment by preventing gut microbiota
dysbiosis, increasing colonic mucus thickness, tight junction protein expression
and decreased colonic systemic inflammation and neuroglial activation (Shi
et al. 2020).
5.4 Individual Dietary Components
5.4.1 Dietary Polyphenols
Polyphenols are a diverse group of phytochemicals that are present in fruits, veg-
etables, nuts, seeds and other plant products. They are comprised of multiple
hydroxyl groups on aromatic rings, forming two main groups, flavonoids and non-
flavonoids, depending on the number and interaction of their phenol rings.
Flavonoids, such as flavones (found in celery and parsley), flavonols (found in
onions, broccoli and leeks), isoflavones (found in soy products), flavanones/flava-
nonols (found in citrus fruits and wine), flavonols (found in green tea and red
wine) and anthocyanins (found in red wine and berries), consist of a C6-C3-C6
structure with two aromatic carbon rings, benzopyran (A and C rings) and benzene
(B ring). The degree of oxidation of the C ring, the hydroxylation pattern of the
ring structure and the substitution of the 3-position vary between subclasses of
flavonoids. The non-flavonoid group is comprised of two classes known as pheno-
lic acids (found in many fruits and vegetables) and stilbenes (found in grapes,
wine and peanuts).
Epidemiological studies suggest polyphenols confer a broad variety of health
benefits. For example, the intake of chocolate and tea was found to be inversely
related to cardiovascular disease (Djoussé et al. 2011). Intervention trials also sug-
gest cardiovascular benefits; however, the majority of these studies use coca-derived
flavanols and modulate markers associated with inflammation, reducing incidences
of atherosclerosis, insulin resistance, lipid profiles, blood pressure and vasodilation/
endothelial function. Indeed, cardiovascular risk is intimately connected to cerebral
blood flow and neuronal metabolism, and thus, they covary with the development of
age-related cognitive impairment, AD, and mood.
Accumulating research is uncovering the beneficial properties of polyphenols in

the CNS. They have been heavily associated with AD prevention via numerous
pathways. First, polyphenols are suggested to be anti-amyloidogenic and therefore
prevent the fibrillisation of amyloid beta (Aβ) both in in vivo and in vitro models.
For example, gallic acid and catechin-rich grape seed polyphenol extract repressed
cognitive decline corresponding with decreased concentrations of soluble oligomers
of Aβ (Pasinetti et al. 2010). The mechanism underlying this process remains
unclear, however, it is suggested that non-amyloidogenic processing of amyloid
precursor protein (APP) may be increased by promoting the activity of α-secretase,
an enzyme capable of cleaving APP at a site which avoids the formation of Aβ spe-
cies and plaques, a hallmark feature of AD (Rezai-Zadeh et al. 2005). On the other
hand, polyphenols may decrease Aβ plaque pathology by preventing amyloid aggre-
gation and fibrillisation due to metal chelation activity (Mandel et al. 2007) or by
promoting the formation of nontoxic oligomers. Second, they improve metabolic
function, a process highly linked with AD and suggested to exacerbate neurological
symptoms (Cai et al. 2012). Finally, polyphenols have a widespread neuroprotective
role in the brain though exerting an anti-inflammatory, anti-apoptotic and antioxi-
dant effect. They are implicated in a variety of vital pathways including the sirtuin-
FoxO pathway, the NF-κB pathway, and the Nrf-2/ARE pathway associated with
neuroprotective benefits (Vauzour 2012).
Curcumin is a polyphenol that forms a major component of the spice turmeric.
Recent evidence highlights its neuroprotective benefits in humans and rodents.
Indeed, curcumin displays anti-Aβ and anti-tau phosphorylation properties to pro-
tect against AD pathology, as well as playing a role in antioxidant, anti-cholesterol
and anti-inflammatory activities. In adult mice, curcumin was found to increase the
proliferation of hippocampal progenitor cells and improve spatial and non-spatial
memory in high concentrations (Kim et al. 2008). Furthermore, curcumin has been
linked with neurogenesis through the modulation of histone deacetylases and his-
tone acetyltransferases (Kang et al. 2006). However, it is of note that curcumin’s
neuroprotective effects may be dose-dependent as curcumin has low bioavailability
due to its hydrophobic nature and is reported as having sub-optimal systemic
absorption from the gastrointestinal tract. Others report the benefits of curcumin
may not solely rely on its bioavailability, but instead come from its interactions with
the gut microbiota (Lopresti 2018). Together, these mechanisms in humans have led
to significant improvements in attention, selective memory and visual memory
when given twice a day (90 mg) (Small et al. 2018).
Berry fruits are also rich in polyphenols and commonly investigated regarding
neuroprotective properties due to links with antioxidant, anti-inflammatory, micro-
biota modulation and cell-protecting effects. For example, blueberry intake has
been associated with reduced oxidative stress, inhibition of inflammatory pathways
and improve vascular health. The mechanisms underlying these protective effects
have been attributed to a high anthocyanin content. Indeed, blueberry and straw-
berry extracts have been found to significantly reverse age-related declines in aged
rodents, with improvements in working memory. In vitro, blueberries can also
reduce the activation of the ERK1/2 pathway, a pathway that is stimulated from Aβ,
to inhibit Aβ aggregation. Whereas, in rodents, blueberry supplementation increased

the proliferation of precursor cells in the dentate gyrus.
Overall, there is a large body of evidence demonstrating the neuroprotective and
beneficial effects of polyphenols on brain health. As a result, polyphenols represent
a promising treatment opportunity for the promotion of healthy ageing and the pre-
vention of neurodegenerative diseases. However, there remain many challenges in
the use and research of polyphenols. First, many studies highlight the hugely benefi-
cial effects of polyphenols in vitro when supplied at a supraphysiological dosage.
This means that in many cases, the research dosage cannot be achieved by normal
food consumption in vivo and does not consider differences in bioavailability and
bioactivity. Moreover, polyphenols can interact with the gut microbiota to produce
a variety of microbial-derived metabolite products, which cannot be accounted for
in in vitro studies. Therefore, moving studies into randomised controlled trials
(RCTs) in humans is essential to extend our knowledge.
5.4.2 Polyunsaturated Fatty Acids
Polyunsaturated fatty acids (PUFAs) form essential elements of neuronal cell mem-
branes, preserving membrane fluidity that is crucial for synaptic vesicle fusion and
enabling neurotransmitter communication within neural networks. Additionally,
membrane PUFAs form precursors for lipid messengers that stimulate signalling
pathways that promote neuronal protection or neuronal dysfunction (Bazan 2005).
However, as we age, the concentration of PUFAs in the hippocampus, cortex, and
cerebellum, brain regions implicated in cognitive and motor processes, is reduced,
with further decreases occurring in AD.
A variety of PUFAs perform different roles within the CNS and body. Each
PUFA is characterised by an acyl chain consisting of one acid end (-COOH) and
one methyl end (-CH3). «Omega-3» (ω-3) reveals that the first double bond is
located at the third carbon from the methyl end (H3C-C-C=), however, «omega-6»
(ω-6) specifies that the double bond nearest to this end is at the sixth carbon. The
most abundant PUFAs in the brain are arachidonic acid (ARA, 20:4(ω-6)), which
consists of 20 carbon atoms with 4 double bonds, and docosahexaenoic acid (DHA,
22:6(ω-3)), which consists of 22 carbon atoms with 6 double bonds. Together,
these two PUFAs account for approximately one-fifth of the brain’s dry weight.
The concentration of another important PUFA, eicosapentaenoic acid (EPA,
20:5(ω-3)), is relatively low due to it being quickly metabolised. Both ARA and
DHA are needed for brain development and functioning. ARA is found in animal
products such as eggs and meat, while DHA and EPA are found in oily fish and
cod-liver oil. At birth, although the brain is fully developed, it is only 25% of its
total adult volume. Therefore, as we grow, glial cells and neurons’ axons and den-
drite expand, and nerve fibres are myelinated. This expansion is greatly reliant
upon long-chain PUFAs and therefore deficiencies can result in permanent mental
deficiencies (Bentsen 2017).
In adults, the effect of PUFAs on cognitive functioning remains inconclusive. A

recent meta-analysis of the cognitive effects of ω-3 PUFA supplementation in the
general population showed no significant benefit, and may only have marginal
effects on individuals who are PUFA deficient (Cooper et al. 2015). On the other
hand, a three-month randomised double-blind intervention (EPA 270 mg + DHA
180 mg or placebo) in moderately malnourished Mexican school-aged children,
indicated improvements in 11 of the 18 neuropsychological variables studies,
including IQ scores, executive functioning, visuoperceptive capacity and processing
speed (Portillo-Reyes et al. 2014). However, notably, these children had signifi-
cantly lower baseline seafood intake than the meta-analysis.
In epidemiological studies, PUFAs from fish oils have frequently been associ-
ated with reduced AD and reduced cognitive decline (Joseph et al. 2009). DHA
reduced Aβ 42 in AD mice (Lim et al. 2005) and production by cultured human
neurons. It is suggested this may be due to a variety of mechanisms including
changes in lipid raft structure (Stillwell et al. 2005), modifications in APP process-
ing, initiation of anti-amyloidogenic chaperones for APP, and Aβ transthyretin.
However, there is some evidence that PUFAs may have limited protection in APOE4
carriers, the largest genetic risk factor of AD (Cole et al. 2009). PUFAs may also
increase survival signalling as in vitro evidence suggests they can block Aβ oligo-
mers toxicity, thereby protecting synaptic and dendritic function.
DHA and EPA have been found to decrease chronic inflammation by reducing
NF-κB activation, which subsequently regulates the expression of pro-inflamma-
tory cytokines TNF-α and IL-α and β. However, the specific mechanisms behind
DHA and EPA’s interaction with the NF-κB pathway remain unclear. During the
ageing process, when inflammation is typically increased, ω-3 PUFAs concentra-
tions are seen to be decreased, alongside neural membrane plasticity.
Neurobiological studies found a markedly decreased concentration of DHA in the
neural membrane of aged healthy individuals and patients with neurological dys-
function. However, these changes can be reversed by the intake of ω-3 PUFAs
(Dyall et al. 2007). In rats, ω-3 PUFA supplementation can reverse age-related
changes and maintains learning and memory performance (Farooqui et al. 2007).
Overall, the results of the protective effects remain inconclusive. Future studies
should perhaps examine cognitive outcomes associated with PUFAs in the context
of genotype (e.g., APOE).
5.4.3 Vitamins
Vitamins are organic compounds that are critical for the normal functioning of cel-
lular and physiological processes, as well as growth and development. All vitamins,
except vitamin D, must be attained from the diet. In the developed world, vitamin
supplements form the most chosen supplements, being taken by approximately a
third of US and European populations (Li et al. 2010). However, ageing is linked
with a higher risk for lower vitamin consumption (Thomas 2006).
Vitamin E (tocopherols) have been linked with decreases in cases of AD or

dementia (Mangialasche et al. 2012). However, the supplementation of vitamin E
did not show positive effects on the risk of AD. This may be as vitamin E supple-
ments often only contain the α-tocopherol and not the range of vitamin E found
in foods such as mangoes, spinach and tomatoes. Consequently, increased intakes
of vitamin E from food sources were linked to a reduction in AD cases (Morris
et al. 2005). The mechanism underlying vitamin E’s beneficial properties is
unclear, but may be related to its lipophilic antioxidant properties, as vitamin E
can be transported across the blood-brain barrier by lipoproteins (Mardones and
Rigotti 2004).
B vitamins play important roles at all levels of the brain as co-enzymes and pre-
cursors of co-factors in enzymatic processes. Sufficient concentrations of folate and
B12 are necessary for the remethylation of the amino acid homocysteine, while B6
forms as a coenzyme in the metabolism of homocysteine to cysteine. High homo-
cysteine levels (e.g., by a shortage of folate and/or vitamins B6, and B12) are sug-
gested to increase dementia risk by promoting a range of negative effects on cellular,
haemodynamic, oxidative and vascular factors (Kennedy and Haskell 2011).
Importantly, vitamin B12 deficiency occurs in 5–20% of the elderly population
(Andrès et al. 2004). Vitamin B6 also contributes to metabolic processes and is vital
to the production of a variety of neurotransmitters, such as dopamine and serotonin,
through its role as a cofactor for aromatic l-amino acid decarboxylase, an enzyme
that catalyses the decarboxylation of a variety of aromatic l-amino acids. However,
these beneficial effects do not seem to translate to clinical investigations. O’Leary
and colleagues conducted a systematic review of 35 cohort studies, of which 21
were good quality. Of these 21, only seven studies showed beneficial associations
between vitamin B12 and cognition (O’Leary et al. 2012). A meta-analysis of RCTs
investigating the effect of vitamin B concluded overall that there was no underlying
effect on cognition in individuals both with and without cognitive decline (Behrens
et al. 2020). Nevertheless, the randomised, double-blind Folate after Coronary
Intervention Trial (FACIT) study investigated 818 participants with daily folic acid
and found a decrease in serum homocysteine concentrations and a significant
increase in memory, processing speed and sensorimotor speed in comparison to a
placebo group (Durga et al. 2007).
Vitamin C (ascorbic acid) is commonly obtained from citrus fruits and leafy
vegetables and accumulates in high concentrations neuron dense areas in the brain,
including the hippocampus, cortex and cerebellum. It plays a role as a powerful
antioxidant, decreasing oxygen, sulfur and nitrogen-oxygen radicals produced
through normal cellular metabolism, as well as converting additional radicals to
their prior structures (e.g., tocopheroxyl to α-tocopherol). It is also involved in
tyrosine, carnitine, catecholamine neurotransmitters and peptide hormones pro-
duction and plays roles in neural maturation and the neuromodulation of the activ-
ity of acetylcholine and the catecholamine neurotransmitters (Kennedy and
Haskell 2011).
Vitamin D is also heavily investigated in relation to cognitive function. It is esti-
mated a large proportion of the general population, particularly the elderly, are
vitamin D deficient. Vitamin D receptors have been detected in the brain. It is sug-
gested these may play a neuroprotective role through regulating neurons from
excessive calcium entry, regulation of inducible nitric oxide synthase (iNOS),
upregulation of the endogenous antioxidant glutathione, and improving synaptic
function and nerve transmission in the neo-cortex and hippocampus via upregula-
tion of neurotrophic factors (Buell and Dawson-Hughes 2008). The NAME
(Nutrition and Memory in Elderly) study also supports these neuroprotective bene-
fits of vitamin D, finding vitamin D concentrations <50 nmol/L were correlated with
a greater prevalence of possible or probable AD (Scott et al. 2006).
5.5 Dietary Patterns and the Ageing Brain
5.5.1 The Mediterranean Diet
The Mediterranean diet refers to a diet composed of a high intake of fruits, vegeta-
bles, olive oil, whole grains and unsaturated fatty acids, moderate intake of fish, low
to moderate intake of dairy products (in the form of yoghurt and cheese) and
restricted consumption of red meats, but regular consumption of alcohol (especially
wine) (Trichopoulou et al. 2003). This diet has been linked to reduced risk of numer-
ous age-related diseases, including stroke, type 2 diabetes, and cardiovascular dis-
ease, which are all risk factors for dementia. Beneficial cognitive effects have been
reported in elderly adults adhering to the Mediterranean diet, particularly in the
domains of global cognition and episodic memory (Loughrey et al. 2017). Adherence
to the Mediterranean diet is associated with a slower decline in cognition (Tsivgoulis
et al. 2013), improved cognitive performance (Zbeida et al. 2014), decreased risk of
cognitive impairment and reduced risk of MCI to AD conversion (Féart et al. 2010).
In fact, a meta-analysis of 34,168 participants linked a high Mediterranean diet
score to a 21% decreased risk of developing cognitive decline and a 40% decreased
risk of AD (Wu and Sun 2017). Furthermore, when investigating where these ben-
eficial effects may extend the ageing process, the Hellenic Longitudinal Investigation
of Aging and Diet (HELIAD) study discovered that Mediterranean diet adherence
was strongly associated with preserving or even improving healthy ageing status,
independent of age, sex and lifestyle factors, suggesting this diet may promote lon-
gevity (Gkotzamanis et al. 2022). The benefits of the Mediterranean diet was also
found to occur in non-Mediterranean countries, an analysis of an older UK popula-
tion indicated high adherence to the Mediterranean diet improved global cognitive
function equivalent to 1.7 fewer years of cognitive ageing (Shannon et al. 2019).
However, the relationship between the Mediterranean diet and cognition is disputed,
with some research studies finding no correlation (Psaltopoulou et al. 2008; Féart
et al. 2009). Contradictory findings may occur due to heterogeneity in research
methods, including dietary intake and cognitive status methods, follow-up time and
population characteristics, which can hinder comparisons. For example, a system-
atic review highlighted a 30% increase in positive significant findings in
Mediterranean countries, in comparison to non-Mediterranean regions (Aridi

et al. 2017).
Potential mechanisms underlying the protective effect of the Mediterranean diet
include anti-inflammatory, antioxidant, and microbiome modulation due to the ben-
eficial roles of major components of the dietary pattern, including fatty acids, vita-
mins, minerals, fibre and bioactive compounds (Fig. 5.2). The Mediterranean diet is
high in fibre, omega-3, polyphenols, arginine, nitrate and melatonin, which have
been associated mechanistically with improved cognition (Radd-Vagenas et al.
2018). The Mediterranean diet is also linked with a lessening glycaemic load
(Rodríguez-Rejón et al. 2014), which is associated with better cognitive function in
adults (Philippou and Constantinou 2014). Furthermore, a low calories Mediterranean
diet was found to reduce circulatory advanced glycation end-products (AGEs)
which are known to contribute to increased stress and inflammation (Rodríguez
et al. 2015).
The Mediterranean diet is also linked to changes in neurological structure and
brain integrity. Observational studies link Mediterranean diet adherence to increased
cortical thickness (Mosconi et al. 2014), larger brain volume, reduced rates of hip-
pocampal atrophy and improved structural connectivity (Gu et al. 2015), supporting
the notion that the Mediterranean diet may protect against neurodegeneration. In
fact, greater adherence has also been linked to a reduction in amyloid (Aβ) accumu-
lation, a protein that forms senile plaques in early AD pathogenesis, in adults and
the elderly (Berti et al. 2018).
Fig. 5.2 Components of a Mediterranean diet pattern and potential mechanisms underlying their
cognitive benefits. (Figure created with BioRender)
5.5.2 DASH
The Dietary Approaches to Stop Hypertension Diet (DASH), similarly to the

Mediterranean diet, promotes a diet rich in fruits and vegetables, nuts and cereals.
However, it places greater importance on a reduction in dairy products, sodium and
alcohol consumption. DASH is currently recommended for improving cardiovascular
health, however, more recently has been investigated for cognitive benefits. Greater
adherence to the DASH diet has been associated with increased cognitive scores in
adults (Wengreen et al. 2013), with reduced declines in cognition (Tangney et al.
2014). However, not all evidence supports these claims, with some comparative stud-
ies suggesting the Mediterranean diet and MIND dietary patterns have better impacts
on cognition (Haring et al. 2016). This may be because the DASH diet does not alle-
viate symptoms of neurodegenerative disorders such as AD; but instead reduces the
risk of disease occurrence by preventing cardiovascular disease, a risk factor of AD.
5.5.3 MIND
The combination of the DASH and the Mediterranean diet is known as the MIND
diet (Mediterranean-DASH Intervention for Neurodegenerative Delay). Unlike the
DASH diet, this dietary pattern was designed specifically to improve cognitive per-
formance, while reducing the risk of developing neurodegenerative diseases based
on findings from the diet-dementia field. The MIND diet promotes an intake of leafy
green vegetables and berries up to six times a week, as these food products have
been linked to better brain health. Similarly, to the Mediterranean and DASH diets,
the MIND diet recommends the intake of vegetables, nuts, whole grains, as well as
pulses, red wine and fish. On the other hand, it suggests restricting the consumption
of red meats, cheese, sweets and fried foods. Research suggests that this combina-
tion approach is more effective in preventing dementia than the Mediterranean diet
and DASH diet alone (Morris et al. 2015). Specifically, the MIND diet has been
found to significantly improve global cognitive function, working memory, visual
memory and verbal recognition memory, processing speeds and attention (Melo van
Lent et al. 2021; Arjmand et al. 2022). MRI results suggest the MIND diet may also
modulate neurobiology, increasing the surface area of the inferior frontal gyrus and
total brain volume (Melo van Lent et al. 2021).
5.6 Conclusions
There is compelling evidence describing the neuroprotective potential of nutri-

tion throughout the ageing process. The pathological manifestation of neurologi-
cal conditions such as AD begins decades before clinical symptoms become
apparent. As such, the identification and implementation of suitable dietary inter-

ventions across an individual’s lifespan could represent a cost-effective and effi-
cacious preventative approach to curb disease incidence. Ageing is linked to an
increase in oxidative stress, neuroinflammation and vascular dysfunction, the
exacerbation of which can promote the development of age-related neurodegen-
erative diseases. Cell, animal and human epidemiological studies suggest that a
diet rich in key nutrients such as long-chain ω-3 PUFAs, B vitamins, antioxidants
such as vitamins C, E, carotenoids, and polyphenols is beneficial for the ageing
brain. However, despite this, RCT evidence investigating these compounds often
presents limited and/or contradictory outcomes. This may in part be due to under-
powered studies (cognitive performance not the primary outcome), or a lack of
adequate trial set-up (duration, dosage, target group or sensitivity) in the method-
ology to evaluate the effect of dietary compounds. In this regard, identifying
relevant and sensitive biomarkers of disease progression becomes increasingly
vital. For example, MRI and fMRI scans outline how changes in dietary interven-
tions can affect neuronal brain structure. Furthermore, it is becoming increas-
ingly apparent that large metabolic heterogeneity exists from factors such as
genetics, epigenetics, microbiome and lifestyle, meaning individuals can differ in
their requirements and responses to nutrients and bioactive molecules. Therefore,
future research may look towards more personalised nutritional approaches by
subcategorising the population based on markers of metabolic variation and use
this knowledge to better estimate each group’s dietary requirements for improved
recommendations and interventions. Finally, current research methods into
dietary intake often involve participants completing an in-depth food frequency
questionnaire in which an individual may have to remember their intake of
between 10–300 food items from the previous year. This may introduce inaccura-
cies to food intake measures and therefore multiple 24 h recalls and food records
may be more expensive, yet appropriate. New technology such as web-based and
smartphone food-based assessments are becoming increasingly popular as they
can be easily accessible to large cohorts and reported near after the time of food
consumption. However, as with all questionnaires, these methods are still sus-
pectable to recall bias and self-reporting inaccuracies. Therefore, some studies
turn to biomarkers as an accurate and unbiased measure. However, currently
there is only a handful of validated food biomarkers, such as plasma vitamin C
for fruits and vegetables, and as such are yet to cover the vast variety of the
human diet.
Nevertheless, although significant work remains to fully develop comprehensive
methods and uncover the complex role of nutrition as a modulator of ageing, the
current evidence provides a promising outlook. Dietary changes, combined with
other lifestyle factors and enrichment may provide the simplest and most effica-
cious method thus far. Intriguingly, although many of the mechanisms underpinning
the beneficial impacts of these dietary approaches still need to be understood, it is
evident that they incorporate reductions in oxidative/inflammatory stress signalling
and increases in protective signalling to defend against the detrimental processes of
ageing and promote healthy cognitive function.
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Chapter 6
Omega-3 Fatty Acids and Ageing Brain
Navya Sree Boga and Sanjay Basak
Abstract Inflammation plays a key role in the pathogenesis of age-related brain

diseases. Hence, it is appropriate to target inflammation for disease prevention. The
long-chain omega-3 polyunsaturated fatty acids (LCPUFAs), such as eicosapentae-
noic acid (EPA) and docosahexaenoic acid (DHA), play essential roles in support-
ing human health and offer protection due to their anti-inflammatory roles. Higher
incorporation of DHA into the synaptic membrane improves signal transduction
and increases the glutamatergic and dopaminergic synaptic activities. Despite sev-
eral unsaturated double bonds in DHA, it can still empower its protection by the
novel antioxidant defence in the brain. The molar ratio of DHA/ARA acts as an
indicator of antioxidant defence. Excess n-6 LCPUFA like ARA levels has reflected
the cells undergoing oxidative stress by increased lipid peroxides. Although inter-
vention studies in older people could not establish an apparent causal effect with a
disease state, nutritional factors like LCPUFAs showed promising benefits in delay-
ing age-related brain disease. The review highlights the mechanism of brain dys-
functions & ageing and the roles of omega-3 fatty acids in its protection.
Keywords DHA · Brain dysfunctions · Ageing · Omega-3 · Neuroinflammation

· Oxidative stress · MicroRNA
N. S. Boga · S. Basak (*)

Molecular Biology Division, National Institute of Nutrition, Indian Council of Medical
Research, Hyderabad, India
e-mail: basak.sanjay@icmr.gov.in
Ltd. 2023
102 N. S. Boga and S. Basak
Abbreviations
ALP Autophagy lysosomal pathway
ARA Arachidonic acid, 20:4n-6
AREs Antioxidant response elements
ASD Autism Spectrum Disorder
ASEAN Association of Southeast Asian Nations
ATP Adenosine triphosphate
Aβ Amyloid-beta
BBB Blood-brain barrier
BDNF Brain-derived neurotrophic factor
CAT Catalase
COX2 Cyclooxygenase-2
CSF Cerebrospinal fluid
DAMPs Damage-associated molecular patterns
DHA Docosahexaenoic acid, 22:6n-3
DMN Default mode network
DNA Deoxyribonucleic acid
DNMT1 DNA methyl transferases1
ECM Extracellular matrix
EPA Eicosapentaenoic acid, 20:5n-3
FAT Fatty acid translocase
FATP-1 Fatty acid transport protein-1
FATP-4 Fatty acid transport protein-4
FC Functional connectivity
GLA Gamma linolenic acid
GSH Glutathione
GSH-Px Glutathione peroxidase
HD Huntington’s disease
IGF-1 Insulin-like growth-factor-1
IL-1β Interleukin 1 beta
IL-6 Interleukin-6
JNK C-Jun N-terminal kinase
LA Linoleic acid, 18: 2n-6
LCPUFA Long chain omega-3 polyunsaturated fatty acids
LOX Lipoxygenase
LTP Long-term potentiation
MAPK Mitogen-activated protein kinase
MCI Mild cognitive impairment
MIA Maternal immune activation
miRNA Micro RNAs
mPFC Medial prefrontal cortex
MUFAs Monounsaturated fatty acid
6 Omega-3 Fatty Acids and Ageing Brain 103
NADPH Nicotinamide adenine dinucleotide phosphate

NO Nitric oxide
NOS Nitric oxide synthase
NOX NADPH oxidase
Nrf2 Nuclear erythroid factor-2
PAMPs Pathogen-associated molecular patterns
PCC Posterior cingulate cortex
PC-DHA Phosphatidylcholine-DHA
PD Parkinson’s disease
PE-DHA Phosphatidylethanolamine-DHA
PFC Prefrontal cortex
PLA2 Phosphatidylcholine 2-acylhydrolase
PRRs Pattern recognition receptors
PUFA Polyunsaturated fatty acids
RNS Reactive nitrogen species
ROS Reactive oxygen species
SERPINA5 Serpin Family A Member 5
SFA Saturated fatty acid
TNF α Tumour Necrosis Factor alpha
TrkB Tropomyosin receptor kinase B
UPS Ubiquitin proteasome system
6.1 Introduction
Ageing is a challenge to all living organisms. Ageing is considered the most signifi-
cant risk for neurodegenerative disorders (Satoh et al. 2017). The progressive cel-
lular damage, a gradual loss of functionality in tissues and organs, increases the
vulnerability to diseases over time. Some declining processes such as defective
repair mechanisms, aggregation of abnormal molecules and disturbed oxidative
stress conditions lead to senescence (van Meer et al. 2008). Telomere shortening,
mitochondrial dysfunction, genomic instability, DNA methylation, and dysregu-
lated gene expression (Lee et al. 2017) are some of the hallmarks of the ageing
process (Foster et al. 2019; Cole et al. 2019). It is essential to understand whether
the cognitive decline during ageing is a normal consequence of ageing process or an
indication of neurodegenerative diseases (Casaletto et al. 2019).
According to WHO, the global human life expectancy raised by 6 years from
66.8–73.4 years in the last 10 years. Asia is top in hosting a rapidly ageing popu-
lation globally (Nations 2017). The average life expectancy in the Association of
Southeast Asian Nations (ASEAN) is 71 years, and it rose to 75 years in Thailand,
China and South Korea. The current Indian life expectancy is 70.19 years, show-
ing a significant increase from the last few years (Lau et al. 2010). But with the
increase in expectancy, a healthy life expectancy is not increasing at the
same pace.
The brain, a complex human organ, comprises primarily two types of cells, i.e.
neurons and glia. Glial cells provide structural and metabolic support, insulation,
and coordination in development. Neuronal cells transmit signals over a long dis-
tance to specific targets. Mitochondrial dysfunction is a common pathology for
brain ageing and neurodegenerative diseases in AD, PD, and Huntington’s (HD).
The lowered efficiency in mitochondrial energy coupling and function is correlated
with alterations in the capacity of respiratory enzymes, mitochondrial content, or
changes in enzyme activities. The impaired mitochondrial functions result in oxida-
tive stress, exposure to mitochondrial permeability transition pores, and enhanced
apoptosis of neuronal cells.
The brain represents 2% of body mass but utilises 20% of total oxygen demands
making this organ susceptible to oxidative damage, which is predominant in the
pathophysiology in the progression of several neurodegenerative disorders in age-
ing. Moreover, the brain contains high levels of lipids (60–65%), and modest anti-
oxidant systems make it vulnerable to oxidative stress. Neurological oxidative stress
has induced either failure of antioxidant protection or overproduction of reactive
oxygen species (ROS) formed during mitochondrial dysfunction.
Brain membrane enriched with glycerophospholipid that contains saturated fatty
acid (SFA) at the sn-1 position of glycerol moiety and PUFA (ARA or DHA) pres-
ent at the sn-2 position. ARA, present in neuronal phospholipids, undergoes oxida-
tion either by enzymatic or non-enzymatic pathways. ARA is released and oxidised
by PLA2 and COX2, while non-enzymatic oxidation of ARA results in the produc-
tion of ROS, pro-inflammatory cytokines, and elevated levels of n-6 fatty acids
derived metabolites. The review will emphasise the latest data on brain dysfunctions
during ageing and omega-3 fatty acids’ roles in its protection.
6.2 Brain and Age-Related Disorders
6.2.1 Structure, Functions and Brain Maintenance
The brain develops in the third week of gestation and changes as life progresses.
The human brain can be macro-anatomically divided into six lobes: frontal, parietal,
temporal, occipital, limbic and insular. The structure and functions of the human
brain exhibits a marked change with ageing. As age advances, the brain’s volume
and the cortices’ thickness decrease (Raz et al. 2010). However, the shrinkage of the
brain varies significantly among different individuals depending on different genetic
and environmental factors. Even within a person, the shrinkage is not uniform
throughout the brain. Some areas show more rapid shrinkage than other areas.
During ageing, the cingulate gyrus area 24, and inferior temporal cortex area 20 are
the most affected brain regions and they exhibit notable variations in fatty acid pro-
files with ageing (Mota-Martorell et al. 2022). During ageing, the forebrain is more
susceptible to ageing complications, followed by the midbrain showing few changes
in substantia nigra region. The hindbrain is unaffected by the ageing process. The
reason for some regions of the brain’s high vulnerability to ageing is still unknown,
and more studies are needed (Mota-Martorell et al. 2022). The ‘last in, first out’
theory of the brain proposes that the complex areas of the brain which take a longer
period to develop are the regions which are more vulnerable to the ageing conse-
quences and degenerate early. Neural stem cells proliferate continuously throughout
life in the brain and are responsible for brain plasticity, memory and learning. But
with mid-age onset, neural stem cell proliferation declines and neuronal output
decreases (Apple et al. 2017). When the brain parts start shrinking with age, the
nerve fibres they contain also start shrinking, which complicates the neurotransmit-
ter system affecting the transport of signals from the brain to different parts of the
body. Brain development occurs in a back-front pattern, leaving the prefrontal cor-
tex’s last part to develop. The prefrontal cortex, responsible for controlling cogni-
tive functions and impulses and for creating and executing plans, is the one to
develop last and is the most disrupted region of the brain during ageing. The degen-
eration of the prefrontal cortex may result in disturbing emotional responses such as
more aggressive behaviour and difficulty in initiating new activities. With brain
ages, the microglia are activated and primed to produce small impulses, which
results in brain damage and neuronal death (Clegg et al. 2013).
The hippocampus is another region at risk of reduced volume and degeneration
with ageing. Hippocampus formation is associated with memory consolidation, pro-
cessing and regulating emotional behaviour. It is considered the critical mediator in
the pathophysiology of cognitive impairment during ageing. With ageing, oxidative
stress and neuroinflammation increase in the hippocampus. Hippocampus is also
expected to be one of the early sites of neurofibrillary tangles development. The
SERPINA5 gene is responsible for the hippocampal vulnerability in Alzheimer’s dis-
ease (AD). SERPINA5 plays a role in blood coagulation and thrombosis. Recent
studies disclosed that this gene plays a crucial role in AD pathogenesis and is also
associated with neurofibrillary tangle pathology (Crist et al. 2021). Different parts of
the brain regions and their degree of degeneration with ageing are depicted in Fig. 6.1.
Fig. 6.1 Different parts of

the brain regions are
numbered in descending
order to their degree of
degeneration with ageing.
1. Prefrontal cortex; 2.
Hippocampus; 3.
Cerebellum; 4. Striatum; 5.
Temporal lobe; 6. Parietal
lobe; 7. Thalamus
6.2.2 Ageing and Brain Functions
Several brain functions, including circadian behaviour, cognition, autonomic func-

tion and emotion, diminish with age and affect the quality of life in social and cog-
nitive aspects. The multiple processes associated with ageing can be divided into
primary and secondary ageing. The inherent or the hereditary factors of decrement
constitute primary ageing, and the defects acquired due to adverse conditions such
as diseases and trauma collectively constitute secondary ageing factors (Hung et al.
2010). The difference between chronologic age and brain age is described as the
‘brain age gap’, which acts as the marker of brain health (Cole and Franke 2017). A
higher brain age gap is associated with poor cognitive phenotypes and is raised in
many brain disorders (Kaufmann et al. 2019). There are also credible associations
between cardiometabolic risk factors such as phosphate, potassium, systolic and
diastolic blood pressure, total cholesterol and age-associated neurodegenerative dis-
orders (Beck et al. 2022).
During ageing, irreplaceable loss of cells occurs noticeably in the heart, brain
and skeletal muscles. In the brain, loss of neurons, particularly in vulnerable regions
such as the hypothalamus, may alter the metabolism and cause emotional and men-
tal aberrations in the elderly. Antioxidant defence mechanisms decline during age-
ing, which may accumulate oxidative damage. In the early stages of life, more than
a million neural connections are formed by the brain every second. But with the
increasing age between 20–60 years, brain weight decreases by about 0.1% per year
and the loss is more rapid after that. The reduction of volume is more dominant in
the prefrontal cortex and hippocampus while least in the occipital cortex (Peters
2006). Hippocampus and frontal cortex perform cognitive functions and their
shrinking affects cognitive abilities. The brain’s outer layer, the cerebral cortex, also
lessens with age. This low density of cortex results in fewer networks contributing
to lowered cognitive processing. The space vacated by the reduced brain volume is
filled with the expanding ventricular system and the CSF (cerebrospinal fluid)
(Esiri 2007).
6.2.3 Brain Dysfunctions and Their Causalities
As proteins carry out biological activities of the cells, any imbalance in protein
homeostasis affects the regular body functions (Xie et al. 2021). Errors in transla-
tional and post-translational processes lead to misfolding of more than 30% of
newly synthesised proteins. These proteins are recognised by molecular chaperons
and attempted to refold. When refolding of those proteins is not possible, ubiquitin
proteasome system (UPS) and autophagy lysosomal pathway (ALP) are responsible
for their cellular clearance (Schubert et al. 2000). If the misfolded proteins are left
uncleared, they may alter the three-dimensional structures of proteins and impairs
their biological functions. The autophagy-lysosomal pathway and the
ubiquitin-proteasome system, which are responsible for clearing misfolded proteins

in the brain, may decline with age and this result in neurodegenerative diseases such
as Alzheimer’s disease (AD), Parkinson’s and Huntington’s disease (Loeffler 2019).
With ageing, the regulation of gene expression and protein degradation is disrupted,
and aggregated proteins’ accretion is observed in all organisms. But in neurodegen-
erative diseases such as AD and Parkinson’s, specific proteins such as amyloid-β
and α-synuclein accumulation are amplified and observed as the hallmarks of those
diseases (Kepchia et al. 2020).
Functional connectivity networks in the brain are crucial in maintaining inter-
actions between different brain regions. The emergence of functional connectiv-
ity (FC) networks in the fetal brain starts during the third trimester and increases
with age up to young adulthood (around 20 years). It stabilises during adulthood
(around 30–40 years) and after 40 years, FC starts declining. This decline pri-
marily involves the reduction in connections within the network connectivity,
and it expands to reductions between the networks with progressing age
(>60 years) (Edde et al. 2021). The interconnectivity networks supervise a range
of diverse cognitive roles, and they are categorised as task-positive and task-
negative networks (DeSerisy et al. 2021). Task positive network comprises fron-
toparietal, dorsal, ventral attention and cingulo-opercular networks. Their
activity increases with an increase in task performance and cognitive demand.
Contrary to them is DMN (Default Mode Network), whose activity increases
when brain is not performing any specific task. One such network is DMN, in
which mPFC (medial prefrontal cortex) is one of the central nodes (Jobson et al.
2021). With ageing, a consistent reduction in functional connectivity between
mPFC-PCC (posterior cingulate cortex) regions are observed. Many pioneering
studies have shown that with reduced functional connectivity between anterior
mPFC and posterior DMN, the white and grey matter measures are decreased in
cingulum tract and in brain regions with high vulnerability to age (Vidal-Piñeiro
et al. 2014). Some studies showed that the reduction in connectivity strength is
observed especially in ventral DMN, which includes the hippocampus. As hip-
pocampus is the key memory region, this is assumed as one of the reasons for
decreased memory in aged individuals (Huang et al. 2015). Any break in the bal-
ance between the integration of brain networks leads to reduced cognitive effi-
ciency of the brain.
Several biological processes such as metabolic dysregulation, increased inflam-
mation, immune reaction and oxidative stress, which are associated with depres-
sion, are also reported in ageing, proposing that major depression and accelerated
ageing may be associated (M. Wolkowitz et al. 2011). Data supported the notion
that distinctive microglial phenotypes are harboured by the aged human brain (Olah
et al. 2018). The brain possesses an extracellular matrix (ECM) comprising perineu-
ronal nets enveloping neurons, a basement membrane surrounding blood vessels
and an interstitial matrix. The ECM regulates ion homeostasis, controls synaptic
plasticity and has a role in regulating neuronal and glial functions. Ageing may alter
the structural composition or stiffness of ECM, which may contribute to developing
neurodegenerative diseases (Hall et al. 2021).
6.3 Oxidative Stress and Ageing Brain
Reactive oxygen species (ROS) are essential for normal physiological functions but
turn toxic at higher concentrations (Ionescu-Tucker and Cotman 2021). In normal
conditions, any adverse effects of ROS are neutralised by antioxidant defensive
mechanisms. Any imbalance in this relationship due to excessive production of
reactive oxygen (ROS) and nitrogen species (RNS) and an inefficacious scavenger
system can result in oxidative stress (Song et al. 2020). Nucleic acids, proteins and
lipids are damaged when reacted with excess ROS and accumulate in various organs
resulting in their age-related functional decline. Oxidative stress also contributes to
age-related conditions such as neurodegenerative diseases, chronic kidney and pul-
monary diseases and cardiovascular diseases (Liguori et al. 2018).
6.3.1 Brain and Protection of Oxidative Stress
Oxidative stress is considered a self-propagating phenomenon as the macromole-

cules damaged by excessive ROS, may become or behave as ROS. Excessive ROS
production in the brain causes immense protein oxidation and lipid peroxidation
resulting in cellular degeneration and functional decline. ROS also alters brain
morphology by increasing blood-brain barrier permeability leading to neuroin-
flammation and neuronal death (Salim 2017). Higher molecular mass antioxidant
enzymes and low molecular mass antioxidants act as protective mechanisms that
operate in the brain to challenge excessive ROS. Higher molecular mass antioxi-
dant enzymes like superoxide dismutase coverts superoxide radicles to H2O2 by
facilitating spontaneous dismutation and the formed H2O2 is further removed by
glutathione peroxidase (GSH-Px) and catalase (CAT) enzymes (Salim 2017;
Liguori et al. 2018). Glutathione, anthocyanins, carotenoids, vitamin A and C con-
stitute lower molecular mass antioxidants (Garaschuk et al. 2018). Studies have
reported that an elevated oxidative stress markers in the cerebral spinal fluid and
brain tissue of mild cognitive impairment (MCI) and Alzheimer’s disease (AD)
patients indicating that oxidative stress may contribute to the pathology of AD (Di
Domenico et al. 2016).
Nuclear erythroid factor-2 (Nrf2) is a stress-responsive transcription factor
that regulates antioxidant gene expression through antioxidant response ele-
ments (AREs). Recent studies showed that omega-3 PUFAs can promote in rais-
ing Nrf2 expression and provide antioxidant defence. Particularly DHA alone or
with vitamin E, is found to be capable of inhibiting oxidative damage and cell
toxicity (Huang et al. 2019). Nrf2 and other antioxidants decrease in human
brain with ageing, enhancing the risk factors such as oxidative stress, neuro
inflammations and DNA damage (Zhang et al. 2015). A comparison of defensive
and degenerative mechanisms in healthy vs. aged brain are illustrated in the
Fig. 6.2.
Fig. 6.2 Adequate levels of antioxidants (SOD, CAT, and GPx) and vitamins (A and C), activated
transcription factors (Nrf2), calcium-binding protein (CALB1), growth factor (BDNF) maintain
homeostasis in the healthy brain (left half) and these are diminished with ageing (right half). Green
arrows indicate an increase, and red arrows indicate a decrease. SOD superoxide dismutase, CAT
catalase, GPx glutathione peroxidases, Nrf2 nuclear factor erythroid 2–related factor 2, CALB1
calbindin 1, BDNF brain-derived neurotrophic factor, GFAP Glial fibrillary acidic protein, AIF
Apoptosis-inducing factor, ROS reactive oxygen species, NFkB Nuclear factor kappa-light-chain-
enhancer of activated B cells
6.3.2 Factors Promoting Oxidative Stress in the Brain
The brain’s high oxygen consumption and higher lipid content make it more vulner-
able to oxidative stress (Salim 2017). The high ATP requirement of the brain
demands oxidation of lipids generating ROS. NADPH oxidase (NOX) is a cluster of
enzymes that generate ROS in pro-inflammatory conditions, or during phagocyto-
sis. In neuronal pathology, the expression of NOX1, NOX2, NOX3, and NOX4 is
induced, mediating the oxidative burst releasing O2.- and H2O2 (Simpson and Oliver
2020). One reason for the brain’s susceptibility to oxidative stress is that the ROS
produced by NOX2 or its isoforms are important in maintaining essential neural
progenitors and regulating long-term hippocampal potentiation and NOX2 deletion
leads to cognitive impairment in mice (Kishida et al. 2006). Ca+2 signalling in the
brain may also contribute to oxidative stress as, in the presence of sufficient O2 and
NADPH. Ca+2 synthesises nitric oxide (NO−) by nitric oxide synthase (NOS)
(Cobley et al. 2018). Glutamate, which plays a role in learning and memory, is also
a source of oxidative stress generation in brain. Excessive glutamate can inhibit
system Xc- cystine/glutamate antiporter, which mediates the exchange of
intracellular glutamate and extracellular cystine. Cystine is reduced to cysteine and

used for the de novo synthesis of glutathione (GSH) which is important in brain
antioxidant defence mechanisms. Excess glutamate’s interference in cystine intake
depletes intracellular GSH and causes oxidative stress. Excess glucose uptake by
the brain to maintain neuronal activities, and oxidative phosphorylation by mito-
chondria can be factors for generating oxidative stress. Redox-active transition met-
als, ample in the brain, can accumulate free radical generation by auto-oxidation of
neurotransmitters like dopamine.
6.3.3 Mechanism of Oxidative Stress in Ageing Brain
Mitochondrial dysfunction and glucose hypometabolism are the initial symptoms of

age-associated disorders in brain (Castelli et al. 2019). The brain continuously
demands high glucose for maintaining synaptic ion gradients and for the resting
potential of neurons. But during ageing, mitochondrial functional ability and glu-
cose availability are altered, disturbing neuronal glucose uptake, increasing oxidant
production and reducing electron − transport chain activity.
Elevated intracellular free radicals affect ageing, which can induce mitochon-
drial dysfunction, leading to altered cellular functions and impairing neuronal
metabolism. Mitochondria and NOX systems are considered prime factors involved
in the excessive generation of cellular oxidative stress (Leyane et al. 2022). Elevated
NOX expression is reported in chronic degenerative diseases (Egea et al. 2017).
Oxidative imbalance is thought to induce the development and advancement of
Alzheimer’s disease. When neuronal mitochondrial metabolism is impaired, it
reduces ATP generation raising oxygen free radicles and accumulating the Aβ
(amyloid-beta) fragments (Menzies et al. 2017). This Aβ accumulation and hyper-
phosphorylation of tau proteins stimulates c-Jun N-terminal kinase (JNK)/p38
MAPK signalling cascades and elevates ROS generation (Leyane et al. 2022). Nrf2,
which upregulates antioxidant defences during oxidative stress, is functionally
impaired in AD. Although the mechanism of how ROS damages the cerebral tissue
is not clear, it activates different molecular signalling pathways like neuroinflamma-
tion and causes neuronal death. Neurons exhibit differential susceptibility to oxida-
tive stress, and the hippocampus, amygdala, and cerebellar granule cells are the
most affected (Castelli et al. 2019).
6.4 Lipids and Their Importance in the Brain
The importance of lipids in the human body is supported by the fact that 5% of all
the genes in the human body are dedicated to lipid synthesis (van Meer et al. 2008).
More than 1000 different species of lipids can be found in any eukaryotic cell with
variations in aliphatic chains and head groups (van Meer et al. 2008). After adipose
tissue, brain is the organ in the human body with higher lipid content constituting
half of its dry weight (Bourre 2009) and 10–12% of fresh weight (Jové et al. 2019).
In the central nervous system, oligodendrocytes form a myelin sheath with 40 or
more compactly wrapped lipid bilayers lining the neurons. The composition of
myelin is 70–85% of lipids and 15–30% of proteins (Poitelon et al. 2020). The main
lipid species present in human brain are fatty acids, glycerolipids, glycerophospho-
lipids, sphingolipids and sterol lipids (Jové et al. 2019).
Dysregulated lipid metabolism is also considered a factor that contributes to neu-
rological disorders or central nervous system damage (Shamim et al. 2018). The
changes in global lipid concentrations are observed in human brain ageing and in
cognitive diseases such as Schizophrenia, Down syndrome and Autism Spectrum
Disorder (ASD) (Yu et al. 2020). Cholesterol plays a vital role in aetiology of
Alzheimer’s (AD) disease, which is a form of dementia. In brain, cholesterol is car-
ried by ‘Apolipoprotein E’ and the gene encoding for ApoE4 is identified as a cru-
cial risk factor for AD, indicating the role of cholesterol in the pathology of AD.
6.4.1 Fatty Acids and Their Requirement

in the Brain Structure
Dietary fats influence brain health and constitute an essential part of human nutri-
tion. Fatty acids are the building blocks of lipids and play a major role in the struc-
ture and function of the brain (Mallick et al. 2021). In addition to metabolic energy
contributors, brain fatty acids or their metabolites exhibit neuroprotective and anti-
inflammatory roles (Romano et al. 2017). Free fatty acids in adipocytes and circu-
lating triacylglycerols undergo lipolysis and release long chain fatty acids (LCFAs),
which bind to plasma albumin. Although diffusion of LCFAs across the membrane
occurs according to the concentration gradient, this passive uptake is too low to
satisfy the tissue’s fatty acid demand. So active cellular uptake of LCFAs involves
multiple chaperon proteins such as fatty acid translocase (FAT), plasma membrane
fatty acid binding protein, and six fatty acid transport proteins (Mallick et al. 2021).
While the brain can synthesise saturated and monounsaturated fatty acids (MUFAs),
polyunsaturated fatty acids (PUFAs) need to be supplied by the blood. The transport
of fatty acids across the blood-brain barrier (BBB) is an intricate process (Duttaroy
2009). It is mediated by protein-mediated transporters, primarily by fatty acid trans-
port protein-1 (FATP-1) and fatty acid transport protein-4 (FATP-4) (Romano et al.
2017). The involvement of BBB in fatty acid transport becomes crucial during
infancy and in ageing as these two stages are associated with immature BBB and
structurally altered BBB, respectively.
PUFAs plays a vital role as nutrients for alleviating diseases. Omega-3 and
omega-6 PUFAs maintain structure and function of cell membranes in the brain
(Mallick et al. 2019). Among PUFAs, omega-3 and omega-6 fatty acids are consid-
ered as essential as they cannot be produced in the human body and should be
consumed through diet. Human body can use the 18-carbon ω-3 fatty acid, as the
precursor and undergo elongation, desaturation and β-oxidation processes to syn-
thesise eicosapentaenoic acid (EPA), a 20-carbon unsaturated ω-3 fatty acid and
then synthesise docosahexaenoic acid (22; 6n-3) from EPA. But the ability of the
human body to elongate and desaturase the short chain fatty acids is limited. So, it
is essential to acquire ω-3 fatty acids from dietary sources. ω-3 fatty acids are
obtained from dark vegetables, plant oils, marine fish and their oils. In the blood-
stream, EPA and DHA can be present in non-esterified form bound to albumin or
esterified into triacylglycerol, phospholipids and as cholesteryl esters as compo-
nents of lipoproteins. EPA and DHA may be circulating in the bloodstream, or
stored in adipose tissue or membrane bound.
Linoleic acid (LA, 18; 2n-6) and arachidonic acid (ARA) are the main omega-6
fatty acids while linolenic acid (ALA, 18; 3 n-3) is the precursor of long chain
omega-3 fatty acids. Vegetable oils like sunflower and soybean contain higher quan-
tity of omega-6 fatty acids and lower quantities of omega-3 fatty acids. LCPUFAs
such as ARA, DHA and EPA have the capability to alter cell membrane composi-
tion and regulate the transcription and cell signalling. Particularly, long chain
omega-3 polyunsaturated fatty acids (omega-3 LCPUFA acquired increasing inter-
est as they are credited with neuroprotective and health-promoting properties
(Zirpoli et al. 2020). EPA and DHA are the precursors of Resolvin E and Resolvin
D which acts as anti-inflammatory lipid mediators. In humans and rats,
Lysophosphatidylcholine-DHA is a circulating form of DHA (Hachem et al. 2020).
Generally, DHA is present in higher concentrations than EPA, but in specific regions
of brain and eye, the contribution of DHA is significantly high and EPA is almost
absent (Duttaroy 2016).
6.4.2 Omega-3 and Omega-6 Fatty Acids

and Brain Development
Omega-3 and omega-6 are the two families of PUFAs, constitute 30–35% of brain’s
fatty acid content (Wood et al. 2022). The beneficial effect of omega-3 fatty acids in
improving cognitive functions in age-related mild cognitive impairment (MCI) or
cognitive decline is supported by several studies (Bowman et al. 2019). From the
gut, dietary PUFAs absorbed into bloodstream, can either be converted into
LCPUFAs or may undergo β-oxidation for energy production. There is a competi-
tion between omega-3 and omega-6 PUFA as they share the same metabolic path-
ways and enzymes to synthesise long chain PUFAs (Layé et al. 2018). In the brain,
omega-3 and omega-6 fatty acids undergo esterification at the sn-2 position into
phospholipids, which are essential to maintain cell membrane structure and func-
tions (Layé et al. 2018). DHA is essential for eye, and brain development, and it
impacts on neuro development and mental health from the fetal development to
adulthood (Basak et al. 2021; Basak et al. 2020a). In humans, DHA accumulation
occurs primarily during the third trimester and 6–10 months after birth. When
infectious stimuli trigger maternal immune activation (MIA), a cascade of cytokines

and altered immune cells are transmitted to the fetus via placenta, amniotic fluid and
maternal serum (Minakova and Warner 2018). The fetal and maternal inflammatory
responses to MIA can cause later life defects in hippocampal connectivity networks
affecting memory behaviour in the offspring (Labrousse et al. 2018) and may
increase the possibility of neurodevelopmental disorders such as autism and schizo-
phrenia (Han et al. 2021). DHA targets the microglia, the primary innate immune
cells in brain, and lowers the production of proinflammatory cytokines, TNFα, IL-6,
IL-1β (Labrousse et al. 2018), protecting MIA. It is suggested that a balanced intake
of omega-3 fatty acids such as ALA, EPA, DHA and omega-6 fatty acids such as
linoleic acid (LA), gamma linolenic acid (GLA), ARA may contribute to a reduc-
tion in inflammation and oxidative stress in aged individuals (Simonetto et al. 2019).
Ageing corresponds to lowered antioxidants in the body, a rise in inflammatory
reactions and abnormal redox homeostasis (Dolopikou et al. 2020). A recent cohort
study on cognitive abilities and dementia has also shown that blood DHA levels
positively impact cognitive functions and can lower the risk of Alzheimer’s disease
and dementia (van der Lee et al. 2018). Many neurophysiological functions such as
cell survival, cellular signalling, neuroinflammation, and protection of BBB integ-
rity are attributed to DHA (Basak and Mallick 2020). Because of its crucial role, any
alteration to DHA metabolism affects neurological and psychiatric conditions.
6.4.3 Omega-3 Deficiency and Brain Development
Recently, it has been revealed that microglia are associated with brain maturation
and immunogenic functions (Bilbo et al. 2018). In regular conditions, microglia
function activity-dependently and guide axons, phagocytes, and apoptotic neurons
(Shigemoto-Mogami et al. 2014). But any imbalance in nutritional intake of fatty
acids, MIA obstruct these processes and results in behavioural defects (Madore
et al. 2020). N-3 PUFA deficiency exacerbates the consequences of MIA on microg-
lia and alters the oligodendrocyte expression in the developing brain (Leyrolle
et al. 2021).
Brain-derived neurotrophic factor (BDNF) is a growth factor essential for brain
functions and maintaining plasticity all through the lifespan. BDNF is expressed in
the mammalian brain by binding to its receptor TrkB (tropomyosin receptor kinase
B) (Bhatia et al. 2011). Any deviations in BDNF signalling and activity of TrkB
receptor might result in anxiety and depression-like conditions (Castrén et al. 2007).
It is evident that, deficiency of DHA during gestation, lactation and infancy enhances
the risk of anxiety-like behaviour in later life. And brain DHA levels proportionally
influenced BDNF signalling through TrkB. DHA deficiency caused a reduction in
BDNF-related synaptic plasticity in frontal cortex, hypothalamus and hippocampus.
This implies that DHA consumption during early life can influence mental health in
adulthood (Bhatia et al. 2011). Long-term potentiation (LTP), which is the process
of strengthening the synaptic connections between the neurons, is reduced in ageing
brain. The NR2B subunit of N-methyl-D-aspartate (NMDA) glutamate receptor is

significantly involved in synaptic mechanisms of spatial memory such as LTP. Diets
rich in DHA and EPA have the potential to reverse the damage of NR2B with ageing
(Cutuli 2017).
6.5 Omega-3 Fatty Acids, Neuroinflammation

and Ageing Brain
In older adults >65 years, 15–20% are affected by age-associated cognitive decline.
Although the exact mechanisms deviating the healthy ageing process are not com-
pletely known, inflammation is proven to be notably involved.
6.5.1 Ageing and Brain Inflammation
With brain ageing, the central nervous system suffers chronic low-grade inflamma-
tion, which alters the morphology and functions of many neuronal cells, including
microglia. With the help of pattern recognition receptors (PRRs), microglial cells
recognise pathogen-associated molecular patterns (PAMPs) and damage-associated
molecular patterns (DAMPs) and initiate immune responses. Aged microglia get
primed and overproduces the inflammatory markers, lowering its homeostasis
capacity. This rise in age-related immune responses develops cognitive deficits, and
diminished synaptic plasticity (Joffre et al. 2020) and loss of homeostasis, leading
to unhealthy brain ageing. Many studies reveal that inflammation during ageing
marked by microglial priming and pro-inflammatory cytokine production contrib-
utes to age-associated cognitive decline.
6.5.2 Neuroinflammation and Brain Disorders
Neuroinflammation is initiated in response to infections, stress or neurodegenera-

tive disorders. Although the purpose of this neuroinflammatory response is to
exhibit protection from stimuli, it may turn detrimental and spread widely, bypass-
ing the altered blood-brain barrier in any infection condition or with ageing.
Inflammation-mediated immune mechanisms are risk factor for psychiatric diseases
such as schizophrenia. Increased inflammation is also associated with reduced con-
nectivity in reward-related brain regions in unmedicated depression patients.
Reduced connectivity between dorsal, ventral striatum and ventromedial prefrontal
cortex results in psychomotor slowing and anhedonia (Thibaut 2017). The continu-
ous inflammatory mechanism in AD brains causes neuronal loss and alterations in
astrocytes, cytokines, microglia and mitochondria. These alterations represent early
onset symptoms of neurodegeneration (Skaper et al. 2018). The elevated serum pro-
inflammatory cytokine levels in AD patients and post-mortem brains indicate the
central role of neuroinflammation in AD aetiology.
6.5.3 Omega-3 and Neuroinflammation
Omega-3 fatty acids and their derivatives, eicosanoids and docosanoids, affect the
inflammatory pathways by down regulating pro-inflammatory gene expression and
prevent or delay age-related neuroinflammation (Zirpoli et al. 2020). DHA, the
main n-3 LC-PUFA in the brain, constitutes 12–14% of brain’s total fatty acid con-
tent. EPA, the other important n-3 LC-PUFA is available in lesser quantities as it
undergoes beta-oxidation. Unavailability or altered metabolism of n-3 LCPUFA in
brain causes neuroinflammation leading to neurodegenerative disorders. n-3 long
chain PUFA sequentially synthesises eicosanoids involved in regulating inflamma-
tion and specialised pro-resolving mediators (SPMs) in the resolution of inflamma-
tion. SPMs induce homeostasis by down regulating pro-inflammatory cytokines and
upregulating anti-inflammatory cytokines. They also compete and limit the pro-
inflammatory oxylipins synthesised by n-6 PUFA. In the brain, several enzymes
such as phospholipases A2 (PLA2), cyclooxygenase 2 (COX2), cytochrome P450
monooxygenases (CYP450) and lipoxygenase (LOX) are responsible for releasing
fatty acids from membranes and converting them into bioactive lipids (Joffre et al.
2020). A study reported that DHA lipoxygenase, can control white blood cell infil-
tration and pro-inflammatory gene expression, delaying the brain damage
(Marcheselli et al. 2003).
With ageing, the intestinal absorption capacity of essential fatty acids decreases,
along with minimised conversion of precursors into LCPUFA. Thus, brain experi-
ences a decrease in n-3 LC-PUFAs predominantly in the cortex, hippocampus and
cerebellum. Studies in mice showed that n-3 PUFA deficiency during adulthood
worsened the inflammatory effects on spatial memory (Delpech et al. 2015). On the
contrary, exposing the aged mice to n-3 PUFA supplemented diet for 2 months
reversed the spatial memory deficits induced by ageing (Labrousse et al. 2012). Few
studies in humans reported that fish oil consumption improved cognitive abilities in
elderly people with cognitive impairments (McNamara et al. 2018) (Danthiir
et al. 2011).
6.6 Epigenetics, Omega-3 Fatty Acids and Ageing Brain
As the human brain continuously responds to nutritional and environmental factors,

a controlled interaction between genetic and environmental factors ensures efficient
functioning. A balanced nutrition positively impacts age-related cognitive decline.
Diet modulates synaptic plasticity, neuroinflammation, neurogenesis and
neuroprotection during early embryonic development via epigenetic changes and

extends throughout adulthood (Polverino et al. 2021). Although ageing is a univer-
sal phenomenon, the rate of ageing differs between individuals. If the biomarkers of
ageing in different individuals can be measured, it helps predicts age-associated
diseases even before the onset of symptoms. The aim of developing therapeutics
targets the delaying of ageing complications (Cole et al. 2018). Leucocyte telomere
length (Vaiserman and Krasnienkov 2021), DNA methylation at CpG islands across
the genome and N-glycan profiling (Paton and Suarez 2021) are some of the ageing
biomarkers which correspond to chronologic age in healthy individuals (Cole
et al. 2018).
6.6.1 MicroRNA and Brain Functions
MicroRNAs (miRNA) are short, non-coding RNAs that play a crucial role in post-
transcriptional gene regulation. They target specific genes involved in oxidative
stress and mitochondrial dysfunction and inhibit their translation by binding to 3′
untranslated regions of the mRNA. miRNA is associated with argonaut protein
which involves in RNA-mediated gene silencing. Depending on the miRNA binding
strength, argonaut is induced to cleave target mRNA and silence the genes. miR-
NA’s ability to get packed into exosomes allows it to be transported into extracel-
lular space by crossing membranes like the blood-brain barrier. This facilitates easy
and inexpensive plasma biomarker analysis for ageing and disease. Brain miRNAs
cross blood-brain barrier using exosomes and enter plasma, offering insights into
the causes of diminishing cognitive function.
miRNAs are also known as modulators of longevity and regulate ageing process.
miRNAs can directly influence lifespan by involving different ageing pathways
such as insulin-like growth-factor (IGF-1) signalling, mitochondrial/ROS signalling
and DNA damage response. These pathways function as adaptive mechanisms for
maintaining the organism’s homeostasis in adverse physiological stress, conditions
and molecular damage. A single miRNA can target several genes simultaneously
and can regulate their functions.
Different varieties of miRNA in the brain play functional roles in various brain
activities. The regulation of miRNA profile in the mammalian brain varies with
different brain regions, and the profile alters with ageing. Studying miRNAs’ role
helps understand age-associated neuropathology (Catanesi et al. 2020). miR-34c,
miR-34a, miR-181-a-1 and miR-30e are age-regulated micro RNAs extensively
studied in mammalian brains. miR-34c is upregulated in humans with AD, con-
tributes to cognitive decline with brain ageing and decreases the expression of
sirtuin 1(sirt 1), a transcription factor that regulates the lifespan. miR-34a is
upregulated in brain and blood samples of aged mouse and down regulates sirt 1.
Expression of miR-34a/sirt 1 in blood and brain may be used as brain ageing bio-
markers (Kinser and Pincus 2020). Although less data are available with brain
miRNA profiling of ageing, it is agreed that dysregulation of miRNAs could result

in neuroinflammation, diminished cognition and neurodegenerative diseases
(Barter and Foster 2018).
6.6.2 DNA Methylation and Ageing
Previously, telomere length was correlated with ageing outcomes because of their
changes in epigenetic alterations and cellular senescence during ageing. However,
recent research suggests that the correlation between ageing outcomes and telo-
mere length is not accurate, alternate biomarkers are explored. Epigenetics is
useful tool in this aspect which can be considered in association with ageing
process.
Epigenetics refers to an alteration of gene activity without changing genomic
sequence. Epigenetic modifications such as DNA methylation or histone modifica-
tions can alter the availability of DNA for binding sites and can upregulate or down-
regulate the gene transcription. Although all the cytosines of DNA can get
methylated, 5-methyl cytosines being the hotspots of CpG dinucleotides, have dis-
tinctive methylation ability on both strands of DNA copied from parent to daughter
strand during cell replication. DNA methyl transferases like DNMT1, DNMT3a
and DNMT3b target five carbon of cytosine and add a methyl group to it, forming
5-methylcytosine (5mC). Methylated DNA blocks the binding of transcription fac-
tors, inhibits gene expression, and gives access to methyl binding proteins that may
involve in gene silencing. DNMT1 maintains genomic stability by confining to
established CpG methylation, while DNMT3a and DNMT3b involve increased
methylation of non-CpGs with ageing (Barter and Foster 2018). A global shift in
DNA methylation transmits epigenetic instability in developing fetuses due to n-3
PUFA deficiency (Basak and Duttaroy 2022).
Global DNA methylation does not change appreciatively during ageing, but a
shift in the CpG methylation pattern is observed. Generally, CpG islands are hypo-
methylated in all tissues in developmental stages. But during ageing and nutritional
deficiency, DNA hypermethylation is observed at many genomic loci in the cerebral
cortex. This variation in methylation pattern during different developmental stages
indicates dynamic control of methylation in differentiated neurons. The fate of gene
expression during DNA methylation depends on the location of CpG islands.
Methylation in the promoter region is negatively associated with gene expression,
while methylation in the gene body positively affects gene expression (Prasad and
Jho 2019). CpG methylation analysis in the human prefrontal cortex (PFC) showed
that age and sex play dominant roles in DNA methylation in CpG islands. The
expression of neuronatin (NNAT), a human brain developmental gene in the pre-
frontal cortex, decreases with age, while DNA methylation shows the opposite pat-
tern. Genes like DRD2, NOS1, NRXN1, and SOX10 related to schizophrenia and
autism also exhibited methylation variations with ageing. DNA methylation
analysis at sites like PIPOX, RHBDD1, DPP8, PTGER3 and FLJ21839 genes
showed clear association with chronological age (Numata et al. 2012). The DNA
methylation capacity reduces with age and hypermethylation occurs in most of the
CpG islands with age. Identifying methylation changes in different cellular signal-
ling pathways in the brain can help in assessing the development and progression of
neurodegenerative diseases.
As chronic inflammation is a significant yet undetected contributor to cogni-
tive ageing, epigenetic analysis of inflammatory markers like CRP helps to under-
stand cognitive ageing mechanisms. Increased DNAm CRP is associated with
brain cortical volume reductions in frontal, medial temporal and anterior lateral
lobes and is proportional to cognitive decline. Variations in the distribution of
proinflammatory receptors in different brain regions may be the explanation for
the higher vulnerability of some regions for inflammation than others (Conole
et al. 2021).
6.6.3 Omega-3 Fatty Acid and Its Epigenetic Regulation

in the Brain
Alterations in one-carbon metabolism and omega-3 fatty acid deficiency can affect
epigenetic modifications, producing long-term brain defects in learning, memory,
cognition and behaviour. It can also cause brain disorders such as depression,
schizophrenia, autism and bipolar disorder. S-adenosyl methionine (SAM) is a
methyl group donor formed in one-carbon metabolism which provides methyl
group for conversion of phosphatidylethanolamine-DHA (PE-DHA) to
phosphatidylcholine-DHA (PC-DHA), which is essential for the transport of DHA
from the liver to brain. When DHA levels are low, methyl groups are unused from
SAM, and this excess methyl group availability may involve DNA methylation.
Again, the impacts of long-term omega-3 PUFA deficiency on gene expression and
epigenetic changes in the fetus could result in a change in cognitive function later in
life (Basak et al. 2020b).
Studies have indicated that adequate omega-3 fatty acid can restore the global
hypomethylation to control levels suggesting the important role of omega-3 fatty
acid, especially DHA, in determining methylation patterns in the placenta (Srinivas
et al. 2021). DNA methylation can control the expression of BDNF gene during
forebrain development in mice. Any epigenetic changes during the developmental
stages may continue throughout life and affect later life quality. Recently evidence
has been reported that prenatal omega-3 supplementation may reverse methylation
trends improving cognition and neuroprotection. In a study where pregnant women
were given omega-3 supplementation (800 mg DHA) from 20 weeks of gestation
till delivery, differences were observed in differentially methylated regions like
TRAK1, LPHN3, SLC12A6, and RFPL2, which affects brain function (van Dijk
et al. 2016). n-3 PUFA deficiency during neurodevelopmental stages may be
responsible for epigenetic silencing of the nuclear receptor genes Rxr and Ppar,
resulting in schizophrenia (Maekawa et al. 2017).
6.7 Conclusion
The rapid dietary transition is associated with decreased accessibility to marine

omega-3 products and the increased intake of LA in the diet globally. Omega-3 fatty
acid (ALA) sourced from various plant oils, and seeds convert only 40–50% to their
longer chain fatty acids such as EPA and DHA due to limited endogenous conver-
sion, especially when LA is high in the diet. Again, higher LA in the diet competes
with the enzymes for its conversion to ARA, which leads to the excess synthesis of
leukotrienes and prostaglandins, mediators of neuroinflammation. The sources of
ROS in the brain are often derived from uncontrollable ARA-cascade, defects in
mitochondrial respiration, activation of NADPH oxidase and others. High ROS gen-
eration activates redox-sensitive NF-kB, resulting in downstream propagation of
inflammatory cascades. Advanced glycation products also promote the production
of ROS due to uncontrollable hyperglycaemia or increased nitric oxides associated
with free radicals due to dysregulated mitochondrial dysfunction. Thus, lowering
LA in diet may protect the brain from oxidative damage triggered by
neuroinflammation.
Mitochondrial dysfunction and dysregulated NOX system are primarily respon-
sible for the excessive generation of cellular oxidative stress. ROS-mediated dam-
age in cerebral tissue triggers different molecular signalling pathways, including
neuroinflammation that leads to neuronal death. Ageing shifts the balance of pro-
inflammatory and anti-inflammatory cytokines in the brain towards the pro-
inflammatory state, which makes the brain more vulnerable to stress, infections and
the onset of neurodegenerative diseases (Gorlé et al. 2016).
DHA is obligatory for human brain development and performs essential roles in
neurotransmission, neurogenesis, and protection from oxidative stress throughout
life. It protects the brain from age-related decline in performance and activities
(Troesch et al. 2020). Although animal studies promise a significant benefit of DHA
in protecting age-related cognitive pathology, additional controlled clinical trials are
required for its clinical use. In vivo and ex vivo data using ageing models of AD,
PD, and HD showed enhancement in mitochondrial function after treatment with
n-3 PUFAs, especially with DHA (Eckert et al. 2013; Lee et al. 2013).
Although the omega-3 supplementation benefits in AD, PD and MCI are not
established, many clinical trials have proved the positive effects. Few clinical trials
of omega-3 supplementation and the effects on neurodegenerative diseases are
listed (Table 6.1). The high half-life of DHA in the human brain warrants life course
intervention with a longer duration, much earlier than the start of healthy ageing.
Nevertheless, it is safely recommended as a prophylactic measure in maintaining
brain health and its delay in ageing.
Table 6.1 Effects of Omega-3 fatty acid supplementation in age-related neurodegenerative

diseases: clinical trials
Trial Fatty acid intervention The major outcome with reference
1 DHA 1200 mg/d, EPA 300 mg/d, Multi-nutrient supply to mild AD patients
along with other nutrients (in improved the memory (in verbal recall score)
Souvenaid form) for 12 wks to AD (Scheltens et al. 2010)
patients (n = 225)
2 DHA 1.7 g/d, EPA 0.6 g/d for 6 mo, Omega-3 supplementation increased plasma TTR,
followed by omega-3 supplementation protecting from amyloid beta plaques (Irving
for another 6 mo to AD patients et al. 2013)
(n = 204)
3 DHA 1.7 g/d, EPA 0.6 g/d for 6 mo to Omega-3 supplementation benefits in mild to
AD patients (n = 171) moderate AD patients, influenced by the baseline
tHcy levels of patients (Jernerén et al. 2019)
4 125 mL of Souvenaid (with specified Mild AD patients who received Souvenaid
nutrients) daily once for 24 weeks to intervention showed better integrity and
patients with mild AD (n = 259) functioning of the brain network organisation in
EEG analysis (de Waal et al. 2014)
5 DHA 1.72 g/d, EPA 0.6 g/d for 6 mo Supplementation increased plasma omega-3 and
and further 6 mo. Omega-3 showed protection from declined cognitive
supplementation for all groups to AD performance measured by ADAS-cog scores
patients (n = 174) (Eriksdotter et al. 2015)
6 Omega-3 fatty acids (flax seed oil) In PD patients, supplementation showed
1000 mg/d, Vit E supplements favourable impact on UPDRS score (Taghizadeh
400 IU/d for 12 wks to PD patients et al. 2017)
(n = 60)
7 EPA 2 g/d, Vit E 364 mg/d, Vit C In schizophrenia patients, adding ethyl-EPA and
1000 mg/d for 16 wks in addition to vitamins to antipsychotic drugs impaired
antipsychotic drugs to schizophrenia psychosis (Bentsen et al. 2013)
patients (n = 99)
8 DHA-2 g/d for 12 mo to MCI patients Supplementing DHA for 12 months delayed
(n = 240) hippocampal degeneration and improved
cognition in MCI patients (Zhang et al. 2017)
9 DHA 880 mg/d, EPA 1320 mg/d for Betterment in brain grey matter volume, white
26 weeks (n = 121) to healthy aged matter integrity and cognitive abilities was
adults observed after omega-3 intervention in elderly
individuals between 50–75 years (Witte et al.
2013)
10 125 mL Souvenaid with specified Multi nutrient supplementation showed benefits
nutrients (DHA 1200 mg/d, EPA on CDR-SB and brain degeneration in AD
300 mg/day) for 24 mo (n = 311) to patients (Soininen et al. 2017)
AD patients
11 DHA group (0.7 g/d), EPA group In AD and MCI patients, although omega-3
(1.6 g/d), EPA + DHA group (DHA supplementation did not lower adverse cognitive
0.35 g/d + EPA 0.8 g/d) for 24 mo. To outcomes, positive impact was seen on oral
AD or MCI patients (n = 163) language ability and constructional praxis scores
(Lin et al. 2022)
Abbreviations: Wk week, mo month, d day, AD Alzheimer’s disease, TTR Transthyretin, tHcy
homocysteine, EEG Electroencephalogram, ADAS-cog Alzheimer’s disease assessment scale-
cognition sub scale, PD Parkinson’s disease, UPDRS unified Parkinson’s disease rating scale, MCI
Mild cognitive impairment, CDR-SB Clinical dementia rating-sum of boxes
Acknowledgments Navyasree Boga is supported by DST-inspire fellowship, Govt. of India.
Author Declarations The authors declare no conflicts of interest. SB is employed at the National
Institute of Nutrition, Indian Council of Medical Research, Hyderabad, India.
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annurev-nutr-082018-124539
Chapter 7
Traditional Foods and Ageing
Damal Chandrasekar Mathangi

and Arambakkam Janardhanam Hemamalini
Abstract With increase in lifespan, aged population is on the rise across the globe.
This underscores the need to explore avenues for healthy ageing and prevention of
age related diseases. This chapter explores the traditional foods across the globe
towards healthy ageing and thus creating a possibility to design integrated diet.
Keywords Ayurveda · Mediterranean diet · Okinawa
Gerontologists are of the view that the physiological impairing processes of ageing
and senescence manifest primarily during the lifetime beyond the natural lifespan of
a species, termed as the essential lifespan. A greater life expectancy, in fact, leads us
to reconsider not only the condition of the elderly, but also what kind of implica-
tions ageing will have in our lifetime. The fundamental reason for ageing and age-
related diseases such as the Alzheimer’s, Parkinson’s, cancer and others is the
imperfect processes of life beyond this essential lifespan. Hence, the approach we
follow for infectious and other disease successfully, i.e. ‘one target, one shot’ bio-
medical treatments does not work successfully on age-related disease (Rattan 2015).
The human lifespan has substantially extended since the 1900s, due largely to
interventions that have reduced infant and childhood mortality, coupled with
medical-surgical advances that have had a particular impact on older people
(Wickramasinghe et al. 2020). While the biological process of ageing is irreversible
D. C. Mathangi (*)
Department of Mind Body Medicine and Lifestyle Sciences, Sri Ramachandra Faculty
of Allied Health Sciences, Sri Ramachandra Institute of Higher Education and Research,
A. J. Hemamalini
Department of Clinical Nutrition, Sri Ramachandra Faculty of Allied Health Sciences,
Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
Ltd. 2023
130 D. C. Mathangi and A. J. Hemamalini
and inevitable, it is mouldable with various easily adaptable techniques. One such
easy adaptable technique is changing one’s life style, i.e. diet and physical activity
which are most important and allows increasing the quality of life of an individual.
A low-cost solution for unmet health needs across all socio-economic states and
ethnicity is food, as it is the daily input consumed to sustain human life from eons.
However, food and drinking water are the most neglected basic human need-based
resources from the respective of health sciences. Food also represents the tradition
and cultural values of the region. Several studies examining the degree of food vari-
ety in different populations have found that those with the highest intake of variety
tend to live the longest. Interestingly, the Japanese have the longest life expectancy
in the world, and promote dietary guidelines that suggest 30 or more different kinds
of food should be eaten daily. Food variety has been shown to correlate (positively)
with nutritional quality, and this probably contributes, at least in part, to health and
longevity.
A good nutrition and a well-planned balanced menu with all essential nutrients
in adequate proportion, enhances the body’s resilient flexibility and plasticity, in
mitigating the ill effects of various metabolic storms. Healthy ageing by a healthy
diet can be influenced by a number of ways including:
• Enhancing bone health by improving its mobility and prevention of muscle mass
loss, which is more common during elderly stage of life.
• Improving vision by maintaining optical density and preventing macular
degeneration.
• Maintaining a healthy heart by avoiding hyper or dyslipidemias and maintaining
normal blood pressure.
• Effective glycemic control.
• Improved cognition and prevention of cognitive impairment.
The derangement in the above-mentioned activities, culminates in poor quality
of life and an unhealthy ageing, where many fall a victim to various diseases dur-
ing their course of life. Therefore, it is essential that an adequate nutrition is
maintained, which could properly enforce the anti and healthy ageing mecha-
nisms, towards an improved quality of life. Intervention studies that have taken a
food-based approach (with variety) have also shown favourable outcomes in
terms of health and survival. In the Dietary Approaches to Stop Hypertension
study, the group that added low-fat dairy products to a diet that was high in fruit
and vegetables showed greater improvements in blood pressure than the group
that emphasised only the fruit and vegetable aspect of the overall diet. The Lyon
Heart study, another food-based intervention study, found patients surviving a
myocardial infarct were at lower risk of subsequent mortality if they followed a
Mediterranean-type diet compared with a diet that presumably followed a more
‘prudent’ western format. Certain dietary patterns are associated with an increased
risk of coronary heart disease and the development of certain cancers (Savige
2002). Hence, it is important to watch the food we eat not just when we are old
but all through our life.
7 Traditional Foods and Ageing 131
The Hippocrates saying ‘Let food be thy medicine’ applies aptly to the tradi-
tional Indian foods, with its diverse food ingredients, carefully chosen and com-
bined to give maximum health benefits. Traditional nutritional knowledge is a
wealth which has now been researched with the modern evidence methodology.
With the innate judicious combination of whole grains, vegetables, spices, fruits
and vegetables in addition to probiotics from fermented foods, the traditional foods
not only ensure an optimal physiological function, but also improves gut health,
enhance immune function, avoid unnecessary weight gain and fat accumulation,
drive away extra lipids, reduce oxidative stress, neurodegenaration and inflamma-
tory responses. Through these innumerable functions, the traditional food combi-
nation enhances the optimal resilience and metabolic flexibility, which is the pivot
of healthy ageing.
Indian traditional foods history dates back to 3000 years back, with influences
from Aryan, Harappan and Vedic civilisations and it has found a prominent position
in the culture and life of the people. According to Ayurveda (a natural system of
medicine, with origin in India 3000 years ago), food is one of the tripods of life to
maintain and promote physical and psychological health of an individual. We should
take food that is compatible to our body, minimal or the right proportion and should
be appropriate to the season. Only such food increase the immunity of an individual
and make them free from diseases both mentally and physically. As per Charaka
Samhita, text book of traditional Indian system of medicine, ‘one should eat accord-
ing to their Prakruti’. According to this, there are certain foods that suit our nature
and certain food are not suitable. The recent research has linked our genes to the
prakruti (or our body constitution). This means our food needs to be customised, a
wholesome meal for one may be incomplete for another. In addition, the diversifica-
tion of our geography, food habits and culture need to be considered when studying
the impact of food on ageing. Hence, as per Ayurveda, there are multiple factors
taken into consideration while prescribing diet which includes the season, tastes and
their constitution. Based on these the cereals and grains, pulses, vegetables, tubers,
fruits, oil seeds, spices, milk and milk products, sugar items, non-vegetarian, water
and even wine are identified (ref). In addition, Ayurveda follows restricted diet,
specific diets as per rituals, fasting and cleansing regimen too as part of the lifestyle
(Sukesh Suni et al. 2021). All these are in practice now in various modern termi-
nologies including calorie restriction, fasting to increase autophagy, etc.
A sloka in Ayurveda states that ‘If food is right, medicine is not needed and
if food is not right, no medicine will work’. So the food one takes is person-
alised based on the individuals Prakruti (body composition), dosha (health
types as per Ayurveda), special needs, age and practices in the context of sea-
sons and daily cycles. Thus, it provides a holistic practical food personalisation.
Hollistic, as it weaves together ‘ahara (diet) and vihara (lifestyle)’ continuum
and a practical system. This is important, because while our genome or the
prakruti, that we are born with can be modulated by multiple inputs, one of
which is food. In addition, the six ritus (seasons) have been detailed, and spe-
cific dietary and lifestyle regimens are also well explained in Ayurveda. There
is a great interconnection between ahara, the gut microbiome and seasons

(Rastogi 2014).
Food and Nutrition of India, over the years have been enriched through food
combinations from primary easily locally available food ingredients, thereby com-
plementing and supplementing each other. This further enhanced the digestibility,
bioavailability which ultimately helps in health protection, disease prevention,
resistance and improve longevity. Indian food traditions emerged from various cul-
tures in addition to Aryans and Harappans. The Mughal invasion, British colonisa-
tion have all contributed highly to the then prevailing food habits and enabled
meaningful interactions. Indian cultures gradually enriched them through long
empirical experience using combinations of a variety of primary food materials,
especially the locally available food grains and vegetables that nutritionally comple-
mented and supplemented each other. This has contributed to better health protec-
tion, improvement of digestibility, resistance to health disorders, and increased
human longevity.
Indian traditional foods are largely cereals, rice and wheat-based, with a variety
of meal adjuncts, milk and milk-based beverages, sweets, steamed foods with ghee
or vegetable oil as the medium of cooking. This versatile combination and composi-
tion enable the Indian traditional food to be rich in dietary fibre, antioxidants, phy-
tochemicals, optimal carbohydrate sources and being low or moderate in fat. Almost
all of these being closely resembling the current days, RDAs, developed based on
evidence-based research.
The traditional Indian foods has been reviewed extensively and compiled by
Srinivasan K., (Srinivasan 2010), where reportedly over 5000 traditional food reci-
pes/combinations have been identified from across 50 cultural cuisines of India. It
would be beyond the scope this chapter to cover all the reported foods. However, the
wide classification under which these different foods are presented with highlight-
ing their potential health benefits. Functional ingredients of traditions Indian foods
have also been detailed well. Dietary fibers are abundant in whole grains (cereals
and legumes), vegetables, fruits and certain spices. Whole grains, vegetables and
fruits are rich sources of polyphenols and phytochemicals. Amla, amchur, tamarind
are major source of acidulants. Fermented milk products are rich in probiotics (6).
Using these raw materials, several traditional foods are prepared which are widely
consumed on a regular basis.
The basic ingredient of many traditional Indian foods are cereals, millets such as
sorghum, finger millet in combination with a variety of pulses. This type of combi-
nations makes up for the limiting amino acids such as methionine and lysine in
cereals and pulses and together exert the beneficial effect. Additionally, they also
provide good soluble and insoluble fibre from their germ and bran portions.
The most commonly used pulses and lentils are black gram, green gram, red
gram and Bengal gram. They are used in the roasted, powdered, sprouted and boiled
forms in gravies, chutneys, snacks, soups, etc., which enhances the taste of the
foods. These pulses form the major source of proteins in the traditional Indian
cuisine. Certain recipes made with cereal pulse combinations after fermentation
namely idly, dosa and dhokla improve the digestibility, exclude unhealthy phytates
and improve gut health through their microbial content.
7.1 Traditional Milk-Based Foods
Dahi (curd) and ghee are the two milk-based foods, traditionally forming the most
important component of the diet. Dahi (fermented milk—curd) with its rich probi-
otic milieu offers a number of health benefits, such as reducing the cholesterol and
triacylglycerols, protection against gastroenteritis, and strengthening of the immune
system promotes optimal resilience against the ageing process. Ghee, although
wrongly considered to be the causative factor for heart ailments, actually renders a
cardio-protective function through its appropriate fatty acid composition and fat-
soluble vitamin profile.
Traditional Indian food main courses are made much healthier and tastier through
a variety of adjunct foods such as papads, wadis, chutneys, pickles, sauces, extracts
(jal jeera made with cumin seeds), etc. The advantages of these adjuncts are that
they make the food easily acceptable to any age of individual, and offer a variety of
micronutrients. The practice of incorporating these adjuncts ensures the availability
of fruits, vegetables and pulses during their lean period also.
Some of the commonly used dietary adjuncts are papads, chutneys, chutney
powders, pickles, spiced and sun dried dumplings and spicy masalas. These are
commonly prepared traditionally at house hold level by using pulse flours, left over
rice, millets, legumes, oil seeds like peanuts, sesame, coconuts, leafy vegetables,
seasonal fruits, seasonal acidic fruits and so on. These adjuncts, not only make the
food tasty and acceptable for any age group, but also offer the benefit of being nutri-
tious, healthy and make seasonal foods available at off seasons too.
The traditional Indian food uses a number of other foods such as amla, kokum
(Garcinia indica), tamarind, etc., all of which are known to exert innumerable health
benefits in promoting gut health and anti-ageing process.
The cooking medium of various healthy recipes are predominantly mustard and
sesame oil. These vegetable oils are an excellent source of vitamin E, magnesium,
calcium, copper, iron, zinc and vitamin B6. This profile of the oils renders them
safer to use and effective in controlling high blood pressure, improving bone health
and various other functions toward modulating the metabolic age of the human
body and hence can be considered to help in graceful ageing.
Over and above these constituents, Indian cuisine is envied for its another very
unique and important component the Spices. Every spice has been documented for
its unique properties (6). Table 7.1, adopted from Srinivasan highlights the signifi-
cant beneficial role played by these various spices in the traditional foods.
Table 7.1 XXX
The Mediterranean diet (MD) is characterised by a high intake of foods of plant

origin (fruit, vegetables, breads, other cereals, potatoes, beans, nuts, and seeds) and
fresh fruit. Olive oil, namely extra-virgin olive oil, is the main source of fat. Dairy
products (mainly light cheeses and yogurt), fish and poultry are consumed in
medium-low quantities; particularly, fish is an excellent source of polyunsaturated
fatty acids (PUFAs), particularly omega-3 fatty acids; egg consumption is limited to
a maximum of four per week; red meat is consumed sporadically and in small quan-
tities, however, no more than once a week. MD has a very low saturated fat content,
which represents no more than 8–10% of the total caloric intake. Caloric intake
from lipids is not more than 30% of total caloric intake. Wine is usually consumed
with meals, but always in moderate doses (1–2 glasses) (Willett et al. 1995). It has
been shown that adherence to the MD significantly reduced the total mortality thus
having a positive effects on the lifespan in the elderly. A greater adherence to the
MD was negatively associated with a risk of death of 17% for an increase in one unit
and over 50% for an increase of four units (Trichopoulou 2003).
Much of the longevity advantage in Okinawa is attributed to their healthy life-
style; this includes the traditional diet, which is low in calories, yet nutritionally
dense, particularly with regard to vitamins, minerals, and phytonutrients, several of
which have neutraceutical potential. The traditional Okinawan cuisine centers on
the staple sweet potato, green-leafy or yellow-root vegetables, and soy (e.g. miso
soup, tofu or other incarnations of this legume) which accompanied almost every
meal. Smaller servings of fish, noodles, or lean meats flavoured with herbs, spices,
and cooking oil often accompanied these staples (Willcox et al. 2014). Similar to
the Ayurvedic diet, dietary pattern in Okinawa is characterised with low caloric
intake, high consumption of vegetables (particularly root and green-yellow vegeta-
bles), legumes (mostly soybean in origin), moderate consumption of fish products
(more in coastal areas) and low consumption of meat products (mostly lean pork),
dairy products, fat intake (high mono and polyunsaturated-to-saturated-fat ratio;
low omega 6:3 ratio). Their emphasis is on low-GI carbohydrates with high fibre
intake and moderate alcohol consumption (Willcox et al. 2007).
In India, food is medicine or a ‘food-first’ approach is used to integrate realities
of today with our culture. This forms the crux of all the traditional diets. Integrating
modern science with traditional knowledge thus has a potential to provide ‘adopt-
able’ simple solutions to our present and future health and wellness challenges
including ageing.
References
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Rattan SI (2015) Biology of ageing: principles, challenges and perspectives. Rom J Morphol
Embryol 56(4):1251–1253
Savige GS (2002) Can food variety add years to your life? Asia Pac J Clin Nutr 11:S637–S641
Srinivasan K (2010) Traditional Indian functional foods. In: Functional foods of the East,
Nutraceutical science and technology, vol 10. CRC Press, Boca Raton, pp 51–76
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(Ahara)—a review. In: Biology and life sciences forum 2021 Oct 14, vol 6, no 1. MDPI, , p 19
Trichopoulou A (2003) Adherence to a Mediterranean diet and survival in a Greek population. N
Engl J Med 348:2599–2608
Wickramasinghe K, Mathers JC, Wopereis S, Marsman DS, Griffiths JC (2020) From lifespan to
healthspan: the role of nutrition in healthy ageing. J Nutr Sci 9:E33. https://doi.org/10.1017/
jns.2020.26
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diet, and healthy aging: the diet of the world’s longest-lived people and its potential impact on
morbidity and life span. Ann N Y Acad Sci 1114:454–455
Willcox DC, Scapagnini G, Willcox BJ (2014) Healthy aging diets other than the Mediterranean:
a focus on the Okinawan diet. Mech Ageing Dev 136:148–162
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61(Suppl. S6):S1402–S1406
Chapter 8
Macronutrients and Their Roles in Aging
Ahamed Basha Abdul Bari and Prince Johnson Samuel
Abstract Macronutrients are the essential nutrients that are needed in high amounts
for healthy aging. Several acute and chronic illnesses such as diabetes, hyperten-
sion, atherosclerosis, other cardio-vascular disorders, dementia, bone morphologi-
cal disorders, etc. are strongly linked to aging. Further, age-related morphological
and functional changes are observed in every cell/organ in almost all living organ-
isms. To cope with age-related illnesses, macronutrients such as carbohydrate, pro-
tein, and fat have to be supplemented in an ideal manner. Macronutrient
supplementation must be planned as per age group, sex, ethnicity, country of origin,
etc. to achieve successful aging. The various diet patterns, like the Mediterranean
diet, the Japanese diet, the Okinawa diet, etc., strongly suggest that they contain
different ratios of macronutrients. Thus, supplementation with the proper ratio of
macronutrients in association with other strategies is the best way to achieve
healthy aging.
Keywords Macronutrients · Carbohydrates · Proteins · Lipids and aging
8.1 Introduction
Macronutrients are nutrients required in large quantities for our well-being. They
provide energy (calories) to maintain normal growth and metabolism and to carry
out day-to-day activities. They are the building blocks of our body and are generally
A. B. A. Bari (*)
Physiology, Chettinad Hospital and Research Institute, Chettinad Academy of Research and
Education, Chengalpattu, Tamil Nadu, India
P. J. Samuel
Physiology, Vels Medical College and Hospital (under VISTAS), Tiruvallur, Tamil Nadu, India
Ltd. 2023
138 A. B. A. Bari and P. J. Samuel
classified as carbohydrates, proteins, and lipids (Venn 2020). Most of the carbohy-
drates that we consume through our diet get digested and simple sugars like glucose
are formed as end products, which act as a primary energy source for our body.
Proteins are made up of amino acid residues and perform a wide range of functions
in our bodies, including cell structure formation and key transporters in the meta-
bolic process. Fats act as an important storage form of food and aid in the mainte-
nance of body structure. These macronutrients must be consumed in adequate and
balanced amounts in our diet to maintain good health. Human communities have
traditionally lived on diets with widely different ratios. Several studies are still
being conducted around the world to determine an ideal macronutrient ratio for the
global population to live a healthy life. According to WHO, the recommended per-
centage of calories in a diet for protein is 10–15%, for fat is 15–30%, and for carbo-
hydrates is 55–75% for young adults (Venn 2020). However, the acceptable
macronutrient distribution ranges for carbohydrates, protein, and fat remain con-
stant from middle age to old age. For the elderly, the recommended macronutrients
for protein are 15–20%, fat is 20–35%, and carbohydrates are 45–60% (Kehoe et al.
2019). Among the macronutrients, unrefined carbohydrates, such as whole grains
and brown rice, are especially important in preventing constipation and other gastro-
intestinal disorders, and may also lower the risk of colon cancer in older adults. A
protein diet should be lean, and fats such as unsaturated and omega-3 fatty acids
should be included in a healthy diet. Thus, every macronutrient has to be a part of
the diet on a daily basis. Making each meal a combination of protein, complex car-
bohydrates, and healthy fats will make this easier. However, it might be challenging
to determine the precise macro-balance that works for you. If there is a deficiency
of carbohydrates in the diet, then it may lead to several disorders such as hypogly-
cemia, diabetic ketoacidosis, and hyperosmolar coma (Kalscheuer et al. 2017; Scott
et al. 2019). Similarly, protein deficiency leads to protein energy malnutrition disor-
ders in different age groups (Leij-Halfwerk et al. 2019), while altered levels of fat
may lead to several cardio-vascular disorders, such as stroke, renal diseases, obesity,
and metabolic syndrome (Carson et al. 2020). Thus, macronutrients play a signifi-
cant role in healthy living (Nassar 2019). The diet that we eat as a child has an
impact on our health as we grow older. A good, healthy macronutrient diet and regu-
lar physical activity can help us live a longer and healthier life. On the other hand,
Irregular bowel habits with a lack of nutrition and exercise, might hasten the aging
process and cause several pathological disorders. The appropriate macronutrients
give several benefits at each and every stage of our lives. They help a new-born
grow, a teenager develops mentally and physically, a young adult reaches his or her
physical peak, and an older adult has to cope with aging and its related issues. At
any age, nutritious meals are the foundation of a healthy lifestyle. Thus, macronu-
trients can address the majority of the nutritional issues that many older people
confront. Furthermore, there are special nutritional issues that impact individuals in
their process of aging. They include medical issues such as disability and disease,
which might have an impact on macro diet and physical and mental activity levels.
For example, as a person becomes old, dental disorders can cause mastication and
swallowing difficulties, making it difficult to maintain a healthy macronutrient diet
8 Macronutrients and Their Roles in Aging 139
(Peyron et al. 2017). Nutritional issues in the elderly can lead to a variety of conse-
quences, including decreased energy levels and chronic health issues such as type 2
diabetes, high blood pressure, heart disease, stroke, and osteoporosis (Jaul and
Barron 2017).
Aging is a normal physiological process that occurs for every living organism,
including humans. The aging process starts in early adulthood and starts to deterio-
rate several body functions as age advances. Over the decades, the life expectancy
of humans has increased to a greater extent, but it does not mean that as age
increases, all humans are living a healthy life. Aging is a complex process with
interconnected aspects at the molecular, macro-cellular, and functional levels that
eventually results in chronic illnesses/disorders (Fig. 8.1). Thus, a healthy diet with
ideal macronutrients is essential for a normal, healthy life. Furthermore, when com-
pared to micronutrients, macronutrients are more essential. Without macronutrients,
the risk factors associated with aging will be dominant and it will affect the quality
of life to a greater extent as age advances. Clinicians and scientists have docu-
mented several biochemical changes or external factors that are linked with aging
(Engelfriet et al. 2013). Further, a necessary dietary pattern can be regularized so
that it can promote healthy aging. However, the main “gap” concerning the types of
macronutrients that could actually improve healthy aging has to be documented.
Additionally, it is thought that these crucial elements may be seen from a life-course
perspective since altering these macronutrient routines might affect human cells or
organs’ aging, postpone the start of chronic illnesses, and enhance mobility, mental
function, and general wellness (Stepaniak et al. 2022). Recent research work has
used a nutritional geometric method known as the Geometric Framework to assess
Fig. 8.1 Common

age-related chronic
disorders
how aging is affected across a landscape of diets that differ orthogonally in macro-
nutrient and total energy content (Simpson et al. 2017a). This chapter is restricted to
only the importance of macronutrients and their influence on the aging process.
8.2 Macro Nutritional Requirement and Aging Process
The United States Department of Agriculture Food Patterns recommends different

macronutrient goals for each age and gender group when evaluating requirements at
different calorie levels (Krebs-Smith et al. 2018). For an infant to a child, and an
adult to old age, it drastically varies to meet the macronutrient demands. Further,
due to variations in body regulatory mechanisms, hormonal section, gastro intesti-
nal related reflex, macronutrient absorption and metabolic rate, desire to eat, etc.,
influences the amount of intake of macronutrients to a greater extent. Moreover,
plenty of researchers have documented in support of the above that in the aging
process, the nutritional pattern varies. For example, during the growing period, a
more carbohydrate and protein-based diet is advised, and in old age, as physical
activity decreases with age, it is important to limit carbohydrates and fats. However,
there is muscle loss and bone fragility, which is prevalent; as a result, protein is
needed to make up for the loss and to promote cell development.
All of the physiological changes mentioned above are strongly influenced by
macronutrients. The slowdown of the digestive functional capacity, along with other
alterations, has the most direct impact on macronutrients and the aging phenome-
non. Digestive secretions significantly decrease, although enzymes are still suffi-
cient. Additionally, constipation is more common in older people than in younger
adults. Normal bowl function, macronutrient digestion and absorption with ade-
quate dietary fiber, exercise, and hydration consumption, on the other hand, can
reduce age-related physiological and pathological changes (Soenen et al. 2016).
Changes also occur in the kidneys, lungs, and liver, which has the ability to generate
new protein tissue (Sheedfar et al. 2013; Glassock and Rule 2016; Maeso-Díaz and
Gracia-Sancho 2020). In addition, aging can slow the immune system’s response to
making antibodies (Sadighi Akha 2018). Beyond this macronutrient oxidation, obe-
sity in many individuals also contributes to the damaging effects of aging (Santos
and Sinha 2021). Apart from macronutrients, micronutrients, gender, race, ethnicity,
demography, physical activity, lifestyle, etc. are also strongly associated with the
aging process (Emerson and Gay 2017).
8.3 Dietary Carbohydrates and Aging
Eating carbohydrate-rich foods such as rice, wheat, bread, potatoes, sugar-based

sweets, etc. may increase the body weight and alter the glucose homeostasis. A
carbohydrate diet with a high glycemic index increases blood sugar levels.
Furthermore, numerous studies have found that consuming an excessive amount of

carbohydrates has a negative impact on an individual’s life span (Seidelmann et al.
2018). The reason behind the decrease in life cycle span is its influence on various
cellular signaling pathways. The common end product of carbohydrate metabolism
is glucose, which acts as a king maker in the process of aging.
One of the best researched carbohydrates that impacts aging is glucose, which
serves as the main energy source for most living things. In various model species,
such as yeast, increased glucose consumption promotes aging. One of the possible
reasons could be due to the downregulation of life enzymes like AMP-activated
protein kinase, which function as energy sensors in the regulation of metabolism
and the life cycle (Lee et al. 2017). Forkhead/winged helix box gene transcription
factor is another growth inhibitory genetic factor that decreases its functional capac-
ity in response to glucose intake via the insulin-like growth hormone-I signaling
pathway (Morris 2005). Furthermore, its low level causes the aquaporin-1/glycerol
channel to be downregulated and modifies the glycerol to tune the life existence
(Lee et al. 2009). Additionally, intake of a diet rich in glucose leads to the formation
of methylglyoxal, one of the end products of glucose metabolism that reduces the
life span of the living organism (Xue et al. 2011). Another group of studies sug-
gested that an increase in glucose level causes changes in glucose transporters and
proapoptotic genes, growth-promoting signaling proteins such as Sch9, Tor1,
glucose-sensing G-protein-coupled receptor Git3p, and proteins involved in the Ras
pathways, resulting in a shorter life cycle (Versele et al. 2001; Wei et al. 2009).
Adding to this, an increase in glucose concentration leads to modification of SIRT3/
Sirtuin 3 (a nicotinamide adenine dinucleotide (NAD)-dependent protein deacety-
lase) expression is also negatively correlated with aging (Chen et al. 2017). Thus, to
conclude, an increase in glucose intake reduces and restricts the same, which accel-
erates aging. In contrast to the pro-aging effects of carbohydrates, several other
carbohydrate metabolites, such as trehalose, act as antistress sugars, increasing the
life span of a group of organisms by upgrading endoplasmic reticulum proteins.
Similarly, other carbohydrates such as pyruvate, malate, fumarate, and
N-acetylglucosamine help in preventing the deteriorating effects of aging in many
species.
Human studies related to aging and carbohydrates are still not conclusive.
Successful aging means high physical, mental, and social functioning in old age
without major diseases. The quantity of macronutrients consumed for successful
aging in humans is primarily determined by the quantity of carbohydrate-based
diets consumed. A few studies have found that eating a low carbohydrate diet
reduces cardiovascular risk and keeps blood sugar levels stable, which is beneficial
in the aging process (O’Neill 2020). Another group of research articles confirmed
that a higher carbohydrate diet leads to obesity and a shorter lifespan (Sartorius
et al. 2018). Further, intake of carbohydrates as a dietary fiber impacted the chance
of effective aging throughout a 10-year period independently, and the data sup-
ported that a fiber-rich diet might be an effective strategy for living a disease-free
and quality life (Park et al. 2011). In another study, a unique relationship was dis-
covered between high cereal fiber consumption and a lower incidence of mild
chronic kidney disease, which was corroborated by a cross-sectional correlation

with dietary glycemic index. In contrast, the same study also confirms that consum-
ing a more energy-dense, nutrient-poor carbohydrate diet may compromise renal
function, presumably through transient hyperglycemia (Mirmiran et al. 2018).
Supplementing this, In an older Australian population, dietary glycemic index,
dietary fiber, and carbohydrate-containing food categories were linked to death due
to non-cardiovascular, noncancer inflammatory illness, and aging (Gopinath et al.
2011). Extending to this, carbohydrate dietary supplementation was assessed for
depression score using Mental Health Index scale and the epidemiologic studies
depression-10 scale, which documents that nutrition factors such as carbohydrate
dietary fiber were shown to have a modest correlation with the occurrence of depres-
sive symptoms (Gopinath et al. 2016). Additionally, plenty of studies proved that a
carbohydrate nutrient diet affects age-related changes in almost all organ systems
(Seidelmann et al. 2018).
Several scientists have studied the relationship between cardiac health and car-
bohydrate diets for many years, initially believing that processed carbohydrates in a
diet lacking fiber were significant risk factors for cardiac health and influenced the
aging process (Duan et al. 2022). However, carbohydrates with a low-carbohydrate
diet were in turn found to have cardioprotective and antiaging effects (Farhadnejad
et al. 2020). Another common age-related disorder is osteoporosis, which occurs
when a high carbohydrate diet affects bone health during the aging process, reflect-
ing its ability to alter calcium metabolism and skeletal homeostasis (Hashemi et al.
2015; Montalvany-Antonucci et al. 2018). In line with this, a low carbohydrate diet
with rich fiber has an inverse relationship with kidney diseases. Furthermore, during
the course of another age-related disorder, dementia, more than 35% of dementia
patients consume more food than they did before the disease (Gentreau et al. 2020).
Over half of patients with dementia are reported by their caregivers to have a signifi-
cant shift in food preferences, specifically an increased preference for sugary foods
and carbohydrate-rich diets. A study, on the other hand, discovered that increasing
carbohydrate-based diet has a beneficial effect on dementia. Further, carbohydrate-
rich diets in the process of aging also influence the majority of body functions such
as decreased vital capacity, gastritis, dermatological disorders, etc. Further, higher
carbohydrate intake, glycemic index, and glycemic load are found to cause meta-
bolic dysregulation of the glucose-insulin axis and adiposity-related processes,
which in turn make the body more prone to the development of various cancers as
age advances (Jung and Choi 2017).
In conclusion about carbohydrates: whether carbohydrates really play a damag-
ing role in the aging process. The solution is a little difficult because carbohydrates
and aging include a wide range of physiological parameters. The availability of
excellent literature supports that taking a carbohydrate-based diet during the differ-
ent stages of aging when paired with an active lifestyle, can really postpone aging
through reduced insulinogenic response. For example, when sports people like ath-
letes take high amounts of carbohydrates, their overall life span is greatly prolonged
when compared to non-sports people. Contradictory to this, intake of more carbo-
hydrates makes our body more prone to inflammation due to the spikes in insulin
secretion and the formation of more glycation end products, which decreases the
life span. Additionally, taking too many carbohydrates coupled with a sedentary
lifestyle decreases life span. On the other hand, at any stage of the aging process, the
recommended amount of carbohydrates in the diet along with a healthy (physical
and mental) lifestyle like exercise, adequate sleep, etc. actually extends the life
span. If a high carbohydrate diet is taken, then calorie levels have to be checked,
because even a high carbohydrate diet with low calories also prolongs the life span.
Thus, to extend the life span or to achieve healthy aging, way of physical and mental
living (healthy lifestyle) and diet (ideal macronutrients – carbohydrates along with
protein, fat, and other micronutrient diet patterns) is recommended.
8.4 Role of Protein Diet in Aging
Proteins and amino acids are one of the key biological macromolecules that func-
tion as structural components, enzymatic reaction catalysts, and act as an energy
source. Numerous studies have shown that dietary proteins are factors that influ-
ence longevity. For example, deficiency of some critical amino acids increases the
longevity of various model organisms (Kitada et al. 2019). Available literature
exhibits a strong negative correlation between protein intake and aging (Simpson
et al. 2017b). Furthermore, several nutrition-related studies on proteins and carbo-
hydrate diets were conducted to determine whether the age-related changes were
caused by the protein or carbohydrate diet. In a study done on experimental organ-
isms, it was found that longevity is connected with a low-protein/high-carbohy-
drate diet; however, overall calorie intake had no influence on longevity (Foscolou
et al. 2019). Furthermore, insulin-like peptides have been found to modulate the
effects of protein and carbohydrate on the life span of an organism by modulating
a brain insulin target that encodes an a-glucosidase. Decreased protein consump-
tion also appears to increase longevity by suppressing the insulin/insulin-like
growth factor-1 or target of rapamycin signaling pathways (van Heemst 2010).
Dietary amino acid content influences longevity by influencing multiple nutrient-
sensing signaling pathways. Adding to this, a human epidemiological statistic also
found an association between the quality and quantity of dietary proteins and long-
term health (Pan and Finkel 2017) and involvement of complex nutrient-sensing
networks which fine-tune the metabolic responses to dietary proteins in a highly
conserved manner. These metabolic reactions, in turn, can influence the emergence
of insulin resistance, obesity, neurodegenerative illness, and other age-related dis-
orders. In yeast, it was found that EIF2A eukaryotic translation initiation factor 2A
kinase and general control nonderepressible 2, which directly bind to uncharged
cognate transfer RNAs and target of rapamycin signaling pathway components that
operate as cellular amino acid sensors to promote lifespan (Pan and Finkel 2017;
Anderson et al. 2021). It further reduces overall protein translation while increas-
ing translation of particular proteins implicated in longevity. Furthermore, dietary
tryptophan limitation protects laboratory animals against renal and hepatic
ischemia damage and decreases inflammation in connection with lower serum

insulin-like growth factor, which also limits the damaging effects of aging (Wu
et al. 2022).
A protein-based diet comes from two different sources, i.e., animal and plant-
derived protein diets. The effects of plant and animal protein on aging are not the
same. A senior population research study found that people aged 50–65 years who
ingested a lot of protein had a 75% increase in overall mortality and a fourfold
increase in their chance of dying from cancer (Levine et al. 2014). Age-related ill-
nesses such as excess weight gain are found to be less common in populations tak-
ing plant protein than animal protein. The probable reason could be that plant
proteins have far less methionine than animal proteins, and this low methionine
level may explain why dietary plant proteins are advantageous in physiologic aging
(Foscolou et al. 2021). In contrast, there are reports that plant-based protein is not
sufficient enough to cope with daily dietary requirements, so animal protein has to
be supplemented to meet the age-related protein demand. Thus, evaluating the effect
of lower protein consumption on longevity may appear to be a simple research sub-
ject. However, nutritional geometry has demonstrated that assessing the influence of
protein limitation on longevity cannot be determined by merely lowering the protein
content of meals (Simpson et al. 2017b).
Among the various bodily changes during the aging process, skeletal muscle
mass and strength deteriorate to a greater extent. A study reported that age-related
changes in sarcopenia can be attenuated by dietary protein and exercise in the older
population. Several nitrogen balance studies in people ranging in age from 56 to 80
years old have revealed that greater protein consumption (1.4–1.6 g/kg/day) might
be beneficial for older people. Individuals who consume more protein lose less lean
mass as they age (Naseeb and Volpe 2017). In contrast, a health, aging, and body
composition study found that dietary protein consumption was not linked with a
5-year change in mid-thigh muscle cross-sectional area measured by computed
tomography in older people (Tuttiett et al. 2021). Thus, the effect of a protein diet
on skeletal muscle in the elderly population is still debatable. Apart from protein
intake, timing of protein intake also affects the aging process, especially in relation
to sarcoplasmic reticulum synthesis and turnover in older adults. Another study cor-
related the impact of dietary protein on lifespan and metabolic health, i.e., amino
acids, methionine, and branched-chain amino acids, have been linked to the control
of lifespan and metabolism by influencing glucose and lipid metabolism, improving
antioxidant status, etc. (Kitada et al. 2019). Although long-term protein intake is
associated with aging effects, one study reported that protein supplementation for a
shorter duration of time does not increase the feeling of food carving and appetite in
middle-aged adult populations. Apart from this, anabolic resistance has been shown
in older individuals, where higher quantities of protein are required to drive muscle
protein synthesis and the response is varied. As a result, the recommended daily
protein intake for elderly people is higher. Many of the proposed pathways for ana-
bolic resistance include the gut flora, either directly or indirectly. The gut microbi-
ota changes with age and is greatly impacted by the amount of protein consumed,
which in turn is reflected in the functional role of skeletal muscle during the various
stages of the aging process (Ni Lochlainn et al. 2018). Expanding on this, load-
dependent gut hormone plasma cholecystokinin and gastric inhibitory polypeptide
responses to orally consumed whey protein were larger in older people than in
younger adults (Tuttiett et al. 2021). In addition to this, the cardio vascular response
to the dietary protein intake showed a fall in blood pressure despite an increase in
heart rate (Giezenaar et al. 2021). Alternative research reported that the fractional
synthesis rate of albumin, which plays a variety of roles in living organisms,
responded well to the aging process of older people (Thalacker-Mercer et al. 2007).
Further, another concept of nutritional approach, protein pulse feeding – a combina-
tion of protein-rich and low-diet in the elderly population, showed positive effects
like optimizing anabolic density, exhibiting positive nitrogen balance (Dickerson
2016), etc. in the elderly population. To summarize the effects of protein diet on
aging, we can say that we are still learning about the potential benefits and chal-
lenges of optimizing dietary protein intake in older people. Eating enough high-
quality protein at each meal, combined with physical activity, may delay the onset
of damaging aging effects.
8.5 Contribution of Fat (Lipids) on Aging
The major structures in biological membranes are dietary lipid components such as
fatty acids, phospholipids, cholesterol, and triglycerides. Aging is greatly impacted
by dietary lipids. Generally, a high-fat diet regardless of age affects the various
organ systems, especially arthrosclerosis, hypertension, and other cardio-vascular
diseases. Further, diabetes has a strong link with dietary lipids, which in turn affects
the mortality rate from adulthood to old age (Kurozumi et al. 2016). At the same
time, there are dietary lipids which are beneficial to health. Hence, dietary lipids
have a dual role of both protective and damaging effects in the physiological process
of aging. Sirtuin1, a NAD-dependent protein deacetylase, peroxisome proliferator-
activated receptors, sterol regulatory element-binding protein 1, carbohydrate-
responsive element-binding protein, superoxide dismutase 3, caspase-1, etc. are the
common genetic factors that regulate high-fat diet-induced pathology in the aging
process. Among the above, Sirtuin 1 was found to be a key factor which controls the
changes associated with aging (Gao et al. 2020). In experimental study, a high-fat
diet induces a spike in fat mass and worsens the age-linked damage to muscular
performance. The probable reason could be due to the quicker build-up of intramyo-
cellular lipids and the initiation of muscle dysfunction in older people than in young
adult organisms (Degens et al. 2021). Adding to this, rats fed with high fat diets
exhibit structural modification in the pancreas, which causes inflammation and
accelerates oxidative damage and aging (Kvitnitskaya-Ryzhova et al. 2021). In the
same manner, age-related changes were observed in non-alcoholic steatohepatitis.
A non-alcoholic fatty liver disease experimental study suggested that animals fed a
high-fat diet cause lipid accumulation in the liver and promote liver aging (Gao
et al. 2020).
Dietary lipids have a direct effect on blood cholesterol level, as the cholesterol
level increases, it causes damage to various vital functions and accelerates aging.
It also leads to the development of various acute and chronic illnesses and may end
up with the faster death of an individual. Dietary trans fats increase the blood level
of low-density lipoproteins (bad cholesterol) and reduce the high-density lipopro-
teins (good cholesterol), which directly affects aging and shortens the life span of
an individual. If the diet contains more natural unsaturated fatty acids, then it
decreases age-related illness and lowers the mortality rate (DiNicolantonio and
O’Keefe 2018). Significant evidence supports the idea that systemic insulin-like
growth factor-I activity dictates the rate of aging. A study reported that a low-fat
diet in addition to other strategies down regulates the insulin-like growth factor-I
and ends up with the slowness of the aging process (McCarty 2003). In another
study, omega-3 polyunsaturated fatty acids, particularly those found in fish, are
well acknowledged to have anti-inflammatory qualities that aid in the prevention
of degenerative diseases linked with aging (Troesch et al. 2020). According to
another study, a diet high in n-6 poly unsaturated fatty acids and low in n-3 poly
unsaturated fatty acids promotes low grade chronic inflammation, resulting in dys-
regulation of the mesenchymal stem-cell lineage, obesity, and osteoporosis, which
is interlinked with aging (Liput et al. 2021). According to the above study, fatty
acids also increase cognitive function in people with mild cognitive impairment.
Thus, to conclude, in the diet pattern specific to the elderly population, it must
contain more low-density lipoprotein and less trans fats to maintain healthy and
successful aging.
8.6 Caloric Restriction and Macronutrients vs. Aging
Calorie restriction is a diet pattern that limits food intake without causing malnutri-
tion. A person’s calorie intake is reduced voluntarily to lose weight. It is indicated
as a viable regimen for body weight control by US dietary standards and scientific
bodies. Reduction of 1/3 of caloric intake without affecting nutrient requirements
has been found to alleviate aging diseases such as cancer, cardiovascular disease,
dementia, and diabetes in humans (Kökten et al. 2021). Further, it also causes weight
loss of up to 8 kg. However, further research is necessary with a wide variety of
populations across the world. The term caloric restriction is a contentious term that
refers to either a total calorie restriction or a reduction in specific macronutrients
such as carbohydrate, protein, or fat (or a combination of the two). Because conven-
tional caloric restriction entails a reduction in total food availability, which leads to
a reduction in all macronutrients, plenty of research articles have proved that protein
and particularly amino acid restriction are the reasons behind the health benefits of
caloric restriction. Studies in experimental organisms’ report that restriction of cer-
tain amino acids leads to the activation of genes that are responsible for stress,
which leads to anti-aging effects and an extension of life span (Le Couteur et al.
2020). In another comparative study in a fly, it was observed that when the protein:
carbohydrate dietary ratio was increased from 1:4 to 1:6, it caused an increase in the
life expectancy of the fly (Fanson and Taylor 2012). Extending from this, protein
restriction in their routine has been shown to extend life and reduce disease risk in
study animals. The reason for much of the beneficial effects due to calorie restric-
tion is the alteration in functional capacity of several nutrient-sensing pathways.
Many experimental approaches have been documented to understand the mechanis-
tic action of nutrient-sensing pathways that mediate the effects of macronutrients
and aging. The significant contributors to the nutrient sensing pathways are (as men-
tioned earlier) mammalian target of rapamycin protein, AMP-activated protein
kinase, insulin/Insulin-like growth factor-1, and Sirtuin (Efeyan et al. 2015). These
regulators interact with one another and share many downstream targets that regu-
late aging-related cellular activities like mitochondrial production, cellular meta-
bolic activity, autophagy, genetic expression, and protein translation and delay
aging (Fig. 8.2). Furthermore, recently, a bunch of research has been initiated to
address the interactions between macronutrients and explain the importance of mac-
ronutrient balance on health and aging. The Geometric Framework for Nutrition
was used to generate details related to such macronutrient interactions. In this, nutri-
tion is defined in an n-dimensional space, where n represents macronutrient compo-
nents. Lifespan can be demonstrated in this n-dimensional space, providing a
detailed picture of the effects of nutrition. Using this framework allows the use of
nutritional geometry to simultaneously interpret the effects of energy, individual
macronutrients, and the interactions within and between nutrients. This framework
has helped to resolve conflicting ideas about the nutritional determinants of health
and aging and to reconcile views on resource-mediated trade-offs between repro-
duction and longevity. This n-dimensional space can be used to explain the lifespan,
with a clear idea of the effect of macronutrients’ functional effects on aging (Efeyan
et al. 2015).
Fig. 8.2 Macronutrients intervention and aging

8.7 Macronutrient Components for Longevity
With the growth of macronutrient-based diets, from low-fat to low-carbohydrate,

discussion of the three basic macronutrients – carbohydrate, proteins, and fats has
become routine when discussing ideal diets. Researchers have begun comparing
various “macronutrient management”-style diets to see which is the most success-
ful. Older people have fewer appetites and a lower caloric need, so they may
require more nutrients than they did previously. Their living patterns differ as
well, which might influence the meals they consume. Fewer macronutrients are
absorbed because of decreased physical activity and calorie intake, leading to the
development of certain nutritional deficiencies. The chance of getting osteoporo-
sis, heart disease, and other chronic conditions rises with age. Further, clinical
malnutrition in aging is caused by an imbalance between macronutrient intake
and need, resulting in a detectable decrease in tissue and, eventually, weight. As a
result, enough calorie intake and greater protein consumption are required as peo-
ple grow. Proper protein consumption is critical to preventing malnutrition.
Protein consumption recommendations are mostly based on the idea of anabolic
resistance, which describes the muscle’s diminished ability to respond to anabolic
stimuli as we age. However, protein consumption in older people has been
observed to be regularly substantially below recommended intake, which is asso-
ciated with a higher risk of malnutrition development. Protein catabolism can be
severe as well, depending on the type of malnutrition and underlying condition.
Protein needs are greatly increased in malnourished or diseased elderly individu-
als. Based on the literature search, it was found that a high-protein, low-calorie
diet can help obese older people lose more weight while retaining muscle mass
and enhancing bone density. The findings of the other three studies imply that a
macronutrient-based dietary strategy may have some advantages, but research
also reveals that although one macronutrient diet may result in weight loss for one
person, it may not be beneficial for another owing to individual variances in genes
and lifestyle. Another study reported that a low carbohydrate diet is highly benefi-
cial for elderly people. Expanding on this low carbohydrate diet, a low-fat diet is
also beneficial in the geriatric population. As a result, a low carbohydrate, high
protein, low fat diet with a low-calorie count may be an ideal macronutrient com-
ponent for aging. Still, a few authors suggest that there is no such thing as the
“ideal” one-size-fits-all diet in the aging process. Hence, further macronutrient-
based research studies must be done in a larger population at the molecular level
to confirm the findings.
The longevity diet is a complex phenomenon involving genetics, the living envi-
ronment, behaviour, and eating habits. The assumption that eating habits have a
significant impact on longevity has shifted the focus to nutrition for longevity. The
most popular diets associated with longevity aging are Japanese (Abe et al. 2020),
fast-mimicking (Brandhorst and Longo 2019), Okinawa (Gavrilova and Gavrilov
2012), Mediterranean (Trichopoulou et al. 2003), and vegan diets (Norman and
Table 8.1 Macronutrient composition of various antiaging diet

S. No Diet type Carbohydrate Protein (%) Fat (%)
1 Japanese diet 65% 10 25
2 Okinawa diet 85% 9 6
3 Fasting-mimicking diet Day 1: 34% 10 56
Days 2–5: 47% 9 44
4 Mediterranean diet 50% 15 35
5 Vegan diet 30% 40 30
The values for carbohydrate, protein and fat are given in percentage of total energy. The standard
deviation range for the above-mentioned diet is ±5%
Klaus 2020). Table 8.1 shows the macronutrient composition of the aforemen-
tioned diets. Japanese diet is an anti-aging diet that has been extensively explored
since the Japanese population’s life expectancy has steadily increased. Rice, noo-
dles, fish, eggs, soy products, seaweed, seasonal vegetables, and green tea are tra-
ditional long-term health foods in the Japanese diet. Fasting-mimicking diet is a
5-day dietary programme that provides vital nutrients while being modest in total
calories, protein, and sugar. It is believed that it regulates calorie restriction.
However, it is not designed to be a long-term diet plan. Hence, it can be followed
intermittently throughout the year for healthy aging. The traditional Okinawan diet
is heavy in carbohydrates and low in calories and fat. It emphasises veggies and soy
products, with minor portions of noodles, rice, pork, and fish. Mediterranean diet
is built on plant-based foods such as whole grains, vegetables, legumes, fruits, nuts,
seeds, herbs, and spices. The major source of additional fat is olive oil. In modera-
tion, fish, seafood, dairy, and chicken are allowed. Red meat and sweets are only
consumed on rare occasions. Vegan or plant-based diet which does not include any
animal products, such as meat, dairy, or eggs. A vegan diet, when followed cor-
rectly, may be very nutritious, minimise the risk of chronic illnesses, and assist in
weight loss.
8.8 Conclusion
Macro nutritional requirements fluctuate as people become older and it widely

affects aging process. To meet the dietary and nutritional demands of senior per-
sons, dietary recommendations should be differentiated by age. Energy demands
drops down when metabolism slows, but because gastro intestinal absorption
becomes less effective, there is a greater need for nutrient-dense meals, which often
include more macronutrients nutrients (particularly carbohydrate, protein and fat).
To achieve a healthy aging, the recommended micronutrients must be supplemented
as per country specific guidelines. Further, age, sex, race, ethnicity, physical activity
must be taken into consideration for successful aging.
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Chapter 9
Micronutrient Status Among Adults
in the Asia Pacific and Potential Impact
on Age-Related Diseases
Stephen French, Taichi Inui, and Akiko Kuwabara
Abstract Improving micronutrient status of populations provides a cost-effective

mechanism to help improve health status. The Asia-Pacific region is home to some
of the world’s most rapidly ageing populations, and many of the non-communicable
diseases associated with older age can be positively impacted by adequate and opti-
mal micronutrient status.
Multiple factors can impact the ease of achieving optimal dietary micronutrient
intakes, including socio-economic and cultural factors. Ageing, associated diseases,
and certain medications can also impact the ability to achieve micronutrient intakes.
Therefore dietary, fortification and supplementation interventions should be consid-
ered to help attain optimal micronutrient intakes.
However, targeting micronutrient interventions can be hampered by inadequate
dietary intake data from national surveys.
In this chapter, we review the health issues associated with ageing and the role
that micronutrients can play in helping to reduce risk. Based on the existing intake
data, there was a high prevalence of insufficiency of vitamins A, D, E, C, B-6, B-12,
folate, and for zinc in many countries. We also present analysis to suggest that, in
the absence of raw data from dietary surveys, the use of mean and standard devia-
tion (SD) is the best data to use when estimating micronutrient status among
populations.
S. French
Applied Health Sciences, School of Public Health, Indiana University, Bloomington, USA
e-mail: sjfrench@iu.edu
T. Inui (*)
DSM Nutritional Products, Tokyo, Japan
e-mail: taichi.inui@dsm.com
A. Kuwabara
Osaka Metropolitan University, Osaka, Japan
e-mail: kuwabara.akiko@omu.ac.jp
Ltd. 2023
156 S. French et al.
Keywords Micronutrient intake · Age-related disease · Micronutrient

insufficiency · Dietary survey · Micronutrient intervention
9.1 Introduction
The Asia-Pacific (APAC) region has a rapidly ageing population and is home to some
of the most aged nations in the world (United Nations 2017). APAC countries, along-
side other areas of the world, have been impacted by the double burden of malnutri-
tion, characterised by the coexistence of undernutrition along with overweight, obesity
and diet-related noncommunicable diseases (NCDs) (WHO 2017). This double bur-
den can be observed at an individual, household, or population level and has multiple
drivers of dietary shifts, relative affordability and availability of different foods,
urbanisation and mechanisation, and demographic shifts to an ageing population.
Life expectancies are increasing and birth rates decreasing, leading to the overall
demographic shifts to an ageing population and increasing burdens of health and
social care for elderly populations (Inui et al. 2021). These effects are further exac-
erbated by NCD impacting health status of older individuals and the increasing time
span requiring health interventions. Nutrition and lifestyle are two factors that are
modifiable and can have significant impacts on health throughout life and particu-
larly in later life.
Currently, global food systems in many low- and middle-income countries
(LMICs) are not delivering nutritionally adequate diets across all populations,
resulting in deficiencies in essential micronutrients (Mkambula et al. 2020).
Micronutrients play an important role in maintaining health, including key health
conditions at a later stage of life (Péter et al. 2015). The impacts of micronutrient
deficiencies on the development of specific diseases have been well understood and
investigated for many decades. We are now beginning to understand the importance
of micronutrients in long term health maintenance and optimal health, with increas-
ing evidence to support the role of specific micronutrients to contribute to health
throughout the lifespan. However, the specific impacts of individual micronutrients
and causal relationships between micronutrients and disease end-state are often
lacking. This is further impacted by inconsistent, and sometimes lacking, national
reporting of diet and micronutrient status across populations.
In this chapter, we provide a brief overview of the role of micronutrients in NCDs
most prevalent in ageing populations, which include vision, cardiovascular health,
cognitive functions, mobility and immunity. To assess micronutrient intakes, we
also provide analysis of the data from national nutrition intake surveys and peer
reviewed journal assessments of the micronutrient gap against the Dietary Reference
Intakes (DRIs) of the national RDIs, and assess different methods of summarising
population data for accuracy when compared with raw data. We also briefly review
the challenges to meeting dietary recommendations for micronutrient intake and the
roles that fortification and supplementation can play in helping to meet these
recommendations.
9 Micronutrient Status Among Adults in the Asia Pacific and Potential Impact… 157
9.2 Diet, Health and Ageing in the Asia-Pacific Region
The Asia-Pacific region is home to many of the most rapidly ageing populations in
the world. 12% of the Asian population was above 60 years in 2017, and this is
projected to reach 24% by 2050. The average life expectancy in the Association of
Southeast Asian Nations (ASEAN) countries is 71 years, which reaches 75 years in
Thailand, Vietnam and Malaysia, and just under 83 years in Singapore (United
Nations 2017).
Ageing, alongside poor diets and lifestyles is leading to rising levels of NCDs
which impact healthy life expectancy and the time of onset of deterioration in health
as a function of total life expectancy. Therefore, although people are living longer,
they are spending a greater period of later life in poor health (WHO 2020a). This
does not only impact the individual; diseases such as type II diabetes, cardiovascu-
lar disease (CVD) and dementia significantly impact quality of life and place sig-
nificant burdens on healthcare and social systems. The impacts of ageing and poor
health on healthcare and social systems are compounded as birth rates across the
region are below those needed for population replacement (United Nations 2017;
Inui et al. 2021), and hence greater reliance outside of the immediate family to sup-
port individuals is needed.
One measure of the health quality in later life is the measure of disability-adjusted
life years (DALYs); one DALY represents the loss of the equivalent of 1 year of full
health. DALYs for a disease or health condition are the sum of the years of life lost
(YLLs) due to premature mortality and the years lived with a disability (YLDs) due
to prevalent cases of the disease or health condition in a population (WHO 2020b).
Figure 9.1 shows the gap between total life expectancy and healthy life expec-
tancy, and hence the potential impact on the individual and burden on health and
social care systems. The gap can be as great as 10 years in certain populations.
Therefore, any interventions that can improve health through the lifespan can bring
potentially significant benefits.
The leading causes of DALY In the Asia-Pacific region per age group include
CVD (primarily ischemic heart disease and stroke); malignant neoplasms (cancers);
neurological diseases (including depression and anxiety, Alzheimer’s disease and
other dementia particularly in older age groups); respiratory diseases, and falls/
frailty (WHO 2019). Figure 9.2 shows the major health issues across the Asia
Pacific region.
It can be seen from this data that the major non-communicable diseases are pres-
ent, and increasing in prevalence, throughout adulthood into older age.
Data is expressed as Disability Adjusted Life Year per 1000 population. Each
color-coded band is expressed as the percentage of the health condition in total
DALY for the age group. Asia-Pacific data was calculated on weighted arithmetic
means by population between data from the South-East Asia Region and the Western
Pacific Region.
Multiple factors contribute to health throughout the lifespan. In addition to
energy intake and physical activity, micronutrients play an important role in
Fig. 9.1 The gap between total life expectancy (TLE) and healthy life expectancy (HLE) among
selected APAC countries (data for both sexes) (WHO 2020a; Inui et al. 2021)
Fig. 9.2 Key health issues in the APAC region per age group (Inui et al. 2021)
maintaining health throughout life, including key health conditions in later stages
of life. The impact of micronutrient deficiencies on disease occurrence has been
widely investigated for many decades, with well recognised relationships between
specific micronutrient deficiencies and disease states (Marriott et al. 2020). Whereas
much investigation has taken place relating to the effects of deficiencies of micro-
nutrients leading to disease states, the concept of optimal health has risen in recent
years, and we are beginning to understand that achieving optimal levels of micro-
nutrients in the diet can support health throughout life. Optimal nutrition through-
out life can support healthy ageing and can contribute to delaying or avoiding the
onset of NCDs impacting DALYs. As mentioned previously, research into the role
of optimal nutrition supporting health has received less attention until relatively
recently.
9.3 Nutrition Gap Analysis
Understanding the micronutrient status at a population level across Asia-Pacific

countries is important to assess the potential impacts on overall nutrition and
health status, and to identify nutritional gaps especially for the micronutrients that
have been reported to impact on the progression and onset of age-associated health
conditions. However, the reporting format of national nutrition surveys differs
between countries and access to the raw data is often restricted. This makes analy-
sis and comparison between countries complex. Hence, we have recently deter-
mined which representative values are required to estimate the distribution of
nutrition intake without raw data. To validate the estimation method of the nutri-
tional intake distribution by a representative value obtained from national health
surveys, the raw data of National Health and Nutrition Survey 2017 (NHNS 2017)
in Japan was obtained from the Ministry of Health, Labour and Welfare (MHLW)
of Japan, and used for analyses. The raw NHNS data were utilised after approval
by the MHLW through official application procedures under Article 33 of the
Statistics Act.
The methodology and data are summarised in the Supplemental Data section to
this chapter. Briefly, the estimated average intake (EAR) cut-point method was used
to estimate the prevalence of inadequate micronutrient intakes (Beaton 1994; WHO
2006). The probability density at the point of EAR of DRIs for Japanese was calcu-
lated by log-normal distribution (Johnson et al. 1994) using the ‘μ and σ2’ calculated
by three parameter combinations as the estimated prevalence of %below EAR. The
three parameter combinations were:
1. the value of mean and standard deviation
2. the value of mean and median
3. the value of median and interquartile range (IQR)
The observed prevalence of %below EAR was also calculated from the raw
NHNS data. To validate the estimation methods of nutritional intake distribu-
tion, a comparison of prevalence of %below EAR between estimated and
observed was made by one-sample t-test. The observed value, which is derived
from the raw NHNS data is considered the most accurate value. Estimated values
among three parameter combinations showed a range of values with as much as
10% differences from the raw NHNS data for %below EAR prevalence
(Supplemental Table 9.1). The results suggested that the prevalence of %below
EAR was most proximate to the raw NHNS data when it was derived from the
combination of mean and SD. Validation of the estimated values derived from
mean and SD were tested for the other micronutrients included in the analysis.
The results showed the estimated log-normal distributions calculated by the
combination of mean and SD were not significantly different from the value
derived from the raw NHNS data across gender and age groups (Supplemental
Table 9.2). Finally, the estimated prevalence of inadequate micronutrient intake
for each nutrient was validated using the percentage of subjects with inadequate
nutrient intake, calculated either by the cut-point method using the raw NHNS
data (reference method) or from the sex- and age-specific mean and SD from
NHNS 2017 for all the micronutrients analysed except of niacin and vitamin
D. Niacin was excluded because the raw NHNS data did not provide the propor-
tion of niacin equivalent derived from tryptophan (Supplemental Table 9.3). The
results described that the ranking of nutrients according to the proportion of
subjects with inadequate intakes was in general agreement with the observed
data in both gender and age. Therefore, estimates can be made using only mean
and SD and would have practical value in assessing the prevalence of inadequate
micronutrient intake.
Table 9.1 Intakes for men and women aged 50 years and over in each country were obtained from
national survey data. Data with mean and SD values were preferentially referred to, and incases
where SD values were not given, the mean and median values were used to calculate the proportion
of those whose intake was below the EAR
9.4 Assessment of Nutritional Gap in Asia-Pacific Countries
Using the methodology described above, national data from countries across the
Asia Pacific region were analysed for a range of micronutrients (see Table 9.1 for
full list of micronutrients and countries assessed). As can be seen, data are missing
in certain countries for some micronutrients. Data are presented as percentage of the
population who are below the Estimated Average Requirement (EAR) for that
micronutrient against EAR set in national RDI. Where national RDI did not state
EAR, we used EAR by US IOM.
The insufficiency of calcium was highly prevalent in all countries among senior
adults. There was also a high prevalence of insufficiency of vitamins A, D, E, C,
B-6, B-12, folate, and for zinc in many countries (Table 9.1). Generally, higher
socio-economic countries in the region tend to have lower overall levels of micro-
nutrient insufficiency (Australia, New Zealand South Korea, Japan, Malaysia and
Thailand), however all countries have more than 50% of the population below the
EAR for at least 1 micronutrient. These data correspond with previous studies,
which have been summarised recently (Inui et al. 2021).
9.5 The Role of Nutrition in Health Ageing in Asia
Examples of the importance of achieving optimal micronutrient status during earlier

life stages to improving health in later life include:
9.5.1 Osteoporosis
Osteoporosis is a bone disease that develops when bone mineral density and bone
mass decreases, or when the quality or structure of bone changes. This can lead to a
decrease in bone strength that can increase the risk of fractures. Osteoporosis tends
to be asymptomatic until the point that a fracture occurs. Osteoporosis is the major
cause of fractures in postmenopausal women and in older men and tends to be a
greater issue for women than men.
Bone mass increases during early life and reaches a peak in women in early
adulthood, levels tend to remain stable until menopause and then sees a rapid decline
in the first years post menopause which slows but continues to decline through the
remainder of life. Several dietary factors, alongside weight bearing exercise are
important in achieving peak bone mass; these include protein, vitamin D and cal-
cium intake (Lewis et al. 2021). Calcium and vitamin D intakes during teenage and
early adulthood improve bone density and peak bone mass; this can significantly
improve later life development of osteoporosis and slow the development of the
multiple causes of frailty in the elderly. It is important to note that weight bearing
exercise and protein intakes are important to maintain bone mass.
Coronary heart disease and stroke are the most common causes of mortality and
morbidity globally for people over the age of 60 (GBD 2016). Cessation of tobacco
use, reduction of salt in the diet, eating more fruit and vegetables, regular physical
activity and avoiding harmful use of alcohol have been shown to reduce the risk of
cardiovascular disease (WHO 2021a). Additionally, replacing saturated fat with
mono- and polyunsaturated fatty acids, such as omega-3 long chain polyunsatu-
rated fatty acids (EPA and DHA) have been recognised by authoritative bodies
such as The European Food Safety Authority (EFSA) in maintaining healthy car-
diac function (EFSA 2022).
Two major studies have investigated the effects of vitamin D and omega-3 long
chain polyunsaturated fatty acids (LC-PUFAs). The VITAL study showed LC-PUFA
did reduce risk of these events by 19% in people with low fish intake although but
not in the overall study population. LC-PUFA also reduced risk of heart attack by
28%, when considered separately from other cardiovascular events (Manson et al.
2019). Vitamin D supplementation did not reduce risk of major cardiovascular
events, however the study found that participants already had vitamin D levels in the
optimal range at the beginning of the study. The REDUCE-IT trial found a 25%
reduction in risk in the primary endpoints of cardiovascular death, myocardial
infarction and stroke, as well as improvement in secondary endpoints including
blood pressure and plasma cholesterol levels (Bhatt et al. 2019). In a recent meta-
analysis, although no effect was seen for the commonly used multivitamins, vitamin
D, calcium, and vitamin C, folic acid and B-complex vitamins had a significant
effect for stroke reduction (Jenkins et al. 2021).
9.5.3 Dementia
Cognitive decline is a major issue in ageing. From the age of around 60 the brain
begins to shrink at a rate of approximately 0.5% per year, and for people with mild
cognitive impairment, this accelerates to approximately 3% a year (Jernerén et al.
2015). Atrophy in the cerebral cortex and the hippocampus have been associated
with elevated homocysteine levels. A recent consensus statement concluded that
elevated plasma total homocysteine is a modifiable risk factor for development of
cognitive decline, dementia and Alzheimer’s disease in older people (Smith et al.
2018). B-vitamins have been shown to reduce levels of serum total homocysteine
(tHcy), as vitamin B-6, folate and vitamin B-12 are co-factors in the conversion of
homocysteine to methionine. Atrophy rates were reduced in subjects taking dietary
supplements containing vitamin B-6, folic acid, and vitamin B-12 and who had
sufficient omega-3 LC-PUFA status (Jernerén et al. 2015).
9.5.4 Immunity
Immune functions generally decline with age, increasing susceptibility to infectious

diseases and leading to poorer responses to vaccination (Castelo-Branco and Soveral
2013). Many vitamins and trace elements have been shown to play an important role
in supporting cells and tissues of the immune system (Calder et al. 2020). Of these,
the best available evidence has been shown for vitamins C and D, and the trace ele-
ment zinc (Gombart et al. 2020; Abioye et al. 2021). A meta-analysis of data for
almost 11,000 people reported that overall taking vitamin D supplement reduced the
risk of having at least one upper respiratory tract infection (Martineau et al. 2017;
Jolliffe et al. 2021).
9.5.5 Vision
The prevalence of visual impairment increases markedly in later life. The main fac-
tors associated with visual impairment in the elderly are amyotrophy, cataracts and
acute macular degeneration (AMD) (WHO 2021b). Oxidative stress is one of the
main causes of lens opacification and therefore antioxidant nutrients have been
investigated for effects on reducing the risk of development of cataracts. One meta-
analysis concluded that supplementation of vitamin A, vitamin E, vitamin C, beta-
carotene, lutein and zeaxanthin was associated with a reduced risk of age-related
cataracts (Jiang et al. 2019). Two further large studies in humans (AREDS 1 and 2)
demonstrated that ingestion of dietary supplements containing vitamin C, vitamin
E, zinc, iron and the carotenoids lutein and zeaxanthin reduced the risk of the pro-
gression of advanced AMD, with individuals taking lutein and zeaxanthin, alone or
in combination with DHA and EPA, having a 10% reduction in the risk of develop-
ing advanced AMD (National Eye Institute 2022). The roles of omega-3 LC-PUFAs
(DHA), vitamin A and zinc in maintaining normal vision are acknowledged by
EFSA (EFSA 2022).
9.5.6 Cancer
Several studies have shown associations between markers of micronutrient status

for various micronutrients and cancer prevalence. Many of these findings may rep-
resent micronutrients as markers of overall dietary quality (fruit, vegetable, or fibre
consumption for example), and causality between specific micronutrient interven-
tions and outcome cannot be determined from these studies (Aune et al. 2018; Dong
et al. 2017; Chowdhury et al. 2014; Maalmi et al. 2018; Schwingshackl et al. 2017;
Bjelakovic et al. 2012). Furthermore, care is needed as several associations between
specific micronutrient supplements and increased cancer risk have been identified.
To better understand the complex role of micronutrients per se and specific cancer
disease outcomes, more randomised control intervention trials are needed.
It is not within the scope of this chapter to review all the relationships and
strength of evidence supporting the role of micronutrients to the main health issues
related to ageing. These have been extensively reviewed recently (Inui et al. 2021).
The Global Burden of Disease study showed that in 2017, 11 million deaths and
255 million DALYs were attributable to dietary risk factors (GBD 2017). The major
NCDs impacting DALYs can be significantly impacted by diet and lifestyle. There
is also increasing evidence to show that micronutrient intakes throughout life can
impact the onset and development of NCDs in later life. This report also identified
micronutrient interventions as the best return on investment. Additionally, three of
the top five challenges to improve global welfare outlined in the 2008 Copenhagen
Consensus are related to improving micronutrient status (Copenhagen Consensus
Centre 2008).
9.6 Challenges to Achieving Optimal Micronutrient Intakes
As described earlier, there is increasing evidence that achieving an optimal micro-

nutrient intake throughout life stages is important to support health into ageing.
Furthermore, multiple micronutrients play a role in overall health, and it is likely
that complex interactions between micronutrients and other dietary factors exist.
Existing randomised controlled studies suggest the intervention may be more
impactful when applied to those with insufficient baseline intake. Currently avail-
able national data concerning intake of certain micronutrients is incomplete which
makes it challenging. Multiple elements exist in impacting the micronutrient intake.
Two drivers that increase the risk of micronutrient insufficiency among elderly are
drug-nutrient interactions and decreased food intake.
9.6.1 Drug Interactions
Drug interactions can affect the absorption and/or metabolism of vitamins, contrib-
uting to malnutrition. Additionally certain medical treatments, including cancer
chemotherapy can suppress appetite. Acid suppressing drugs and proton pump
inhibitors, anti-hypertensives and diuretics, and medicines to treat diabetes can all
affect micronutrient status (Onoue et al. 2018; Mohn et al. 2018; König et al. 2017).
These treatments can make achieving adequate micronutrient intakes more chal-
lenging. The term polypharmacy has been defined as the use of 5 or more oral pre-
scription medications per month (Onoue et al. 2018). Polypharmacy and
hyperpolypharmacy (more than ten medicines) increase the risk of unwanted drug
interactions, and a wide range of prescription medications can increase the risk of
nutritional inadequacy (Mohn et al. 2018). The prevalence of polypharmacy varies

amongst populations in Asia, and more research is required to define any specific
problems and relevant nutritional interventions.
9.6.2 Decreased Food Intake
Ageing itself presents problems in meeting adequate nutritional status. Energy

metabolism and lean body mass decrease as people age, leading to a decreasing
need for energy, reduced appetite, and lower intake. Despite this decrease energy
need, micronutrient requirements remain and need to be met. This has led to the
concept of hidden hunger in the elderly and can be further compounded for
micronutrients in which metabolism and absorption are impaired with age, such
as vitamins B-12 and D (Eggersdorfer et al. 2018). Oral disease and decrease in
oral function can lead to difficulties in swallowing (dysphagia) which can in
turn affect food intake leading to undernutrition; the prevalence of periodontal
disease in a Center for Disease Control Study (CDC) from 2012 reported that
47.2% of adults over the age of 30 in US had some form of periodontal disease,
and this increases to 70.1% for people over the age of 65 (Eke et al. 2012).
The difficulty in achieving adequate micronutrient intakes can be further com-
pounded under certain dietary patterns. Certain micronutrients are found in higher
density in foods of animal origin. Vitamin B12 deficiency has been found to be more
prevalent amongst groups for whom a high intake of animal products is not possible
for economic, cultural or religious reasons (Allen 2009). Anti-nutritional factors are
compounds which reduce the nutrient utilisation and/or nutrient intake from plants
or plant products used as human foods. For example, phytates and oxalates can
inhibit the absorption of calcium and iron, and phenol compounds can inhibit the
absorption of certain minerals (especially zinc). It is not within the scope of this
chapter to review this area in detail; however, these have been recently reviewed
elsewhere (Thakur et al. 2019).
Nutrient density is defined as the ratio of nutrient to energy, and therefore in situ-
ations where energy intakes or dietary choices are limited achieving the recom-
mended micronutrient intakes becomes more challenging and the nutrient density of
the foods consumed becomes more critical.
9.7 Potential Approaches to Optimise Nutrient Intakes
Because the barriers to achieving optimal micronutrient intakes are multifactorial,

cross-disciplinary collaboration and approaches are needed to promote food intake
with high micronutrient density. These can include consumer education, setting
appropriate RDA, food labelling, and personalised nutritional advice. However as
highlighted earlier in this chapter achieving optimal micronutrient levels is
challenging, and fortification and supplementation should be considered as safe and

effective methods to deliver nutrients and meet recommendations for dietary intakes.
Some countries are beginning to adapt dietary guidelines for the elderly focusing
on, for example, nutrient dense foods, adapting diets to account for lower energy
intakes (e.g. inclusion of snacks), particularly focusing on protein and calcium (See
Inui et al. 2021 for further references).
9.7.1 Supplementation
Supplementation can be a useful adjunct to food-based approaches to improve

micronutrient status. However, long-term compliance with supplementation pro-
grams has been suggested to be challenging to maintain, although this has been
more successful in certain situations where the need for additional micronutrient
intake is for a relatively short period of time (such as supplementation of pregnant
and lactating women, or children in school) (Allen 2008). Folic acid supplementa-
tion during pregnancy and preconception has long been recommended by authorita-
tive bodies such as US CDC and UK NHS (CDC 2022; NHS 2022). In 2021,
multiple micronutrient supplements (MMS), containing 10 vitamins and 5 minerals,
was added to the World Health Organization (WHO) model Essential Medicines
List (EML) as an antenatal supplement for pregnant women (WHO 2021c).
9.7.2 Fortification Programmes
Several countries have implemented fortification of certain food categories, these have
been demonstrated to be safe and effective. Some of these programmes are voluntary,
whilst others have been implemented as mandatory fortification of certain foods.
One of the widest fortification programmes has been the fortification of salt with
iodine. Iodine deficiency is a major cause of preventable mental retardation, and
UNICEF estimate that worldwide, 89% of people consume iodised salt
(UNICEF 2021).
Systematic vitamin D food fortification is an effective approach to improve vita-
min D status in the general population and this has already been introduced by
countries such as the US, Canada, India and Finland. Recent advances in our knowl-
edge on the safety of vitamin D treatment, the dose-response relationship of vitamin
D intake and 25(OH)D levels, as well as data on the effectiveness of vitamin D
fortification in countries such as Finland provide a solid basis to introduce and mod-
ify vitamin D food fortification to improve public health with this likewise cost-
effective approach.
Fortification of milk and dairy products with vitamin D in Finland has resulted in
an increase to 91% of the population reaching the recommended levels of serum
vitamin D biomarker concentrations (Jääskeläinen et al. 2017).
Many countries have regulations permitting voluntary fortification of calcium,

and UK has mandatory fortification of flour (235–390 mg calcium carbonate per
100 g flour) (Cormick et al. 2020). An analysis in the UK assessed that if calcium
fortification prevented 2% of fractures annually, stopping mandatory calcium forti-
fication would increase social care costs by £3.06 million per year and by £22.39
million per year in the National Health Service (UK Government 1998). Sandman,
in 2015, estimated that the annual costs for 200 mg calcium per day was EUR 0.22
per person in 2014 and that the implementation of a vitamin D plus calcium fortifi-
cation program in Germany would cost EUR 41 million per year while saving EUR
315 million per year because of reduced fracture costs (Sandmann et al. 2015).
Mandatory folic acid fortification programs in the USA, Canada, Costa Rica, Chile,
and South Africa are associated with significant increases in blood folate concentra-
tions and declines of 25–50% in the prevalence of neural tube defect (NTD) affected
pregnancies (Murphy and Westmark 2020). Reported NTDs in the USA decreased
from 10.8/10,000 births in 1995–1996 to 6.9/10,000 births in 2006 (CDC 2010). A
systematic review (179 studies) and meta-analysis (123 studies) covering the preva-
lence of spina bifida in response to folic acid fortification status, geographic region
and study population indicate a lower prevalence of spina bifida in geographic regions
with mandatory folic acid fortification (33.86 per 100,000 live births) versus voluntary
fortification (48.35 per 100,000 live births) (Atta et al. 2016; March of Dimes 2006).
Fortified foods are also useful for sustainability. Food production has a significant
impact on greenhouse gas emissions (Poore and Nemecek 2018), and meeting sus-
tainability challenges will therefore also require shifts in dietary habits. Some gov-
ernments have already included sustainability into national dietary guidelines (Lang
2017). Recently Bruins and Létinois (2021) modelled the dietary shifts needed to
achieve vitamin D intakes whilst aiming to achieve limits to the carbon footprint
expressed as kg CO2 equivalents. This study showed that achieving adequate vitamin
D intakes through diet alone was not possible without greatly increasing CO2 equiva-
lents or energy intakes above recommended levels. Inclusion of vitamin D fortified
bread, milk and oil into the diet, alongside dietary shifts towards fish and plant based
nutrient dense foods, did allow vitamin D intakes to be achieved within a 2000 kcal
diet and without a significantly increased carbon emission. Whilst this study only
assessed one micronutrient, and vitamin D status varies due to exposure to sunlight,
it does highlight the complex interactions between diet, nutrient status and sustain-
ability. Fortification itself had only minimal impacts on carbon footprint.
9.8 Discussion
As populations continue to age, and birth rates remain low, the focus on health
through ageing is critical to ensure that the years of life lost to disability can be mini-
mised. We have highlighted in this chapter some of the key nutrient interventions that
can be effective to support health throughout the lifespan and particularly into older
age. Key micronutrients that should be considered as insufficient are vitamin A
(under supervision), vitamin D, vitamin E, vitamin C, B vitamins, zinc, and Omega-3

LC PUFAs. There was also a high prevalence of insufficiency of vitamins A, D, E, C,
B-6, B-12, folate, and for zinc in many countries. Multiple socio-economic factors
and constraints on food systems impact on the ability of populations to meet ade-
quate and optimal nutrient intakes. Having a clear understanding of these require-
ments are necessary to target appropriate interventions to address these nutritional gaps.
To analyse nutritional status at a population level effective monitoring is required.
We have shown the importance of consistent reporting and analysis of population
nutrition status to allow meaningful comparison and to support effective targeting of
nutrition interventions. Currently national data are collected using a variety of
methodologies and summary data are produced using different statistical methods
making this comparison difficult. The data and analysis presented as supplemental
data shows that, in the absence of raw data, the best proximate method for compari-
son is to use mean and SD.
Reviewing the available data from national nutrition surveys across APAC coun-
tries identifies a wide range of sub-optimal micronutrient levels in adulthood, and
particularly in the over-50 age group. Several of the most common age related non-
communicable diseases prevalent across the region can be positively impacted by
nutritional status. As shown in Fig. 9.2, the progression of non-communicable diseases
tends to develop over years or decades, with the majority of diseases present through-
out adulthood. Many NCDs begin in middle age before any clinical signs of the dis-
ease are recognisable, and these early phases of the progression of the diseases are
often modifiable, and potentially reversable through dietary and lifestyle interventions.
Therefore, nutritional sufficiency along with other lifestyle factors should be consid-
ered throughout the life course to have the greatest impact in reducing health impacts
in later life. This can be most clearly seen for osteoporosis, a leading cause of frailty in
later life. Osteoporosis is a progressive decline in bone mass and structure throughout
adulthood, and peak bone mass which occurs around the age of 30 is an important
protective factor. Therefore, optimal nutritional status alongside physical activity is
critical during adolescence and early adulthood to support peak bone mass development.
Therefore, the optimal nutritional interventions to support health in later life may
require long-term intake of micronutrients in addition to an overall healthy diet and
lifestyle. It is important to meet the RDI through various means for these micronu-
trients to help impact on NCDs. However, beyond our knowledge of the impacts of
nutritional deficits on disease status, our current understanding of the optimal nutri-
tional status and the effectiveness of specific interventions to reduce the risk of
disease in later life is still relatively low and requires further research to be unequiv-
ocally elucidated. Many of the studies highlighted in this chapter rely on associative
data linking micronutrient status to health outcomes. In addition, it can be seen in
several studies that micronutrients were only effective in a subset of the population
group where baseline data indicated that there was a micronutrient deficiency.
Hence, studies measuring baseline status and targeting groups with low or marginal
nutritional status would be helpful to better understand the impact of specific inter-
ventions on health outcomes. This may be especially relevant for populations in the
Asia-Pacific as we have seen a broad range of micronutrient insufficiencies across
all countries in the region. Finally, designing randomised controlled intervention

studies would be important to further understand the potential role of specific micro-
nutrients to support long-term health.
Multiple factors need to be considered in terms of estimating micronutrient suffi-
ciency. However, in this chapter we have highlighted the importance of considering
absolute energy intakes and nutrient densities, and also the impacts of meeting sus-
tainability goals whilst achieving micronutrient sufficiency. Absolute intakes of
micronutrients over a period of time from dietary sources will be determined by
overall energy intake and nutrient density of foods consumed. Recently researchers
of the United Nations Food Systems Summit 2021 Scientific Group prepared a
Summit Brief on the role of Science, Technology, and Innovation for Transforming
Food Systems in Asia. This report highlights outputs of the DELTA model (SNi
2022) that has recently been developed and calculates nutrient availability to con-
sumers from differing global food production scenarios. The model predicts that the
current food system would provide sufficient energy and protein for the forecast 2030
global population of 8.6 billion, however, it would fail in supplying several micronu-
trients (calcium, iron, potassium, zinc, and vitamins A, E, B-2 and B-12) (UN
FSS 2021).
9.9 Conclusions
Within this chapter we have reviewed data that demonstrates that multiple micronu-
trients play important roles in maintaining health throughout adulthood and can help
to delay the onset of age-related non-communicable diseases prevalent in ageing. To
better target nutrition-based interventions, high quality and consistent information is
required from national dietary surveys to assess the most effective nutritional strate-
gies. Based on the existing intake data, there was a high prevalence of insufficiency
of vitamins A, D, E, C, B-6, B-12, folate, and for zinc in many countries. These
micronutrients are known to play key roles in maintaining health in ageing, espe-
cially for the health conditions that pose high burden among the ageing population
in the Asia-Pacific. Currently, the data is collected and reported in heterogeneous
ways; our data suggest that, in the absence of access to raw data, values derived from
mean and SD provide the most accurate approximation to the original data.
Access to data in a more consistent manner would allow a better evidence base
to further elucidate optimal as opposed to adequate nutrition requirements. Meeting
the RDI should be a first target to support health through adulthood into ageing
using a variety of methods – diet shifts through national programs, setting RDA,
consumer education, food labelling, fortification and supplementation.
Additionally, better information concerning the dietary status of populations and
specific demographic groups would provide a base to develop intervention studies
to help establish causal effects of nutrients in preventing diseases of ageing. Better
data is also needed to define the optimal intake levels of micronutrients to support
health into ageing.
These strategies would help to build further on the already recognised cost-
effectiveness of nutrition strategies to address life-long health, and as a result reduce
healthcare costs and medical treatments.
Supplemental Data
The Method for Estimating sDistribution of Nutrient Intake
The mean, median and standard deviation of each nutrient intake reported in the
National Health Nutrition Survey 2017 in Japan (NHNS 2017) were used to esti-
mate the distribution of nutrient intake from the following equation.
• Parameter combination 1. the value of mean and standard deviation
(
m = ln X ( ) X / (1 + s 2 / X ( ) X 2 )
(1/ 2 )
)
s 2 = ln (1 + s 2 / X ( )X2)
• Parameter combination 2. the value of mean and median
m = ln ( median )
s 2 = 2* ln ( X ( ) X / median )
• Parameter combination 3. the value of median and interquartile range (IQR)
z = (X - m) /s
z = ( X i - X m ) / NIQR
(NIQR = IQR/1.3489 = IQR*0.7413)
alidation of the Estimated Distribution in Each Nutrient

V
from the National Health Nutrition Survey 2017 in Japan
(Supplemental Tables 9.1 and 9.2)
To validate the estimation methods of nutritional intake distribution, a comparison

of prevalence of %below EAR between estimated and observed was made by one-
sample t-test. The estimated and observed prevalence of inadequate micronutrient
intake (vitamin A, D, E, C) were shown in Supplemental Table 9.1. The estimated
values calculated by parameter combination 3 (median and interquartile range,
hereafter IQR) tended to be high compared with those observed. One-sample t-test
showed no significant differences in any vitamins except vitamin D which had a
high skewness between estimated and observed prevalence used parameter combi-
nation 1 (mean and standard deviation, hereafter SD). These results suggested that
the prevalence of %below EAR was most proximate to the raw NHNS data when it
was derived from the combination of mean and SD.
For a more detailed examination of the estimated distributions using the mean
and SD, we compared each percentile value of the raw data with the percentile
values obtained from the estimated equation. The results showed that there were no
significant differences between the measured and estimated values for all nutrients
for any age and gender (Supplemental Table 9.2). The intake of niacin equivalent
is used for the assessment of inadequacy intake of niacin. Since the NHNS 2017
does not list niacin equivalents, it was excluded from the analysis due to a lack of
comparability. As shown in Supplemental Table 9.2, there was no significant dif-
ference between the estimated and observed percentile values for any gender and
age group in the Student’s t-test, suggesting that there is a certain validity in the
estimation of the intake distribution.
Supplemental Table 9.1 The prevalence of %below EAR estimated by three patterns
Age
categories Parameters Vitamin A Vitamin D Vitamin E Vitamin C
18–30 years AV & SD Male 76.4 86.9 93.1 65.8
AV & Median 74.9 86.8 94.1 66.6
Median & 82.4 96.1 97.2 66.1
IQR
The observed 78.4 83.9 92.1 62.3
prevalence
(%)
AV & SD Female 70.0 89.7 95.0 53.3
AV & Median 69.3 89.2 95.6 54.3
Median & 75.9 99.2 99.8 53.5
IQR
The observed 72.8 87.8 95.3 52.8
prevalence
(%)
31–50 years AV & SD Male 78.2 83.6 93.2 66.5
AV & Median 76.6 84.2 94.8 66.7
Median & 86.4 91.6 97.5 67.7
IQR
The observed 80.6 79.3 93.1 65.7
prevalence
(%)
AV & SD Female 72.5 86.9 93.6 51.7
AV & Median 68.5 86.8 95.1 52.7
Median & 74.5 96.6 98.7 52.5
IQR
The observed 71.9 83.8 94.9 53.1
prevalence
(%)
(continued)
Supplemental Table 9.1 (continued)

Age
categories Parameters Vitamin A Vitamin D Vitamin E Vitamin C
51–70 years AV & SD Male 72.3 73.6 90.2 46.0
AV & Median 71.3 75.6 92.2 40.7
Median & 76.6 76.8 94.0 43.2
IQR
The observed 72.9 70.0 90.3 43.2
prevalence
(%)
AV & SD Female 61.1 78.3 91.3 25.1
AV & Median 59.4 79.1 92.9 20.7
Median & 60.2 81.9 97.5 30.1
IQR
The observed 59.0 73.6 92.8 28.2
prevalence
(%)
71 years AV & SD Male 72.9 70.6 91.1 28.8
AV & Median 67.7 71.5 93.9 25.6
Median & 72.1 70.5 96.3 34.1
IQR
The observed 71.1 65.9 91.9 31.8
prevalence
(%)
AV & SD Female 64.9 73.6 92.9 17.8
AV & Median 57.0 73.9 94.2 14.3
Median & 57.4 72.6 97.9 26.2
IQR
The observed 58.1 67.7 93.0 20.8
prevalence
(%)
The ratio of predicted %below for
observed (95%CI)
AV & SD −0.032 to 0.035–0.071 −0.011 to −0.095 to
0.053 (p < 0.001) 0.004 0.037
(p = 0.576) (p = 0.285) (p = 0.333)
AV & Median −0.051 to 0.037–0.083 0.003–0.195 −0.213 to
−0.017 (p < 0.001) (p = 0.015) 0.031
(p = 0.002) (p = 0.122)
Median & IQR 0.012–0.056 0.088–0.146 0.043–0.054 −0.010 to
(p = 0.008) (p < 0.001) (p < 0.001) 0.134
(p = 0.082)
The ratio of predicted %below for observed one was calculated as below; The predicted prevalence
of %below EAR/the observed prevalence of %below EAR
AV & SD; %below EAR estimated from AV & SD, AV & Median; %below EAR estimated from
AV & Median, Median & IQR; %below EAR estimated from Median & IQR
One-sample t-test (The observed prevalence of %below EAR was used for reference (=1))
Analysis was conducted for all age groups and all genders combined
Supplemental Table 9.2 Validation of the estimated distribution in each nutrient from the
National Health Nutrition Survey 2017 in Japan
Male n = 689
19–49 EAR/ P P P p
years AI 2.5 5.0 P 10 P 25 P 50 P75 P 90 P 95 97.5 value
Calcium 650/600 Actual 134 160 191 275 390 563 747 881 1079 0.969
(mg) Estimated 153 178 212 284 393 543 727 866 1007
Irona (mg) 6.5 Actual 3.2 3.6 4.3 5.6 7.2 8.9 11.1 12.4 14.1 0.933
Estimated 3.4 3.8 4.4 5.5 7.0 9.0 11.3 12.9 14.5
Zinc (mg) 9 Actual 4.3 4.9 5.7 7.1 8.8 10.8 13.2 15.1 16.3 0.869
Estimated 4.3 4.8 5.5 6.9 8.8 11.3 14.1 16.1 18.0
Vit. A 600/650 Actual 63 99 136 218 362 565 857 1221 1496 0.819
(μgRAE) Estimated 58 76 104 175 315 576 1004 1407 1893
Vit. Db (μg) 8.5 Actual 0.3 0.4 0.7 1.4 2.9 7.7 15.5 22.7 26.7 0.834
Estimated 0.6 0.8 1.1 1.9 3.7 7.0 12.6 17.9 24.2
Vit. Eb (mg) 6.0 Actual 2.4 2.7 3.3 4.5 6.2 8.5 11.3 12.6 14.3 0.985
Estimated 2.5 2.8 3.4 4.4 6.1 8.3 10.9 12.9 14.9
Vit. B1 (mg) 1.2 Actual 0.39 0.44 0.47 0.63 0.85 1.17 1.55 1.85 2.09 0.839
Estimated 0.38 0.44 0.51 0.68 0.92 1.25 1.65 1.95 2.25
Vit. B2 (mg) 1.3 Actual 0.42 0.50 0.60 0.79 1.03 1.36 1.79 2.12 2.44 0.913
Estimated 0.44 0.51 0.59 0.76 1.01 1.34 1.73 2.02 2.31
Vit. B6 (mg) 1.1 Actual 0.5 0.5 0.6 0.8 1.1 1.4 1.7 1.9 2.2 0.812
Estimated 0.5 0.6 0.7 0.8 1.1 1.4 1.8 2.1 2.4
Vit. B12 (μg) 2.0 Actual 0.6 0.8 1.3 1.9 3.3 6.7 12.1 17.9 23.6 0.892
Estimated 0.7 1.0 1.3 2.2 3.9 6.9 11.5 15.7 20.4
Folate 200 Actual 84 103 129 168 236 309 408 463 575 0.931
(μg) Estimated 89 103 123 165 228 316 424 505 589
Vit. C 85 Actual 9 14 22 35 57 92 139 173 201 0.921
(mg) Estimated 16 19 25 37 58 91 137 175 216
Female n = 705
19–49 EAR/ P P P p
years AI 2.5 5.0 P 10 P 25 P 50 P 75 P 90 P 95 97.5 value
Calcium 550 Actual 138 168 202 286 403 558 747 848 973 0.914
(mg) Estimated 146 170 203 272 376 520 697 830 966
Irona (mg) 8.5/9.0 Actual 3.2 3.5 4.0 5.0 6.1 8.1 9.8 11.1 12.5 0.916
Estimated 2.7 3.1 3.6 4.6 6.1 8.1 10.5 12.3 14.0
Zinc (mg) 7 Actual 3.5 4.1 4.6 5.6 7.0 8.6 10.2 11.2 13.0 0.800
Estimated 3.6 4.0 4.5 5.6 7.1 9.0 11.1 12.7 14.1
Vit. A 450/500 Actual 81 110 158 235 365 540 790 1047 1511 0.371
(μgRAE) Estimated 60 74 94 141 223 355 555 739 966
Vit. Db (μg) 8.5 Actual 0.3 0.5 0.9 1.5 2.6 6.8 14.2 20.6 24.8 0.787
Estimated 0.5 0.7 1.0 1.7 3.3 6.3 11.2 15.9 21.6
Vit. Eb (mg) 5.0/5.5 Actual 2.0 2.5 3.0 4.1 5.7 7.7 10.3 11.9 14.2 0.941
Estimated 2.0 2.4 2.8 3.8 5.3 7.5 10.1 12.0 14.0
Vit. B1 (mg) 0.9 Actual 0.32 0.37 0.43 0.54 0.70 0.96 1.25 1.46 1.63 0.825
Estimated 0.32 0.37 0.43 0.56 0.76 1.02 1.33 1.57 1.80
(continued)

Female n = 705
19–49 EAR/ P P P p
years AI 2.5 5.0 P 10 P 25 P 50 P 75 P 90 P 95 97.5 value
Vit. B2 (mg) 1.0 Actual 0.40 0.46 0.59 0.74 0.98 1.33 1.67 2.03 2.47 0.742
Estimated 0.43 0.49 0.57 0.72 0.93 1.22 1.55 1.79 2.02
Vit. B6 (mg) 1.0 Actual 0.4 0.5 0.5 0.7 0.9 1.2 1.5 1.7 1.9 0.946
Estimated 0.4 0.5 0.5 0.7 0.9 1.2 1.5 1.8 2.0
Vit. B12 (μg) 2.0 Actual 0.5 0.8 1.0 1.6 2.8 5.5 9.4 13.4 18.7 0.922
Estimated 0.6 0.7 1.0 1.7 3.0 5.5 9.3 12.7 16.7
Folate (μg) 200 Actual 92 110 128 169 222 290 384 440 508 0.950
Estimated 86 100 118 155 211 287 379 448 517
Vit. C 85 Actual 12 17 22 36 57 97 142 179 206 0.982
(mg) Estimated 16 20 25 37 59 92 137 174 215
Male n = 1370
≥50 P P P p
years EAR/AI 2.5 5.0 P 10 P 25 P 50 P75 P 90 P 95 97.5 value
Calcium 600 Actual 182 211 259 356 513 695 891 1048 1222 0.970
(mg) Estimated 202 233 274 361 489 664 874 1030 1188
Irona (mg) 6.5/6.0 Actual 3.9 4.4 5.1 6.5 8.3 10.3 12.5 14.1 15.9 0.946
Estimated 3.9 4.4 5.0 6.3 8.1 10.3 12.9 14.8 16.6
Zinc 9 Actual 4.5 5.0 5.6 7.0 8.6 10.4 12.3 13.9 15.6 0.863
(mg) Estimated 4.4 4.9 5.6 6.8 8.6 10.8 13.3 15.0 16.7
Vit. A 600/650 Actual 89 119 161 269 426 659 1032 1251 1574 0.643
(μgRAE) Estimated 44 60 87 163 329 668 1270 1870 2618
Vit. Db (μg) 8.5 Actual 0.2 0.7 1.3 2.4 5.4 12.2 20.3 25.5 31.4 0.874
Estimated 1.0 1.3 1.8 3.0 5.4 9.8 16.6 22.8 30.0
Vit. Eb (mg) 7.0/6.5 Actual 2.2 2.8 3.3 4.7 6.7 9.0 11.5 13.6 16.0 0.848
Estimated 2.6 3.0 3.6 4.8 6.6 9.2 12.4 14.8 17.2
Vit. B1 (mg) 1.1/1.0 Actual 0.37 0.44 0.51 0.66 0.87 1.16 1.52 1.75 1.96 0.919
Estimated 0.38 0.44 0.51 0.67 0.89 1.19 1.55 1.81 2.07
Vit. B2 (mg) 1.2/1.1 Actual 0.54 0.62 0.73 0.94 1.21 1.55 1.93 2.21 2.53 0.962
Estimated 0.56 0.63 0.73 0.92 1.20 1.56 1.97 2.27 2.57
Vit. B6 (mg) 1.1 Actual 0.5 0.6 0.7 1.0 1.3 1.6 1.9 2.2 2.5 0.869
Estimated 0.6 0.6 0.7 0.9 1.2 1.6 2.1 2.4 2.7
Vit. B12 (μg) 2.0 Actual 0.8 1.1 1.5 2.5 4.9 8.8 15.7 19.4 23.6 0.868
Estimated 1.0 1.3 1.8 3.0 5.2 9.2 15.3 20.8 27.1
Folate 200 Actual 119 142 171 232 309 400 507 560 627 0.916
(μg) Estimated 128 146 171 222 296 395 513 600 687
Vit. C 85/80 Actual 14 21 31 56 94 149 221 265 324 0.978
(mg) Estimated 31 37 46 65 97 144 206 255 307
Female n = 1664
≥50 P P P p
Calcium 550/500 Actual 184 217 267 359 500 697 883 1024 1144 0.955
(mg) Estimated 196 226 266 351 477 648 854 1007 1163
Female n = 1664
≥50 P P P p
Irona (mg) 9.0/5.5/5.0 Actual 3.5 4.2 4.8 5.9 7.5 9.5 11.6 12.9 14.7 0.970
Estimated 3.7 4.2 4.7 5.8 7.3 9.3 11.4 13.0 14.5
Zinc 7.0/6.0 Actual 3.7 4.2 4.8 5.9 7.2 8.8 10.1 11.6 12.8 0.872
(mg) Estimated 3.7 4.1 4.7 5.7 7.2 9.0 11.0 12.4 13.8
Vit. A 500/450 Actual 87 117 175 281 430 662 953 1209 1524 0.624
(μgRAE) Estimated 38 53 78 150 310 645 1254 1872 2654
Vit. Db (μg) 8.5 Actual 0.3 0.7 1.1 2.2 5.0 11.2 18.7 24.3 28.7 0.890
Estimated 0.8 1.1 1.5 2.7 4.9 9.0 15.5 21.6 28.7
Vit. Eb (mg) 6.0/6.5 Actual 2.2 2.6 3.2 4.5 6.2 8.4 10.8 12.6 14.9 0.885
Estimated 2.4 2.8 3.4 4.5 6.2 8.5 11.4 13.5 15.7
Vit. B1 (mg) 0.9/0.8 Actual 0.32 0.39 0.45 0.58 0.77 1.02 1.28 1.50 1.71 0.964
Estimated 0.35 0.40 0.46 0.59 0.77 1.02 1.30 1.51 1.72
Vit. B2 (mg) 1.0/0.9 Actual 0.47 0.56 0.68 0.87 1.14 1.47 1.80 2.05 2.29 0.994
Estimated 0.52 0.59 0.68 0.85 1.10 1.42 1.79 2.05 2.31
Vit. B6 (mg) 1 Actual 0.5 0.5 0.6 0.8 1.1 1.4 1.7 1.9 2.1 0.862
Estimated 0.5 0.6 0.7 0.8 1.1 1.4 1.8 2.0 2.3
Vit. B12 (μg) 2 Actual 0.6 0.9 1.2 2.1 4.1 7.2 12.8 16.8 20.9 0.875
Estimated 0.9 1.2 1.6 2.6 4.5 7.9 13.0 17.5 22.7
Folate 200 Actual 122 142 172 223 296 383 487 548 628 0.836
(μg) Estimated 106 122 143 189 257 351 466 553 642
Vit. C 85/80 Actual 18 26 36 61 102 162 225 266 318 0.976
(mg) Estimated 31 38 47 67 100 149 213 265 319
Student t-test
a
The reference value of iron in female = EAR of female without menstruation
b
Vitamin D and Vitamin E intake were assessed by % above AI
alidation of the Estimated Prevalence of Inadequate

V
Micronutrient Intake in Each Nutrient from the National
Health Nutrition Survey 2017 in Japan (Supplemental Table 9.3)
NHNS 2017 data including 4428 subjects (males/females: 2059/2369), aged 19 years
and older, excluding pregnant and lactating women, were analysed with stratification by
gender and age (younger; 19–49 years vs., older; 50 years and older) for micronutrients
intake status, including calcium, iron, zinc, vitamin A, vitamin B-1, vitamin B-2, vita-
min B-6, vitamin B-12, folate, and vitamin C. Percentage of subjects with inadequate
nutrients intake was calculated either by the cut-point method using the raw NHNS data
(Observed) or from the sex- and age-specific mean and SD (Estimated) from NHNS
2017. The ranking of nutrients according to the proportion of subjects with inadequate
intakes was in general agreement with the observed data in both gender and age.
Differences [observed value-estimated value)/observed value*100%] were relatively
smaller (would be good to define the threshold, i.e. less than 10%) in calcium, vitamin
A, and vitamin B-1, and larger (more than 20%) in iron, vitamin B-6, and folate. These
results indicated that an estimate can be made with mean and SD alone would be of
practical value in assessing the prevalence of inadequate micronutrient intake.
Supplemental Table 9.3 Validation of the estimated prevalence of insufficient intake in each nutrient from the National Health Nutrition Survey 2017
176
in Japan
% of population with intakes below the EAR or above AI
Folic
Gender Age group Calcium Irona Zinc Vit.A Vit. Eb Vit.B1 Vit. B2 Vit.B6 Vit.B12 acid Vit.C
19–49 years
Male Observed proportion 79.6 39.1 52.9 80 54.5 75.9 70.6 42.7 28 34.8 71.2
Estimated proportion 81.8 44.6 57.8 77.5 50.6 77.3 70.8 56.8 26.6 39.2 73.2
Difference (Observed-estimated) −2.2 −5.5 −4.9 2.5 3.9 −1.4 −0.2 −14.1 1.4 −4.4 −2.0
Difference (Observed-estimated)/ −2.8 −14.1 −9.3 3.1 7.2 −1.8 −0.3 −33.0 5.00 −12.6 −2.8
observed*100
Female Observed proportion 73.9 36.3 49.8 69.9 54.5 70.5 51.9 60 35 41.3 68.5
Estimated proportion 77.1 40.5 53.6 70.1 49.8 72.5 55.5 64 33.7 45.3 73.4
Difference (Observed-estimated) −3.2 −4.2 −3.8 −0.2 4.7 –2.0 –3.6 −4.0 1.3 −4.0 –4.9
Difference (Observed-estimated)/ −4.3 −11.6 −7.6 −0.3 8.6 −2.8 −6.9 −6.7 3.7 −9.7 −7.2
observed*100
≥50 years
Male Observed proportion 63 21.9 55.6 70.9 48.2 68.2 45.5 35.7 17.4 16.5 42
Estimated proportion 66.2 28.1 58.5 73.7 57.4 71.6 51.6 40.3 14.4 14.2 46.2
Difference (Observed-estimated) −3.2 −6.2 −2.9 −2.8 −9.2 −3.4 −6.1 −4.6 3.0 2.3 −4.2
Difference (Observed-estimated)/ −5.1 −28.3 −5.2 −4.0 −19.1 −5.0 −13.4 −12.9 17.2 13.9 −10.0
observed*100
(continued)
S. French et al.
9
Female Observed proportion 55.3 14.7 40.4 57.5 49.3 62.5 33.5 41.4 23.2 17.3 38.3
Estimated proportion 60.7 22.4 48.7 63.2 50.7 65.8 40 45.4 20.7 21.2 43.2
Difference (Observed-estimated) −5.4 −7.7 −8.3 −5.7 −1.4 −3.3 −6.5 −4.0 2.5 −3.9 −4.9
Difference (Observed-estimated)/ −9.7 −52.4 −20.5 −9.9 −2.8 −5.3 −19.4 −9.7 10.8 −22.5 −12.8
observed*100
Observed proportion: %below EAR or % above AI from National Health and Nutrition Survey 2017 in Japan
Estimated proportion: %below EAR or % above AI from Top-up Nutrition APAC Data calculated by parameter combination
Niacin was excluded because the raw NHNS data did not provide the proportion of niacin equivalent derived from tryptophan
a
The reference value of iron in female= EAR of female without menstruation
b
Vitamin E intake were assessed by % above AI
Micronutrient Status Among Adults in the Asia Pacific and Potential Impact…
177
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Chapter 10
Gut Microbiome and Its Metabolites
in Ageing
Soumam Dutta and Asim K. Duttaroy
Abstract Ageing is a complex biological process which has significant effects on

host physiology. It is associated with an altered gut microbiome structure and func-
tion characterised by a lower diversity, stability, increase in pathogenic microorgan-
isms (such as Clostridium, Escherichia, Staphylococcus, Streptococcus,
Proteobacteria, etc.) and a decrease in beneficial microbes (such as Actinobacteria).
Age-associated impairment of the gut mucosal barrier (also known as ‘leaky gut’)
allows such pathogenic microbes and microbial components to enter the circulation,
causing hyperinflammatory responses and inflammageing leading to several dis-
eases. Gut microbes utilise different dietary components to produce a wide range of
metabolites, such as short chain fatty acids (e.g. acetate, propionate, butyrate), aryl
hydrocarbon receptor ligands (e.g. metabolites of tryptophan), polyamines (e.g.
putrescine, spermidine, spermine), etc., thereby exerting local effects and mediating
cross-talks between the gut and other organs such as the brain, liver, kidney, heart,
eye, bone, muscle, adipose tissue, etc. Age-related gut dysbiosis is associated with
the production of harmful metabolites which impair health outcomes. Specific gut
S. Dutta
Food and Nutrition Division, University of Calcutta, Kolkata, India
A. K. Duttaroy (*)
e-mail: a.k.duttaroy@medisin.uio.no
Ltd. 2023
184 S. Dutta and A. K. Duttaroy
microbial metabolites, such as trimethylamine (TMA), p-cresol, and indole, are

related to clinical conditions such as cardiovascular diseases, renal diseases, liver
diseases, respiratory diseases, diabetes, etc. Supplementation with probiotics, prebi-
otics, synbiotics, and dietary and lifestyle modifications may be helpful to improve
and maintain gut eubiosis, although results are still inconclusive. In this chapter, we
will highlight the age-associated changes in gut microbiome composition and asso-
ciated metabolite profile, along with its involvement with commonly encountered
age-associated conditions.
Keywords Elderly · Ageing · Gut microbiome · Inflammation · SCFA · TMAO
10.1 Introduction
The human gastrointestinal tract is home to trillions of microorganisms, including

bacteria, fungi, protozoa, archaea, eukarya and viruses (Matijašić et al. 2020). The
terms ‘Microbiome’ and ‘Microbiota’ are often used interchangeably to refer to
the sum of all genomes present in these microorganisms and specific microorgan-
isms present in the body. The gastrointestinal tract of humans provides an ideal
infrastructure for the host, microbes and the environment to interact, thereby regu-
lating host physiology. The human gut microbiome (GM) is highly diverse. It may
include around 1000 bacterial species with about 2000 genes per species, which
accounts for an aggregate of 2,000,000 bacterial genes, which is about a hundred
times greater than 20,000 human genes (Gilbert et al. 2018). For millions of years,
we have coevolved with this wide variety of microorganisms to share a symbiotic
relationship. The relationship between the host and microbes inhabiting it consti-
tutes a ‘Superorganism’ which can be considered a step of integration in evolution
(Salvucci 2019). The gut microbiota undergoes extensive changes throughout the
lifespan. GM colonisation may begin in utero by the placental and amniotic micro-
bial communities characterised by low diversity and predominance of Proteobacteria
(Collado et al. 2016). During birth, the baby comes in direct contact with the envi-
ronment, for example, the vaginal fluid and skin microbiota of the mother, which
shapes the microbiome makeup of the neonate (Hasan and Yang 2019). Up to 2
years of age, the human GM remains highly susceptible to environmental altera-
tions that determine the individual’s future health status. The community of
microbes gradually mature and becomes quite stable in adulthood, especially at the
phylum level. Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria,
Fusobacteria and Verrucomicrobia are the predominant intestinal microbial phyla,
with the two phyla Firmicutes and Bacteroidetes accounting for 90% of gut micro-
biota (Rinninella et al. 2019). Firmicutes to Bacteroidetes (F/B ratio) is an essen-
tial index for GM composition and health. An increase in the F/B ratio may be
observed in obesity and metabolic disorders, whereas a decreased ratio may be
observed in inflammatory conditions (like inflammatory bowel disease) (Stojanov
et al. 2020).
10 Gut Microbiome and Its Metabolites in Ageing 185
Acute perturbations do not usually alter the composition of host GM, and slight
changes, if any, will return to the initial composition rapidly. But continuous expo-
sure to various environmental hazards, stress factors and modern lifestyle factors
may lead to ‘dysbiosis’, which exerts deleterious effects on the health. These gut
microbes are found to produce a plethora of metabolites from dietary components
which in turn exert numerous biological effects locally as well as in other target
organs. For instance, Short Chain Fatty Acids (SCFAs) such as acetate, propionate
and butyrate are produced from undigestible dietary carbohydrates by the gut
microbes which help in maintaining intestinal barrier integrity, prevent inflamma-
tory damages, maintain immune homeostasis, establish link between gut and other
organs such as the brain, lung, liver, pancreas, bone marrow, adipose tissue (Tan
et al. 2014). Similarly, other metabolites such as aryl hydrocarbon receptor (AHR)
ligands (for example, metabolites of tryptophan) (Dong and Perdew 2020), poly-
amines (such as putrescine, spermidine, spermine) (Tofalo et al. 2019) produced by
the gut microbes have numerous physiological functions. A dysbiotic gut may pro-
duce potentially harmful metabolites and/or cause an imbalance of beneficial
metabolites.
Ageing is a complex biological process determined by several host and environ-
mental factors.
It affects various genomic, physiological, biochemical, metabolic and immuno-
logical functions. Age-associated changes in physiological processes influence gut
microbiome composition and vice-versa (Ragonnaud and Biragyn 2021). Increasing
evidence suggest the intricate involvement of gut dysbiosis in various age-associated
diseases. A major converging point for most mechanistic pathways underlying age-
ing and age-related disorders is inflammation. Chronic, sterile, low-grade inflam-
mation is a vital contributor to ageing, also known as inflammageing (Xia et al.
2016). The gut microbiota and their metabolites directly interact with the gut muco-
sal cells and immune system, thereby regulating several complex pathways involved
in inflammageing. As seen in centenarians, healthy ageing is characterised by a
eubiotic GM composition that does not activate inflammatory pathways. Thus, it is
essential to understand the role of GM and their metabolites in ageing to target the
specific factors which can result in successful ageing. In this chapter, we aim to
highlight the age-associated changes in GM composition, its involvement with
common age-associated disorders and the molecular mechanisms underlying these
processes.
10.2 Gut Microbiome Composition and Ageing
The ageing process has significant effects on the host physiology and microbi-
ome composition, thereby influencing their interactions. It is often difficult to
comprehend whether alterations of gut microbiome composition are cause or
consequence of ageing. As people age, the overall stability and diversity of gut
microbiota are found to be reduced (Nagpal et al. 2018). At the phylum level, an
increase in inflammation-related proteobacteria and a reduction in beneficial

actinobacteria may be observed. The relative abundance of commensals such as
bifidobacteria, lactobacilli, bacteroides are decreased and opportunistic patho-
gens such as Clostridium perfringens, Clostridium difficle, and Enterobacteria
are found to increase (Nagpal et al. 2018). However, the average and success-
fully ageing individuals have higher alpha diversity (species diversity within a
single host/ local environment), functional pathways and metabolites, especially
among the oldest-old individuals (Badal et al. 2020). Beta diversity (species
diversity between different environments/ communities) is found to differ sig-
nificantly between younger-old and oldest-old adults. Interestingly, the oldest-
old individuals are found to have a higher predominance of beneficial taxa and
SCFA production, which help them maintain an anti-inflammatory condition
leading to successful ageing (Badal et al. 2020). The gut microbiome composi-
tion may vary among elderly individuals in different geographical locations.
Disruption of gut microbial eubiosis, diversity and functionality in old age has
numerous adverse consequences. Dysbiosis, along with reduced gut microbial
metabolic capacities in elderly individuals, such as a reduction in SCFA produc-
tion, are associated with age-related frailty, weight loss, appetite reduction, sar-
copenia, arthritis, cognitive decline, and other non-communicable diseases. As
mentioned before, altered gut microbiome metabolism and functionality may
change the levels of several microbial metabolites directly related to human
health. Studies on animal models have shown an age-dependent increase in
Proteobacteria and a decrease in Firmicutes along with alteration of tryptophan,
purine, nicotinamide and amino acid metabolisms (Wu et al. 2021). Notably,
primary ageing in mice was found to be associated with a decrease in circulating
levels of gut microbial metabolites indole and indole-3-lactic acid, which may
result in compromised barrier function and a pro-inflammatory state. Additionally,
an increase in kynurenine and a decrease in nicotinamide may be observed
which are associated with physiological ageing (Wu et al. 2021). Similarly, sig-
nificant increase in metabolites involved in inflammatory and cytotoxic path-
ways can be observed in non-human primate models (Pallikkuth et al. 2021).
However, clinical studies on these parameters are relatively scanty. The com-
monly encountered reasons behind these age-related changes in gut microbiome
profile are changed lifestyle, dietary habits, reduced mobility, altered intestinal
functionality, gut morphology, immunosenescence, recurrent infections, hospi-
talisations, use of medications and so on. Some overlooked factors such as
romantic relationship dissolution (for example, death of a beloved person), com-
monly faced by the elderly individuals, may also alter gut microbiome composi-
tion due to social isolation, depression and changes in food habits (Chuang
2021). The underlying physiological and molecular mechanisms involved in
age-related disorders and GM composition are highly complex, which are dis-
cussed in the next section.
10.3 Mechanisms Involved in Gut Dysbiosis and Ageing:

Role of Gut Microbial Metabolites
As we discussed earlier, gut dysbiosis and ageing have a two-way connection.

Ageing is associated with certain physiological and environmental changes which
may be detrimental to gut eubiosis. For instance, decreased gut motility and
increased gut permeability are frequently encountered in elderly people (Nagpal
et al. 2018). As per existing evidence, gut microbial changes in old age may be
associated with increased TNF levels αIL-6 and IL-8, although it is unclear whether
such associations are direct or indirect. The intestinal epithelial cells secrete a muci-
nous component which, along with intercellular junctions (like tight junctions) form
the gut barrier and separate the systemic compartment from the external environ-
ment. Under healthy eubiotic conditions, gut microbes produce SCFAs that help
maintain gut barrier integrity. At the same time, gut microbes regulate antimicrobial
peptide (AMP) production from the epithelial cells and influence mucus production
(Nagpal et al. 2018). Secreted IgA (sIgA), produced by plasma cells, binds to cer-
tain microbes and soluble antigens in the lumen, thereby preventing their adherence
to the epithelium and invasion through the gut barrier. If this homeostasis is dis-
turbed, several harmful conditions may set in, including inflammatory damage and
gastrointestinal disorders. A ‘leaky gut’ allows pathogens, bacterial components
(lipopolysaccharides, flagellins, nucleic acids), mucus, histamine, etc. to enter the
lamina propria, increasing antigenic load and triggering hyper-inflammatory
responses (Nagpal et al. 2018). These processes may ultimately increase the suscep-
tibility of the hosts to various systemic and gut-related disorders by perturbating the
gut-brain axis, gut-liver axis, gut-lung axis, etc.
Apart from SCFAs, other gut microbial metabolites may also significantly affect
host ageing. For instance, gut microbes use certain amino acid decarboxylase
enzymes to produce polyamines (e.g. spermidine, spermine, putrescine), which have
a wide range of biological activities (Tofalo et al. 2019). Preclinical studies have
shown that the supplementation of probiotics leads to an increase in gut polyamine
concentration, inhibiting cellular senescence and promoting longevity. Mice supple-
mented with arginine, and Bifidobacterium LKM512 exhibited increased putrescine
concentration in the colon and higher levels of spermidine and spermine in the blood
(Kibe et al. 2014). Such changes were associated with suppressed inflammation,
reduced age-related cognitive impairment and increased longevity, thereby prevent-
ing the age-associated decline in quality of life. In humans, higher consumption of
dietary spermidine is found to be associated with reduced age-associated conditions
such as cardiovascular disorders and lower mortality (Madeo et al. 2018).
Similarly, in a study on geriatric human subjects with elderly-type gut microbi-
ome composition, an increase in specific metabolites (such as trimethylamine, cho-
line, N8-acetylspermidine) was observed to be linked with age-associated with
conditions like arteriosclerosis and colorectal cancer (Yoshimoto et al. 2021). These
changes may serve as effective points for targeted interventions to promote longev-
ity and healthy ageing (Fig. 10.1).
Fig. 10.1 Ageing-associated gut microbial, physiological and environmental changes and their
consequences
10.4 Changes in Gut Microbiome and Its Metabolites

in Common Age-Associated Conditions
As we have already discussed, age-associated changes in gut microbial composition

and metabolite profile significantly impact host physiology. Dysbiosis promotes
systemic inflammation and immune-senescence, which are associated with poor
prognosis of several communicable and non-communicable diseases in aged indi-
viduals. In the following sections, we will highlight the changes observed in gut
microbiome composition under certain age-dependent clinical conditions.
10.4.1 Cardiovascular Diseases
Ageing is a non-modifiable risk factor for cardiovascular morbidities. The imbal-

ance of gut microbes, commonly associated with ageing, is an important contributor
to cardiovascular diseases (CVDs) (Masenga et al. 2022). Studies have shown that
CVDs are associated with an abundance of Escherichia, Shigella, Streptococcus,

and Enterococcus species along with a decrease in Faecalibacterium, Roseburia,
Bacteroides fragilis, Subdoligranulum and Eubacterium rectale, the latter group
having anti-inflammatory effects (Masenga et al. 2022). Dietary components such
as choline, phosphatidylcholine, and carnitine, primarily found in animal products,
are converted into trimethylamine (TMA) by certain gut microbes, which is further
oxidised in the liver to produce trimethylamine oxide (TMAO). TMAO has athero-
genic properties, promotes inflammation, impairs reverse cholesterol transport and
increases platelet hyper-responsiveness (Zhu et al. 2016; Masenga et al. 2022). In
mice, ageing is associated with dysbiosis and an increase in plasma TMAO, thereby
increasing the risk of arterial dysfunction and CVDs (Brunt et al. 2019). Apart from
this, SCFAs produced by gut microbes are found to regulate blood pressure through
distinct G-protein coupled receptors (GPCRs) (Masenga et al. 2022). Certain
SCFAs, like acetate and propionate, exert antihypertensive effects by reducing sys-
temic inflammation and atherosclerosis development. Other SCFAs like butyrate
and lactate may also regulate blood pressure by modulating vasoconstriction and
vasodilation (Razavi et al. 2019). Depletion of SCFA-producing microbes, as
observed in ageing, may lead to hypertension. The composition of GM may also
influence bile acid homeostasis, which in turn is associated with lipid metabolism,
glucose metabolism and inflammation. Complex interactions among diet, gut
microbes and bile acids contribute to several cardiometabolic phenotypes.
Dysregulated bile acid homeostasis may lead to CVD development which is com-
mon among elderly individuals. Such effects are mediated mainly by specific
GPCRs like Takeda G-protein–coupled receptor 5 (TGR5) and specific nuclear
receptors such as Farnesoid Xenobiotic Receptor (FXR), Liver Xenobiotic Receptor
(LXR) and Pregnane Xenobiotic Receptor (PXR) (Callender et al. 2022).
10.4.2 Diabetes
Diabetes mellitus (DM) is a metabolic condition characterised by higher than nor-

mal blood glucose levels. The three major classes of DM are Type 1 DM/T1DM
(characterised by autoimmune destruction of insulin-producing pancreatic beta
cells), Type 2 DM/T2DM (characterised by insulin resistance) and Gestational DM/
GDM (diagnosed first time during pregnancy). Among these three types, T2DM is
adult-onset and commonly observed in the geriatric population (Bradley and Hsueh
2016). The gut microbes are found to exert significant effects on host glucose
metabolism. They interact with dietary components, alter inflammatory responses,
regulate gut permeability and modulate insulin sensitivity. Therefore, perturbation
of GM composition may be a risk factor for T2DM development in elderly individu-
als. Studies have shown that the abundance of Bifidobacterium, Faecalibacterium,
Akkermansia, Roseburia, and Bacteroides is negatively associated with T2DM,
whereas Ruminococcus, Blautia and Fusobacterium have positive associations
(Gurung et al. 2020). An increase in inflammatory and a decrease in anti-
inflammatory cytokines and chemokines can be commonly observed in
T2DM. Certain species of Akkermansia, Lactobacillus, and Roseburia induce anti-

inflammatory IL-10 formation, which helps protect against an age-related decrease
in muscle insulin sensitivity (Gurung et al. 2020). Similarly, Roseburia intestinalis
may induce anti-inflammatory IL-22 formation, which helps to restore insulin sen-
sitivity. On the contrary, the predominance of certain pathobionts such as
Ruminococcus gnavus and Fusobacterium nucleatum trigger pro-inflammatory
responses (Gurung et al. 2020). Increased gut permeability, commonly associated
with T2DM, results in metabolic endotoxemia and hyperinflammatory responses, as
discussed earlier. Such responses further complicate disease prognosis. Certain pro-
biotic species (such as Bifidobacterium lactis) downregulate hepatic gluconeogene-
sis-related genes, increase glycogen synthesis, and promote translocation of GLUT4
and insulin-dependent glucose uptake (Kim et al. 2014; Gurung et al. 2020).
Treatment with probiotics and maintenance of eubiosis may be an effective way to
protect against T2DM in the elderly population.
10.4.3 Neurodegenerative Diseases and Cognitive Impairment
Ageing-associated dysbiosis is essential to age-related neuro-inflammation, neu-

rodegeneration and cognitive impairments. Dysbiosis leads to the aggregation of
stress proteins in the healthy brain resulting in neuroinflammation, neuronal
apoptosis and astrocyte activation (Alsegiani and Shah 2022). Lower GM diver-
sity can be observed among elderly individuals with memory impairments com-
pared to healthy subjects. Age-associated decrease in GM diversity and dysbiosis
reduce the synthesis and secretion of specific neurotrophic factors such as Brain-
Derived Neurotrophic Factor (BDNF), Gamma Amino Butyric Acid (GABA),
N-methyl-d-aspartate (NMDA) receptor, etc. (Askarova et al. 2020). Certain gut
microbes such as Bacillus subtilis, Escherichia coli are found to be associated
with amyloid fibre production which has the potential to cross the intestinal and
Blood-Brain Barrier (BBB). This may result in amyloid-β protein formation and
accumulation in the brain leading to Alzheimer’s Disease (AD) pathogenesis
(Askarova et al. 2020). Patients newly diagnosed with AD or Mild Cognitive
Impairment (MCI) are found to have a GM with a decrease in protective
Bacteroides and an increase in inflammation- promoting Prevotella. The
Apolipoprotein E (APOE) genotype, one of the strongest risk factors for AD, is
also associated with a particular GM composition. The APOE4 genotype which
carries the highest risk of AD is associated with a decrease in SCFA and butyrate-
producing microbes which may regulate neuropathology (Tran et al. 2019). A
reduction in SCFA-producing microbes is also consistently observed among
patients having Parkinson’s Disease (PD) (Romano et al. 2021). Huntington’s
Disease reported lower diversity, richness, evenness and dysbiosis (Wasser et al.
2020). Similarly, many studies have found significant associations between gut
dysbiosis and Lateral Sclerosis (Boddy et al. 2021), Depression (Limbana et al.
2020), Vascular cognitive impairment (Li et al. 2018), etc. Such effects mostly
result from prolonged exposure of the brain to different deleterious gut microbial
metabolites and pro-inflammatory cytokines.
10.4.4 Kidney Diseases
Gut dysbiosis in ageing is associated with multiple renal diseases and patholo-
gies. A “leaky gut”, as discussed before, allows pathogens to enter the circula-
tion, activating the immune system. Such activated immune cells may penetrate
the kidney and initiate inflammatory reactions. The GM of CKD patients can be
characterised by a reduction in Lactobacillaceae and Prevotellaceae (normal
colonic microbiota) and a relative increase in Enterobacteria and Enterococci
(usually pathogenic) (Ramezani and Raj 2014). Patients undergoing haemodialy-
sis have a lower level of Bifidobacterium and a higher level of Clostridium per-
fringens. Patients with End Stage Renal Disease (ESRD) are at increased risk of
having Clostridium difficle-associated diarrhoea. Dysbiosis in Chronic Kidney
Disease (CKD) patients leads to the retention of uremic toxins, which in turn
contributes to the progression of CKD (Ramezani and Raj 2014). Specific gut
microbial metabolites such as p-cresol and indole are found to predict CKD pro-
gression and reduction in glomerular filtration rate (GFR). These metabolites are
produced by the fermentation of tyrosine and tryptophan by the gut microbes,
respectively. After absorption, these are converted to p-cresyl sulfate and
p-indoxyl sulfate in the liver. Levels of these two compounds are negatively asso-
ciated with kidney function (Lin et al. 2011). Higher p-cresol levels are associ-
ated with an increased risk of death in ESRD (Ramezani and Raj 2014). TMAO,
produced by gut microbes, is also found to be elevated in patients with CKD and
is associated with 2.8 folds higher risk of all-cause mortality (Tang et al. 2015).
Kidney diseases are found to be associated with increased use of antibiotics,
metabolic acidosis, slow colonic transit, intestinal wall congestion, oral iron
intake and low dietary fibre intake (al Khodor and Shatat 2017). Such factors
may perturbate gut microbial homeostasis, increase pathogenic growth, reduce
intestinal tight junctions and increase gut permeability, thereby triggering
immune responses. CKD is also associated with increased secretion of urea in
the gastrointestinal tract, which is broken down by gut microbes to produce large
quantities of ammonia. This may alter the gut microbial balance and affect the
growth of commensals.
10.4.5 Liver Diseases
The gut microbes and their metabolites can significantly alter hepatic health as they
can enter the liver through the portal circulation. Under normal conditions, small
amounts of microbial products go into the liver, which is eliminated by the Kupffer
cells with minimal activation. But, due to dysbiosis, intestinal barrier disruption and
other related conditions, higher amounts of microbes and microbial products go to
the liver, activating Kupffer cells and hepatic stellate cells (Minemura and Shimizu
2015). For instance, pathogen-derived lipopolysaccharides may bind to the Toll-like
Receptor 4 (TLR4) in these cells, thereby activating them. Such activation may lead
to increased production of pro-inflammatory cytokines and associated inflammatory
damages. Other microbial components such as flagellin, nucleic acids, and formyl-
peptides are also detected by certain Pattern Recognition Receptors (PRRs), thereby
initiating adverse responses in the liver. Liver diseases are associated with dysbiosis
and bacterial overgrowth in the intestine. It may disrupt bile acid metabolism, which
alters hepatic metabolism through transcription factors such as LXR, FXR, and
TGR5 (Li et al. 2021). Alcohol consumption is associated with gut mucosal barrier
disruption, which increases microbial translocation into the portal vein. Dietary and
microbiota-derived ethanol can damage the hepatocytes by generating reactive oxy-
gen species (ROS) (Li et al. 2021). Choline utilised by the gut microbes to produce
TMA may result in a choline-deficient state. Choline deficiency may lead to reduced
Very Low-Density Lipoprotein (VLDL) excretion from the liver, which may cause
triglyceride accumulation (Mehedint and Zeisel 2013). TMAO may also exert sig-
nificant adverse effects on the liver and is associated with non-alcoholic fatty liver
disease (NAFLD) and non-alcoholic steatohepatitis (NASH) (Li et al. 2021). Gut
dysbiosis may affect other tissues (such as adipose tissue) and alter local and sys-
temic immune systems, which may indirectly affect liver health.
10.4.6 Cancer
The incidence of cancer increases substantially with an increase in age. Ageing

decreases GM diversity and the levels of beneficial microbes in the gut, which are
involved in the control of pathogens and maintenance of the gut mucosal barrier. Age-
associated dysbiosis may exert adverse effects on the host immune system which may
impair mutant and senescent cell removal, thereby facilitating tumour outgrowth and
cancer development (Biragyn and Ferrucci 2018). Gut dysbiosis in ageing provides a
selective benefit to oncogene-expressing and malignant cells. Dysbiosis impairs the
ability of plasmacytoid dendritic cells to induce adaptive immune responses against
neoantigens and decreases phagocytosis of monocytes, neutrophils and macrophages
(Biragyn and Ferrucci 2018). Thus, deficient immune surveillance and inflammage-
ing may promote carcinogenesis. Inflammageing is promoted by gut dysbiosis, which
is associated with an increase in various pro-inflammatory pathways, thereby sustain-

ing the production of various pro-inflammatory cytokines from monocytes and mac-
rophages such as Interleukin-1α/β (IL-1α/β), Interleukin-6 (IL-6) and Tumour
Necrosis Factor-α (TNF-α) (Biragyn and Ferrucci 2018). Higher concentration of
TNF-α is found to be proapoptotic and pronecrotic, whereas chronic low concentra-
tions of TNF-αare tumourigenic. Higher TNF-α is also found to impair the fitness of
hematopoietic stem cells in ageing bone marrow, thereby promoting leukaemogene-
sis and acute myeloid leukaemia (Biragyn and Ferrucci 2018).
10.4.7 Respiratory Diseases
GM dysbiosis, decreased GM diversity, and increased gastrointestinal permea-

bility are associated with respiratory health issues. Increased levels of gut
microbe-associated TMAO are found to be associated with mortality in Chronic
Obstructive Pulmonary Disorder (COPD) patients (Enaud et al. 2020). Cystic
fibrosis (CF) patients with intestinal inflammation have a higher abundance of
Streptococcus, Staphylococcus and Escherichia coli in the gut. Similarly, asso-
ciations can be found between dysbiosis, asthma and acute lung infections
(Enaud et al. 2020). Specific perturbations in GM composition may also affect
the lung microbiome. For instance, a decrease in gut Parabacteroides may cause
an increase in lung P. aeruginosa (associated with infections). Gut microbes may
also significantly affect the lung immune system via CD8+ T cells, T helper 17
cells (TH-17), prostaglandin E2, IL-25, IL-13 and NF-kB pathways (Enaud
et al. 2020).
10.4.8 Impaired Musculoskeletal Health
GM composition significantly affects bone and muscle health among elderly indi-
viduals. Gut dysbiosis and leaky gut are associated with an inflammatory pheno-
type. This leads to an increase in IL-17-producing TH-17 cells, which is related to a
reduction in bone mass by stimulating osteoclast differentiation (Cooney et al.
2021). GM composition’s perturbation is correlated with conditions such as osteo-
porosis and osteopenia.
On the contrary, gut eubiosis leads to better nutrient absorption (such as Calcium,
Magnesium, Phosphorus, Vitamin B, and Vitamin K), produces beneficial SCFAs,
promotes bile acid metabolism and maintains the balance between regulatory T cell
(Treg) and TH-17 cells which are associated with an increase in bone formation and
decrease in bone resorption (Ding et al. 2020). Butyrate produced by the beneficial
gut microbes stimulates the differentiation of Treg cells, promoting bone formation.
Treg cells stimulate CD8+ T cells, which release Wnt10b, promoting osteoblast dif-
ferentiation (Cooney et al. 2021). Gut microbes may also promote bone health by
producing serotonin (5-HT). Similarly, perturbed GM may be associated with sar-
copenia. A reduction in GM diversity and butyrate producers (such as Lachnospira,
Roseburia, Eubacterium, etc.) can be observed in patients having sarcopenia. An
increase in LPS biosynthesis and a decrease in phenylalanine, tryptophan and tyro-
sine biosynthesis may also be observed (Kang et al. 2021).
10.4.9 Poor Ocular Health
GM composition may influence ocular health, which suggests the existence of a

Gut-Eye axis. Dysbiosis may be an important contributor to the development of
ocular diseases such as uveitis, dry eye, macular degeneration and glaucoma.
Dysbiosis impairs intestinal homeostasis and the gut mucosal barrier, which allows
microbial products and activated immune cells to reach the eye. This may induce
ocular inflammation through direct effects on the eyes (Napolitano et al. 2021).
Eyes are usually prone to develop inflammatory diseases, even in the absence of an
infectious component, which can be attributed to a dysbiotic GM. Prominent asso-
ciations can be found between intestinal inflammatory diseases and ocular dis-
eases. For instance, ten per cent of subjects suffering from inflammatory bowel
diseases (IBD) may suffer from various ocular diseases (Scuderi et al. 2022).
Associations have been found between GM composition and autoimmune uveitis,
age-related macular degeneration (ARMD), glaucoma, chalazion, etc. Age-related
gut dysbiosis may lead to premature senescence of retinal cells. This results in the
release of pro-inflammatory cytokines and angiogenic factors, which in turn causes
neovascularisation and disruption of vascular repair (Napolitano et al. 2021;
Scuderi et al. 2022). Dysbiosis may lead to diabetes development through several
physiological pathways. Dysbiosis-associated retinal inflammation, disruption of
the blood-retinal barrier, apoptosis and neovascularisation may lead to the pro-
gression of diabetic retinopathy. Zinkernagel et al. have shown that ARMD can be
characterised by a predominance of Anaerotruncus, Oscillibacter, Ruminococcus
torques and Eubacterium ventriosum. This composition is associated with gluta-
mate degradation and upregulation of arginine biosynthetic pathways (Zinkernagel
et al. 2017). The reduction of glutamate leads to deficient neurotransmission in the
retina, whereas an increased level of arginine is associated with chorioretinal atro-
phy and retinal degeneration. There was also a decrease in bacteria responsible for
fatty acid elongation pathways. On the contrary, subjects without ARMD were
found to have a higher level of Bacteroides eggerthii, which may exert protective
effects through SCFAs production (Zinkernagel et al. 2017). Such evidence sug-
gest a crucial link between gut microbes, their metabolites and ocular health in
ageing (Fig. 10.2).
Fig. 10.2 Association of ageing-associated gut dysbiosis with common age-associated conditions.
BDNF brain-derived neurotrophic factor, CD8+ T Cells cluster of differentiation 8 T cells, GABA
gamma amino butyric acid, GFR glomerular filtration rate, GLUT4 glucose transporter 4,
IL-1β/6/10/13/25 interleukin-1β/6/10/13/25, NF-kB nuclear factor kappa B, TH-17 T helper 17 cell,
TNF-α tumour necrosis factor-α
10.5 Targeting Gut Microbiome for Healthy Ageing
From the above-mentioned evidence, it can be clearly understood that the composi-
tion of GM and the wide range of metabolites produced by them have significant
effects on host physiology. Ageing-associated gut dysbiosis, disruption of the gut
mucosal barrier, loss of tight junctions and entry of microbial components through
the leaky gut lead to hyperinflammatory responses resulting in several age-associated
diseases. At the same time, maintenance of gut eubiosis may lead to healthy ageing
and better quality of life. Thus, GM is a vital intervention site to prevent age-
associated diseases. Following strategies may be suitable to maintain a healthy GM
composition in ageing,
10.5.1 Probiotics
Probiotics are live microorganisms which exert beneficial effects when consumed
in adequate amounts. Certain factors such as strains, dosage and duration are
essential regarding probiotic supplementation. Probiotics are beneficial for modi-
fying GM composition in healthy elderly individuals and exert modest effects on
immune functions. In a meta-analysis, short-term probiotic supplementation was
found to improve polymorphonuclear phagocytic activity and Natural Killer (NK)
cell tumouricidal activity among elderly individuals (Miller et al. 2019). Probiotics
are found to reduce chronic inflammatory status, as seen in ageing. Certain probi-
otic strains such as Bifidobacterium and lactic acid bacteria may exert immuno-
modulatory effects. They are found to produce specific bioactive metabolites from
various dietary components. For instance, dietary isoflavones, lignans and ellagi-
tannins can be metabolised to produce equol, enterolignans and urolithin respec-
tively, which are more bioavailable and exert anti-inflammatory, anti-oxidant and
anti-carcinogenic effects (Landete et al. 2017). A recent meta-analysis suggests
that probiotics may improve cognitive and gastrointestinal symptoms in patients
having AD, PD and MCI, by reducing inflammatory responses and improving
lipid metabolism (Xiang et al. 2022). Although, the effects of probiotics on other
physiological functions are still inconclusive, often showing conflicting results.
10.5.2 Prebiotics
Prebiotics are edible substances which selectively promote the growth and activity
of beneficial microorganisms in the gut. The most widely consumed prebiotics
include fructo-oligosaccharides, galacto-oligosaccharides and inulin. Prebiotics
may be useful for maintaining gut eubiosis in elderly individuals. Usually, the major
targets of these prebiotics are Bifidobacterium and Lactobacillus in the gut
(Jayanama and Theou 2020). Several clinical studies have been conducted on the
effectiveness of prebiotics in reversing age-related changes. Prebiotic supplementa-
tion is found to improve frailty parameters (exhaustion and hand grip strength)
among elderly individuals (Jayanama and Theou 2020). Supplementation with a
commercial resistant starch may increase the predominance of Bifidobacteria and
Bacteroides in the gut of elderly subjects (Alfa et al. 2018). Galacto-oligosaccharide
administration may stimulate Bifidobacteria growth and exert immunomodulatory
effects by increasing phagocytosis, NK cell activity, anti-inflammatory cytokines
(such as IL-10) and reducing pro-inflammatory cytokines (such as IL-1β, IL-6,
TNF-α) (Vulevic et al. 2008 2015). Administration of enteral formula with
prebiotics may improve Bifidobacterium count and lead to better influenza vaccine
response (Akatsu et al. 2016). Although, in free-living elderly subjects no signifi-
cant effects of prebiotic supplementation are found on influenza vaccine response.
10.5.3 Synbiotics
Synbiotics are combinations of prebiotics and probiotics which act in synergism.

Studies have shown that synbiotics may be beneficial for improving GM composi-
tion in elderly individuals. Synbiotics may promote the growth of bifidobacteria and
lactobacilli in the gut (Ale and Binetti 2021). They may improve stool frequency,
and gut mucosal health, enhance SCFA (like butyrate) production and lipid metabo-
lism and diminish pro-inflammatory responses. Synbiotics are also found to improve
the markers of metabolic health, cardiovascular health and decreased insulin resis-
tance in elderly subjects. Synbiotics may reduce total serum cholesterol, triglycer-
ides, and fasting glycaemia and increase HDL cholesterol (Ale and Binetti 2021).
Sometimes, certain synbiotic combinations work more effectively than individual
prebiotics or probiotic. For instance, a combined regimen of live binary Bacillus
subtilis and lactulose worked better than individual components for treating consti-
pation. Synbiotic therapy is also associated with increased Actinobacteria and
Firmicutes and a reduction in Proteobacteria (Ale and Binetti 2021).
10.5.4 Other Strategies
Several strategies may be used to promote GM composition in elderly individuals

other than probiotic, prebiotic and synbiotic supplementation. For instance, dietary
modifications play an essential role in promoting gut eubiosis. Western dietary pat-
terns, characterised by calorie-dense food items, high fat, high sugar, high salt,
refined carbohydrates, processed meat, saturated fats, and additives, lead to a dysbi-
otic condition (Shi 2019). A healthy, balanced diet, characterised by whole grains,
fresh vegetables, fruits, nuts, herbs and fish consumption, promotes GM diversity
and maintains eubiosis. A Mediterranean dietary pattern is associated with an
increase in beneficial microbes and a decrease in opportunistic pathogens (Nagpal
et al. 2019). Supplementation with gut microbial metabolites (such as SCFAs) may
have a promising role in reversing age-associated health impairments. Novel thera-
pies such as Fecal Microbiota Transplantation (FMT) may also be beneficial in
future. Some latest innovative interventions to modify GM composition in elderly
individuals are listed in Table 10.1.
Table 10.1 Innovative intervention strategies to modify gut microbiome in elderly individuals
198
Strategy Study subjects Intervention/duration Major outcomes References

Dietary Influenza vaccinated free-living Probiotic Food Reduced number of subjects with symptoms Sandionigi et al. (2022)
modifications elderly subjects (age 60–80 years) Supplement of common infectious diseases and reduced
25 subjects in the intervention group (Lactobacillus plantarum, duration of symptoms in the intervention
vs. 25 subjects in the placebo group Bifidobacterium animalis, group. Improved total anti-oxidant capacity
Bifidobacterium longum and β-defensin 2 levels. Increased abundance
subsp. infantis, of beneficial gut microbes associated with
Bifidobacterium longum SCFA production
subsp. longum.)/28 days
Elderly individuals (age ≥60 years) Polyphenol Rich Diet (3 Positive association with butyrate producing Peron et al. (2021)
51 subjects in the intervention group servings of polyphenol bacteria and negative association with
rich food per day)/8 zonulin (marker of ‘leaky gut’)
weeks
Healthy Caucasian seniors (age Chicory Long-Chain Higher gut microbial diversity with an Kiewiet et al. (2021)
55–80 years) Inulin/2 months abundance of Bifidobacterium in the
13 subjects in the intervention group intervention group. Immune responses were
vs. 13 controls unchanged
Non-frail or prefrail elderly subjects Mediterranean Diet/12 Increased abundance of specific taxa is Ghosh et al. (2020)
(age 65–79 years) across five months associated with lower frailty, reduced
European countries inflammation and improved cognition.
324 cases vs. 289 controls Increased production of SCFAs and
decreased production of secondary bile acids,
ethanol, p-cresol and carbon dioxide
Elderly individuals (age >75 years) Biscuits containing Improved innate and adaptive immune Finamore et al. (2019)
45 subjects in the intervention group Probiotics (mix of function. Increase in naïve and activated
vs. 34 subjects in the placebo group Bifidobacterium longum memory T cells, regulatory T cells, B cells,
Bar33 and Lactobacillus Natural Killer activity and modulation of
helveticus Bar13, 1:1)/30 cytokine activity
days
Elderly individuals (age 70–96 years) Potato Resistant Starch/3 Reduction in Proteobacteria and increase in Alfa et al. (2018)
S. Dutta and A. K. Duttaroy
22 subjects in intervention group vs. months Bifidobacterium. Increase in faecal SCFA

22 subjects in placebo group levels
10
Lifestyle Elderly Chinese individuals (age Mindfulness Awareness Improvement of cognitive function Khine et al. (2020)
modifications 60–85 years) diagnosed with mild Practice/9 months associated with specific changes in gut
cognitive impairment bacterial profile. Abundance of
46 cases vs. 77 controls Ruminococcus was associated with four
cognitive functions.
Elderly Japanese subjects (age 62–76 Endurance Exercise Decrease in Clostridium difficle and increase Taniguchi et al. (2018)
years) Programme/5 weeks in beneficial Oscillospira. Gut microbial
33 subjects in randomised crossover changes in the intervention group were
trial correlated with improvement in
cardiometabolic risk factors
Dietary and Healthy adult males (age 50–72 Diet and Lifestyle Reduction in DNA methylation age Fitzgerald et al. (2021)
lifestyle years) Intervention (sleep, (epigenetic age) by 3.23 years in intervention
modifications 22 subjects in intervention group vs. exercise, relaxation group as compared to controls
22 controls guidance, probiotics and
phytonutrient
supplements)/8 weeks
Gut Microbiome and Its Metabolites in Ageing
199
10.6 Conclusion and Future Perspectives
Ageing is an obvious and non-reversible biological process. However, age-associ-

ated changes in physiological processes, which often lead to several complications,
maybe reversible. From the above-mentioned evidences, it can be clearly under-
stood that GM composition changes significantly with chronological age and cor-
relates with altered physiological processes. Both, structural and functional
attributes of GM are altered with age, resulting in dysbiosis and systemic inflamma-
tion. The metabolites produced by the gut microbes (such as SCFAs, polyamines,
AHR ligands, etc.) are mostly involved in the cross-talk between gut and other
organs such as the heart, kidney, liver, brain, bone, muscles, pancreas, etc. Healthy
ageing, on the other hand, is associated with better GM composition and gut metab-
olite profile. Thus, maintenance of eubiosis should be an essential component of
geriatric health interventions. Strategies such as probiotics, prebiotics, synbiotic
supplementation, dietary and lifestyle modifications maybe helpful to improve
health outcomes and quality of life. However, further research is required to have a
better understanding of the molecular mechanisms underlying GM alteration,
inflammation and ageing to identify suitable targets for intervention. Deciphering
the GM-induced epigenetic changes, such as DNA methylation, histone modifica-
tions and regulation of non-coding RNAs, may give us thorough understanding of
the pathogenesis of several metabolic diseases as seen in ageing. In this regard,
transfer of gut microbes from healthy and diseased elderly individuals to germ free
animal models may give us stronger evidences. Although, it is quite difficult to
define a healthy baseline GM, since the composition is highly variable based on dif-
ferent host-associated and environmental factors, making it difficult to get compari-
son groups. Thus, unfolding the dynamic changes in age-related GM composition
and associated metabolome, through large scale community sequencing studies are
in demand. Solving these queries are urgently required to support healthy ageing
and reduce healthcare burden.
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Chapter 11
Importance of Functional Foods Against
Aging of Adult Stem Cells
Jayanta Kumar Das , Theodore Lemuel Mathuram,

Andres Dominguez Solano, and Madhumita Das
Abstract Functional foods offer vital nutrients that can protect against different
diseases in humans. These functional foods are exclusively full of antioxidants that
can remove many detrimental compounds including free radicals (ROS/RNS) to
protect from adult stem cell damage to different diseases including cancer, diabetes,
chronic obstructive pulmonary disease (COPD), and cardiovascular lesions, namely,
fibrous obliterative pericarditis and rheumatoid granulomas, vasculitis, valvulitis,
and nonspecific myocarditis. Functional foods are ingredients that give health ben-
efits beyond the nutritional value. Some types of functional foods contain supple-
ments or additional ingredients intended to recover health. Recently, scientific
studies showed that functional foods rich in fruits and vegetables are important
having anticancer effects of phytochemicals which are also focused to aim cancer
stem cells (CSCs). Several preclinical and clinical investigations are still ongoing
J. K. Das (*)
Florida Memorial University, Miami Gardens, FL, USA
e-mail: jayanta.das@fmuniv.edu
T. L. Mathuram
Department of Biochemistry, University at Buffalo, Buffalo, NY, USA
A. D. Solano
M. Das
Ltd. 2023
206 J. K. Das et al.
on the effects of dietary phytochemicals on adult stem cells and the prevention of
aging and against CSCs of different cancers. The population of adult stem cells
(ASCs) is reduced, unable to regenerate and reprogram, and showed the failure of
tissue homeostasis during aging. The developing therapeutic methods with func-
tional foods could modulate the major signaling pathways of losing adult stem cell
populations, as well as could sustain healthy stem cell pool reprogramming to
increase human lifespan.
Keywords Antioxidants · Phytochemicals · Adult stem cells · Aging
11.1 Introduction
Upon hearing the term “functional food,” the vast majority will be puzzled, despite
them already knowing the meaning. Doubts may clear after hearing some examples
of commercialized products with the word “fortified” or “enriched.” Functional
foods are those nutritional products with an additional purpose besides providing
the consumer with nourishment. These products seek to help lower the risk of dis-
ease and contribute to health and well-being. Examples of these foods can be found
naturally, such as some fruits or vegetables, although there are also minimally pro-
cessed functional foods such as grains and legumes. Another puzzling yet famous
term to most is “stem cell.” This is yet another word multiple people hear daily, but
do not know its exact meaning. In biology, stem cells are those bases from which a
cell with specialized function derivates. A stem cell doesn’t have a specific function,
but grows, develops, and differentiates to create the different cells in our body, such
as skin, bone, blood, and muscle cells. There are different types of stem cells. For
instance, embryonic stem cells aid in embryonic growth and development, to create
a functional human that will develop to become a baby in the womb. These cells
have the ability to differentiate into any type of cell. In contrast, there are also adult
stem cells. These are present in adults in a moderate quantity and aid in cell replace-
ment, as opposed to growth and development. When the old cells in the body age,
stem cells help grow new ones to replace those which are now deteriorated.
Additionally, adult stem cells have a limited ability to differentiate, in comparison
with embryonic stem cells. As humans age, stem cells follow. When stem cells age,
they also slowly deteriorate, which affects their ability to differentiate and replace
old cells. Some reasons why stem cells age include cell cycle regulators, shortening
of chromosomes’ telomeres, DNA damage, signaling pathways, and other gene-
related factors. The aging of adult stem cells plays a role in many disorders related
to age. This has led many to inquire if there is anything that could be done to prevent
the aging of adult stem cells. Many believe functional foods could play a role in the
prevention of this issue. Scientific studies showed that aging is a risk factor for
chronic disease in humans and intercessions with functional food could reduce the
occurrence and harshness of many chronic diseases which should outcome in
healthy aging or “successful aging” (Franceschi et al. 2018a, b). Therefore,
11 Importance of Functional Foods Against Aging of Adult Stem Cells 207
nutrition/functional food would pay significantly to improved human lifespan and/

or healthspan (Baghdadi et al. 2022). The ASCs showed an important part in sus-
taining good health and have the ability to regenerate tissues and organs during the
lifespan. The onset and progression of chronic disease in humans showed reduced
sensory ability, response-ability, and pliability, along with increased organ system
haphazardness related to the post-maturation aging process (Tierney et al. 2018;
Lee and Kimmel 2020; Levy et al. 2020).
11.2 Different Functional Foods and Adult Stem Cell Aging
There are many different types of functional foods. Each has different character-
istics and molecules that act through different mechanisms and are important to
prevent aging in adult stem cells. Throughout this chapter, the effect of various
functional foods in regard to adult stem cell aging will be discussed to highlight
the importance of fortified foods and a good diet on longevity and aging
prevention.
11.2.1 Fruits
A common type of food consumed by many daily is fruit. Many know fruits are
healthy, but fail to understand how fruits contribute to health and wellness.
Fruits are the fleshy products of plants that contain seeds. For years, humans
have used fruits as means of nourishment. Fruits contain various nutrients essential
for life and cell maintenance, such as vitamins, potassium, dietary fiber, and folate.
In the adult stem cell context, many may have heard that fruits contain antioxidants
that help reduce aging. But what are antioxidants?
Antioxidants are stable molecules that bind to free radicals in the body. Free radi-
cals are molecules with unpaired electrons produced in the body due to metabolic
processes such as respiration and phagocytosis or caused by external factors such as
pollutants and radiation. Since free radicals have unpaired electrons, most are unsta-
ble and highly reactive. In biology, they can serve as powerful oxidants or reduc-
tants. When an imbalance of free radicals occurs in the body, free radicals can
damage DNA, throw off homeostasis, and negatively affect the macromolecules
necessary for cell survival. For a while, they have also been linked to cancer.
The condition caused by poor free radical balance is called oxidative stress.
Oxidative stress damages cells by deteriorating their membranes since they attack
the macromolecules from which they are composed, and it affects stem cells by
altering their differentiation and regenerative capabilities, leading to aging.
Antioxidants donate their electrons to the aggressive free radicals and neutralize
their negative effect on cells by breaking the chain of reaction, which prevents fur-
ther cell damage and hence reduces aging. If a sufficient amount of fruit is
consumed daily, the antioxidants present in them will keep a healthy balance of free
radicals in the body, preventing aging by giving stem cells the optimal biological
conditions required for proliferation (Lobo et al. 2010).
11.2.2 Vegetables
Another functional food group famously associated with optimal health is the
vegetable group. A vegetable is a part of a plant, such as the roots or leaves, used
for nutrition. There are many reasons why vegetables are considered ideal for
daily consumption. Vegetables are low in calories and contain essential nutrients
such as potassium, folate, dietary fiber, and vitamins A and C. In addition, vegeta-
bles contain another molecule that is not as well-known as the previously men-
tioned. Sulforaphane, or SFN, is an organosulfur and isothiocyanate which is
abundantly present in cruciferous vegetables, such as kale, cabbage, cauliflower,
bok choy, broccoli, and Brussels sprouts. It is the product of the hydrolysis of
glucoraphanin. SFN is known for having anti-inflammatory and antioxidant prop-
erties. These properties exhibited in SFN target the issues that lead to adult stem
cell aging, such as poor homeostasis, inflammation, and mitochondrial and genetic
modification.
For instance, during aging, proteasome activity declines, which leads to cell
stress due to an abnormal accumulation of damaged protein. However, SFN can
reactivate proteasomal activity through the reactivation of the NRF1 (Das et al.
2018, 2022) and Nrf2 molecule (a regulator of cellular resistance to oxidative dam-
age) through transcriptional regulation. Further research has also proven that mod-
erate amounts of SFN can prevent aging by protecting stem cells from senescence
and apoptosis. Plus, SFN is an antioxidant and hence protects DNA from oxidative
damage and modulates epigenetic modifications such as DNA methylation and his-
tone modification. It can also prevent skin aging by maintaining appropriate colla-
gen levels and protecting the skin against UV-ray damage through mechanisms of
action such as inhibition of AP-1 activation and expression of metalloproteinases
(Santín-Márquez et al. 2019).
11.2.3 Nuts
Nuts are fruits protected by a tough shell with an edible kernel inside. They are rich
in multiple oils, vitamins, and minerals the body needs to ensure proper physiologi-
cal function. Of all these nutrients, an important one for adult stem cells is alpha
lipoic acid, often abbreviated as ALA, an impactful molecule on human health.
Different organs in the body have various mechanisms of aging. When intestinal
stem cells age, the performance of the endocytosis-autophagy network declines,
which negatively affects the process of human digestion. Despite this, a proven way
to prevent these effects caused by aging is through the consumption of foods that are
high in alpha lipoic acid (ALA). ALA is an antioxidant made in the body, which can
also be present in enriched foods, especially nuts. It is an organosulfur deviated
from caprylic acid, used to break down carbohydrates and convert them into energy
used by the body. The importance of ALA for adult stem cells is that its oral admin-
istration has a positive effect on intestinal health by reversing age-associated hyper-
proliferation of stem cells. ALA does this by promoting the activation of the
age-degraded endocytosis-autophagy network.
It is important to note that humans naturally produce ALA. However, as the
human body ages, the production of ALA declines significantly. Hence, consuming
plenty of functional foods which contain ALA is crucial to prevent age-related dis-
orders and organic dysfunctions.
In addition to the benefits regarding intestinal health mentioned previously, ALA
has also proved to reduce the loss of hematopoietic cells. Hematopoietic cells are
those stem cells that differentiate into different types of blood cells, such as eryth-
rocytes, leukocytes, and platelets. ALA lowers ROS, or oxygen-containing reactive
species levels in the body, which affects apoptosis, and saves these cells (Du
et al. 2020).
11.2.4 Seafood
Seafood is food such as fish and shellfish. Throughout the years, various cultures
have used seafood and fish as their primary source of nourishment. Today, seafood
has proved to be extremely important for human health, especially in adult stem cell
aging. This is because seafood contains a type of fatty acid named omega-3, which
many may have heard of and used as a supplement. Omega-3 helps regulate the
growth of fat cells in the body.
Cells detect the omega-3 fatty acids through primary cilia, a type of organelle
acquired from evolution. Once these fatty acids are detected and bound to the recep-
tors on the cell, signaling encourages stem cell proliferation, which in return creates
more fat cells. Having a significant number of fat cells is extremely important
because when there are too few fat cells, as energy is stored in them, they get bigger.
These large fat cells are far from the oxygen supply, have poor signaling, and are
prone to bursting, which releases toxins in the body. Large fat cells are also associ-
ated with inflammation, insulin resistance, and diabetes.
Through seafood consumption, omega-3 fatty acids are acquired and healthy
stem cell proliferation is ensured. In addition, research has also proven that consum-
ing food rich in omega-3 can not only regulate fat stem cell proliferation but also
contribute to healthy neural stem cells and reduce triglycerides to prevent issues in
cardiac stem cell behavior (Birgisdottir and Johansen 2020).
11.2.5 Tea and Coffee
In various cultures worldwide, it is habitual to drink tea or coffee every day, espe-
cially in the mornings. Coffee is a beverage made from roasted and ground coffee
beans, while tea is the water-based boiled product of dry and crushed leaves of
specific plants. It has been argued in the scientific community that both beverages
contain substances such as caffeine that could be detrimental to human health.
However, the positive effects of consuming these drinks are often overlooked. In
the case of tea, it is a source of antioxidants, which, as previously discussed, can
slow down adult stem cell aging by preventing an excess of free radicals in the
body, which would otherwise damage cells and DNA. When it comes to coffee, it
has proven to prevent severe cardiovascular diseases and cognitive impairment
that would otherwise come as a consequence of aging. Coffee is known to contain
polyphenols which improve heart health and lower fat accumulation. In the case of
stem cells, caffeine can increase the phagocytosis of neutrophils in mesenchymal
stem cells, which can reduce the production of reactive oxygen substances.
Caffeine can also prevent dermal stem cells from aging by activating A2AR/
SIRT3/AMPK-mediated autophagy (a mechanism that protects stem cells from
oxidative stress).
11.2.6 Fortified Dairy (Low Fat)
In addition to coffee, another drink that many consume daily during breakfast,
sometimes even combined with coffee, is milk. Milk is a white fluid composed
mainly of fat and protein secreted by mammal mothers to nourish their newborn
offspring. Additionally, people may consume dairy products that are derived from
milk, such as cheese, yogurt, or butter. Dairy products are known to provide essen-
tial amounts of calcium for optimal bone health and proper child growth and devel-
opment. As a functional food, milk and dairy products have often added nutrients
such as vitamin D, vitamin A, folic acid, iron, and zinc. Many are not aware of the
significant benefit milk has when it comes to adult stem cell aging and its preven-
tion. The various nutrients in dairy products have been demonstrated to target the
main issue regarding aging, the shortening of the telomeres. As milk prevents this
change in the DNA, the aging process slows down since cells will not lose physio-
logical function caused by genetic material loss. Zinc, specifically, is required for
cellular division and proliferation. Without a significant amount of zinc in the body,
adipose-derived mesenchymal stem cells, or AD-MSCs, the type of stem cells
which can differentiate into neurons, can be impaired. In addition, milk is critical
for humans to keep good muscle health as the body ages. However, this only applies
to low-fat and nonfat milk, as high-fat milk tends to induce aging instead of prevent-
ing it, since it can cause oxidative stress and inflammation. Moreover, vitamin D
also plays a crucial role in adult stem cell aging, since it stimulates MSC osteogenic
differentiation, which can reduce aging by encouraging proliferation (Tucker 2019;

Moon et al. 2018; Mares 2016; Fujita et al. 2021).
11.2.7 Eggs
Eggs are oval or round objects laid by birds, fish, or reptiles. They contain a devel-
oping embryo inside, surrounded by a shell or a membrane, depending on the spe-
cies. Eggs are considered essential nutrients since they are a great source of protein,
selenium, phosphorus, choline, and vitamins. Eggs also can lower triglycerides
since they contain high-density lipoprotein, or HDL, a healthy type of cholesterol
essential for good heart health. When it comes to impeding damage to adult stem
cells to help prevent aging, eggs have vitamins like D, E, and A, which work as
antioxidants to combat free radical imbalance in the body to inhibit damage caused
by oxidative stress. This process has been demonstrated to prevent skin wrinkles in
adults. Additionally, eggs contain lutein and zeaxanthin, two naturally occurring
xanthophylls (oxygen-containing carotenoids). These carotenoids can also protect
the body from oxidative stress and contribute to optimal eye health by preventing
vision damage caused by aging, as they absorb damaging light.
Eggs also contain choline, a water-soluble and vitamin-like cation. It has been
demonstrated choline plays a critical role in neural stem cells by increasing prolif-
eration, differentiation, and maturation. This is because they are crucial for cellular
membrane synthesis and can regulate epigenetic pathways. For instance, they can
regulate DNA methylation, a process that plays a role in the differentiation of neural
stem cells by adding methyl groups to DNA (Soto et al. 2020).
11.3 Different Compounds of Functional Foods to Prevent

Adult Stem Cell Aging
11.3.1 Carotenoids
Plant-derived carotenoid—β-carotene—has been known to have ROS-quenching abil-

ity and hence has been used to treat erythropoietic protoporphyria (EPP) (rare inherited
metabolic disorder) (Krinsky 1989). Interestingly, in a study conducted by Cho et al.,
β-carotene increased type 1 collagen mRNA levels, thereby improving facial wrinkles
and rigidity in photoaged female subjects. However, due to its capacity to decrease
minimal erythema dose (MED), β-carotene made the skin more predisposed to
UV-induced erythema. A key factor is the dosage, as low doses (30 mg/day) seem to be
more beneficial in cutaneous photoaging compared to higher doses (90 mg/day), where
oxidative DNA damage is not significantly affected (Cho et al. 2010). Differentiation
studies conducted by Mahtab et al. showed significantly higher potential for differentia-
tion if mouse ciliary epithelium-derived MSCs into retinal cells (Haghighat et al. 2021).
11.3.2 Astaxanthin
Astaxanthin, a xanthophyll carotenoid found in bacteria, microalgae, and yeasts, is

an antioxidant with anti-inflammatory properties (Higuera-Ciapara et al. 2006).
Cho et al. found that astaxanthin along with collagen improves facial skin elasticity
and decreases MMP-1 and MMP-12 mRNA expression in human subjects (Cho
2014). Interestingly, it has been reported to induce proliferation of neural progenitor
cells (NPCs) via upregulation of stemness acting signals (OCT4, SOX2, Nanog, and
KLF4) (Kim et al. 2010a). Astaxanthin has also been reported to induce adipose-
derived mesenchymal stem cells potency (Choi et al. 2019). Astaxanthin has been
reported to improve motor impairments and activate mitochondrial biogenesis in
spinal cord injury (Mohaghegh Shalmani et al. 2020).
11.3.3 Polyphenols and Isoflavones
11.3.3.1 Resveratrol
Resveratrol is a polyphenol found in fruits and mainly in red wine with the ability
to possess anti-inflammatory properties and anticancer properties (Frombaum et al.
2012). Interestingly, resveratrol improves the functionality and facilitates the regen-
eration of autologous MSCs (Wang et al. 2018). Resveratrol a sirtuin 1 (SIRT1)
activator has also been reported to play a significant role in neuronal differentiation
with slightly increased calcium intensity (Songsaad et al. 2020). Resveratrol has
also been extensively reviewed to ameliorate oxidative stress and inflammation and
improve mitochondrial bioenergetics (Zhou et al. 2021).
11.3.3.2 Apigenin
Apigenin is a naturally occurring polyphenol with beneficial effects in diabetes,

Alzheimer’s disease, cancer, etc. (Salehi et al. 2019). Apigenin was also able to suc-
cessfully reduce Ca2+ signals and caspase-3/7-mediated apoptosis in iPSC-derived
Alzheimer’s disease neurons (Balez et al. 2016).
11.3.3.3 Luteolin
Luteolin is a flavonoid with anti-oxidative, anti-tumor, and anti-inflammatory

properties (Luo et al. 2017). Luteolin has been reported to promote proliferation
of skin epidermal stem cells through increased expression of β-catenin, c-Myc,
and cyclin expression (Wan et al. 2019). Luteolin has also been reported to mod-
ulate neural stem cell fate determination, thus placing itself as an astrocytogenic
potential (Achour et al. 2021). In PC12 cells, luteolin increased heme oxygen-
ase-1 (HO-1) mRNA and protein levels, thus enhancing the cholinergic activity
(Lin et al. 2010). Interestingly, luteolin has been reported to eliminate p53-depen-
dent hPSCs and not smooth muscle cells or perivascular progenitor cells (Go
et al. 2020).
11.3.3.4 Quercetin
Quercetin is a naturally occurring flavonol known for its anti-inflammatory and

wound-healing abilities (Salehi et al. 2020). Quercetin has also been reported to
affect adipose tissue aging by reducing senescence and oxidative stress and down-
regulates miRNA-155-5p, through the NF-κB and SIRT-1 (Zoico et al. 2021).
Another interesting observation was the ability of quercetin to rejuvenate senescent
fibroblasts (Chondrogianni et al. 2010). Quercetin can also induce dental pulp stem
cells upregulating stemness-associated genes (OCT4, NANOG, SOX2, and cMyc)
(Fageeh et al. 2021). Interestingly, quercetin stimulates bone marrow mesenchymal
stem cell differentiation enhancing BMP2, Smad1, Smad4, and other osteogenic
differentiation markers like RUNX2, OSX, and OPN (Pang et al. 2018).
11.3.3.5 Hesperidin
Hesperidin, a flavanone, is known to be a neuroprotective agent (Hajialyani et al.

2019). Hesperetin, a known metabolite of hesperidin, is also known to induce osteo-
genesis of human mesenchymal stem cells (Xue et al. 2017). Additionally, hesper-
etin has also been reported to alleviate signals that suppress osteogenic differentiation
in periodontal ligament stem cells by regulating ROS levels and cell proliferation
signaling pathways (Kim et al. 2013).
11.3.3.6 Taxifolin
Taxifolin is a strong antioxidant flavonoid known to improve skin viscoelasticity

(Micek et al. 2021). Interestingly, taxifolin also has been reported to protect dental
pulp stem cells under hypoxia and inflammatory conditions (Fu et al. 2021).
Osteogenic differentiation of human bone marrow mesenchymal stem cells has also
been reported by taxifolin via NF-κB pathway (Wang et al. 2017). As far as aging,
taxifolin reduces oxidative stress, thereby ameliorating d-galactose-induced aging
process through inhibiting Nrf2 (Liu et al. 2021).
11.3.3.7 Catechin
Catechin is a flavanol known to target neurodegeneration through antioxidant path-

ways (Farzaei et al. 2019). Epigallocatechin gallate (EGCG) a monomer is known
to have antiaging activities while exhibiting significantly higher EGFR proteins
(Chen et al. 2017).
11.3.3.8 Genistein
Genistein an isoflavone induces adipogenic differentiation from mesenchymal stem

cells by upregulating PPAR γ. It also significantly inhibited Runx2 and type 1 col-
lagen which are involved in osteogenic differentiation (Zhang et al. 2016). Genistein
could also be a promising anti-aging agent for the skin suggesting it prevents skin
aging after menopause for topical use.
11.3.3.9 Daidzein
Daidzein, an isoflavone, has been known to repress adipogenic differentiation of

human adipose tissue-derived mesenchymal stem cells through the stimulation of
lipolysis using Wnt/β-catenin signaling (Kim et al. 2010b).
11.3.3.10 Anthocyanins
Anthocyanins are water-soluble flavonoids, known to reduce aging-induced oxida-

tive stress and further induced autophagy via the AMPK pathway (Mattioli et al.
2020; Li et al. 2019). Anthocyanin has also been reported to accelerate NSC prolif-
eration while decreasing NSC senescence markers via downregulation of TNF-α
protein levels (Gao et al. 2020).
11.4 Molecular Biomarkers, Adult Stem Cell (ASC) Aging

Process, and Functional Foods
The ASC aging process is related with seven different mechanisms, namely, stem
cell enervation, reduced adaptation to stress, metabolic disquiet, damage of proteo-
stasis, epigenetic alterations, macromolecular injury, and inflammation (Stover
et al. 2022; Kim et al. 2010a; Kennedy et al. 2014). Therefore abovementioned
seven different mechanisms, associated biomolecular markers, as well as clinical
actions are also prognostic and typical of chronic disease illness and death (Arbeev
et al. 2016). There are several changes observed due to the onset and progression of
aging and chronic diseases, and those are mainly blood lipid levels, cardiovascular
performance indices (blood pressure as well as pulse rate), body mass index,
hypothalamic-pituitary-adrenal (HPA) axis activation, and inflammation, as well as
markers of organ system function (such as the kidney, nervous system) (Arbeev
et al. 2016; Partridge et al. 2018). Therefore, the identification of the causal and
predictive biomarkers of molecular stem cell signaling pathways is necessary to
prevent chronic disease and aging process and to initiate the development of effec-
tive lifestyle and/or pharmaceutical interventions by functional foods (Balez et al.
2016; Jia et al. 2017) (Fig. 11.1).
Fig. 11.1 ASC signaling with or without functional food during aging
The biomarkers for “biological age” have been demarcated with specific norms
by the American Federation for Aging Research as follows: (a) record the phases of
aging and expect mortality more consistently than linear age; (b) describe about the
output of a range of organ; and (c) authorize following changes over time (Balez
et al. 2016). The genes or metabolic pathways in the organ systems are altered dur-
ing aging process that should be explored more (Wagner et al. 2016). Therefore,
biomarkers will demonstrate the molecular mechanism of the damaging effects of
different risk exposures and will specify the efficiency of antiaging interventions
with functional foods to stop physiological deterioration and inability to reprogram-
ming of ASCs during aging. Finding and confirming specific ASC biomarkers of
aging through interposition investigations will augment the lifespan andwill avoid
diseases that are preferably aimed at younger persons specified that age-associated
chronic diseases consequence from any lifetime of exposures. Recently, the most
scientific studies of aging are completed within elder population who have previ-
ously established age-associated chronic diseases and therefore did not explain the
lifelong exposures that move the aging. One scientific study highlighted the rela-
tionship of disease biomarkers to biological age in the Dunedin cohort (the 38-year-
old birth cohort; New Zealand; 1972–1973) (Belsky et al. 2015). Belsky et al.
explained both the static “biological age” of the individuals in cohort and the more
dynamic “pace of aging,” or the rate of biological age changes. These determina-
tions showed different biomarkers of organ system function, cardiovascular health,
metabolism, inflammation, and DNA damage. The “multibiomarker algorithm,”
associated with the biological age of cohort individuals at the single time point by
joining all measurements from ten individual biomarkers, has been shown in the
data of National Health and Nutrition Survey (NHANES) (Belsky et al. 2015;
Levine 2013). The individuals in the cohort, restrained at age 38 years, were mostly
free of any chronic disease, and the mean biological age in the cohort was similar as
their chronological age. However, the distribution of biological age was calculated
from the multibiomarker algorithm range (21–61 years). The Dunedin cohort “pace
of aging” was shown in individuals over 12 years with additional period of the
study. The score of 18 biomarkers was observed on distinct elements of cardiovas-

cular, immune, organ, and metabolic function. The robust relationship between the
biological age and the pace of aging was found among the participants of chronical
age 26–38 years and showed the marked variation of the biological aging rate
among individuals in the cohort. The significant connections were reported between
the pace of aging and functional measures of successful aging, namely, cognitive
function and physical strength (Belsky et al. 2015). Therefore, the measures with
functional food consumption, status, and function are also judgmentally wanted.
Scientific studies also showed that the aging of human intestinal stem cells
(ISCs) stem cell biomarker, schlafen-3involved in to rise in colorectal cancer occur-
rence with age (Schultz and Sinclair 2016; Patel et al. 2009a, b), but this remains
hypothetical because it not yet identified how cells expressing mammalian ISC stem
cell markers alteration in occurrence and role with age. There are two interconvert-
ible populations of ISCs observed, namely, proliferative Lgr5-expressing cells in
the base of the crypt as well as quiescent label-retaining cells above the crypt base
(Takeda et al. 2011). Before these molecular biomarkers were found, irradiation
experiments recommended that the intestine was more delicate to damage with age
as the total number of clone-forming units or cancer stem cell numbers increase
(Martin et al. 1998).
The characteristic of hematopoietic stem cells (HSCs) aging showed twisted dif-
ferentiation latent. The aged HSCs have more tendency to differentiate as the
myeloid lineage (Rossi et al. 2005). This founding is fully reliable with the reflec-
tion that the adaptive immune system drops with age (Linton and Dorshkind 2004)
and also reported that acute lymphoblastic leukemia, the primarily juvenile disease,
drops with age, whereas the acute myeloid leukemia rises with age (Lichtman and
Rowe 2004). The aging of HSCs might subsidize to moderate anemia found among
elderly population (Guralnik et al. 2004). Therefore, more scientific investigations
are needed to find the intervention of differentiation both ISCs and HSCs by func-
tional foods during aging process (Table 11.1).
The DNA methylation, a repressive epigenetic biomarker of HSCs, declines in
aging, and the hypomethylation is linked to the proliferation of HSCs, indicating
why they are programmed to persist as quiescent (Beerman et al. 2013). The
H3K4me3, an epigenetic modulator (Ortega et al. 2020; Das et al. 2021a, b), is
Table 11.1 The changes of different types of stem cell population with aging
Names of stem cell population Population changes with aging; causes References
Germline stem cells (GSCs) Reduction; reduced differentiation Ryu et al. (2006)
Melanocyte stem cells Reduction; reduced differentiation Inomata et al. (2009)
Neuronal stem cells (NSCs) Reduction; reduced differentiation Ahlenius et al.
(2009)
Hematopoietic stem cells Rising, differentiation Beerman et al.
(HSCs) (2010)
Intestinal stem cells (ISCs) Rising, differentiation to cancer stem Patel et al. (2009a,
cells b)
Fig. 11.2 Changes of

epigenetic biomarkers
(DNA methylation,
H4K16Ac, H3K4me3, and
H3K27me3) in ASCs
during aging
highly expressed with age at loci that reprogrammed HSC self-regeneration,

potentially underlying the upregulation of HSCs found with aging (Sun et al.
2014). The reduction of H4K16Ac was found with aging in HSCs, and the inhibi-
tion of CDC42 returns the H4K16Ac levels to reprogrammed new population of
HSCs that converses the phenotypes of HSC aging in the transplantation studies
(Florian et al. 2012). The H3K4me3 levels modestly reduce with age, whereas the
levels of the repressive alteration of H3K27me3 rise with age, and it has also been
found that the expression of histones themselves reduces with age (Liu et al. 2013)
(Fig. 11.2).
11.5 Conclusions
The role of functional food in diet can be shown in the inhibition, management, and
the reverse of chronic diseases during aging. The recommended daily intake of
nutrients or nutrient reference values (NRVs) is offered to individuals and popula-
tions on intake levels of essential vitamins and minerals needed to avoid any nutri-
ent deficiencies. The United States National Academy of Sciences, Engineering
and Medicine established the framework entitled “Guiding Principles for
Developing Dietary Reference Intakes Based on Chronic Disease” in 2017. This
framework offers an approach for establishing nutrient intake recommendations
based on chronic disease reduction. The role of functional food needs in ASCs of
tissues for renewal as well as regeneration is developing as vital consideration in
starting nutrition necessities in chronic, acute disease and trauma recovery and dur-
ing aging. Therefore, the full potential for founding nutrient references for chronic
disease decrease will need the main developments in our empathetic of the biologi-
cal pathways and mechanisms of aging, ASCs, as well as chronic disease. Hence,
the functional food is essential in reducing the rates of aging.
Acknowledgments This work was part of the honors option project (HOP) of Andres Dominguez
Solano mentored by Dr. Jayanta K. Das, at MDC Eduardo J. Padrón campus, Miami, FL, USA.
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Chapter 12
Advantages of Functional Foods
in Supporting and Maintaining Hair
and Skin Health
Vijayalakshmi Muraleedharan, Gayathri S Kamath, Greeshma Sasikumar,

and Sreejith Parameswara Panicker
Abstract The skin, the body’s largest and most visible organ, is crucial in shielding
us from many external factors. Alterations in diet and current lifestyle exponentially
affect the organ’s degeneration. While many synthetic skincare products are avail-
able, their prolonged use can cause skin irritation, redness, peeling, the “bleach
panda” effect, blister formation, dark pigmentation, and more. Consequently, the
only cure is to utilize natural products and adopt a healthy diet. Degeneration is one
of the leading causes of skin and hair disorders and aging, which is affected by the
effect of both internal and external factors. So the mere intake of food is not suffi-
cient, but the intake of a nutritive and organized diet is necessary to trigger regenera-
tion and growth of the integumentary system. The term “functional foods” is used
to describe those that provide health benefits beyond those provided by their nutri-
tional value. Using them is a great way to treat health problems naturally. Wrinkles
and the aging process can be slowed or stopped using various nutraceuticals rich in
collagen, lipids, proteins, vitamins, and minerals. Plants like Hibiscus rosa, ginger,
grape (Vitis vinifera), etc. can delay aging and cease hair loss. The use of marine
goods such as seaweed, microalgae, corals, shelled organisms, etc. is very effective
in treating skin problems. Several of these have been shown to be effective in reduc-
ing hair loss. They promote hair development by activating potassium-ATP chan-
nels, decreasing 3-oxo-5-alpha-steroid 4-dehydrogenase activity, and increasing
Wnt/beta-catenin and extracellular signal-regulated kinase (ERK) activity. Collagen,
polyphenols, polysaccharides, lipids, vitamins, and minerals are some active ele-
V. Muraleedharan · G. S. Kamath · G. Sasikumar

Department of Zoology, University of Kerala, Thiruvananthapuram, Kerala, India
S. P. Panicker (*)
Advanced Centre for Regenerative Medicine and Stem Cell Research in Cutaneous Biology
(AcREM-Stem), University of Kerala, Thiruvananthapuram, Kerala, India
e-mail: psreejith@keralauniversity.ac.in
Ltd. 2023
224 V. Muraleedharan et al.
ments in functional meals that maintain the physique of skin and hair. Ayurveda and
regional foods and medicines have also been used to prevent skin and hair damage.
Having access to nutritious foods and ensuring timely consumption are fundamental
to maintaining a healthy lifestyle.
Keywords Nutraceuticals · Antioxidants · Regional food · Microbiome · Ethnic

food · Antiaging · Collagen synthesis
12.1 Introduction
The skin keeps the body safe from heat, light, cuts, and diseases. It is part of the
same system as the hair, nails, nerves, and glands. This system acts as a barrier
between us and the outside world (Yousef et al. 2017). Apart from the latter, it also
helps to regulate the body temperature, store water and fats, and prevent water loss
and the entry of microorganisms and produces vitamin D with exposure to the sun.
Human skin shows topographic differences in structure, i.e., a structural variation
from part to part. For example, the skin structure on the forehead and cheek differs
from that of the lips and their borders. There is seldom visible hair on the forehead
and cheek, whereas in the lips and its borders, hair is absent. In males, thick hair
growth is seen in the jaw regions when compared to low or no hair growth of females
(Montagna et al. 2021).
The layers of human skin can be into the epidermis, dermis, and hypodermis
(Prost-Squarcioni et al. 2008). The significant role of the epidermis is to produce
new skin cells; melanin, which defines the skin’s color; and protect the body from
the external environment. The epidermis primarily consists of keratinocytes which
act as a physical barrier against invading microorganisms, heat, UV radiations, and
water loss. It contains another type of cell called melanocytes which gives pigmen-
tation to the skin and also guards the skin against UV rays. The epidermis is devoid
of blood vessels. The epidermis consists of five strata: stratum corneum, lucidum,
granulosum, spinosum, and germinativum. Stratum germinativum or stratum basale
forms the epidermis’ innermost layer, and the basement membrane (basal lamina)
separates it from the dermis. Hemidesmosomes attach the stratum basale to the
basement membrane. Stratum basale includes cuboidal to columnar-shaped cells,
producing keratinocytes through continuous mitosis. Stratum basale also has
melanocytes.
The next layer forms the stratum spinosum, which contains spines and dendritic
cells, which are cytoplasmic processes and are made of polyhedral cells. These
spines extend toward the neighboring cells forming desmosomes. The third layer of
the epidermis, stratum granulosum, includes diamond-shaped cells with lamellar
granules and keratohyalin granules and contains glycolipids and the precursor mol-
ecules of keratin. Stratum lucidum is present only in regions where the skin is thick,
like in the palms and soles. This layer produces the transformation product of kera-
tohyalin, eleidin. The stratum corneum’s topmost layer is highly keratinized as it is
12 Advantages of Functional Foods in Supporting and Maintaining Hair and Skin... 225
made of horny scales of dead keratinocytes. The dead keratinocytes, also called the
anucleate squamous cells, secrete defensins that act as a first-line immune defense
(Yousef et al. 2017).
The dermis makes up the majority of the skin and serves as a barrier between the
body and the outside world (Montagna et al. 2021). The dermis is a layer of amor-
phous and fibrous connective tissue that has blood vessels, nerves, appendages from
the top layer of skin, fibroblasts, macrophages, and mastocytes. The most common
types of fibrous connective tissue are elastic and collagen tissue. The elastic connec-
tive tissue is made up of premature elaunin fibers, oxytalan fibers, and mature elas-
tic fibers that form a continuous network. Oxytalan fibers exclusively possess
microfibrils, whereas fully grown elastic fibers and elaunin possess both the compo-
nents of the microfibrillar and amorphous matrix (Prost-Squarcioni et al. 2008). The
dermis encompasses collagen and glycosaminoglycans, which can store a lot of
water and keep the skin turgid. The dermis is highly packed with blood vessels, and
the epidermis gets the nutrients through diffusion from the dermis. Nerves and sen-
sory organs are also found in the dermis at various levels (Montagna et al. 2021).
The hypodermis forms the thickest and innermost sheet of the skin which con-
nects the dermis to the muscles and the bones and is also known as the subcutaneous
fascia (Yousef et al. 2017). Fibroblasts, fat cells, connective tissue, bigger nerves,
blood vessels, and macrophages are found in the hypodermis, which supports the
immune system and protects against invaders. It contains fatty lobules and skin
accessory organs such as hair follicles, sensory neurons, and blood vessels (Yousef
et al. 2017). They store energy in the adipose tissue and regulate the body tempera-
ture by protecting against heat (by sweating) and cold (by insulating).
12.1.1 Skin: Accessory Organs
The skin’s accessory organs—hair, nails, sebaceous glands, and sweat glands—
embryologically develop from the epidermis, which is referred to as an “append-
age” because it can extend downward through the dermis into the hypodermis
(Gawkrodger and Ardern-Jones 2016). The skin appendages are a collection of
ectodermal origin appendages that include apocrine and eccrine glands, piloseba-
ceous units, nails, and ducts that are formed as epidermal down-growths during the
development. When an appendage is abrated, keratinocytes can move from the
appendage epithelium to the epidermal surface and reepithelialize it. Because the
face and scalp have more pilosebaceous units than the torso and limbs, which has
fewer appendageal structures, they reepithelialize faster (James et al. 2006).
Eccrine sweat glands are seen more on the feet soles and less on the back as they
regulate heat (Sato and Dobson 1970; Murphy 1997). Sweat glands are developed
from the epithelial cell layers that are extended downward from the dermal ridges
(Mauro and Goldsmith 2008). During development, this tubuliform structure is
transformed to produce the three combined sections of the eccrine sweat unit:
intraepidermal spiral tube, straight dermal part, and twined secretory duct. The
spiral duct is made up of dermal duct cells that have ascended and opened onto the
skin’s surface. Cornification occurs within the duct, and thus produced corneocytes
eventually form part of the cornified layer (James et al. 2006; Mauro and Goldsmith
2008). Eccrine glands are mainly responsible for heat regulation, whereas apocrine
glands are responsible for body odor. Apocrine sweat glands are mostly seen in the
axillae and perineum of humans. Like apoeccrine-eccrine glands, apocrine glands
are not exposed straight to the dermal surface. Instead, the intraepithelial duct goes
into the infundibulum above the sebaceous duct and opens into pilosebaceous fol-
licles (Murphy 1997). The AEG, apocrine sweat gland, originates from eccrine-like
precursors throughout puberty and opens straightly to the dermal surface. The
apoeccrine sweat gland was detected in the adult axillae while isolating the human
axillary sweat from patients with axillary hyperhidrosis. Axillary hyperhidrosis is a
condition in which the patient experiences a rapid increase in the perspiration rate.
The frequency of it varies from individual to individual. The AEG, as eccrine glands,
opens straight to the dermal surface. Because the apoeccrine sweat gland secretes
tenfold more than the eccrine gland, it is believed to endow axillary hyperhidrosis
(Mauro and Goldsmith 2008).
The pilosebaceous unit is made up of the follicle, sebaceous gland, shaft, and
arrector pili muscle (Agarwal et al. 2000). The hair follicle is epidermal in origin
and lengthens deep into the dermis and rarely into the subcutis for follicles that
produce terminal hairs. Meanwhile, vellus hair follicles only extend to the top retic-
ular dermis. The isthmus, infundibulum, and lower follicle are three major hair fol-
licle segments present on the head (Poblet et al. 2002). The infundibulum fragment
starts from the epidermis’ surface, which forms the top piece of the follicle and
lengthens to the sebaceous duct’s orifice. The isthmus is the space amidst the open-
ing of the sebaceous duct and the bulge. Finally, the inferior section of the hair fol-
licle extends from the bulge to the base. The bulb is included in this segment. It
contains the follicular matrix surrounding the dermal papilla’s sides and top. In the
dermal papilla, you can find capillaries. The matrix and the papilla work together,
and the papilla has the highest rate of cell division of any organ. The hair shaft is
made when matrix keratinocytes multiply in a hair that is growing. Melanocytes are
mixed with matrix cells to give the hair shaft its color (Glover et al. 2017; Tapia-
Paniagua et al. 2018).
The medulla is the innermost layer of the hair shaft. The cortex, the bulk of the
hair, encloses it. Shaft cuticle cells form a layer of cellular activity. Three layers of
cuticle are wrapped around the shaft to form the inner root sheath. After the hair
follicle emerges from the matrix, the inner sheath becomes a critical structural com-
ponent of the hair shaft. Keratinization of the inner sheath occurs inward and ends
at the follicle’s isthmus. Finally, the outer root sheath completely encases the hair
follicle. Trichilemmal keratinization occurs in this layer at the isthmus (Poblet et al.
2002; Tapia-Paniagua et al. 2018).
Sebaceous glands are holocrine glands that are seen with hair follicle and are
prominently found on the face and scalp. These gland cells are rich in lipid droplets
called sebum and are organized in lobules. These lipid-filled cells are produced by
basaloid germinative cells surrounding the lobule, and they are ejected toward the
infundibular region of the hair follicle along the sebaceous duct (Thiboutot 2004;
Danby 2005).
The arrector pili muscles attach to the papillary layer of the dermis and insert at
the level of the bulge. Sympathetic activation makes these muscles shrink in cold
weather. This lifts the skin’s level slightly and causes hair to stand erect, giving the
appearance of “goose bumps” (Poblet et al. 2002).
12.2 Degeneration and Regeneration of Skin
Degeneration is the thinning and deterioration of the skin and hair cells due to
intrinsic and extrinsic factors. The skin’s growth and development can cause the
skin’s expansion both intrinsically and extrinsically as the cells should expand
themselves to cover the skeleton and the tissues, which is undergrowth, and it has to
overcome the mechanical forces produced by the external environment. The degen-
eration of the skin occurs with aging. Aging is the major factor that contributes to
the degeneration process. During the process, the epidermal layers deteriorate,
thereby causing skin layer thinning. Degeneration leads to the early occurrence of
wrinkles, chronic wounds, loss of elasticity and plasticity, dryness, etc. Rather than
the skin, the hair follicle also undergoes degeneration once in 7–8 years. The hair
cycle includes anagen (growth phase), catagen (degenerative phase), telogen (rest-
ing phase), and exogen (shedding phase). When the hair follicles are retained in the
catagen phase, the hair growth rate retards, leading to degenerative diseases like
alopecia. Hair degeneration in alopecia is characterized by the apoptosis of kerati-
nocytes, melanocytes, dermal papilla, and Langerhans cells. In androgenetic alope-
cia, hair shaft thins, and the hair follicle undergoes degeneration leading to constant
hair fall. This is mainly due to the physiological changes caused by the binding of
androgens like dihydroxy testosterone to the androgen receptors. Degeneration can
also be due to the intake of an unhealthy diet that includes a high glycemic index,
processed foods, alcohol, fatty meats, and dairy products. To avoid degeneration,
the cells should be rejuvenated and should undergo regeneration (Meydani 2000;
Kartikey et al. 2019).
Regeneration is the process of restoration and replacement of lost or damaged
cells and their organization to retain its function. Regeneration is mainly studied for
treating injuries and diseases, thereby resulting in a new field of science called
regenerative medicine. Every organism has the ability to regenerate to maintain its
tissue organization and structure. Through regeneration, the injuries and the ampu-
tated body parts are repaired or regrown. The degree of regeneration decreases with
the increase in the complexity of the organisms. In higher organisms like mammals,
the regeneration is restricted to tissue repairing, wound healing, and the regrowth of
the skin and hair cells. They increase remodeling of the skin and the tissues which
promote wound healing. In hair, regeneration occurs when the hair follicle re-enters
the anagen phase after the telogen resting phase. Here the hair follicle stem cells
maintained in the bulge undergo continuous division to produce new hair. Skin cells
undergo rejuvenation every 27 days to properly maintain the skin structure. Recent
studies on skin regeneration have shown that 40–56 days is the average time taken
for the epidermis turnover. The period of epidermal turnover increases with age. As
age increases, the regenerative capacity of the individual decreases (Yu et al. 2008).
Stem cells play a significant role in tissue regeneration. The basal layers of the
epidermis contain stem cells that undergo rapid division to produce new cells which
differentiate to form various types of skin cells. The degree of keratinization and the
morphological and biochemical changes in such cells determine various layers of
the skin. So, skin cells are made at the base of the epidermis and moved to different
layers through a process called “differentiation.” This process ends with apoptosis
in the skin’s outermost layer. Collagen is a crucial part of tissue repair, so skin cells
should have it in adequate amount for wound healing. Regeneration takes place
through a cascade of processes that includes inflammation of the skin cells, prolif-
eration, and remodeling. Throughout these phases, collagen plays a crucial role in
tissue repair; in case of any deficiency, it can lead to chronic wounds (Mahjour
et al. 2012).
Food does play an important role in regulating the degeneration and regeneration
of skin and hair. Unhealthy diet can cause inflammation and premature aging of the
skin. Eating healthy can supply nutrients and minerals necessary for adequately
maintaining the skin and hair. It is necessary to have an adequate supply of nutrients
like vitamins C, B, and D, iron, zinc, and proteins to rejuvenate the skin and hair
cells. Proteins from fish, legumes, beans, low-fat meats, and dairy products can help
provide supplements necessary for regeneration (Takeo et al. 2015).
12.2.1 Human Skin Cell Aging: An Overview
Healthy skin is something that society strives for, and some people go to great
extents to attain it. As opposed to real age, the mere appearance of age predicts
crucial aspects of health and well-being (Porcheron et al. 2013). Skin beauty has
always been a significant indicator of one’s health that has existed in the course of
history and cultures. Furthermore, healthy skin influences social characteristics
such as self-confidence, charisma, and etiquette (Jones et al. 2016). The look of
youth and beauty can positively influence people’s social behavior and fecundity
(Blanpain and Fuchs 2006). Different elements, like skin disorders, individual char-
acteristics, and internal and external elements, influence skin aging (Tan et al. 2018).
12.2.1.1 Cutaneous Aging
The histological, morphological, and physiological skin changes caused by chrono-

logical and environmental factors can be defined as a skin cell or cutaneous aging. It
is the accumulation of various harmful changes in cells and tissues with increased
aging, leading to an increased risk of disease and death (Harman 2000). Cutaneous
aging results from a combination of biological aging and external aging influenced
by elements like UV radiation, smoking, pollution, and inflammation (Cho 2014).
Wrinkling, loss of elasticity, laxity, and a rough-textured look are all signs of skin
aging. The aging process causes phenotypic differences in skin cells and structural
and functional alterations in extracellular matrix elements, including collagen and
elastin (Zhang and Duan 2018). Cutaneous aging is caused by intrinsic and extrinsic
factors (Krutmann et al. 2017). Intrinsic aging is a natural physiological process that
makes the skin thin, dry, and prone to tiny wrinkles and dermal degeneration over
time. On the other hand, extrinsic aging is caused by factors like air pollution, smok-
ing, a unbalanced diet, and sun exposure, making the skin look rough, saggy, and
wrinkled (Huertas et al. 2016). Diet is an essential fact in the process of aging. A
poor and unhealthy diet can cause premature aging. It is important to have a nutrient-
rich and balanced diet for healthy aging. Healthy habits bring about healthy aging.
Using tobacco and alcohol can affect the lipid concentration of the skin and increase
skin necrosis and pigmentation and proliferation of keratinocytes (Cao et al. 2020).
Intrinsic Aging
Intrinsic skin aging is a physiological alteration that occurs throughout time. Photo-
protected areas, such as the palm, age mainly due to genetic or metabolic causes,
whereas exposed skin ages due to exogenous factors, particularly solar UV radia-
tion (Mancini et al. 2014). The most noticeable histological alterations in such aged
skin happen in the basal cell layer. According to studies, the proliferation of cells in
the basal layer decreases as people age (Makrantonaki and Zouboulis 2007). The
epidermis thins, and the surface area of touch between the corium and the epidermis
shrinks, giving a decreased area for exchanging the nutrition delivery to the epider-
mis and deteriorated basal cell growth (Moragas et al. 1993). Cellular senescence is
the process of cells such as keratinocytes, fibroblasts, and melanocytes losing their
ability to proliferate. There was a rise in the expression of the age marker-galactosi-
dase with age in dermal fibroblasts and epidermal keratinocytes in skin samples
from human donors of various ages, demonstrating that aged skin includes more
senescent cells (Dimri et al. 1995).
Extrinsic Aging
Extrinsic aging is mainly caused due to external factors like sun exposure, air pol-
lution, smoking, poor diet, and other factors like the impact of stress and sleep
deprivation (Wong and Chew 2021). External variables will have a long-term impact
on skin physiology (Tobin 2017). Excessive and unprotected sun exposure is the
primary cause of extrinsic aging (also known as photoaging), which is mainly
restricted to the face, neck, and hands, with the lower arms and legs less affected.
Low-grade chronic UVR exposure is responsible for over 80% of facial skin aging.
However, it induces sunburn, skin coloration, inflammation, immune suppression,
and harm to skin connective tissue (Leyden 1990; Young 2006). Coarse wrinkling,
rough texture, sallow complexion with uneven coloration, and loss of skin elasticity
are extrinsically aged skin characteristics mainly caused by UVR (Seité et al. 2006).
In pale-skinned Caucasians’ initial sign of extrinsic aging (on exposed sites) can be
observed during the early age of 15 years, although alterations to nonexposed areas
do not appear until the age of 30 (Grove 1989). Unfortunately, the great value placed
on the golden tan in Western culture is linked to the increased rates of skin cancer
and premature aging (Seité et al. 2006). Photoaged skin is characterized by deep
wrinkles, looseness, roughness, a sallow or yellow tone, increased fragility, the
development of purpura, mottled pigmentary changes, telangiectasia, slow wound
healing, and benign and malignant growths. The severity of these alterations is
determined by the amount of sun exposure accumulated over time. The second
major cause of extrinsic aging is cigarette smoking (Yin et al. 2000, 2001).
Wrinkles, laxity, and pigmentary abnormalities are some of the most noticeable
symptoms of aging on the skin (Halder and Ara 2003). Extrinsic and intrinsic fac-
tors can accelerate aging (Perner et al. 2011). The deterioration and fragmentation
of the dermal collagen matrix is a significant feature of aging skin (Fligiel et al.
2003). In aged skin, the destruction of the extracellular matrix guides to the destruc-
tion of fibroblasts in the dermis, as these cells no longer receive mechanical signals.
Collagen production is reduced as a result, and collagen-degrading enzymes (matrix
metalloproteinases) are increased (Varani et al. 2001, 2006).
It is challenging to design a diet to maintain young and healthy skin. Premature
aging is mainly caused due to the intake of unhealthy food along the diet. Healthy
skin can be maintained with the help of a proper diet. Maintaining antioxidant activ-
ity, tissue stability, regeneration, and the synthesis of various metabolites is neces-
sary to maintain healthy skin. Drinking water can maintain internal balance and
tissue functioning. Taking proteinaceous food along the diet can improve tissue
repair, protein synthesis, and physiological functions of the skin. Trace elements
like zinc, selenium, copper, and iron are essential for the synthesis of protein and
keratinocytes and the activity of the antioxidant enzymes of the skin. Vitamin-rich
diet is helpful for reducing lipid peroxidation, excreting reactive oxygen species,
collagen synthesis, and so on. An organized diet can prevent aging caused by exter-
nal factors with necessary supplements.
12.3 Nutraceuticals, Functional Foods, and Healthy Aging
Due to constant desquamation, which starts with the division of multiplying cells in
the inner layer to make keratinocytes that change as they are pushed outward by cell
divisions, the skin needs to be constantly renewed (Fuchs and Raghavan 2002;
Milstone 2004). The continuous renewal of the skin cells has functioned with the
help of various components that can be supplied through a healthy and nutritious
diet. The components like water, proteins, nutrients, and vitamins are necessary for
maintaining the proper health of the skin, which can be attained from various plants
and animals through diet, which is otherwise referred to as functional foods (Cao
et al. 2020). Nutraceuticals, another term for functional foods, offer a wide variety
of bioactive compounds that go beyond the nutritional benefits of individual foods.
Maintaining the skin’s internal balance and ensuring proper tissue functions are
crucial in the face of aging and inflammation, and water intake plays a vital role in
both (Palma et al. 2012, 2015). Proteins are the body’s metabolic, physiological,
and repair workers. Copper, zinc, iron, and selenium are some essential trace ele-
ments for healthy skin. Copper aids in the synthesis and stabilization of extracellu-
lar matrix and angiogenesis-related skin proteins (Borkow 2014). Epidermal
keratinocytes rely on zinc for proper differentiation and cell growth (Ogawa et al.
2016, 2018). In the skin, iron plays a significant role in how effective the enzymes
are at neutralizing free radicals (Reelfs et al. 2010). The antioxidant enzyme activity
of keratinocytes and their development are both aided by selenium (Sengupta et al.
2010). Vitamins A, B, C, D, and E are just as important for skin health as trace
elements.
Along with these valuable components, other components negatively impact
the skin functions, thereby damaging the skin. The components like fats, tobacco,
alcohol, sugar, and baked goods are all harmful to the skin (Cao et al. 2020).
Essential fatty acids like linoleic acid, omega-3 fatty acids, and omega-6 fatty
acids are involved in lipid synthesis in the skin and metabolism. However, high-
fat diet content can lead to skin inflammation (Balić et al. 2020; Zhang et al.
2015). Consumption of tobacco can alter the thickness of the cuticle and increase
skin pigmentation and necrosis (Dupati et al. 2014). Alcohol promotes the prolif-
eration of the keratinocytes and changes skin permeability. It destroys the skin’s
barrier function and affects the skin’s lipid composition (Park and Kim 2012).
Sugar products and baked foods are associated with the alteration of the skin
thickness, AGEs, autophagy, and inflammation of the skin (Nguyen and Katta
2015; Wu et al. 2019).
The free-radical theory states that DNA damage, inflammation, and lipid peroxi-
dation are the fundamental reasons for skin aging, disease, and malfunction. As a
result, a medical insurrection was centered on antioxidants and free-radical scaven-
gers for avoiding skin aging and treatment (Ratnam et al. 2006; Callaghan and
Wilhelm 2008). Oxygen-free radicals are present throughout the cellular processes.
They can react with DNA, proteins, and polyunsaturated fatty acids in the body,
resulting in DNA fragmenting, oxidative damage, protein-protein cross-linking,
protein-DNA cross-linking, and lipid metabolism oxidation. Reactive oxygen spe-
cies have been related to a variety of diseases like cardiovascular disorders, malig-
nancies, and the aging process. In vivo oxidation leads to organism’s aging.
Therefore, extracellular antioxidant supplements, with food as a significant source,
have become a research issue (Kandola et al. 2015). The following shows the influ-
ence of natural antioxidants (such as collagen peptides, polyphenols, vitamins,
polysaccharides, and fatty acids that are extracted from food products) on skin aging
(Cao et al. 2020).
Collagen is a long cylindrical polymeric protein seen as mammals’ wealthiest
and most readily scattered functional protein. Collagen is the main component of
the animal extracellular matrix (ECM) and has unique physiological functions. It
accounts for about 25–30% of total protein in mammals, whereas, in some
organisms, it can be up to 80% or more collagen. It is broadly used in tissue engi-

neering, medicine, cosmetics, food, and other fields (Nagai and Suzuki 2000).
Collagen peptides and other protein peptides may help to slow down the aging pro-
cess in three ways. After digestion and absorption, the protein or peptide enters the
bloodstream and subsequently acts as a precursor to collagen formation in the skin
fibroblasts, preserving the aged skin. Subsequently, when collagen peptides reach
skin cells, they have anti-senescent benefits by eliminating reactive oxygen species
(ROS), maintaining the cell’s inherent antioxidant defense system, and lowering
oxidative damage and inflammatory responses. Peptides that cross the cell mem-
brane have been shown to have multiple effects on the skin, including the promotion
of collagen and hyaluronic acid production, the suppression of inflammation
through the regulation of cytokines and the activation of TGF/SMAD or other sig-
naling pathways, and the prevention of collagen degradation through the suppres-
sion of the expression of proteases such as nuclear transcription-activating protein-1
(AP-1), MMP-1, and MMP-3 (Cao et al. 2020).
Polyphenols are plant secondary metabolites found in various foods, including
vegetables, fruits, tea, and other plants. Polyphenols have been one of the chief
substances utilized in cosmetics and nutritional cosmetology to counteract skin
aging due to their noticeable antioxidant effects. In recent years, flavonoids, tea
polyphenols, curcumin, grape resveratrol, and silymarin have been the much inves-
tigated antiaging polyphenols. Polyphenols have antioxidant and anti-inflammatory
properties that reduce oxidative damage and inflammation in the skin, primarily by
inhibiting collagen degradation, inhibiting inflammation, and increasing collagen
synthesis, including the regulation of cytokines, signaling pathways, and matrix
metalloproteinases (e.g., Nrf2, NF-B, MAPK, and others) (Chuang et al. 2017;
Davinelli et al. 2018).
Many vitamins are known for their antioxidant properties. They can minimize
ROS in aging skin cells to low-activity molecules and thereby reduce the oxidative
damage to critical constituents of skin cells. Coenzyme Q10, lipoic acid, and vita-
mins A, B (B3 and B12), D, C, and E have all been the subject of several scientific
investigations. The most popular antiaging medications that treat and slow skin pho-
toaging include retinoids (such as retinoic acid, which stops skin aging by modify-
ing genes and MMPs) (Fuchs and Green 1981; Fisher et al. 1999). B vitamins have
been demonstrated to slow down skin aging by reducing inflammation and pigmen-
tation (Brescoll and Daveluy 2015). Vitamin C is a potent antioxidant, and its con-
tent in the skin is linked to biological processes of the skin. It is frequently employed
as a positive control in skin aging tests. It works as an enzymatic factor and as an
antioxidant to increase collagen synthesis and eliminate cellular ROS, which helps
to retard the aging activity of the skin (Pullar et al. 2017). As light helps in the syn-
thesis of vitamin D, it also promotes skin aging. The conclusion that vitamin D can
cure skin photoaging appears to be paradoxical. On the other hand, vitamin D has
been shown to protect the skin by reducing DNA damage, inflammation, and photo-
carcinogenesis produced by UV rays (Gordon-Thomson et al. 2014). Vitamin E
protects the skin against chemical stressors and UV-induced irritation and damage
by blocking lipid peroxidation in the skin, which can be activated by combining
vitamins E and C (Schempp et al. 2012; Wu et al. 2013). Coenzyme Q10 is a vita-
min-like molecule in meat diets with antiaging properties (Suganuma et al. 2012).
Vitamins are frequently combined with other antioxidant compounds (such as col-
lagen, astaxanthin, carotenoids, and others) to boost their anti-senescent properties
due to their instability, limited water solubility, and low usage during storage (Cao
et al. 2020).
Polysaccharides are polymer carbohydrates made up of several monosaccharides
that have been dehydrated and condensed. Polysaccharides’ pharmacological prop-
erties, such as improved immune function, tumor and viral inhibition, glucose and
oxidant neutralization, blood cholesterol lowering, and low cytotoxicity, make them
a useful active component in functional foods and medicines (He et al. 2012). One
of the features of polysaccharides is antioxidant activity, which is beneficial for skin
aging. Lycium polysaccharides, agaric polysaccharides, lingzhi polysaccharides,
mushroom polysaccharides, and algal polysaccharides have been stated to deceler-
ate the aging process of the skin. Dietary polysaccharides help to enhance the
appearance of aged skin. Oral polysaccharides work by increasing the activity of
skin antioxidant enzymes, removing reactive oxygen species (ROS), and reducing
oxidative damage. They prevent apoptosis and modulate the production of Bcl-2,
Bax, and caspase-3 through triggering Nrf2/ARE and other pathways. Finally, poly-
saccharides prevent collagen deterioration by suppressing the development of
enzymes like MMP-1 and MMP-9, allowing for a constant collagen ratio, skin heal-
ing, and moisture retention (Wen et al. 2016; Ye et al. 2018).
Lipids are an essential component of the skin’s epidermal barrier function, the
structure of the membrane, internal environment balance, and damage repair. Aging
is associated with a decrease in fat content, primarily because of the loss in the abil-
ity of skin cells to generate and produce fat (Pappas et al. 2013). Furthermore, dietary
fat consumption is linked to the composition of lipids in the body and skin tissues. A
deficiency in necessary fatty acids or aberrant fat metabolism can result in signifi-
cant skin disorders (Horrobin 1989). Polyunsaturated fatty acids like omega-3 fatty
acids and omega-6 fatty acids are very important in human skin barrier function, as
well as preventing and treating skin inflammation (Balić et al. 2020). In mice, orally
administered olive oil inhibits skin aging caused by persistent psychological stress
via acting on the NF-B NRF2 pathway (Romana-Souza and Monte-Alto-Costa
2019). In mice, oral 7-MEGATM 500 (fish oil supplement with 50% palmitoleic acid,
omega-7) was demonstrated to reduce UV-B and H2O2-induced skin oxidative stress,
inflammation, and aging and promote skin regeneration (Song et al. 2018; Park et al.
2019). The anti-inflammatory effects of fatty acids derived from W. somnifera seeds
are enhanced on psoriasis by lowering the production of pro-inflammatory factors
(TNF- and IL-6) (Balkrishna et al. 2020). By decreasing the activity of PM2.5-
induced reactive oxygen species and matrix metalloproteinases and by stopping the
mitogen-activated protein kinase/activator protein 1 (MAPK/AP-1) pathway, fer-
mented fish oil protects skin against aging (Hyun et al. 2019).
Apart from those mentioned above, certain foodborne antioxidants and the com-
binational usage of several antioxidants have been reported to be effective against
skin aging. Recent studies have proved the usage of dietary probiotics and their
products against skin aging. Probiotic fermentation is an example in which it can

boost Agastache rugosa leaves’ anti-photoaging activity. In some, probiotic extracts
are used to treat early aging of the skin (Tsuji et al. 2018; Shin et al. 2018). Rather
than the contents mentioned above, there are furthermore plants and animal prod-
ucts that are functional foods used against skin aging.
Some active ingredients and their functions

Property of the
Active ingredients compound Functional food
Carotenoids, lycopene Antioxidant; Solanum lycopersicum (tomato), Daucus
anticarcinogenic; carota (carrot), Capsicum annuum (bell
anti-inflammatory; pepper), green leafy vegetable, fruits,
inhibits LDL oxidation palm oil
Curcuminoids, bis-p- Decrease lipid oxidation Curcuma longa (turmeric)
hydroxy-cinnamoyl
methane,
diferuloylmethane,
p-hydroxycinnamoyl
methane
Anthocyanin, catechin, Antioxidant activity; Peels, juice and wine of Vitis vinifera
cyanidin, flavanols, inhibits LDL oxidation, (red grapes), berries like Vaccinium sect.
myricetin, and quercetin superoxide scavenger Cyanococcus (blueberry), Rubus subg.
Rubus (blackberry)
Fiber phytochemicals Reduces total and LDL Oat cereals, fortified juices, Chondrus
cholesterol crispus (Irish moss)
Flavonoids (flavanols, Antioxidant; Apium graveolens (celery), Petroselinum
flavanones, flavanes, antiproliferative; crispum (parsley), citrus fruits, Allium
flavan-3-ol) antihypertensive; cepa (onion), Camellia sinensis (tea),
anticarcinogenic; Phaseolus vulgaris (green beans),
antithrombic; inhibition Theobroma cacao (cocoa), Solanum
of LDL cholesterol lycopersium (tomato), Malus domestica
(apple), berries like Vaccinium sect.
Cyanococcus (blueberry), Rubus subg.
Rubus (blackberry), certain beans, and
chocolates
Phenolic acids and Anti-inflammatory Coffea arabica (coffee), cereal brans,
monosaturated fatty acids fruits, black tea and green tea (Camellia
sinensis), and extra virgin olive oil
Sesaminol Inhibits LDL oxidation; Rice and rice oil (Oryza sativa), seeds
decreases cancer risk; and oils of sesame (Sesamum indicum)
stimulates growth
Stilbenes Antioxidant; protects Vitis vinifera (grapes), Arachis hypogaea
from cardiovascular (peanuts)
problems
Tocopherols, ubiquinol, Decrease blood Prunus dulcis (almond), nuts, flax seeds,
tocotrienols, ω-3 fatty cholesterol; inhibit lipid fish oil, olive oil, and fat
acids, phytosterols peroxidation
Source: Plaza et al. (2008), Siró et al. (2008), Gry et al. (2007), Shahidi and Ambigaipalan (2015),
Patil et al. (2009)
12.4 Functional Foods and Their Active Ingredients

with Antiaging Properties
The dietary fiber content of berries like raspberries and blackberries is high, and
they also contain essential micronutrients like vitamins C and K and the minerals
manganese and copper. It contains a wide variety of bioactive compounds, includ-
ing glycosides, steroids, terpenes, and phytochemicals. The skin benefits from these
substances’ anti-inflammatory, antioxidant, and antiaging properties. They cause
more dermal follicular cells to proliferate, as well as more collagen fibers and
growth factors to be produced (Zambrano et al. 2018).
Rice bran is high in macronutrients such as dietary fiber, proteins, and lipids.
Rice bran contains a wide range of bioactive chemicals, including antioxidants such
as ubiquinones, tocopherols, tocotrienols, and oryzanol. The nutraceuticals derived
from rice bran have anticancer, anti-inflammatory, and antidiabetic properties in
addition to antioxidant activity. They help enhance hair growth and prevent hair loss
by promoting the release of growth factors like VEGF, TGF, etc. (Danilenko et al.
1996; Sharif et al. 2014).
Ginseng is a Panax genus plant that has been used in traditional herbal treatment
for centuries. The primary bioactive components of ginseng include saponins like
ginsenosides. They are highly beneficial for body functions, including anticancer,
anti-fatigue, anti-obesity, anti-oxidative, antimicrobial, anti-inflammatory, antidia-
betic, and defensive effects on the immune system, respiratory system, neurologic
system, and cardiac system (Baek et al. 2016).
Stem cells extracted from plants are also extensively used in reducing aging. The
stem cells extracted from plants like Malus domestica, Vitis vinifera, and Saponaria
pumila were shown to have antiaging properties as they reduced wrinkle formation
and improved the activity of the epidermal stem cells. The extracts from ginger leaf
cells (Zingiber officinale) have glycerin extracts from other plants like Iris pallida,
Olea europaea, Hibiscus rosa, and Camellia sinensis that can also be used to pre-
vent aging (Miastkowska and Sikora 2018).
Marine products like seaweeds, shelled organisms, microalgae, corals, fishes,
eggs, etc. are highly useful in treating skin disorders. Various compounds derived
from the animals are known to prevent hair loss and aging. They help reduce
5-alpha-reductase activity, activate the ATP-potassium channels, and upregulate
ERK and Wnt/β-catenin pathways, promoting hair growth.
Because of its antioxidant capabilities, β-carotene has been shown to play a sig-
nificant role in the hindrance of inflammation and oxidative stress through its ability
to suppress the activities of singlet oxygen, oxidize, and scavenge free radicals.
Reactive oxygen species (ROS), such as organic peroxides, hydrogen peroxide,
superoxides, singlet oxygen, hydroxyl radicals, and peroxyl and alkoxyl radicals,
play a role in skin physiology. Nutritional supplementation or a diet rich in
β-carotene has been found to prevent early skin aging, skin cancer, and cellular
damage. β-Carotene is a 40-C chain (most of it has a straight-chain structure).
β-Carotene cannot be synthesized by the human body and should be obtained from
food sources. Pumpkin, sweet potato, spinach, carrots and carrot juice, turnip
greens, cantaloupe, and squash have all been found to contain β-carotene (Vollmer
et al. 2018).
Astaxanthin is a keto-carotenoid with a structure similar to -carotene. While
there are multiple astaxanthin stereoisomers in nature, the all-trans 3S,3S′astaxanthin
appear to be the most common molecular organisms in everyday foods, nutritional
supplements, cosmetics, and food industries. Haematococcus pluvialis (chloro-
phyte algae) is known to have a high quantity of astaxanthin, which can be used for
its production. By conducting electrons down the length of the molecule, 3S-3S′
astaxanthin orientation of the transverse cell membrane provides anti-inflammatory
or reduced oxidative stress. Plants, animals, and algae are all sources of astaxanthin.
Astaxanthin can be seen in a diversity of seafood, such as Salmo salar, Oncorhynchus
mykiss, Caridea, and Homarus americanus. There have also been reports of antiag-
ing effects in animal and human studies, including anti-inflammatory, antidiabetic,
anticancer, gastro-protective, ethyl alcohol and drug-protective, free-radical scaven-
ger, hepato-protective, skin-protective, eye (ocular)-protective, and skin-protective
effects (Vollmer et al. 2018).
12.5 Functional Food for Skin and Hair Regeneration
Regeneration is essential for the maintenance of healthy skin. It can be carried out
with the help of functional foods containing vitamin C, vitamin B, vitamin E, vita-
min A, alpha-lipoic acid, hyaluronic acid, and retinoic acid. Vitamin C or l-ascorbic
acid is highly seen in citrus fruits, cruciferous vegetables, Capsicum annuum (bell
pepper), Fragaria ananassa (strawberry), Solanum lycopersium (tomato), Solanum
tuberosum (potatoes), etc. Vitamin C during the inflammatory phase aids neutro-
phils’ death and subsequent clearance. Furthermore, it is essential for the synthesis
of collagen. Thiamine, riboflavin, niacin, pantothenic acid, pyridoxine, biotin,
folate, and cobalamin are all part of the vitamin B complex. They are rich in foods
like Salmo salar (salmon); Oncorhynchus mykiss (trout); leafy green vegetables like
Spinacia oleracea (spinach); Brassica oleracea var. viridis (collard); Brassica rapa
(turnip greens); Lactuca sativa var. longifolia (romaine lettuce); Leguminosae fam-
ily (legumes); liver and meat of animals like beef, chicken, lamb, and pork; milk and
milk products; oysters, clams, and mussels; egg; yogurt; fortified cereals; and sun-
flower seeds. Vitamin B helps cell proliferation and decreases inflammation, dry-
ness, and acne formation. Vitamin E is seen in seeds of Helianthus annuus
(sunflower) and Prunus dulcis (almond), Spinacia oleracea (spinach), Beta vulgaris
var. cicla (Swiss chard), Capsicum annuum (bell pepper), and Asparagus officinalis
(asparagus). Vitamin E is known to help moisturize the skin and also helps in modu-
lating cell signaling during wound healing. Vitamin A is seen mainly in vegetables
like Daucus carota (carrot), Ipomoea batatas (sweet potato), Cucurbita maxima
(winter squash), Cucumis melo var. cantalupensis (cantaloupe), Prunus ameniaca
(apricots), Brassica oleracea var. sabellica (kale), Brassica oleracea var. viridis
(collard greens), and Spinacia oleracea (spinach). Compounds like alpha-lipoic

acid, retinoic acid, and hyaluronic acids are also necessary to rejuvenate the skin
(Takeo et al. 2015; Yamada et al. 2021).
12.6 Regional Food and Skin Health
The digestive system plays a crucial role in skin health. Skin health can be main-
tained through proper nutrition, diet, and digestion. Gut, liver, stomach, and proper
bowel movement are necessary for glowing skin. People from different regions add
a range of dishes—known for their nutrient richness—to their diets for better diges-
tion and health.
The Mediterranean diet (a dietary pattern) is gaining favor as a way to prevent,
cure, and manage several health problems. The diet includes mainly a glass of red
wine per day; a high intake of fruits, vegetables, and virgin olive oil; a high intake
of fruits, vegetables, and virgin olive oil; and a limited intake of fish and meat. The
Mediterranean diet mainly includes virgin olive oil as it has a high level of benefi-
cial phenolic compounds. The high quantities of resveratrol and lycopene in red
wine and tomatoes are also important. People who ate a Mediterranean-style diet
rich in vegetables and herbs had a 56–57% lower risk of getting androgenetic alope-
cia. In a C57BL/6 mouse model, hair growth can be promoted using Lycopersicon
esculentum extracts. The administration of Lycopersicon esculentum extracts
resulted in enhanced VEGF, KGF, and IGF, leading to enhanced hair growth both
histologically and via gene expression. Red oranges, an essential part of the
Mediterranean diet, have been proven to impact keratinocyte populations in the epi-
dermis favorably. The red-orange extract treatment in human keratinocyte cell lines
helped to decrease the inflammatory activity, as mentioned by inflammatory mark-
ers (Fortes 2018).
Indian diet is rich in minerals and nutrients that are highly useful for skin health.
The Indian diet includes quality food like yogurt, turmeric, fruits, leafy vegetables,
green tea, cucumber, fish, and meat. Yogurt is rich in probiotics that enrich the gut
microbiome, which helps appropriately digest food. Usually, every Indian meal
contains yogurt as a dish. It helps in preventing the dryness of the skin, and it
enhances the radiance of the skin. Green leafy vegetables like Spinacia oleracea
(spinach), Coriander sativum (coriander), Murraya koenigii (curry leaves), and
Brassica oleracea var. italic (broccoli) are rich in vitamins and minerals. Indian
dishes like palak paneer, thaali meals, or Sadhya are rich in leafy vegetables, fruits,
and Indian spices that are known for their antioxidant properties. Fruits like Citrus
sinensis (orange), Citrus limon (lemon), Vitis vinifera (grapes), etc. are rich in vita-
min C. Malus domestica (apple), Actinidia deliciosa (kiwi), and berries are good for
clear and radiant skin. Dishes are primarily prepared with turmeric. Turmeric is
known for its antibacterial, antifungal, and anti-inflammatory properties and helps
in clear and radiant skin. The skin benefits from the inclusion of Camellia sinensis
(green tea), Cucumis sativus (cucumber), and Aloe vera in the diet since these foods
contain vitamins A, K, and C and help to prevent skin issues including wrinkles,
acne, dark spots, and wrinkle formation (Kaur and Kapoor 2003; Krishnaswamy
2008; Mukherjea et al. 2013).
Like homeopathy, Chinese medicine, and western medicine, Ayurveda is a medi-
cal practice that has a natural solution for most skin and hair issues without causing
many side effects. Ayurveda classifies individuals into three main doshas: Vata,
Pitta, and Kapha. These three doshas determine the type of the individual and the
treatment in Ayurveda is carried out based on these doshas. According to these
doshas, the characteristics of the skin and hair of the person can differ from dry and
rough to oily and cold. Basically, every skin type should be nourished with appro-
priate nutrients, as eating healthy can make the skin healthy. The diet should include
components with anti-inflammatory, antiaging, and rejuvenating properties that
keep the integumentary system intact. Natural products like turmeric, saffron, tulsi,
sweet potatoes, and bell peppers are rich in nutrients that efficiently rejuvenate the
skin and reduce pigmentation, acne formation, and blemishes. Fruits and vegetables
rich in vitamins A and C and those that can help in collagen and protein synthesis
can keep the skin and hair healthy. Fishes like salmon, mackerel, and herring are
known for the presence of the omega-3 fatty acids that are necessary for skin and
hair regeneration (Hazra and Panda 2013).
12.7 Gut Microbiome Modulations and Skin
Gut microbiomes play a significant role in skin health. The trillions of microorgan-
isms that make up the gut and skin microbiota come in hundreds of diverse strains
and coexist in a complex ecological ecosystem. These microbiotas, as well as their
metabolic waste products and interactions with the host, directly influence healthy
physiology and disease. Skin illnesses such as atopic dermatitis, psoriasis, acne
vulgaris, dandruff, and even skin cancer are promoted by dysbiosis in the skin and/
or gut microbiome, which is linked to an altered immune response. The makeup and
metabolic processes of the gut microbiome are greatly influenced by diet and probi-
otics, which influence the skin. The bacteria in a person’s gut—Bacteroidetes,
Firmicutes, Actinobacteria, and Proteobacteria—can change over time, but adults
typically have a diverse mix of these four types. Some believe that the gut and the
skin are connected in a two-way communication pathway that allows for a variety
of neurological and immunological responses to shifts in the microbiota (O’Neill
et al. 2016). The mechanisms by which the gut flora may affect the skin include
neurotransmission, anti-inflammatory effect, and increased intestinal permeability.
To a person’s general and intestinal immune systems, the gut microbiome’s function
in regulating epithelial cell renewal and intestinal integrity is critical. So, the gut
microbiome is essential in maintaining skin and hair health. Food products contain-
ing dietary fibers, a protein-rich diet, probiotics, and prebiotics help in the mainte-
nance of healthy and valuable microbiomes in the gut (Yan et al. 2017; Lunjani
et al. 2019).
12.8 Nanonutraceuticals and Good Health
Marrying nutraceuticals to nanotechnology, we get the alluring field of nanonutra-

ceuticals. The term “nutraceutical” refers to bioactive ingredients that provide
health benefits above and beyond their nutritive value. However, they fall short as
far as the bioavailability of these compounds is concerned. Nanotechnology helps
us effectively encapsulate these bioactive ingredients in nanocarriers that winnow
the challenges. Such thoughtful techniques bring about effective delivery of the
concerned compound alongside enhanced bioavailability (Shende and Mallick 2020).
12.8.1 Ethnic Foods to Combat Skin Aging
Ethnic communities around the globe have, in their culinary repository, a concate-
nation of recipes for what has now been called “ethnic foods.” Such foods, originat-
ing from the rich cultural past, have many lesser-known ingredients, some of which
could potentially cure chronic human diseases. Ethnic cuisines predate our current
understanding of ingredients, and an extensive study of the same could open a win-
dow to cure many dreaded lifestyle diseases (Kwon 2015; Shukla 2021).
12.9 Rasayana Therapy and Healthy Aging
The Rasayana therapy is a rejuvenating Ayurvedic therapy to slow down the multi-
faceted aging process using a combinatorial formulation of Rasa, the essence of
nutrition, and Ayana, the channel or tracts of the body. Such therapies are promising
in the face of accelerated aging and deteriorating skin vitality. Rasayana therapy
aims at holistic mind-body recuperation by targeting the system as one comprehen-
sive entity. All this and more, the future of Rasayana therapy looks bright enough
(Singh and Rastogi 2011).
12.10 Conclusion
Healthy skin is something that society strives for, and some people go to great
extents to attain it. Furthermore, it influences social characteristics such as self-
esteem, attractiveness, and behavior. To produce healthy skin, cosmetic companies
produce products made of synthetic compounds like hydroquinone, ascorbic acid,
and retinoic acid, which may have harmful effects on the skin. On continuous use,
these synthetic compounds cause skin irritation, redness, excess skin peeling, bleach
panda effect, blister formation, dark coloration, etc. The natural compounds are
highly useful in preserving healthy skin and hair. The utilization of functional foods
which contain high nutritional value is very much valuable for maintaining healthy
skin and hair. The plant-derived compounds from rice bran, Mediterranean diet,
berries, ginger, and aloe vera are rich in collagen, elastin, polyphenols, and vita-
mins, which can increase collagen production. Marine organisms are also rich in
compounds that improve skin health. So, it is always better to switch to functional
foods as they are perfect for healthy skin and hair. They trigger the regrowth of the
skin and hair cells with the help of the corresponding stem cells within the organ.
Ayurveda is another medical care that can implement skin and hair care via natural
products. So, the proper rejuvenation of the integumentary system at regular inter-
vals is necessary which can be attained by having a nutritive and healthy diet as they
can provide the necessary supplements in the most efficient way than any skin care
product.
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Chapter 13
Delineating the Role of Phytochemicals
in Targeting Age-Related Cardiovascular
Diseases Through the Lens of Network
Medicine
Monojit Kamilya , Asim K. Duttaroy , and Subhajit Dutta
Abstract The most significant risk factor for cardiovascular disease is, sadly,
aging, which is an unavoidable aspect of life. There are still many open concerns
regarding how the genetic processes governing aging in model species affect cardio-
vascular aging, even though countless studies in the cardiovascular area have taken
into account both young and old humans. Similar to this, there isn’t much research
that comprehensively evaluates how these longevity pathways affect cardiovascular
health in the field of the molecular biology of aging. Thankfully, this chasm is start-
ing to close, and these two fields are combining. We present an overview of some of
Monojit Kamilya and Subhajit Dutta contributed equally with all other contributors.
M. Kamilya
Department of Biotechnology, National Institute of Technology,
College of Medicine and Health Sciences, University of UAE,
Al Ain, Abu Dhabi, UAE
A. K. Duttaroy
e-mail: a.k.duttaroy@medisin.uio.no
S. Dutta (*)
Department of Biotechnology, National Institute of Technology,
Functional Genomics and Metabolism Research Unit, Department of Biochemistry and
Molecular Biology, University of Southern Denmark, Odense M, Denmark
e-mail: subhajit@bmb.sdu.dk
Ltd. 2023
246 M. Kamilya et al.
the central genes involved in regulating longevity pathways, including insulin-like

growth factor 1, AMP-activated protein kinase, forkhead transcription factors, sirtu-
ins, and mammalian target of rapamycin, as well as their implications in cardiovas-
cular health. In addition, we provide insight into network medicine-based approaches
to identify additional genes connected with longevity genes within an interactome
space that are involved in regulating the age-related cardiovascular signaling axes.
In this context, we addressed many in vitro, in vivo, and human clinical trial studies
to better appreciate how essential phytochemicals can be in the fight against age-
related cardiovascular disorders.
Keywords Aging · Cardiovascular disease · Longevity genes · Network medicine

Phytochemicals
13.1 Introduction
Over the years, one of the primary causes of mortality and morbidity around the
globe has been cardiovascular diseases (CVDs). The World Health Organization
(WHO) estimated that approximately 18 million deaths which account for more
than 31% of all deaths worldwide were caused by CVD in 2019, and every year the
numbers are rising steadily (WHO 2021). Cardiovascular diseases are more preva-
lent in elderly people than in younger ones across all sex (Our World in Data 2022).
A study from Global Burden of Disease (Roth et al. 2020) reported that the number
of prevalent cases of CVD has nearly doubled from 271 million cases to 523 million
cases, with around 12.1 million to 18.6 million global deaths in 1990 and 2019,
respectively, the rate of which is climbing substantially every year (Fig. 13.1).
Almost all nations outside of high-income countries continue to see an increase in
the burden of CVD, and alarmingly, the age-dependent rate of CVD has started to
rise in some places where it was previously declining in high-income nations (Roth
et al. 2020).
Additionally, the cost of treating cardiovascular disease will soon soar to unprec-
edented heights (North and Sinclair 2012). Therefore, we must still comprehend
why aging is such a crucial factor in the etiology of CVD. But until recently, study-
ing the biology of aging and the pathophysiology of cardiovascular diseases
remained largely separate fields. The majority of rodent studies on atherosclerosis
or cardiomyopathies were conducted in young mice, whereas genetic studies on
increasing longevity rarely assessed whether CVD or heart function is improved.
Nevertheless, current findings linking cardiovascular disease to aging are springing
up. In this book chapter, we understand the interrelation between aging and cardio-
vascular diseases using concepts of biological network theory, discuss a few essen-
tial longevity genes that have controlling action on both lifespan and cardioprotective
properties, and introduce the role of phytochemicals in treating age-related cardio-
vascular disease signaling axes.
13 Delineating the Role of Phytochemicals in Targeting Age-Related Cardiovascular… 247
Fig. 13.1 Age-related global deaths from cardiovascular diseases (in millions) from 1990 to 2019.
(Adapted from IHME, Global Burden of Disease, 2019)
13.2 The Link Between Aging and CVD
With advancing age, several physiological processes degrade, eventually culminat-

ing in illness and severe health issues. In the process, the cardiovascular systems are
significantly impacted, increasing the risk of cardiovascular diseases like athero-
sclerosis, hypertension, myocardial infarction, and stroke (Lakatta and Levy 2003).
Aging causes a decrease in cardiac output, which causes the myocardium to be
stimulated to grow muscle by undergoing cardiac hypertrophy. Although this may
momentarily increase cardiac output, the long-term effects of hypertrophy weaken
the heart’s capacity to pump blood effectively (Levy et al. 1988). Contrarily, with
growing age, vascular dysfunction triggers diverse pathological manifestations,
such as inadequate tissue perfusion and vascular development leading to ischemia
and hypertension, respectively. Following tissue damage, the endothelial cells cease
to multiply and migrate (Wessells et al. 2004). Furthermore, nitric oxide synthase
(eNOS) activity in endothelial cells also decreases with cellular aging, resulting in
less NO, a vasodilator involved in various pathological manifestations like abnor-
mal cellular proliferation, thrombotic events, etc. (Collins and Tzima 2011).
The cardiac system faces complicated alterations that influence its cellular
makeup as it ages. In the process, the increase in apoptotic and necrotic events
causes a decrease in cardiomyocytes, which are also vulnerable to oxidative stress.
In older adults, oxidative stress is generally higher, leading to the formation of reac-
tive oxygen species (ROS), which kills cardiomyocytes and mediates significant
changes in cardiomyocyte functions. However, a recent study shows that eliminat-
ing senescent cardiomyocytes may not be the only way to correct heart
abnormalities in some aging models (Chimenti et al. 2003). Understanding the rela-
tionship between aging and CVD (AGE-CVD) will require measuring cardiac-spe-
cific senescence, DNA damage, levels of apoptosis, and necrosis, along with fibrosis
assessments in aging animal models. Senescence is accompanied by the expression
of essential genes, including p53, p21, p16, and senescence-associated-galactosidase
activity, which immunoblotting or histological techniques detect.
Although being assumed to be post-mitotic, cardiomyocytes divide and regener-
ate, and studies have revealed cardiac regeneration as one of the critical mechanisms
for sustaining cardiovascular health. However, in the elderly, the regeneration rate
may not be sufficient to maintain cardiomyocyte numbers in response to cardio-
myocyte loss (Anversa et al. 2006). A small pool of cardiac stem cells and a minor-
ity of tiny, incompletely differentiated cardiomyocytes that can reenter the cell cycle
are thought to be involved in heart tissue regeneration.
It is widely acknowledged in aging and cardiovascular disease that a low-calorie
diet and regular exercise will lengthen mammals’ healthy lives. But obesity and a
sedentary lifestyle have the reverse impact. The conventional understanding holds
that CVD is triggered by an accumulation of cholesterol and fatty acids in tissues
which impairs tissue function and stimulates the generation of inflammatory cyto-
kines and ROS. However, a diet high in calories without exercise may be harmful
because it suppresses the expression of “longevity genes,” which support cellular
defenses against aging and age-related cardiovascular diseases (Sinclair 2005).
13.3 Involvement of Longevity Genes and CVD
A variety of longevity genes have been found in model species apart from humans,
which includes the yeast Saccharomyces cerevisiae, the nematode Caenorhabditis
elegans, and the fly Drosophila melanogaster. Many of these genes and the linked
pathways have since been investigated for their function in controlling mouse lifes-
pan and to start investigating their involvement in cardiovascular disease (CVD).
13.3.1 IGF-1
IGF-1 was one of the first genes identified as a longevity gene, with knockout result-
ing in an increase in lifespan in C. elegans (Kenyon et al. 1993). Furthermore, it was
discovered that genes associated with the IGF-1 pathway are associated with lon-
gevity signaling axes and functions by upregulating mTOR activity (Fig. 13.2a, b)
via the regulation of Akt activity. A pleiotropic role of IGF-1 was observed where
its overexpression in the mice heart reduced ventricular dilation, hypertrophy, and
diabetic cardiomyopathy while also preventing myocardial cell death after infarc-
tion (Li et al. 2007). On the other hand, a study reported that overexpression of the
same gene resulted in ventricular hypertrophy, failure, and delayed recovery of
Fig. 13.2 (a) Pathway enrichment analysis of longevity genes associated with cardiovascular dis-
eases. We generated the enrichment plot using the web tool Web-Gestalt (http://www.webgestalt.
org/) accessing KEGG pathways, and pathways having FDR q-value < 0.05 were considered sig-
nificant. (b) Construction of a longevity subnetwork. Longevity genes involved in lifespan and
related cardiovascular diseases were mapped to protein-protein interactome (PPI) to generate a
subnetwork that shows interconnections among sirtuins, AMPK (PRKAA1), IGF1, FOXO, and
mTOR. We retrieved the interactome from the String database (13,478 nodes and 647,548 edges)
and implemented the subnetwork using Gephi software
heart function following an acute ischemia challenge (Prele et al. 2012). The dele-
tion of the IGF-1 homologue (InR) in Drosophila sp., which has a primitive cardio-
vascular system, delayed the effects of aging on the fly cardiovascular system
(Wessells et al. 2004). Even though it has been demonstrated that the IGF-1 path-
way is crucial for controlling cardiovascular health, more investigation is needed to
fully comprehend the mechanism and explain the discrepancies that have been
observed.
13.3.2 AMPK
Several studies suggest the involvement of AMP-activated protein kinase in different

signaling pathways associated with longevity, autophagy (Fig. 13.2a), lipid and glu-
cose metabolism, gene expression, cellular polarity, and cell growth. AMPK pro-
motes mitophagy and the formation of new mitochondria via activating mitochondrial
biogenesis (Hardie 2011). By assessing the relative AMP:ATP ratio, AMPK
(PRKAA1) serves as a metabolic sensor within the longevity subnetwork. It controls
mTOR by phosphorylating the TSC1/2 complex directly (Fig.13.2b). AMPK has a

regulatory effect on the IGF-1 pathway through the extracellular signal-regulated
kinase (Erk) cascade, and by adjusting the levels of NAD and nicotinamide phos-
phoribosyltransferase, it regulates sirtuins activity. AMPK protects the heart from
damage during ischemia and reperfusion. Myocardial infarction aggravated in
mouse models with dominant-negative AMPK (Russell et al. 2004). It has been
observed that metformin which activates AMPK minimizes pressure overload-
induced ventricular hypertrophy in mice (Zhang et al. 2011). Mutations in the regu-
latory two subunits of AMPK (PRKAA1/PRKAA2) cause a hereditary disease with
hypertrophic cardiomyopathy and ventricular pre-excitation (Blair et al. 2001).
13.3.3 Forkhead Transcription Factors (FOXOs)
FOXOs are one of the major transcription factors associated with the expression of
the genes involved in cell growth, proliferation, differentiation, and lifespan
(Fig. 13.2a). FOXOs are also downstream effectors of the IGF-1 signaling cascade
and are controlled by sirtuins-mediated deacetylation (Fig. 13.2b). FOXO1 deletion
causes embryonic fatality in mice, resulting in poor vascular and cardiac growth,
including an underdeveloped dorsal aorta and defective cardiac looping (Furuyama
et al. 2004). A cardiac-specific overexpression of FOXO1 results in embryonic
lethality, reduced myocardium thickness, heart size, and heart failure. In mouse
hearts, FOXO3a expression decreased cardiomyocyte size and suggested the role of
FOXO in preventing cardiac hypertrophy (Potente et al. 2005). More investigation
is required to fully comprehend the function of these transcription factors in regulat-
ing cardiovascular development, process, and disease and to clarify how FOXO
factors interact with other downstream members within the longevity subnetwork in
cardiovascular tissues.
13.3.4 SIR2
Sirtuins are NAD-dependent deacetylases and ribosyltransferases that remain con-

served throughout evolution. Seven sirtuins (SIRT1–7) are found in mammals that
govern a wide range of cellular processes, including DNA damage repair, cell cycle,
metabolic response to nutrition availability, defense against neurological deteriora-
tion, and, most importantly, longevity (Fig. 13.2a). From yeast to mammals, sirtuins
have been demonstrated to control aging. Nevertheless, several studies have con-
firmed that sirtuins are essential to the longevity subnetwork (Fig. 13.2b). Through
deacetylation of the liver kinase B1, SIRT1 has been shown to regulate the AMPK
pathway (Zu et al. 2010). SIRT1 modulates the IGF-1 pathway via regulating UCP2
levels and directly influencing the IGF-1 signaling pathway. Additionally, SIRT1
interacts with TSC1/2 by reducing mTOR activity. SIRT1 knockout mice exhibit
increased injury in response to ischemia-reperfusion studies, whereas SIRT1 trans-

genic mice exhibit reduced harm with regard to cardiovascular illness development.
Mice that overexpress SIRT1 exhibit delayed age-dependent cardiomyopathies and
reduced stress-induced apoptosis. However, a 20-fold increase in SIRT1 overex-
pression led to cardiomyopathy, oxidative stress, and apoptosis (Kawashima et al.
2011). Even SIRT1 has been found to control the development of blood vessels in
zebrafish. By avoiding arterial calcification brought on by hyperphosphatemia,
SIRT1 also regulates artery stiffness. SIRT3 is located in the mitochondria, and
knockout mice show age-dependent as well as exercise/pressure overload-induced
cardiac hypertrophy. On the other hand, SIRT7 knockout mice experience an
upsurge in fibrosis, heart hypertrophy, and inflammatory cardiomyopathy.
Cardiomyocytes exhibit increased apoptosis and lower oxidative stress tolerance in
SIRT7 knockout mice. The molecular processes by which sirtuins regulate the heart
and vasculature are still poorly understood, even though sirtuins have various effects
on cardiovascular health.
13.3.5 Target of Rapamycin (TOR)
The bacterial product rapamycin inhibits the serine-threonine protein kinase known
as target of rapamycin (TOR). The conserved gene TOR controls cell size, growth,
proliferation, longevity (Fig. 13.2a), motility, protein synthesis, and transcription by
integrating insulin, growth factor signaling, and intracellular amino acid level moni-
toring. It has been noted that rapamycin administration or TOR deletion can lengthen
life in flies, yeast, worms, and mammals. mTOR typically functions as an effector of
upstream sirtuin/AMPK/IGF-1 activity within the longevity network (Fig. 13.2b).
Inhibiting mTOR signaling in the heart suppresses pressure-induced cardiac hyper-
trophy, possibly through limiting mTOR control of protein translation and cell
growth. Furthermore, mTOR controls hypoxia-inducible factor-1 to mediate
hypoxia-induced angiogenesis in tumors through its participation in the PI3K/AKT
signaling pathway. When mTOR is inhibited, either by nutritional deprivation or by
the drug rapamycin, autophagy is activated, allowing for the degradation of damaged
molecules and organelles and enhancing the health of cardiovascular tissues (Halapas
et al. 2008). The PI3K/AKT/mTOR pathway is at the confluence of many signaling
pathways, making it an essential mediator of aging and the cardiovascular system.
These five genes and evidence from different studies also shed light on the
involvement of Pit1, Clock1, p66shc, and catalase genes in AGE-CVD pathophysi-
ology. Network-based strategies shall help identify other novel proteins (or genes)
associated with essential longevity genes and predict possible metabolic reactions,
protein-protein interactions, protein-transcription factor interactions, protein-
protein co-expression, and disease-drug interactions with AGE-CVD signaling
axes. The use of principles of network theory in understanding the causes and mech-
anisms of diseases has led to the emergence of a new avenue called “network
medicine.”
13.4 Emerging Role of Network Medicine in the Treatment

of Human Diseases: AGE-CVD
Barabási AL et al. (Barabási et al. 2011) developed and expanded the concept of
network theory to explain how disease-relevant genes interact in an interactome. It
relies, in essence, on the hypothesis that a disease phenotype results from a compli-
cated network of genes interacting with one another. The players involved in the
pathophysiology of a disease have a propensity to group together in this process in
a nonrandom manner. We refer to these nonrandom clustered subnetworks as dis-
ease modules because they cooperate together to contribute to the phenotypic pre-
sentation of the disease. It has been discovered that within such networks, genes
linked to the disease not only have a tendency to remain proximal but are also
intricately interconnected with each other. The network theory also hypothesizes
that a disease module may contain clusters of potential therapeutic targets linked to
that disease module (Dutta et al. 2022). We may postulate that for phytochemicals
to be effective against age-related cardiovascular diseases, they must target genes
that are inside or proximal to the disease modules.
Systems-based techniques are likely to become more essential in revealing the
higher-order interactions underlying features, including atherosclerosis, cardiac
hypertrophy, cardiovascular system complexity, and cardiovascular system and car-
diovascular illnesses. These methods must be useful in the real world because they
provide a framework for designing therapeutic interventions and put the numerous
genetic variants linked to disease in a biological context. In cardiovascular research,
network medicine has several uses, such as identifying novel disease mechanisms,
redefining complex clinical entities, predicting patient outcomes, finding novel bio-
markers, and discovering and repurposing drugs. To dissect complex mechanisms in
coronary artery disease and myocardial infarction (MI), for example, network con-
struction and analysis using the existing inflammation- and MI-related PPIs revealed
a few highly interconnected but distinct modules with unique biological properties
and endophenotypes, such as coagulation, cell death, wound healing, and immune
responses. On the other hand, pulmonary arterial hypertension (PAH) is now con-
sidered to be a complicated disease distinguished mostly by the interaction and
cross-talk of numerous pathogenic signaling pathways. About 25% of patients with
suspected idiopathic PAH will have an identified pathogenic variation (e.g., BMPR2,
EIF2AK4, SOX17, others). Early studies on network medicine in pulmonary vascu-
lar disease addressed posttranscriptional events relating to BMPR-2 bioactivity and
found that hypoxia, inflammation, or genetic BMPR-2 inhibition upregulates
miR-21 in pulmonary artery endothelial cells (Parikh et al. 2012).
Considering the molecular relationships between the targets of polyphenols and
the proteins linked to diseases, a network medicine-based framework has already
been used to identify the mechanisms by which polyphenols improve health. The
proximity of disease proteins to the polyphenol targets within a human interactome
strongly indicates the molecule’s potential therapeutic benefits. The study con-
firmed established relationships between epigallocatechin-3-O-gallate and type 2
Fig. 13.3 Sankey diagram illustrates the positive benefits of potential phytochemicals on the age-
related cardiovascular system mediated by the AMPK/SIRT1 signaling axes
diabetes and predicted that rosmarinic acid directly influences platelet function,
offering a novel mechanism through which it may impact cardiovascular health (do
Valle et al. 2021). These phytochemicals target the CVDs by modulating the lon-
gevity signaling axes (described in Sect. 13.5, Fig. 13.3), and it can be presumed
that predicting phytochemicals through network medicine-based approaches will
reveal the downstream gene associations, molecular mechanisms, and other under-
lying complexities associated with age-associated cardiovascular diseases.
13.5 Phytochemicals in the Treatment of AGE-CVD
Plants supply essential nutrients for life and additional bioactive phytochemicals
that promote health and prevent diverse diseases. In the context of cardiovascular
disease, dietary food supplements containing phytochemicals are doing a remark-
able job as antioxidants by scavenging reactive oxygen species, which is detrimen-
tal for tissues in age-related cardiovascular disease and reduces the risk of it. The
phytochemicals can reduce inflammation and modulate mitochondrial function in
the human body. Various studies have proved that phytochemical plays a pivotal role
in modulating cell signaling pathways. Resveratrol, curcumin, Brassica oleracea
(BO), and berberine are engaged in various cardioprotective events (Table 13.1) and
are the most studied phytochemicals in age-related cardiovascular diseases. Network
medicine, which interprets diseases to be the result of perturbed interconnections
Table 13.1 Essential phytochemicals targeting age-related cardiovascular disorders

SR.
no. Phytochemicals Source Targets Cardioprotective properties
1 Resveratrol Peanuts, SIRT1, AMPK 1. Shows antihypertensive
Polygonum properties where it impacts the
cuspidatum, sympathetic nervous system and
berries, grapes, causes blood pressure to fall
and their 2. Protects against ischemic heart
processed disease, and a lower dose is
products effective against myocardial
infarction, stable angina, and
acute coronary syndromes
3. Prevents heart hypertrophy and
dysfunction
2 Sulforaphane and Brassica NF-κB, Nrf2, 1. Consumption of dried broccoli
anthocyanins oleracea MAPK, JNK, sprouts significantly increases
AKT/PKB, and glutathione which activates the
AMPK/SIRT1/ heart
PPARA/UCP2 2. Anthocyanins support ideal
platelet function and have
antithrombotic properties
3. 150 mL of kale juice per day
for 12 weeks dramatically
decreased the risk of coronary
artery disease in
hypercholesterolemic males
4. Consumption of anthocyanins
(8.4–23.6 mg/day) has been
linked to decreased arterial
stiffness and central blood
pressure in females
3 Curcumin Curcuma p38MAPK, 1. Smaller doses were linked to
longa AMPK/UCP2, more significant reductions in
JAK2/STAT3, total HDL and LDL cholesterol
AKT/NRF2, levels in acute coronary syndrome
ICAM-1, ERK, 2. With a single dose of 15 mg/kg
JNK, IL-8, and curcumin, superoxide anion,
MCP-1 xanthine oxidase,
myeloperoxidase, and lipid
peroxides appear to be decreased
4 Berberine Hydrastis Nrf2, AMPK/ 1. Most of the 100 arrhythmic
canadensis MAPK/SIRT1 patients who received berberine
treatment had their premature
beating reduced by >89%
2. Significant decrease in total
cholesterol, triglycerides, and
LDL cholesterol levels, as well as
a small but significant increase in
HDL cholesterol
3. Berberine functions by
reducing inflammation
(continued)

SR.
no. Phytochemicals Source Targets Cardioprotective properties
5 Epigallocatechin Camellia IκB kinase, cJUN, 1. Older persons drinking five or
gallate (EGCG) sinensis AP1, FAS more cups of green tea daily had
receptor, STAT1, a significantly lower mortality
catalase, HO-I, rate related to cardiovascular
and Nrf2 disease
2. EGCG therapy affects VSMC
migration and proliferation,
which slows the development of
atherosclerosis
3. Slows down the heart’s aging
6 Quercetin Apples, AMPK/SIRT1 1. Quercetin consumption was
grapes, citrus found to be inversely related to
fruits, berries, hypertension in both animal
onions, and models and humans
others 2. Decreases ventricular
hypertrophy by largely
modulating angiotensin II
3. Inhibits telomere shortening to
lower cardiac myocyte apoptosis
LDL low-density lipoprotein, HDL high-density lipoprotein, VSMC vascular smooth muscle cells
across various interrelated biological components, is essential to understanding age-

related clinical manifestations and cardioprotective effects of plant-derived
phytochemicals.
13.5.1 Resveratrol
Resveratrol is one of the most extensively studied polyphenols in age-related car-

diovascular research, commonly found in peanuts, Polygonum cuspidatum, berries,
grapes, and their processed products. Resveratrol (3,5,4′-trihydroxy-trans-stil-
bene) appears with both cis and trans configurations, with trans-resveratrol being
the most physiologically active. Resveratrol, present in red wine, was assumed to
be one of the reasons for France’s low CVD incidence, and the suggested amount
of 20 mg/kg/day of resveratrol daily was thought to provide adequate protection.
The SIRT1/AMPK pathway is the primary molecular mechanism mediating the
biological effects of resveratrol (Fig. 13.3) (Cao et al. 2014). Resveratrol triggers
SIRT1, but the underlying mechanism by which it does so is not well understood.
Resveratrol’s most significant health benefits are related to oxidative stress, vascu-
lar inflammation, and platelet aggregation. It upregulates the superoxide dismutase
enzymes in endothelial cells (ECs) and cardiac myoblasts and downregulates ROS
production. Resveratrol alters the activity of cyclooxygenase-2 (Cox-2) and phos-
pholipase A2 and also inhibits inflammatory mediators like tumor necrosis factor-α
(TNF-α), nuclear factor-κB (NF-κB), interleukin-6 (IL-6), monocyte chemotactic

protein-1 (MCP-1), and inducible nitric oxide synthase (iNOS) activity (Zarzuelo
et al. 2013). Resveratrol alters ROS formation and platelet-mediated signaling by
increasing nitric oxide production (Table 13.1). Several studies shed light on the
downregulation of protein kinase C activation and intracellular calcium release,
which results in the blockage of phosphoinositide metabolism.
13.5.1.1 Hypertension
Resveratrol shows antihypertensive properties by both endothelium-independent

and endothelium-dependent mechanisms. It participates in VSMC (vascular smooth
muscle cell) contractility inhibition via decreasing the expression of vasoconstrictor
molecules like angiotensin-II and endothelin-1. It takes the route of the extracellular-
signal-
regulated kinase (ERK1/2 pathway) to suppress the endothelin-1 gene
expression (Liu et al. 2003). This overall process impacts the sympathetic nervous
system, which causes blood pressure to fall.
13.5.1.2 Atherosclerosis and Dyslipidemia
Resveratrol inhibits the expression of intercellular adhesion molecule-1 (ICAM-1)

and vascular cell adhesion molecule-1 (VCAM1) on endothelium and increases the
hepatic absorption of low-density lipoprotein (LDL) through an AMPK-independent
mechanism in the very early stages of atherosclerosis. Additional in vitro investiga-
tions have shown that resveratrol inhibits the production of MCP-1 and chemokine
receptor type 2 in monocytes, most likely through the phosphatidylinositol 3-kinase
(PI3K)/protein kinase B (PKB or Akt) pathway (Cullen et al. 2007). Resveratrol
inhibits oxidized LDL uptake and increases cholesterol transporters’ expression,
which limits foam cell development. A conventional dose of resveratrol (20 mg/kg/
day) has been demonstrated to have hypocholesterolemic effects in several in vivo
investigations. The phytochemical boosted the expression of cholesterol-7-
hydroxylase (CYP7A1) in the liver of high fat-fed rats, which resulted in increased
bile acid production and secretion, decreasing plasma total and LDL choles-
terol levels.
13.5.1.3 Ischemic Heart Disease
Preclinical studies shed light on multiple mechanisms that explain how resveratrol
protects against ischemic heart disease. Nitric acid (NO) and antioxidant enzyme
heme oxygenase-1 (HO-1) appear to be the primary mediators of the precondition-
ing effect of resveratrol. Through an increase in oxidative-stress-related proteins
like Trx-1 and HO-1, resveratrol boosted VEGF expression in cardiomyocytes and
endothelial cells (Wang et al. 2007). Resveratrol administration significantly
improved the altered microRNA expression in the ischemic heart. Few clinical trials
with favorable outcomes examined the effectiveness of resveratrol at conventional
and lower dosages in patients with prior myocardial infarction, stable angina, and
acute coronary syndromes.
13.5.1.4 Hypertrophy and Heart Failure
There is evidence that resveratrol prevents heart hypertrophy and dysfunction.

The underlying molecular mechanism relies on the reduced expression of the
hypertrophic genes, and increased Ca2+ handling subsequently lowers the oxida-
tive stress.
13.5.2 Sulforaphane and Anthocyanins
The active secondary metabolites sulforaphane and anthocyanins obtained from

Brassica oleracea have an essential role in age-related cardiovascular disease.
The NF-κB, Nrf2, MAPK, JNK, AKT/PKB, and AMPK/SIRT1/PPARA/UCP2
(uncoupling protein-2) are some of the molecular targets of phytochemicals of
Brassica oleracea. These genes participate in different molecular signaling axes
exhibiting antioxidant, anti-inflammatory, and antithrombotic properties
(Table 13.1).
Sprouted broccoli possesses essential cardioprotective properties. The active
constituent sulforaphane boosted the expression of many nuclear factors, including
Nrf2, which is involved in ROS eradication (Fig. 13.3), and upregulation of detoxi-
fication enzymes, the so-called “ARE” (antioxidant response element) targets. The
most common “ARE” targets are nicotinamide adenine dinucleotide (NADH), qui-
none reductase, HO-1, and glutathione transferase. Sulforaphane activated Nrf2,
reducing the synthesis of VCAM-1, thereby preventing p38MAPK expression in
endothelial cells. With the consumption of dried broccoli sprouts, a significant
increase in glutathione content was observed along with increased glutathione
reductase and peroxidase (GPx), which activates the heart. In 32 hypercholesterol-
emic males, 150 mL of kale juice per day for 12 weeks dramatically decreased
plasma LDL cholesterol and elevated HDL cholesterol and GPx activity, decreasing
the risk of coronary artery disease (CAD). On the other hand, anthocyanins support
ideal platelet function and possess antithrombotic properties. They upregulate
MCP-1 secretion in primary human endothelial cells and exhibit a protective effect
against TNFα. Anthocyanins inhibited VEGF expression in vascular smooth muscle
cells (VSMC) driven by PDGF-AB with p38MAPK and c-JNK suppression.
Consumption of anthocyanins (8.4–23.6 mg/day) has recently been linked to
decreased arterial stiffness and central blood pressure in females (Pagliaro et al.
2015). More studies on human subjects are required to understand the mechanism
of action by which it controls AGE-CVD.
13.5.3 Curcumin
Diferuloylmethane, commonly known as curcumin, is a phenolic phytochemical

extracted with yellow color from spice turmeric. This chemical has gained a lot of
attention because of its diverse biological and immense pharmacological effects,
particularly in inflammatory diseases. There is mounting evidence that curcumin
may play a role in preventing many CVDs. The molecular targets of curcumin are
p38MAPK, AMPK/UCP2, JAK2/STAT3, AKT/NRF2, ICAM-1, ERK, JNK, IL-8,
and MCP-1 (Duan et al. 2012) (Table 13.1, Fig. 13.3), and these genes are involved
in various antioxidant and anti-inflammatory signaling axes. With a single dose of
15 mg/kg curcumin, superoxide anion, xanthine oxidase, myeloperoxidase, and
lipid peroxides appear to be decreased, whereas glutathione-S-transferase, catalase,
SOD, and GPx appear to be enhanced. In acute coronary syndrome (ACS) patients,
the impact of curcumin administration on lipid profile was assessed at ascending
levels (low dose, three times 15 mg/day; moderate dose, three times 30 mg/day; high
dose, three times 60 mg/day). This study unexpectedly demonstrated that smaller
doses of curcumin were linked to more significant reductions in total HDL and LDL
cholesterol levels. On the other hand, in a diverse population, a meta-analysis could
not demonstrate the preventive benefits of curcumin on the levels of cholesterol and
triglycerides. However, more investigation is required to understand the mode of
action and the signaling axes through which curcumin targets AGE-CVD.
13.5.4 Berberine
Traditional Chinese treatment has an ancient legacy of using berberine, an alkaloid

derived from Hydrastis canadensis, and many other plants belonging to the
Berberidaceae and Ranunculaceae families. Several studies suggest that berberine is
helpful in the treatment of hyperlipidemia and cardiac conditions. Upregulation of
SOD and UCP2 and downregulation of NADPH oxidase expression, particularly
about NADPH oxidase 2/4 subunits, appear to be the key molecular mechanisms
mediating antioxidant effects (Table 13.1). The Nrf2 pathway, which is essential for
antioxidant and anti-inflammatory activity, is activated by berberine treatment (Mo
et al. 2014). By AMPK-dependently suppressing the MAPK pathway expression,
berberine may reduce inflammation. The majority of the 100 arrhythmic patients
who received berberine treatment had their premature beating reduced by >89%,
while the remaining patients had their premature beating reduced by >50%. These
outcomes were verified separately. There was a significant decrease in total choles-
terol, triglycerides, and LDL cholesterol levels, as well as a small but significant
increase in HDL cholesterol, according to a meta-analysis that included 11 random-
ized controlled studies and 874 Chinese participants with hyperlipidemia, type 2
diabetes, or both diseases. The network-based analysis will provide an in-depth idea
of berberine targets-age-related cardiovascular disease relationship.
13.5.5 Epigallocatechin Gallate: EGCG
Epigallocatechin gallate is a phytochemical abundant in green tea, Camellia sinen-

sis. A study reported that older persons who drank five or more cups of green tea
daily had a significantly lower mortality rate related to cardiovascular disease.
EGCG reduces inflammation by indirectly controlling NF-κB and angiotensin II. In
addition, EGCG impacts endothelium and smooth muscle cells’ IκB kinase, cJUN,
AP1, FAS receptor, STAT1, catalase, HO-I, and Nrf2. Additionally, EGCG therapy
affects VSMC migration and proliferation, which slows the development of athero-
sclerosis (Table 13.1, Fig. 13.3). It has been demonstrated that EGCG inhibits
cyclins D1 and E, resulting in a G1 arrest. EGCG modulates platelet function by
regulating PDGF, which subsequently regulates ERK1/2, cFOS, and EGR1 mitotic
genes. EGCG activates ERK1/2, which downregulates IκBα, NF-κB, TNFα,
IL-12p40, and p38MAPK pro-inflammatory genes and reduces inflammation
(Stangl et al. 2012). The advantages of incorporating EGCG in a daily diet cannot
be overstated because it is beyond question that it has a preventive impact against
the development of cardiovascular disease and slows down the heart’s aging.
13.5.6 Quercetin
Quercetin is a plant flavonol in various fruits and vegetables, such as apples, grapes,
citrus fruits, berries, onions, and others. Plums, like broccoli and green and black
tea, contain quercetin, the most prominent polyphenol accounting for almost two-
thirds of the polyphenolic content. Quercetin is associated with decreased levels of
plasma lipid peroxidation. Quercetin consumption was found to be inversely related
to hypertension in both animal models and humans. It inhibits clotting by competi-
tively binding plasminogen and modulating plasmin levels via urokinase plasmino-
gen activator (uPA) regulation (Mozzicafreddo et al. 2008). The anti-proliferative
impact of quercetin on VSMC is predominantly achieved through inhibiting the
JNK and AP-1 signaling pathways (Table 13.1, Fig. 13.3). Additionally, it has been
shown that quercetin decreases ventricular hypertrophy by largely modulating
angiotensin II and inhibiting telomere shortening to lower cardiac myocyte apopto-
sis. However, more studies must be conducted to elucidate the mechanism of action
of quercetin in AGE-CVD.
13.6 Conclusion
Despite being an inherent cardiovascular risk factor, aging may outweigh all other
risk factors taken together. Therefore, gaining a better knowledge of the fundamen-
tal processes at a molecular level that control aging could result in considerable
improvements in both the preventative and therapeutic management of cardiovascu-

lar disease. In this book chapter, we shed light on the studies that possibly link aging
to cardiovascular diseases and offer insight into novel and intriguing areas to
research by combining these two closely related fields of study. Many mechanistic
investigations and drug development efforts have recently relied heavily on gene
associations predicted by various interactomes. We shed light on using the concepts
of the network biology approach to identify the hidden complexities associated with
AGE-CVD signaling axes. We presented different preclinical studies to understand
the effect of the most essential phytochemicals, such as resveratrol, sulforaphane,
curcumin, berberine, EGCG, and quercetin, on age-related cardiovascular diseases.
The antioxidant, anti-inflammatory, and antithrombotic characteristics appeared to
be the most important. Researchers and clinicians tested the effects of phytochemi-
cals on humans as a result of the excellent outcomes of both in vitro and in vivo
investigations. However, there is ongoing debate regarding the limited clinical trial
data on the preventive effects of these substances in several CVDs. The critical
drawback of current clinical trials is the variability and limited sample size of these
studies. Therefore, there is a need for more extensive and well-controlled human
clinical trials. Moreover, we may adopt different network medicine-based strategies
and machine learning approaches in the future to predict potential phytochemicals
that can target the deregulated signaling axes associated with age-related cardiovas-
cular diseases.
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Chapter 14
Plant-Derived Natural Products Targeting
Multiple Pathways as Potential
Therapeutics in the Treatment
of Parkinson’s Disease
Amulya Vijay and Anandan Balakrishnan
Abstract Parkinson’s disease (PD) is a chronic neurodegenerative disorder (ND)

characterised by gradual degradation of dopaminergic neurons in the substantia
nigra pars compacta (SNpc) area of the human midbrain, which results in a reduc-
tion in dopamine levels. After a certain age, neurodegeneration becomes an
extremely important factor in human life. Given its high incidence rate, PD contin-
ues to be one of the NDs that represent a serious hazard to adults over 60.
Neuroinflammation, oxidative stress, mitochondrial dysfunction, and apoptosis are
all recognised as contributing factors to the pathophysiology of PD, despite the fact
that the precise origin of the disease is still unknown. There is a need for a highly
tailored therapy strategy for PD, as different pharmacological combinations are
only available to manage the symptoms. This is where the use of plant-derived natu-
ral compounds as a neuroprotective agent has been in the spotlight. With their anti-
oxidant properties, which are thought to help in repairing the damage caused by free
radicals, as well as their antiapoptotic and anti-inflammatory properties, flavonoids
are one of the main classes of phytochemicals that have demonstrated their effec-
tiveness in acting as a neuroprotective agent for PD. These properties could activate
pathways that target mitochondrial dysfunction and induce neurotrophic factors by
exhibiting a neuroprotective effect. The scientific literature on the anti-
neurodegenerative and neuroprotective functions of phytochemicals is reviewed in
this chapter, with a particular emphasis on the potential of flavonoids as natural
products for the prevention and treatment of PD.
Keywords Phytochemicals · Flavonoids · Parkinson’s disease · Therapeutics
A. Vijay · A. Balakrishnan (*)

Department of Genetics, Dr. ALM PG IBMS, University of Madras,
e-mail: banandan@unom.ac.in
Ltd. 2023
264 A. Vijay and A. Balakrishnan
Abbreviation
6-OHDA 6-Hydroxydopamine
α-Syn Alpha-synuclein
DA Dopaminergic
MPTP Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
NDs Neurodegenerative disorders
SNpc Substantia nigra pars compacta
14.1 Introduction
Neurodegeneration is a pathological condition that affects the neurons in different

regions of the brain. Several NDs have been discovered; among them, the most com-
mon are Alzheimer’s disease (AD), PD, amyotrophic lateral sclerosis, and Huntington’s
disease (Young et al. 2018). The gradual loss of nerve cells is the common pathogenic
process in all NDs. Since a considerable number of neurons have been lost (or a spe-
cific area of the central nervous system has been damaged), the process leading to the
development of the initial symptoms starts significantly earlier and is asymptomatic
for a very long period. Finally, a number of neurological injury symptoms have an
impact on motor and cognitive abilities (Hajdusianek et al. 2021). Among several
NDs, PD is the second-most prevalent degenerative condition after AD. PD affects the
human central peripheral and enteric nervous systems which leads to a progressive
loss in the dopaminergic neurons in the substantia nigra pars compacta (SNpc) part of
the midbrain. Evidences also state that deregulation in the growth of neuronal pro-
cesses affecting the neuronal cytoskeleton could also give rise to PD (Foley and
Riederer 1999; Graybiel et al. 1990; Morrish et al. 1998). As per reports, the preva-
lence rate of PD has seen a hike from 2.5 million in 1990 to 6.1 million in 2016 mak-
ing it the second most common neurodegenerative disease (Hajdusianek et al. 2021).
The neuropathology of PD is characterised by the degeneration of dopaminergic
(DA) neurons in the SNpc region of the brain (Feraco et al. 2021). The DA neurons
synapse with neurons in the striatum; thereby their loss leads to the depletion of
striatal dopamine. PD is also characterised by the presence of Lewy bodies which
are cytoplasmic protein aggregates found in the remaining DA neurons of the SNpc.
The Lewy bodies are aggregated form of the protein alpha-synuclein (α-Syn). α-Syn
plays a key role in the pathogenesis of Parkinson’s disease (PD). These aggregated
forms of α-Syn protein accumulate within the neurons which leads to impairment in
the neuronal functioning. As a result of which, the neurons die. The motor symp-
toms associated with PD such as gait, resting tremor, and bradykinesia are the end
result of the neuronal destruction in the substantia nigra (Alam et al. 2022).
14 Plant-Derived Natural Products Targeting Multiple Pathways as Potential… 265
There is currently no test to identify PD before the appearance of motor symp-

toms, and the present therapies only work to alleviate the symptoms rather than treat-
ing the underlying cause or slowing the disease’s development. Importantly, striatal
dopamine is lowered by 80% by the time the first symptoms arise, and 60% of the
DA neurons of the SNpc would have entirely perished (Maher 2019). The need for
enhancing and introducing new modalities for treating or managing PD has emerged
as a result of the disease’s high prevalence and adversity. Dopamine replacement
therapy, using primarily levodopa (l-Dopa), in conjunction with dopamine receptor
agonists, monoamine oxidase (MAO) inhibitors, or catechol-O-methyltransferase
(COMT) inhibitors, is one among the very few and commonly used treatment options
available that only focuses on extending control of symptoms in PD patients. The
hunt for innovative therapeutic drugs with fewer side effects is crucial because there
is currently no full cure that stops the pathogenic pathways that cause illness devel-
opment (Vuletić et al. 2021). Growing interest has recently been shown in the thera-
peutic use of natural products for Parkinson’s disease, particularly those derived
from plants. Compared to synthetic medications, natural products are recognised to
have fewer negative effects (Jung and Kim 2018). Experimental and epidemiological
data have shown that flavonoid polyphenols, in particular, ameliorate neuronal loss
and show neuroprotective properties in models of PD (Mandel et al. 2004).
Natural products continue to be a source of great chemical variety, biochemical
specificity, and diverse molecular properties that make them excellent for modulat-
ing many signalling pathways/cascades in various clinical states including cancer
and neurological illnesses (Hussain et al. 2018). This book chapter will give a gen-
eral overview on the neuroprotective advantages of plant-derived flavonoids in
PD. Flavonoids are phytonutrients which are found in practically all fruits and veg-
etables. The chapter will also focus on the mechanisms by which these flavonoids
may prove beneficial for PD. Variety of flavonoids have been studied over the
decade and are found to be promising candidates for the treatment of PD and other
14.2 Parkinson’s Disease
PD is an ND which is associated with severe disability leading to adverse effects on

life quality. In PD, motor dysfunctions such as quiescence, muscle stiffness, and
postural instability are commonly observed. PD is also associated with autonomic
nervous dysfunction, sleep disorders, psychiatric symptoms, and other non-motor
symptoms such as olfactory impairment, pain, autonomic dysfunction, impaired
sleep, fatigue, and behavioural changes. Degeneration of dopaminergic neurons in
the SNpc, Lewy body accumulation, and neuroinflammation are the main patho-
logical features of PD. The death or dysfunction of dopaminergic neurons in the
dense part of the substantia nigra leads to dopamine deficiency in the basal ganglia
and motor dysfunction. The formation of the Lewy body is associated with the mis-
folding of α-Syn, which becomes insoluble and abnormally aggregated. The
pathogenesis of PD is believed to involve oxidative stress, disruption to mitochon-

dria, alterations to the protein α-Syn, and neuroinflammatory processes (Aryal et al.
2020; Liu et al. 2021). Figure 14.1 depicts the different pathways involved in the
pathophysiology of PD (Kanehisa and Goto 2000).
The primary cause of PD, a progressive neurological movement condition, is the
loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc).
Environmental factors and mutations in genes linked to familial Parkinson’s disease
(PD), such as SNCA, parkin, DJ-1, PINK1, and LRRK2, are connected to the aetiol-
ogy of PD. Due to oxidative stress, impaired intracellular Ca2+ homeostasis, mito-
chondrial dysfunctions, and altered protein handling, these pathogenic mutations
and environmental variables are known to induce disease and compromise the func-
tion and survival of DA neurons as represented in Fig. 14.1. The loss of dopaminer-
gic input to the striatum caused by the death of DA neurons in the SNpc is thought
Fig. 14.1 Pathways involved in Parkinson’s disease (pathway retrieved from KEGG (Kyoto
Encyclopedia of Genes and Genomes)) (Kanehisa and Goto 2000)
to impair movement by causing hypo- and hyperactivity in striatal spiny projection

neurons (SPNs) of the direct (dSPNs) and indirect (iSPNs) pathways in the basal
ganglia, respectively (Kanehisa and Goto 2000).
14.3 Phytochemicals
Phytochemicals are compounds generated by plants. However, the word is com-

monly used to describe plant-derived compounds that may have an impact on health
but are not required nutrients. While there are plenty of data to support the health
advantages of diets high in fruits, vegetables, legumes, whole grains, and nuts, there
is little evidence that these effects are attributable to specific nutrients or phyto-
chemicals. Because plant-based diets are complex combinations of bioactive com-
ponents, research on individual phytochemicals’ potential health impacts is related
to information on the health consequences of foods containing those phytochemi-
cals. These secondary metabolites have shown significant biological and health-
promoting effects (Sajad et al. 2022). Figure 14.2 depicts the different classes of
phytochemicals and further elaborates the subclasses of polyphenols, which is one
of the most abundant classes of phytochemical.
These plant-derived compounds, or phytochemicals, have long been employed
as medicinal treatments. Traditionally, whole plant parts were utilised to cure a vari-
ety of ailments. Phytochemicals are now regularly collected from plant components
and employed by the modern pharmaceutical industry to synthesise pharmaceuti-
cals, including medications and bioenhancers for cancer chemotherapeutic therapy.
The biggest, most diverse, and most researched class of phytochemicals is flavo-
noids. It has been reported that plant foods contain more than 6000 different flavo-
noids. Here, the chapter will focus on how flavonoids can be used as a neuroprotective
agent for PD.
Fig. 14.2 Classification and structure of main classes of phytochemicals

14.4 Flavonoids
Phenolic molecules are one of the most significant types of secondary metabo-
lites. They come in a variety of forms and are in charge of giving meals and drinks
made from plants their fundamental organoleptic qualities, notably their colour
and flavour. Additionally, they aid in the nutrient retention of fruits and vegeta-
bles. One of the most prevalent groups of phytochemical substances is flavonoids.
A deeper knowledge of their processes and biological traits enables them to be
employed as medicinal medications as well as monitor and control food quality
due to their significance to food organoleptic features and human wellness (Tapas
et al. 2008).
It is crucial to think about the therapy choices accessible for PD given the rise in
the disease’s incidence rate. Through several research, the natural chemicals known as
flavonoids have demonstrated their effectiveness against neurological illnesses.
Flavonoids have demonstrated positive benefits on the cellular stress response, mak-
ing them potentially effective treatment choices for neurological diseases and NDs. In
recent years, there has been a lot of interest in these compounds. Although their mode
of action has to be further investigated, evidence suggests that flavonoids may be used
to provide neuroprotection through a variety of mechanisms, including antioxidant,
anti-inflammatory, and antiapoptotic capabilities. This book chapter sheds light on the
possible contribution of flavonoids to PD neuroprotection (Devi et al. 2021).
The neurodegeneration observed in PD appears to be caused by a number of
mechanisms, including neuroinflammation, glutamatergic excitotoxicity, elevations
in iron, depletion of endogenous antioxidants, and an increase in reactive oxygen
species (ROS). According to a growing body of research, flavonoids may be able to
lessen the neuronal damage that underlies a variety of diseases and hence shorten
the duration of the sickness. Flavonoids have an impact on biochemical signalling
pathways involved in neurodegeneration, neuroinflammation, learning, and mem-
ory. Their ability to interact with crucial brain neuronal signalling cascades, which
in turn inhibits the apoptosis produced by neurotoxic species and instead promotes
neuronal survival and differentiation, appears to be what underpins this variety of
effects (Vazour et al. 2013).
14.4.1 Neuroprotective Effects of Flavonoids
Numerous research have focused on the underlying neuroprotective molecular

mechanism of flavonoids and their metabolites during the last decade. Recent
research has demonstrated the positive neuropharmacological effects of different
flavonoids, including anti-inflammatory, antidepressant, anticonvulsant, antioxidant
(Table 14.1), as well as memory and locomotor boosting properties (Hajialyani
et al. 2019).
Several in vivo and in vitro models that are unique to neurodegenerative illnesses
were used, as this chapter demonstrates, to assess the underlying
Table 14.1 Flowchart representing the modes by which flavonoids exert neuroprotection
Neuroprotective Properties shown by Flavonoids ANTI-OXIDATIVE

Free radicals are major causative agent for cellular damage in
modern world. Increase in ROS results in neurodegeneration.
Various flavonoids show anti-oxidant properties that prevent
the actions of ROS by inhibiting enzymes, pathways etc. they
tend to act by downregulating Pathways like p38 MAPK and
JNK. Mitochondrial dysfunction caused by increase in amyloid
beta peptide. Flavonoids have capacity to pass through
mitochondrial membrane and prevent from neuronal cell death.
(Ahmadinejad et al. 2017)
ANTI-INFLAMMATORY
Upregulation in neurological activities are performed by
flavonoids as it has a property of crossing over the Blood Brain
Barrier (BBB). In PD, aberrant alpha-synuclein protein buildup,
or Lewy bodies, causes inflammation in the brain.NF-kB
pathway responsible for inflammatory responses in the body are
triggered by PD. Apigenin,a flavonoid studied in mouse shows
a positive result in reduced NF-kB pathway (Choudhury et al.
2018)
ANTI-APOPTOTIC
PD causes increased functioning of the apoptotic pathway and
results in neuronal loss. Flavonoids like Hesperidin, myricitrin
targets the pathway p38, JNK, Akt/PkB. In Akt/PkB the
flavonoid works in activation and p38 and JNK flavonoid act in
down regulation of signalling pathways (Erekat 2018)
Note: p38 MAPK mitogen-activated protein kinase, JNK Jun N-terminal kinase, NF-κB nuclear
factor kappa B, Akt/PkB PI3K (phosphatidylinositol 3-kinase) and Akt (protein kinase B)
neuropharmacological processes of different flavonoids. The neuroprotective poten-

tial of flavonoid involves a variety of pharmacological targets, such as the enhance-
ment of brain growth factors and endogenous antioxidant defence capabilities, which
reduce neuro-inflammatory and apoptotic pathways and ROS pathways (Table 14.1).
14.4.1.1 Anti-inflammatory Properties
Numerous flavonoids have been proven to have anti-inflammatory activities in both

in vitro and in vivo investigations. An important mechanism for anti-inflammatory
action is inhibition of eicosanoid-producing enzymes like phospholipase A2,
cyclooxygenases, and lipoxygenases, which leads to lower levels of prostanoids (a

subclass of eicosanoids) and leukotrienes (eicosanoid inflammatory mediators pro-
duced in leukocytes). Other methods include histamine release, phosphodiesterase
inhibition, protein kinase inhibition, and transcriptase activation (Rathee et al.
2009). A coordinated collection of cell activation mechanisms, the majority of
which are connected to prostanoid production through arachidonic acid digestion,
are involved in an inflammatory reaction. Arachidonic acid is released from phos-
pholipids by phospholipase A2, which is subsequently oxidised by cyclooxygenase
(COX) or 5-lipoxygenase (LOX) into prostaglandins or thromboxanes, respectively.
Numerous plant flavonoids are essential in inhibiting the formation of prostaglan-
dins. Hesperidin and diosmin have been demonstrated to inhibit the formation of
prostaglandins in vivo (Damon et al. 1987). A flavonoid called quercetin triggers the
cyclooxygenase cascade. The enzymes COX-2 and 5-LOX, which are involved in
the production of eicosanoids from arachidonic acid, are powerfully inhibited by the
compound quercetin, which may be found in onions, fruit juices, and tea (Kimata
et al. 2000). Flavonoids bind to platelet membranes in vitro, and reports claim that
over time, they have an accumulative impact (Van Wauwe and Goossens 1983).
According to study, flavones prevent lipopolysaccharide (LPS)-activated monocytes
from transcriptionally activating cyclooxygenase (Kim et al. 1998). Apigenin inhib-
its a specific LPS-induced kinase, which may be why it reduces the LPS-induced
activation of NF-kB transcriptional activity (Middleton Jr and Kandaswami 1992).
Studies have demonstrated that these natural compounds can delay the late stages
of allergy responses by reducing histamine release. Histamine release during an
allergic response is tightly controlled by leukotrienes generated by lipoxygenase-
catalysed processes. While methoxylated flavones have a significantly lesser inhibi-
tory impact than hydroxylated flavones, many hydroxylated flavones, or aglycones,
block this mechanism (Petkov et al. 1981). Inhibiting phosphodiesterase is crucial
in the management of allergy and chronic inflammation. A variety of medicinal
plants naturally inhibit phosphodiesterase, and flavonoids have been linked to this
inhibitory effect in many conventional drugs (Kusano et al. 1991). Four licorice
flavonoids and biflavones from Ginkgo biloba were discovered to inhibit cAMP
phosphodiesterase in vitro. In LPS-activated human monocytes, citrus flavones have
been observed to suppress phosphodiesterase activity. In a number of studies, the
competitive binding of flavonoids at nucleotide-binding sites has been connected to
flavonoid inhibition of protein kinases (Ferriola et al. 1989). Due to their distinct
method of action and high in vivo efficacy, flavonoids are regarded as intriguing
candidates for new anti-inflammatory medicines. There is growing evidence that the
events leading to progressive neuronal disruption in neurodegenerative illnesses
including PD and AD may be triggered by inflammatory processes.
14.4.1.2 Antioxidant Properties
According to Halliwell and Gutteridge, the mechanism of antioxidant action includes

(1) repressing ROS formation by inhibiting enzymes or chelating trace elements asso-
ciated with free radical production, (2) scavenging reactive oxygen species, and (3)
upregulating or defending antioxidant capacity (Halliwell and Gutteridge 2015).

Flavonoids have been reported to satisfy the aforementioned criteria. As a result, their
impact has been multiplied by twofold. Flavonoids, such as xanthine oxidase and pro-
tein kinase C, inhibit superoxide anion-producing enzymes. Flavonoids have also been
demonstrated to inhibit enzymes involved in the formation of reactive oxygen species,
such as cyclooxygenase, mitochondrial succinoxidase, lipoxygenase, NADH oxidase,
and glutathione S-transferase (Brown et al. 1998). Several flavonoids are effective in
chelating trace metals that are necessary for oxygen metabolism. Dietary flavonoids
are thought to give their initial antioxidant protection in the digestive system by limit-
ing the generation and scavenging of reactive oxygen species. They continue to be
antioxidants until they are absorbed, either as aglycones or glycosides (Pietta 2000).
The antioxidant activity of flavonoids was the first biological mechanism stud-
ied, particularly in terms of their protection against cardiovascular disease. Most
oxidising chemicals, including singlet oxygen and numerous free radicals, are par-
ticularly effective flavonoid scavengers (Bravo 1998). The imbalance generated by
oxidants, which form ROS, free radicals, and antioxidants, which eliminate free
radicals, is referred to as oxidative stress. The levels of oxidants and antioxidants are
nicely balanced in healthy people. However, excessive ROS generation and a defi-
ciency in antioxidants lead to oxidative stress, which may be the reason for speeding
up the onset of neurodegenerative disorders. This suggests that lowering oxidative
stress and limiting ROS formation is essential for both the treatment and prevention
of NDs, including Parkinson’s disease (Kim 2021).
14.4.1.3 Antiapoptotic Properties
Apoptosis has been suggested as the primary cause of neuronal death in PD, as
indicated by the discovery of DNA fragmentation and apoptotic chromatin altera-
tions in PD patients’ dopaminergic neurons. Apoptosis is mediated by a number of
initiator and executioner caspases and can occur via either the intrinsic or extrinsic
routes. The intrinsic route, also known as the mitochondria-mediated pathway, is
mediated by activation of initiator caspase-9 (Erekat 2018). Cell damage caused by
oxidative stress has long been linked to the process of ageing as well as a number of
neurological illnesses such as PD. Numerous investigations have revealed that oxi-
dative stress is a primary source of cellular damage in a variety of neurodegenera-
tive illnesses. ROS such as hydrogen peroxide, superoxide anion, and hydroxyl
radical easily damage biological molecules, and such damage can eventually lead to
cellular apoptosis or necrosis. Removal of excess ROS or suppression of their gen-
eration by antioxidants could be how flavonoids can exert their importance and
neuroprotective role in order to prevent oxidative cell injuries that cause apoptosis.
Treatment of dopaminergic cells (e.g., SH-SY5Y, PC12 cells) with neurotoxins
like 6-hydroxydopamine (6-OHDA) or methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP) elevated pro-apoptotic genes and other genes that induce cellular death,
according to studies on the PD model. As a result, medicinal medicines targeting
these genes may protect neurons from the apoptotic process and neuronal death
(Magalingam et al. 2015).
14.4.2 Neuroprotective Effects of Flavonoids on PD
Despite the fact that the underlying disease mechanisms of PD that lead to the
degeneration of nigrostriatal DA neurons are still unknown, it is well-known from
evidence-based information that the upregulation of risk factors is involved in the
pathogenesis and progression of PD and that the following factors are particularly
important for its onset: neuroinflammation, improper management of apoptosis and
autophagy, genetic mutations, neurotrophic support failure, and oxidative stress.
Among them, oxidative stress is regarded as a major contributor to the development
of PD since it can lead to neuroinflammation, increased ROS generation from dopa-
mine metabolism, mitochondrial malfunction, and iron deposition in the SNpc
(Devi et al. 2021). Table 14.2 summarises main groups of flavonoids, some derived
compounds with neuroprotective properties, and their food sources.
Introducing flavonoids might lessen the negative effects of cellular events
brought on by stress. Therefore, by using these flavonoids, the harmful effects of
environmental stress and cellular stress response might be reduced (Kim et al. 2020).
It is widely recognised that there is no effective treatment for PD, and the medi-
cations that are now available are primarily intended to treat its symptoms. When it
comes to PD, flavonoids have demonstrated preventive properties such as the
Table 14.2 Flowchart representing the main groups of flavonoids, some derived compounds with
neuroprotective properties, and their food sources
prevention of dopamine decrease, ROS production, TH protein loss, and mitochon-

drial complex 1 deficiencies. In addition, flavonoids boost cell survival, stop apop-
tosis, and lower pro-inflammatory cytokines (Aryal et al. 2020).
The treatment of an animal model of PD with a toxin, such as a pesticide or another
hazardous substance that has been linked to PD in vivo, is typical. The two most popu-
lar models are 1-MPTP and 6-OHDA. PD has also been modelled using the pesticide
rotenone and the herbicide paraquat (PQ). In contrast to the age-dependent progres-
sion of PD in actual patients, none of these models accurately simulates every compo-
nent of human PD, and most have start times that are far faster. Despite the fact that
animal models have been created in which one or more of the genes linked to familial
PD are mutated, the majority of these genetic PD models do not exhibit nigrostriatal
degeneration. Additionally, there is a problem with inconsistent phenotypes between
different mouse lines carrying the same mutation. As a result, they have not been
widely utilised to investigate putative medicinal substances (Maher 2019).
In both in vivo and in vitro PD toxin models, a sizable variety of flavonoids from
most of the main classes have been investigated. Some of these have already been
discussed, but the following table reviews and describes some of the outcomes
(Table 14.3).
Table 14.3 Protective mechanism of various phytochemicals in Parkinson’s disease

S.
no. Key findings References
1. By scavenging free radicals and maintaining the activity of several Siddique
antioxidant enzymes, the natural flavonoid kaempferol (Ka) has (2021)
neuroprotective properties that delay the onset and progression of
neurodegenerative diseases
Kaempferol has several targets and can cross the BBB, making it a promising
dietary supplement for the prevention and treatment of neurodegenerative
disorders
2. Citrus reticulata (mandarin) flavonoids have neuroprotective properties. In Cirmi et al.
6-OHDA-induced SH-SY5Y human neuroblastoma cells, the neuroprotective (2021)
effects of mandarin juice extract (MJe) were investigated. It demonstrated
antioxidant effects by lowering the ROS and nitrogen species that 6-OHDA
produced, as well as by restoring the potential of the mitochondrial
membrane and preventing the oxidative DNA damage that 6-OHDA elicited
Additionally, MJe corrected the imbalance of PD-related genes (SNCA,
LRRK2, PINK1, parkin, and DJ-1) affected by 6-OHDA oxidative stress,
indicating that MJe protects SH-SY5Y cells from 6-OHDA-induced cell
death through a combination of its antioxidant properties and specific
interactions with intracellular pathways
3. A perennial plant in the Asteraceae family called Coreopsis lanceolata L. Kim et al.
(CL) is noted for having flavonoids in its flowers that have a variety of (2021)
bioactivities
By altering the expression of genes associated with apoptosis and further
decreasing caspase-3 activation, CL has neuroprotective benefits against
oxidative stress (OS)-induced apoptosis in PC12 cells in Parkinson’s disease
model mice. These findings suggest that CL may have therapeutic benefit in
the management of neurodegenerative illnesses that worsen over time
(continued)

S.
4. In pertinent cellular models, the dietary flavonoid fisetin was assessed Rosado-
against the primary PD markers Ramos et al.
The findings demonstrated that fisetin performs modulatory actions against (2021)
typical cellular diseases prevalent in PD; surprisingly, it controls α-Syn
aggregation, supporting the notion that diets high in this substance may be
advantageous
5. A flavonoid known as baicalein that is obtained from the plant Scutellaria Zhao et al.
baicalensis Georgi. displays anti-PD action by easing the disease’s motor (2021)
symptoms
Repeated baicalein administration decreased α-Syn aggregation, prevented
neuroinflammation, and preserved the equilibrium of neurotransmitters.
Additionally, in the PD-related depression mouse model, baicalein therapy
was observed to significantly preserve synaptic plasticity and activate the
BDNF/TrkB/CREB pathway
Baicalin therapy enhanced the behaviour of an MPTP-induced Parkinson’s Lei et al.
disease mice model and decreased dopaminergic cell loss in the substantia (2020)
nigra, which was linked to the inactivation of pro-inflammatory cytokines
and oxidative stress. Thus, our investigation provided evidence that baicalin
inhibited C/EBP via redox homeostasis, suggesting that it may be a useful
therapeutic therapy for Parkinson’s disease
In PD mouse models, baicalein treatment restored MPTP-induced motor Rui et al.
impairment, dopaminergic neuron loss, and pro-inflammatory cytokine (2020)
increase. Baicalein also reduced the activation of caspase-1 and NLRP3, as
well as the gasdermin D (GSDMD)-dependent pyroptosis. The findings
imply that baicalein can inhibit the NLRP3/caspase-1/GSDMD pathway to
prevent mice from developing neuroinflammation brought on by MPTP
6. A unique Ginkgo biloba leaf extract supplement from China called the Yu et al.
Ginkgo biloba dropping pill (GBDP) has the potential to be utilised as an (2021)
alternative treatment for Parkinson’s disease. It is anti-inflammatory and
neuroprotective. According to in vitro research, the neuroprotective effects of
GBDP may be mediated through the Akt/GSK3 pathway. These findings
showed that GBDP could help control PD by providing neuroprotective
advantages
7. Pomegranate seed extract (PSE) and juice (PJ) preadministration Fathy et al.
substantially decreased the PQ-induced oxidative stress by reducing the (2021)
MDA level and raising the activities of antioxidant enzymes. PSE and PJ
significantly reduced levels of pro-inflammatory cytokines, CD11b, and
TGF-β while significantly increasing levels of interleukin-10 (IL-10), GDNF,
and ATP in comparison to animals treated with PQ. They also greatly
reduced the expression of the NF-кB gene in the striatum
8. Another experiment using the flavonoid icaritin improved mitochondrial Wu et al.
dysfunction by stabilising the levels of proteins essential for mitochondrial (2021)
function, such as voltage-dependent anion channel (VDAC) and ATP
synthase subunit beta, as well as molecules involved in energy metabolism,
such as ATP and ADP (ATP5B). Using molecular docking, it was also shown
that icaritin can interact with NLRP3, VDAC, ATP5B, and a variety of
BBB-related proteins. These results highlight the fascinating therapeutic
potential of icaritin in Parkinson’s disease

S.
9. Silibinin (silybin), a flavonoid isolated and extracted from the fruit of S. Liu et al.
marianum, was examined to determine its potential in protecting against (2021)
motor damage in PD model mice produced by MPTP
In addition to reducing mitochondrial damage by suppressing pro-
inflammatory response and α-Syn aggregation, silibinin’s neuroprotective
action also involves enhancing the oxidative defence system. In particular, the
enhancement of mitophagy, which results in the elimination of the toxic
effects of damaged mitochondria, is responsible for the preservation of
dopaminergic neurons. These results imply that silibinin has the potential to
be explored further as a treatment option for Parkinson’s disease
10. A flavanone called naringenin has been shown to inhibit the activation of Clairembault
microglia and to reduce the activity of the glial fibrillary acidic protein et al. (2014)
(GFAP)
When 6-OHDA is used to produce neurotoxicity in zebrafish larvae as a Kesh et al.
model for Parkinson’s disease, naringenin lowers the levels of oxidative (2021a)
stress indicators and downregulates the PD genes
11. In the zebrafish model, flavanone hesperidin was observed to downregulate Kesh et al.
kinases such gsk-3 and lrrk2, suggesting a potential therapeutic candidate for (2021b)
the treatment of Parkinson’s disease
In a study employing the 6-OHDA-induced animals PD model, hesperidin Antunes
decreased the 6-OHDA-induced loss in glutathione peroxidase and catalase et al. (2014)
activity, total reactive antioxidant capacity, and levels of dopamine and its
metabolites in the striatum of aged mice
Chronic hesperidin treatment attenuated the effects of 6-OHDA on reactive
oxygen species levels and glutathione reductase activity in the striatum
12. Valeric acid (Val), a naturally occurring straight-chain alkyl carboxylic acid Jayaraj et al.
found in the plant Valeriana officinalis, has been used to treat neurological (2020)
illnesses. In rat models of Parkinson’s disease, Val was found to protect
against the rotenone-induced rise of pro-inflammatory cytokines, oxidative
stress, and α-Syn expression, resulting in an increase in crucial antioxidant
enzymes
13. Parkinsonism cell model using rotenone-treated dopaminergic PC12 cells Buratta et al.
with the natural substance curcumin, recognised for its antioxidant qualities. (2020)
It has been shown that rotenone treatment of PC12 cells results in significant
protein damage, including the creation of carbonylated and nitrotyrosine-
derived proteins, but co-exposure to curcumin has protective benefits by
lowering the amounts of oxidised proteins. Additionally, curcumin
encourages proteasome activity, which eliminates rotenone’s inhibitory
effects on this degradative pathway
14. The most prevalent and strong green tea catechin, epigallocatechin-3-gallate Tseng et al.
(EGCG), has significant antioxidative, anti-inflammatory, and (2020)
neuroprotective properties. The study looked at whether EGCG may protect
rats from motor and neurochemical dysfunctions brought on by ROT. It was
shown the antioxidative impact, prevention of mitochondrial dysfunction,
protection of neurochemical insufficiency, anti-neuroinflammatory action,
and antiapoptotic effect of EGCG against ROT-induced motor impairments
(continued)

S.
15. Procyanidin (PC), a bioflavonoid antioxidant with a unique molecular Zhang et al.
structure that is extensively present in plants like grapes and is capable of (2019)
efficiently removing free radicals from the human body. In rats and PC12
cells, it was shown that PC had a protective effect against 6-OHDA-induced
neurotoxicity. This effect may have been caused by activating the PI3K/Akt
signalling pathway
16. Proanthocyanidins (PA) are natural flavonoids that are abundantly found in Ma et al.
many fruits, vegetables, nuts, and seeds, particularly grape seeds. (2018)
Significantly reduced rotenone-induced activation of caspase-9, caspase-3,
and cleavage of poly(ADP-ribose) polymerase (PARP), which are
biochemical characteristics of apoptosis. Significantly improved cell survival
against rotenone neurotoxicity. The outcomes showed that PA inhibited p38,
JNK, and ERK signalling pathways to reduce rotenone-induced ROS
formation and prevent apoptosis in SH-SY5Y cells
17. Chrysin is an active flavonoid with shown neuroprotective properties. In the Ahmed et al.
rat PD model, chrysin-treated animals had a substantial decrease in the (2018)
motor behavioural alterations, loss and degradation of nigrostriatal
dopaminergic neurons, and enhanced positivity to anti-TH antibody. In the
rat model of PD, it was found that chrysin confers neuroprotection
18. Rutin, a glycoside of the flavonoid quercetin, is found in a variety of plants Enogieru
and fruits, including buckwheat, apricots, cherries, grapes, grapefruit, plums, et al. (2018)
and oranges. Rutin has been found to have positive effects in a variety of
illness states according to pharmacological investigations, and its therapeutic
potential in a number of ND models has generated a lot of interest.
Pro-inflammatory cytokines are decreased, antioxidant enzyme activity is
increased, the mitogen-activated protein kinase cascade is activated,
PD-linked and pro-apoptotic gene mRNA expression is downregulated, ion
transport and antiapoptotic genes are upregulated, and mitochondrial
complex enzyme activity is restored
19. Studies on the flavonol fisetin’s beneficial effects in PD models found that by Maher
lowering inflammation, protein aggregation, and mitochondrial dysfunction, (2017)
it may be able to lessen the impacts of PD on brain function
20. A flavonoid called myricitrin that was discovered in the root bark of the plant Cai et al.
Myrica cerifera has strong antioxidant capabilities. When SN4741 cells were (2015)
incubated with myricitrin, the neurotoxin MPTP’s ability to cause cell death
was dramatically decreased. This was demonstrated by the protective effects
of myricitrin against MPTP-induced mitochondrial dysfunction in SN4741
cells. Myricitrin may be a helpful treatment for age-related
neurodegenerative disorders, notably Parkinson’s disease, since it has been
proposed that it reduces MPTP-induced mitochondrial dysfunction and
boosts cell viability via DJ-1
14.5 Summary and Conclusion
The development and application of flavonoids as neuroprotective medicines for the

treatment of PD has emerged as one of the most significant goals of neuropathologi-
cal research into this condition. Research to find natural substances capable of
stopping or reducing the progression of neurological degeneration has been sparked

by the growing understanding of the molecular processes underlying the degenera-
tive process of PD. Flavonoids are recognised as natural substances that are also
well-known for having a variety of bioactivities that promote health, such as anti-
oxidation, anti-inflammation, and antiapoptotic, as well as providing neuroprotec-
tive properties.
One of the most prevalent neurodegenerative illnesses, PD, causes a slow loss of
dopamine neurons due to a rise in ROS levels and inflammation. Although the entire
pathophysiology of the disease is still unknown, these elements are thought to be
crucial in the development of the illness. The choices for treating Parkinson’s dis-
ease are severely constrained to a few medications and pharmacological combina-
tions that solely address the symptoms. Therefore, in terms of PD or any other NDs,
the need for therapeutic alternatives is urgently needed. Numerous flavonoids with
neuroprotective qualities have gained attention during the past decade.
This chapter provides a thorough summary of the neuroprotective properties of
phytochemicals that have recently been researched, with a focus on their neurores-
cue/neurodegenerative activity in PD. This chapter explores the potential mecha-
nisms through which flavonoids may provide positive outcomes when tested in a
variety of in vivo and in vitro PD models. Many or most of the natural compounds
reviewed in this chapter have shown promising neuroprotection which makes them
potential drug candidates for treating NDs.
Acknowledgement This book chapter was supported by a grant from RUSA 2.0.
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Chapter 15
Aging in Indian Women: Health Status
Nirmalasaravanan Narayanasamy, Audinarayana N, and Arindam Das
Abstract Young India will be greying in a decade or so. And there will also be an
increase in older women than older men by 18.4 million by 2050. Most elderly per-
sons are likely to suffer from one or the other morbidity conditions. This study
assesses the acute and chronic morbidity conditions the elderly widows are suffer-
ing from and their principal determinants.
Keywords Elderly widows · Acute morbidity · Chronic morbidity · Puducherry ·

Determinants
15.1 Introduction
Globally aging is an inevitable phenomenon. India’s aging is comparatively slow

than other developing countries. By 2050 there will be nearly 320 million aged
people. Young India will be graying in a decade or so because of the projected
increase in the life expectancy of males at 71.8 years and females to 75.7 years by
2050. There will be an increase from 23 older people per 100 children in 2001 to 53
older people per 100 children in 2050. And there will also be an increase in older
women than older men by 18.4 million. Health determines the quality of life of the
elderly enabling them to be functional and participate in activities.
N. Narayanasamy
Faculty of Mother Teresa Post Graduate and Health Sciences, Puducherry, India
A. N
Department of Sociology and Population Studies, Bharathiar University,
Coimbatore, Tamil Nadu, India
A. Das (*)
Research, IIHMR, Jaipur, Rajasthan, India
Ltd. 2023
282 N. Narayanasamy et al.
Generally, people say that “aging is a synonym for ill health” as most elderly
persons are likely to suffer from one or the other morbidity conditions. It is natural
that as persons become older or age increases, the functions of human organs
weaken; in addition to a decrease in their immunity, such conditions would lead to
disease. Of course, such diseases may last long for a few days (like in the case of
acute morbidity) if they take curative medicine on time and if their organs in the
body respond promptly to those medicines. However, some diseases will be difficult
to cure completely, and these diseases are likely to end up with partial/absolute dis-
ability (chronic morbidity). Another principal dimension of ill health among the
elderly is psychological. Such adverse psychological conditions would likely take
place mainly because being aged persons, the majority of them are likely to live
alone and are considered a burden by their family members, in addition to the lack
of physical and emotional care, and also most of them (especially elderly widows)
primarily lack economic autonomy. All these situations would lead to loneliness,
depression, and psychological distress. In addition to these, elderly persons would
lose their headship status and decision-making capacity, besides respect at the fam-
ily level. All these further deteriorate both their physical and psychological health.
15.2 Theoretical Consideration and Earlier Research
This research attempts to collect information from the respondents (elderly widows)
about their physical and psychological health conditions with the above discussion.
Based on this data, this chapter helps to understand to what extent they are suffering
from acute and chronic morbidity conditions and also to know the magnitude of
psychological stress and their state of subjective well-being (patterns). Further, the
differentials in all these dimensions are examined across their selected background
characteristics and attempted to determine the principal determinants of these four
outcomes.
15.3 Materials and Methods
This paper is based on a community-based cross-sectional survey. Originally, the

required sample size was estimated as 315 based on Daniel (1999) formula, sample
size (n) = Z2 (1-P)P/d2 keeping the proportion of elderly widows (i.e., 60 years and
above) as 0.051 (5.1%) and precision (d) as 0.5 × P (i.e., 0.255) with a confidence
level (Z) as 95%. Adding 10% of the non-response rate and the design effect of 1.25,
the sample size was increased to 390. These elderly widows (60+ years) were
selected by giving due representation to rural and urban areas of Puducherry dis-
trict, Puducherry Union Territory. To this end, at the first stage, 30 clusters were
formed—20 rural primary sampling units (PSUs) (villages/parts of villages) and 10
15 Aging in Indian Women: Health Status 283
PSUs from urban areas (wards/parts of streets)—and selected the same using a sim-
ple random sampling technique. At the next stage, from these 30 PSUs adopting the
systematic sampling technique, the required sample size of 390 was selected by
allocating a sample of 13 widows to each PSU (20 × 13 = 260 from rural areas and
10 × 13 = 130 from urban areas). However, while selecting the sample widows, the
following inclusion criteria were used: (1) all those widows who completed 60
years of age, (2) those who gave informed consent, and (3) widows who are ill/
bedridden at home with proxies. The exclusion criteria followed included (1) elderly
widows who are in old age homes; (2) who are physically and mentally ill and,
thereby, not able to speak; (3) who are absent (for a longer time) at their residence
during the period of data collection in the respective clusters; and (4) those elderly
who refused/not interested to participate. From the sample respondents, the required
information was collected from January to May 2019 making use of a structured
schedule assisted by a personal interview method.
Dependent Variable For the present paper, response on physical health is mea-
sured based on the respondents who have been asked to provide information about
selected acute morbidity conditions from which they suffered 30 days before the
survey date—analyzing this information in detail in this section of their patterns,
differentials, and determinants.
Information about several chronic morbidity conditions from which the elderly
were suffering for more than 30 days was collected, and an analysis of such data has
been carried out looking into their patterns, differentials across their socioeconomic
characteristics, and the factors that influence the same.
Independent Variables Independent (Explanatory) Variables: About 13 selected
background characteristics of the elderly widows have been taken into account as
the independent variables, which are categorized in nature (2–4 categories) and
mostly self-explanatory (Table 15.2), except 3 of the following, viz., the standard of
living index, exposure to mass media (index), and self-reported health status. The
standard of living index (SLI) of households is a good indicator to measure the eco-
nomic status of the elderly widows indirectly. In the present study, the SLI of house-
holds has been computed based on (weighted) scores provided to the housing
structure-related aspects and household amenities and possession of household
goods. The analysis of data is carried out on the following lines. At first, the back-
ground characteristics of the elderly widows and “whether the elderly widows are
suffering from psychological distress or not have been analysed through frequency
tables. Then, the differentials in ‘whether respondents suffering from psychological
distress or not” are looked into across their background characteristics under con-
sideration with the help of cross-tabular analysis and Chi-square test of significance.
In the last stage, adopting the binary logistic regression analysis, the researcher
examined to find out the principal factors that are likely to determine/influence the
elderly widows suffering from psychological distress. All these analyses have been
carried out with the assistance of IBM SPSS software (version 20.0).
15.3.1 Patterns in Acute Morbidity
Table 15.1 reveals that 14% of the sample elderly widows reported suffering from
cold and cough, and another one-tenth of them (10%). On the other hand, few of the
elderly stated to be suffering from leg problems (7.4%) and arthritis (5.6) followed
by gastric problems (3.6%), headache (3.6%), and asthma/wheezing (2.8%), which
are somewhat common among elderly (Fig. 15.1).
Table 15.1 Acute morbidities from which the elderly widows are suffering
Acute morbidities Percentage Frequency
Cough and cold 14.1 55
Fever 10.3 40
Leg problems 7.4 29
Arthritis 5.6 22
Gastric problems 3.6 14
Headache 3.6 14
Asthma/wheezing 2.8 11
Diabetes 1.3 5
Blood pressure 1.3 5
Malaria 1.0 4
Diarrhea 0.8 3
Suffering from any acute morbidity
No 66.4 259
Yes 33.6 131
Total 100.0 390
Fig. 15.1 Prevalence of

acute morbidity among
elderly widows
15.4 Background Characteristics of the Elderly Widows
Table 15.2 (columns 2–3) reveals that two-thirds of the elderly widows are residing
in urban areas (66.7%). About two-fifths (41%) and one-third (32%) are in the age
groups of 66–75 and 60–65 years, respectively. A sizeable percentage of the elderly
widows (60%) are illiterates and one-fifth studied up to primary school (22%). One-
third of the elderly widows (36%) belong to families that have low monthly income
(₹3000 and less), whereas one-third (33.3%) belong to a fairly higher-income
bracket (₹9001 and above). On the other hand, a little less than two-fifths {38%)
Table 15.2 Factors influencing elderly widows suffering from any acute morbidity (results based
on multivariate logistic regression analysis) (with living arrangements)
95% CI for
Odds Exp(B)
Explanatory variables β-Coefficient ratio p-Level Lower/upper
Place of residence (ref: rural) –0.102 0.903 0.738 0.495–1.645
Urban
Current age (ref: 60–65 years) 0.078 1.082 0.816 0.559–2.090
66–75 0.382 1.456 0.383 0.621–3.458
76+
Educational level (ref: illiterate) –0.446 0.640 0.173 0.337–1.216
Up to primary school –0.765 0.453 0.05 0.212–1.010
Middle school and above
Monthly personal income (ref: ≤ ₹2000) 0.629 1.875 0.05 1.013–3.469
2001+
Monthly family income (ref: ≤ ₹3000) –0.670 0.512 0.120 0.220–1.191
3001–6000 –1.609 0.182 0.001 0.075–0.440
6001+
Caste (ref: scheduled castes/tribes) 0.236 1.267 0.485 0.652–2.460
Most backward castes –1.609 0.200 0.001 0.079–0.508
Backward castes –0.803 0.448 0.10 0.183–1.097
Forward castes
Economic dependency (ref: not 0.734 2.082 0.01 1.190–3.643
dependent)
Partially/fully dependent
Have debt (ref: no) 0.483 1.620 0.190 0.787–3.334
Yes
Living arrangements (ref: co-residence) –0.364 0.695 0.385 0.306–1.581
Living alone
Physical disability status (ref: no 0.519 1.680 0.10 0.949–2.971
disability)
Have disability
Have any habits (ref: no) 0.146 1.157 0.618 0.652–2.054
Yes
–2 log likelihood 399.508
Chi-square; df; sig.; N 98.348; 16; 0.001; 390
Cox and Snell R square (in %) 22.3
Nagelkerke R square (in %) 30.9
Elderly widows in the age group of above 76 suffered from more acute morbidities followed by
those in the age group of 66–75. Elderly widows with middle school education suffered from more
acute morbidity. Acute morbidity was less in elderly widows who had an income above 6000
belong to households with a middle-level standard of living (index), and one-third

of them belong to a comparatively low standard of living (index). More than two-
fifths of the elderly widows belong to the most backward castes (MBCs), while
one-fifth (21%) belong to the backward castes (BCs), and about 17 and 18% belong
to forwarding castes (FCs) and scheduled castes/tribes (highest and lowest standing
in social strata), respectively. More than two-fifths of the elderly widows (44%)
have ownership of a house, 58% are economically (partially/fully) dependent, and a
greater percentage (79.5%) have a BPL ration card. Two-fifths of the elderly wid-
ows (41%) are having exposure to mass media to a moderate extent followed by a
higher extent (36%). A large percentage of the elderly widows (66%) are suffering
from one or the other physical disability, whereas 53% and 30%, respectively, are
suffering from any one and two or more chronic morbidities. On the other hand,
around 37% of each of them reported being “fair” and “good” in their health status,
and the rest 26% reported their health status as “poor.”
15.5 Factors Influencing Elderly Widows Suffering from Any

Acute Morbidity
One of the study’s specific objectives is to identify the principal factor that affects
the magnitude of those suffering from any acute morbidity among elderly widows.
To this end, this study attempts to use multivariate logistic regression analysis. For
this, the dependent variable was measured as “those suffering from any acute mor-
bidity” (coded as “1”) and “not” (coded as “0”). However, two logit models have
one without the inclusion of living arrangements and another with living arrange-
ments. The latter model is essential as the present research work’s chief aim is to
understand the interrelationships between living arrangements, morbidities, and
care-seeking behavior. Therefore, all those variables having theoretical importance
and statistical significance (at least up to 10% level), except in living arrangements,
with the dependent variable, have been included in the model. The following two
variables, the standard of living index of households and exposure to mass media
index, are not included in the model as they are highly correlated with other explan-
atory variables considered for the analysis. Results are based on the binary logistic
regression analysis in Table 15.2.
Overall, results presented in Table 15.2 reveal that of the 11 variables included in
the model, 6 variables and their categories have exhibited significant (at different
levels of significance) net effects in influencing the extent of acute morbidity from
which the elderly widows have suffered. Among all the variables, economic status-
related factors appeared to be the most prominent ones affecting acute morbidity
among the elderly, however in different directions. As expected, the probability of
suffering from acute morbidity is strikingly lower in the elderly with reasonably
higher monthly family income bracket, viz., ₹6001 and above (OR = 0.182; 95% CI,
0.075–0.440; p < 0.001), than in lower monthly family income bracket (₹3000 and
less). Likewise, it is also pertinent to note that the likelihood of elderly widows who
suffered from any acute morbidity is lower among those who belonged to backward
castes (OR = 0.200; 95% CI, 0.079–0.508; p < 0.001) and also to some extent
among those in the forward castes (OR = 0.448; 95% CI, 0.183–1.097; p < 0.10).
This finding supports the fact that elderly widows in higher social class (strata; BCs
and FCs) have a lesser chance of suffering from any acute morbidity than their SC/
ST counterparts (poor/lower in socioeconomic strata). It is pertinent that the odds of
suffering from any acute morbidity are 2.1 times higher and also apparent among
economically dependent on others (OR = 2.082; 95% CI, 1.190–3.643; p < 0.01).
This finding specifies that those elderly widows who are either partially or fully
dependent on others for financial-related matters have a higher tendency to suffer
from acute morbidity than their counterparts. On the other hand, contrary to the
expectation, elderly widows whose personal monthly income (through social pen-
sion) is comparatively higher have shown a higher tendency to suffer from acute
morbidity than those whose personal income is less (OR = 1.875; 95% CI,
1.013–3.469; p < 0.05). One of the principal reasons for such a pattern is that these
elderly widows are higher in age by which they use to get a higher amount of old-
age pension.
Among the other variables under investigation, educational status has exhibited
the expected net negative effect on acute morbidity. The result shows that the odds
of elderly widows suffering from acute morbidity are strikingly lower among those
who have completed middle school and above level of education (OR = 0.453; 95%
CI, 0.212–1.010; p < 0.05) than their illiterate counterparts. Likewise, the odds of
suffering from any acute morbidity are relatively higher by 1.7 times among those
who have difficulty from one or the other physical disability than their matching
ones, but the statistical significance in this regard is very weak (OR = 1.680; 95%
CI, 0.949–2.971; p < 0.10).
15.6 Chronic Morbidity
The elderly suffer from one of the other chronic morbidities, and in fact, some of
them are likely to suffer from multi-morbid conditions. Therefore, in this study,
attempts are made to collect information about several chronic morbidity conditions
from which the elderly were suffering for more than 30 days.
15.7 Patterns in Chronic Morbidity
Information provided in panel 1 Table 6.4 suggests that more than one-third of the
sample elderly widows suffered from poor vision/cataract conditions (36%) fol-
lowed by arthritis (31.5%), (high) blood pressure (30%), and diabetes (29%). As
stated earlier, all these are mostly related to the lifestyles followed during adult-
hood. Next to these, back pain/slipped disk is the major chronic morbidity condition
(12%) followed by an ulcer or gastric problem and kidney trouble (8% each), osteo-
porosis (5%), lung problem/asthma (4.6%), and heart disease (4%). Other chronic
morbidities under study exist among the sample elderly, between 0.3% (one person)
and 1.8% (seven persons).
In Table 15.3 it is evident that slightly more than one-quarter of the elderly wid-
ows (27%) are believed to be suffering from two chronic morbidities under study,
followed by any one chronic morbidity (26%). While a little over one-sixth and
one-tenth of them, respectively, are suffering from three (17%) and four (11%)
chronic morbidities, just about 2% of them are suffering from five or more chronic
morbidities. Overall, a higher percentage of the sample elderly widows (83%) suffer
from one or more chronic morbidities. On the other hand, about one-sixth (17%) of
the elderly widows are not suffering from any morbidities enquired in this study
(Fig. 15.2).
Table 15.3 Distribution of elderly widows by chronic morbidities from which they are suffering
(N = 390)
Chronic morbidities Percentage Frequency
Poor vision/cataract 35.9 140
Arthritis 31.5 129
Blood pressure 30.3 118
Diabetes 28.7 112
Back pain/slipped disk 12.3 48
Ulcer or gastric problem 8.2 32
Kidney trouble 8.2 32
Osteoporosis 4.9 19
Lung problem/asthma 4.6 18
Heart disease 4.1 16
Renal disease 0.5 2
Skin diseases 1.8 7
Dental problems 1.8 7
Chronic lung disease 1.3 5
Cancer 1.3 5
Tuberculosis 0.3 1
No. of chronic morbidities among the elderly widows
0 16.7 65
1 25.9 101
2 27.4 117
3 16.9 66
4 11.4 44
5 1.8 7
Total 100.0 390
Fig. 15.2 Distribution of elderly widows who are suffering from chronic morbidity conditions
In Table 15.4, one can notice that the average number of chronic morbidities the
elderly widows are suffering is a little bit higher among those in the category of
higher standard of living (index) households (2.07) as compared to those in the
categories of lower and moderate standard of living (index) households (1.73 and
1.81, respectively). However, the one-way ANOVA test results turned out as signifi-
cant to a lesser extent (p < 0.10). Result related to the mean number of chronic
morbidities across their living arrangements (panel 7 of Table 6.5) highlights that
elderly widows living alone appear to be suffering from a fairly higher mean num-
ber of chronic diseases than those who are co-residing with children/others (2.03 vs.
1.75). The t-test result related to this finding has emerged as moderately significant
(p < 0.05).
Table 15.4 suggests that the mean number of chronic morbidities from which the
elderly widows were suffering was observed as higher among those who have expo-
sure to mass media to a higher extent (2.09) as well as to a lower extent (1.92). In
contrast, the similar figure is much lower (1.61) among those who have such expo-
sure to a moderate extent. Nevertheless, the one-way ANOVA test results in this
regard have emerged as highly significant (p < 0.01). Furthermore, as expected,
from panels 9 and 11 of Table 6.5, it is clear that the mean number of chronic mor-
bidities from which the elderly suffer is significantly higher among those who suffer
from one or more physical disabilities as well as who have savings than their coun-
terparts (2.10 and 2.41 vs. 1.39 and 1.77, respectively; p < 0.001 in each case). On
the other hand, the mean number is moderately lower among those elderly widows
who are economically dependent on others than those who are economically inde-
pendent (panel 10; 1.75 vs. 2.01; p < 0.05).
Table 15.4 Mean no. of chronic morbidity conditions among elderly widows suffering across
their background characteristics
Chronic
morbidities
Background characteristics of the elderly widows Mean S.D. Total t/F-value; sig. level
1. Place of residence 1.33 1.19 130 6.023
Rural 2.12 1.28 260 0.001
Urban
2. Current age (in years) 1.60 1.19 126 5.965
60–65 2.11 1.29 159 0.01
66–75 1.78 1.38 105
76+
3. Educational level 1.78 1.29 234 6.605
Illiterates 1.66 1.23 85 0.001
Up to primary school 2.34 1.32 71
Middle school and above
4. Monthly family income 1.91 1.16 141 3.547
3000 and less 1.61 1.27 119 0.05
3001–6000 2.03 1.44 130
6001 and above
5. Caste 1.53 1.22 68 8.820
Scheduled castes/tribes 1.66 1.29 172 0.001
Most backward castes 2.04 1.21 81
Backward castes 2.46 1.29 69
Forward castes
6. Standard of living index 1.73 1.23 131 2.342
Low 1.81 1.22 149 0.10
Middle 2.07 1.47 110
High
7. Living arrangements 1.75 1.36 242 2.116
Co-residence with others 2.03 1.18 148 0.05
Living alone
8. Exposure to mass media 1.92 1.22 92 5.406
Lower 1.61 1.34 159 0.01
Moderate 2.09 1.27 139
Higher
9. Physical disability 1.39 1.03 134 5.323
No 2.10 1.35 256 0.001
Yes
10. Economic dependency 2.01 1.18 164 1.963
Not dependent 1.75 1.37 226 0.05
Partially/fully dependent
11. Have savings 1.77 1.26 336 3.399
No 2.41 1.45 54 0.001
Yes
Total 1.86 1.30 390
Note: t-test of significance is computed for those variables which have two categories
F-test of significance is computed for those variables which have three to four categories
15.8 Factors Influencing the Chronic Morbidity Conditions

Among Elderly Widows
One of the key objectives of this research work is to find out the different factors that
influence (or determinants of) the extent of elderly widows suffering from chronic
morbidity conditions. Fulfilling this objective, multiple linear regression analysis is
carried out as the dependent variable is the number of chronic morbidity conditions
from which the elderly widows are suffering, which is discrete (ranges between “0”
and “5”). All those variables which have theoretical importance and found to be
having statistical significance (at least up to 10 percent level) with the dependent
variable are included in the model, except the following two variables, standard of
living index of households and exposure to mass media index, as they are highly
correlated with other explanatory variables. For using multiple linear regression, the
structure of explanatory (independent) variables is considered as given below.
Results are based on the multiple linear regression analysis presented in Table
15.5. On the whole, eight variables included in the regression model together have
explained a 17.4% variation in the number of chronic morbidities from which the
elderly widows are suffering at the time of the survey. As expected, among all the
variables, those suffering from one of the other physical disabilities have shown a
higher tendency to suffer from chronic morbidities to a greater extent than their
counterparts (β = 0.211; p < 0.001). Next to this, the urban residence appears to be
triggering the elderly widows to suffer from more chronic morbidities than those
residing in rural areas (β = 0.150; p < 0.01). Following these, both caste background
and years of schooling have exhibited positive net effects on the number of chronic
morbidities. These results indicate that the chances of elderly widows suffering from
more chronic morbidities are likely to be increasing with an increase in their caste
(social strata) background (β = 0.139; p < 0.01) as well as with their educational
level—years of schooling (β = 0.137; p < 0.01). Monthly family income has exhib-
ited a net positive influence on the number of chronic morbidities, i.e., the extent of
Table 15.5 Factors influencing the number of chronic morbidities from which elderly widows are
suffering (results based on multiple linear regression analysis)
Explanatory variables β-Coefficient t-value p-Level
Constant – 1.526 0.126
Place of residence (urban) 0.150 2.785 0.01
Current age (in years) –0.033 –0.636 0.924
Educational level (years of schooling) 0.137 2.548 0.01
Monthly family income (in ₹) 0.105 2.167 0.05
Caste (four categories) 0.139 2.564 0.01
Living arrangements (living alone) 0.084 1.661 0.10
Economic dependency (dependent) 0.002 0.040 0.968
Physical disability status (yes) 0.211 4.149 0.001
R-Square (in %) 17.4
N 390
suffering from more number of chronic morbidities among the elderly widows has
shown a tendency to increase with an increase in their household/family monthly
income (in) and statistically also significant at a moderate extent (β = 0.105; p <
0.05). Another pertinent finding here is that controlling for all the variables included
in the model, elderly widows who are living alone have more susceptibility to suf-
fering from more chronic morbidities than those who are co-residing with children/
others, but statistically significant to a lesser extent only (β = 0.084; p < 0.10).
Of the remaining two variables, as expected, economic dependency’s role is pos-
itive on the number of chronic morbidities from which the elderly widows are suf-
fering; contrary to the expectation, current age has exhibited a negative net effect on
chronic morbidities. However, statistically both these net effects are insignificant.
The point of interest in this research work is the role of living arrangements on
acute morbidity. By and large, as expected, elderly widows who are living alone
have shown a lesser likelihood of ever suffering from any acute morbidity than
those who are living with children/others. Likewise, the sample elderly living in
urban areas also displayed lower odds of ever suffering from acute morbidity than
their rural counterparts. However, the Wald test findings are not significant.
Conversely, the odds of ever suffering from any acute morbidity are higher among
those elderly widows in higher age groups, viz., 66–75 and 76+ years, who have
some form of debt and are habituated to adverse habits (that affect health) as against
their respective counterparts. However, the Wald statistics related to these results
were not significant even at the 10% level.
Overall, one-third of the respondents are suffering from any one or more acute
morbidities. Bivariate analysis results showed that the percentage of elderly widows
suffering from any acute morbidity is significantly higher in 76+ years old, having
higher social pension income, economically dependent, debt, habituated to betel
nut/tobacco, and presence of any physical disability than their respective counter-
parts. On the other hand, a similar percentage of suffering from any acute morbidity
is noted as significantly (at different levels) lower among the urban residents, edu-
cated (primary/middle school+), belonged to moderate/higher family income and
SIL of households, belonged to relatively higher social status communities (back-
ward and forward castes), and have higher exposure to mass media than their respec-
tive counterparts. Furthermore, multivariate logistic regression analysis reiterated
that the odds of elderly widows suffering from any acute morbidity are significantly
lower in families of higher monthly income brackets, backward castes (to some
extent forward castes also), and studied middle school and above than their corre-
sponding others. In contrast, similar odds are modestly higher among the elderly
widows who perceived themselves as economically independent, getting fairly
higher social pension, and to a small extent among those with one or more physical
disabilities than their respective counterparts.
Findings from some studies are analogous about the positive influence of current
age, presence of disabilities, and economically dependent on acute/any morbidity/
ailment, whereas a negative role in the case of the following: level of education,
urban residence, and household income/SLI/wealth quintiles (Ranjan and

Muraleedharan 2020; Agrawal and Patel 2017; Afshar et al. 2015; Agrawal and
Keshri 2014; Arokiasamy et al. 2015; Singh 2015; Wandera et al. 2015; Audinarayana
2005, 2017; Mini 2009; Rahman et al. 2007; Woo et al. 2007; Khan et al. 2005;
Kumar et al. 2005; Zimmer and Kwong 2004). However, in a few studies from
India, the prevalence of acute or any morbidity among the elderly is noted as higher
among those who belonged to higher household income quintiles/higher SES and
SC/ST/BC communities (Kaur et al. 2019; Agrawal and Patel 2017; Agrawal and
Arokiasamy 2010).
The preceding analysis and interpretation bring out the following findings. As
high as 83 percent of the sample elderly widows reported to be suffering from one
or more chronic morbidities at the time of the survey, and on average, it comes out
as 1.86 ± 1.30. Bivariate analysis results revealed that the mean number of chronic
morbidities from which the elderly suffer is significantly (at different levels)
higher among the urban residents, 66–75 age group, studied middle school and
above, households of higher (family) income and SLI, belonged to backward and
forward castes, living alone, having one or more physical disabilities, and have
some savings than their respective counterparts. Conversely, a similar meaning is
lower among those who are said to be economically dependent than independent.
Further, most of these findings are also found to be intact in the case of multiple
linear regression analysis. For example, the probability of suffering from one or
more chronic morbidities has shown an increasing tendency with an increase in
the sample widows’ educational level (p < 0.01), social status (caste; p < 0.01),
and monthly family income (p < 0.05). Equally, the tendency of suffering was
observed to be higher among those who are experiencing one or more physical
disabilities (p < 0.001), residing in urban areas (p < 0.01), and to a small extent
living alone (p < 0.10). Overall, it appears that elderly widows from higher socio-
economic status categories appeared to be suffering from more chronic morbidi-
ties. Few studies from India on any acute/chronic morbidity among the elderly
have exhibited, more or less, a similar type of findings, especially in the case of
urban areas, higher family income brackets, social status (caste), and also, to
some extent, educated (Ranjan and Muraleedharan 2020; Kumar et al. 2017;
Audinarayana 2005, 2017, 2018; Himanshu and Talukdar 2017; Agrawal and
Keshri 2014; Agrawal and Arokiasamy 2010).
On the other hand, few studies from abroad and India have conclusively sup-
ported that the magnitude of chronic morbidity is higher among elderly in advanced
age, economically dependent, living alone, and having a disability, whereas a simi-
lar magnitude is lower among those who belonged to lower SES categories (Ranjan
and Muraleedharan 2020; Audinarayana 2017, Sudarshan and Chethan 2016; Ha et
al. 2015; Nunes et al. 2015; Phaswana-Mafuya et al. 2013; Khanam et al. 2011;
Marengoni et al. 2008; Jatrana and Chan 2007; Wandera et al. 2015; Banjare and
Pradhan 2014; Audinarayana 2005, 2017; Mini 2009; Medhi et al. 2006; Kumar et
al. 2005; Joshi et al. 2003).
15.9 Conclusion, Discussion, and Implication
This research measures physical morbidity in terms of acute morbidity (reference

period is <30 days) and chronic morbidity (reference period is 30 days and above)
conditions from which the elderly widows are suffering before the survey period.
This research highlights that one-third of the sample of elderly widows (34%) stated
to be suffering from one of the other acute morbidity conditions, which are cough
and cold (14%) and fever (10%) higher followed by leg problems (7%) and arthritis
(6%). While assessing the factors affecting (multivariate logistic regression), the
following results have emerged. Similarly, elderly widows suffering from acute
morbidity conditions are noted as high among families having a higher monthly
income (₹6001 and above), backward and forward castes, and have education up to
middle school and beyond than their counterparts. Conversely, the odds of suffering
from acute morbidity conditions are higher among those perceived as economically
(fully/partially) dependent, getting modest higher personal monthly income through
a social pension (₹2001 and above), and experiencing one or more physical disabili-
ties. Besides these, bivariate analysis results showed that the percentage suffering
from one or more acute morbidity conditions is relatively lower among those resid-
ing in urban areas, belonging to households of high SLI, and having higher mass
media exposure. In opposition to this pattern, the corresponding percentage is
higher among those having some debt and afflicted with adverse personal habits,
whereas a similar did not vary across their living arrangements. The majority of
these findings agree with those observed in studies carried out in different settings
of the world and India.
An analysis of chronic morbidity conditions and their associated factors suggests
that 83 percent of the elderly widows are suffering from chronic morbidities, of
which the following ones are stated as major ones: poor vision/cataract (36%),
arthritis (31.5%), blood pressure (30%), and diabetes (29%). In addition, elderly
widows suffering from multiple morbidities appeared high (27%, 17%, and 13%,
respectively, two, three, and four chronic morbidity conditions). On average, the
sample of elderly widows is suffering from 2.08 ± 1.22 chronic morbidities. Multiple
linear regression analysis results highlighted that the likelihood of elderly widows
suffering from chronic morbidities is noted as increasing with an increase in their
years of schooling (educational status), monthly family income, and caste hierarchy
(social strata). Similarly, those conditions are high among those suffering from one
or more physical disabilities, dwelling in urban areas, and to some extent living
alone. The cross-tabular analysis also found that the mean no. of chronic morbidi-
ties from which the elderly widows are suffering is high among the age group of
66–75 years, those dwelling in households of high SLI, those having higher expo-
sure to mass media, and also those having some savings; the comparable mean is
lower among economically (partially/fully) dependent. Similar findings were seen
in several studies conducted in different settings of the world and India.
These findings indicate that the elderly suffering from acute morbidities has to be
provided with curative services at their doorsteps by mobile clinics to the selected
areas at least weekly once from the nearby hospitals/clinics and NGOs to cure their
ailments at the earliest. Likewise, geriatric wards have to be established in the gov-
ernment hospitals/PHCs, so that those suffering from chronic morbidities and phys-
ical disabilities (especially those living alone) could benefit from utilizing the
healthcare services free of cost.
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Chapter 16
Energy Restriction on Cellular
and Molecular Mechanisms in Aging
Leila Haghshenas , Mohsen Nabi-Afjadi , Hamidreza Zalpoor ,

Maryam Bakhtiyari , and Francesco Marotta
Abstract Energy restriction (ER) or calorie restriction (CR) refers to adequate

intake of essential nutrients while being accompanied by energy restriction. Aging
is known to be a risk factor for neurodegeneration, vascular disease and heart fail-
ure, and increased general inflammation that leads to type 2 diabetes by aging
mechanisms. Energy restriction has been proven to prevent age-related chronic dis-
eases, cancers, and increase average and maximum lifespan, and protect against
neurodegenerative diseases, diabetes, hypertension, and vascular disease.
The effects of CR on lifespan may be caused by various mechanisms, including
changes and enhancements in metabolism energy, oxidative stress, insulin sensitiv-
ity, and structural changes in the sympathetic and neuroendocrine systems.CR with
mechanisms such as apoptosis reduces damage to stem cells and protects them,
maintains balance and tissue size and homeostasis, and prevents the occurrence of
diseases related to aging.
L. Haghshenas
Postdoc Association Member of Harvard Medical School, Boston, MA, USA
M. Nabi-Afjadi
Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University,
Tehran, Iran
H. Zalpoor
American Association of Kidney Patients, Tampa, FL, USA
M. Bakhtiyari
Department of Medical Laboratory Sciences, Qazvin University of Medical Sciences,
Qazvin, Iran
F. Marotta (*)
ReGenera R&D International for Aging Intervention and Vitality and Longevity in Medical
Science Commission, FEMTEC World Federation, Milano, Italy
Ltd. 2023
298 L. Haghshenas et al.
Energy restriction is beneficial to promote mitochondrial turnover by increasing

the biogenesis of new mitochondria and the destruction of damaged mitochondria
that generate superoxide radicals. Mitochondrial biogenesis reduces the production
of ROS (reactive oxygen species), and in addition to preventing the loss of mito-
chondrial function in muscles, protecting fat tissue and affecting the energy metabo-
lism of lipids on carbohydrates, glucose production, and glycolysis.
We also elucidated the characteristics of the senescence-associated secretory
phenotype (SASP) by which senescent cells provoke self-immune antagonism. The
SASP response expresses instructions at the transcriptional level. Post-translational
modifications activate a number of SASP genes, especially interleukins.
Agingomics studies RNAs groups together that affect transcription and tran-
scription can classify aging. Age-related gene expression is used to classify aging
biomarkers.
Cellular fitness evolves as a final result of entropy through chromosome organi-
zation, transcriptional regulation, and nuclear export/import in the nucleus to pro-
tein translation, autophagy recycling of organelles, cytoskeleton suspension, and
subsequently extracellular matrix suspension and extracellular signaling.
In addition, we mentioned the studies on the antioxidant and anti-aging proper-
ties of some plants, which were confirmed by Professor Marotta and his colleagues,
and the effect of functional foods by Professor Barbagallo et al and the Mediterranean
diet in the use of foods with oily polyphenols, as well as ketone therapy, by some
other scientists and we described their effect on the cell with the molecular mecha-
nisms of pathways such as NADH and P450 cytochrome enzymes.
Keywords ER (energy restriction) · CR (calorie restriction) · Ageing · Oxidative

stress · SASP (senescence-associated secretory phenotype) · Agingomics ·
Functional foods · P450 cytochrome
16.1 Energy Restriction: Definition and Characteristics
ER, or energy restriction, also known as caloric restriction, is the only nutritional
intervention that maintains adequate intakes of essential nutrients, while restricting
energy intake by up to 50% (severe ER). The effectiveness of ER has been proven
in yeast, worms, fish, rats, mice, and humans without chronic disease to prevent
chronic age-associated diseases/disorders and to increase their median and maximal
lifespan. CR’s effects on lifespan may be mediated by a variety of mechanisms,
including changes in energy metabolism, oxidative damage, insulin sensitivity, and
structural alterations in the sympathetic and neuroendocrine systems. DNA, lipids,
and proteins are all damaged by reactive oxygen species (ROS) produced in mito-
chondria, which accelerates biological aging. Research has also centered on CR’s
ability to protect against age-related changes in endocrine and physiological factors/
genes, including leptin concentrations, plasma insulin levels, DHEAS levels, and
thyroid hormone levels. To decrease the risk of such diet-related diseases, food and
16 Energy Restriction on Cellular and Molecular Mechanisms in Aging 299
Fig. 16.1 The role of energy restriction and natural products in aging-related diseases such as
neurodegenerative disease, cancers, diabetes, and cardiovascular disease, which lead to healthspan
longevity. Energy restriction condition or natural product usage,improve aging-related diseases via
modulation of several hyper/hypo-activated factors/pathways
health agencies like the USDA (United States Department of Health and Human
Services and United States Department of Agriculture) recommend eating foods
high in vitamins and minerals, but low in energy density (up to moderate) (Kunduraci
and Ozbek 2020; Cantero et al. 2017; Nikolai et al. 2015; Mitchell et al. 2015; Most
et al. 2017; Kord et al. 2021; Stern et al. 2016; Mattson et al. 2017; Redman et al.
2018; Pearl 1928; Hambly and Speakman 2005; De Cabo and Mattson 2019;
Heilbronn et al. 2006; Organization WH, Canada PHAO, Canada CPHAO 2005;
Flanagan et al. 2020; Willcox et al. 2006) (Fig. 16.1).
16.1.1 Energy Restriction (ER) and Cancer and Diseases
Caloric restriction (CR) is recognized as the best organic process intervention for
extending life and delaying age-related diseases, as well as cancer interference and
chronic diseases (Omodei and Fontana 2011). Different sorts of energy restriction,
like periodic fast, intermittent fast, or fasting-mimicking diets, with or while not
total caloric intake reduction, mimic the chronic CR effects and supply a spread of
health advantages, as well as anticancer properties (Castejón et al. 2020). Additional
studies in animal models have found that CR exerts a task in suppressing spontane-
ous neoplasias and/or tumorigenesis in p53-deficient mice; chemically induced
breast cancer, cancer of the liver, bladder cancer, prostate cancer, ovarian cancer,
and pancreatic cancer; or cancers caused by radiation (Gross and Dreyfuss 1990;
Dunn et al. 1997; Fu et al. 2020; Cohen 2018; Hursting et al. 1994; Chen et al. 2012;
Lanza-Jacoby et al. 2013; Bonorden et al. 2009).
It has been advised that ER and CR shield nonhuman and human primates against
numerous chronic diseases together with neurodegenerative diseases (Xie et al.
2020), diabetes, abdominal avoirdupois, high blood pressure, and vessel diseases
(Omodei and Fontana 2011). Caloric restriction (CR) is understood to increase life-
time in most organisms, indicating that nutrient and energy restrictive mechanisms
impact aging. The best risk factor for neurodegeneration is age; therefore, the anti-
aging effects of CR may decrease progressive necrobiosis and avert the aggregation
of abnormal proteins related to neurodegenerative unwellnesss like Alzheimer’s dis-
ease (Ntsapi and Loos 2016), Considerably attenuated psychological feature deficits
and amyloid pathology in transgenic mouse models of AD (Alzheimer’s disease),
presumably by targeting γ-secretase-dependent amyloid precursor macromolecule
(APP) metabolism. Psychological feature operation and underlying cellular, molec-
ular, and physiological mechanisms are celebrated to decrease age (Bettio et al.
2017; Padgaonkar et al. 2017).
Intermittent energy restriction (IER) is an alternate technique to attain weight
loss, which may be used for the management of type 2 diabetes (T2D) (Carter
et al. 2016). Energy restriction not solely may be helpful for hindrance of T2D
(Barnosky et al. 2014); however it can also be helpful for T2D treatment. The
worldwide raise in lifetime can cause a dramatic increase in age-related diseases
within the coming back decades. During this context, vessel diseases together with
coronary artery disease and heart failure (HF) increase exponentially with age.
Moreover, type 2 diabetes mellitus (T2DM) is closely connected to aging and may
be a major risk factor for age-associated diseases like coronary artery disease and
HF (Beckman et al. 2002). The aging method itself and the way it interacts with
diseases are incompletely understood. Aging has been related to a change in meta-
bolic pathways. As an example, insulin resistance and changes in body composi-
tion are the most important age-related mechanisms leading to diabetes (Morley
2008). Additionally, aging has been related to general inflammation (Franceschi
and Campisi 2014), which may be a cause moreover as a consequence of diabetes.
It is well incontestable that in response to an amount of restricted provision of
energy and nutrients (energy restriction), an adaptational decrease in whole-body
energy expenditure happens, and this can be part owing to a rise in metabolic
potency (Ramsey et al. 2000). This adaptation permits the organism to spare energy
and slows the speed of depletion of fat stores (Barzilai and Gabriely 2001).
16.1.2 Energy Restriction, Reproduction, and Tissues
It has long been proverbial that obesity, particularly central obesity, will adversely
have an effect on fertility in each man and woman (Hunter et al. 2021; Bond et al.
2020). Fat aggravates a predisposition to polycystic ovary syndrome (PCOS) that
may be a major reason behind ovulatory sterility (Nehir Aytan et al. 2016;
Gambineri et al. 2002; Martinez-Bermejo et al. 2007). PCOS is characterized by
hyperandrogenism and oligo, additionally to having polycystic ovaries. In men,
overweight or fat decreases the amount and quality of sperm and will increase the
chance of dysfunction (Kratzik et al. 2005; Lim et al. 2007). CR has been shown to
scale back oxidative stress, improve hormone sensitivity, and alter system responses
and central nervous system (CNS) performance in animals. CR has notably pro-
found and complicated actions upon reproductive health. At the theory level, the
foremost crucial physiological performance of any organism is its capability to
breed. For a roaring species to thrive, the balance between accessible energy (food)
and also the energy expenditure needed for reproduction should be tightly coupled.
A capability to coordinate energy balance and fecundity involves advanced interac-
tions of hormones from each of the peripheral and also the central nervous system
and primarily centers upon anterior pituitary as the master endocrine (Martin
et al. 2008).
Food energy is often held on as fat or glycogen which might then be mobilized
for procreative functions like time of life maturation and fertility itself. The fore-
most basic style of reduced energy intake in laboratory experiments is glucose
deprivation, as this is often the prime supply of energy for many mammals. It’s been
incontestible in animal models (mostly rodents, sheep, or primates) that fast or glu-
cose deprivation affects procreative performance by suppressing pulsatile LH
release from the pituitary gonadotropes. The glucose energy deficit is so apace
detected and is maybe sent to the hypothalamus where GnRH secretion is noncon-
tinuous to attenuate the pulsatile LH release and to ultimately conserve energy in
times of low glucose convenience (Martin et al. 2008).
16.1.3 Energy Restriction and Stem Cells
Importantly, the homeostasis of physique tissues in adults depends on the renova-

tion of stem cells. These cells are self-renewing and regenerative and can also dif-
ferentiate. Also, these cells are of two types: (1) dormant/quiescent stem cells that
do not enter the cell cycle until arrival of a powerful stimuli and (2) active stem/
progenitor cells that often enter the cell cycle to take care of tissue homeostasis. It’s
essential to apprehend that as soon as these cells lose their potency, it’s an important
and essential spark for the onset of aging-related illnesses (Hoggatt and Scadden
2012; Li and Xie 2005; Cheung and Rando 2013). By decreasing damage to stem
cells and keeping them, CR will keep tissue equilibrium and prevent the event of
growing older-related ailments (Maharajan et al. 2020).
16.1.4 Energy Restriction and Programmed Cell Death
Apoptosis is a necessary element of the cellular regulation of tissue size regulation

and homeostasis (Thompson et al. 2004). The incidence of a neoplasm represents a
failure of tissue size regulation. ER inhibits mammary carcinogenesis and ends up
in a marked reduction in neoplasm size, effects probably to be explained by

ER-mediated induction of programmed cell death (Thompson et al. 2004).
Additionally, the role of ER in kidney protection has additionally been elucidated.
In diagnosing studies, adjusting total energy intake or consumption of specific nutri-
ents has prophylactic or therapeutic effects on aging-related disease and acute and
chronic renal injury. ER will increase Sirt1 expression within the kidneys of aged
rats, inhibits renal tubular epithelial cell programmed cell death, and reduces
cisplatin-induced AKI (Ning et al. 2013). In animals, ER will scale back the extent
of inflammatory cytokines and mitigate inflammation. The NF-κB transcription and
pro-inflammatory protein levels increase with age (Csiszar et al. 2014).
16.1.5 Obesity, Energy Restriction, and Aging
Obese people have shown hyperbolic susceptibleness to infections, bacteremia, and

poor wound healing after surgery (Lamas et al. 2004). Fat disorders cause changes in
fat distribution and performance, with vital effects on cytokines, chemokines, endo-
crine expression, and therefore the composition of immune cell populations present
in adipose tissue (Weber et al. 1986). Obesity has additionally been related to a poor
protein response to hepatitis B plasma immunizing agent (Weber et al. 1986) and
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine
(Watanabe et al. 2022). Despite these clear connections, the molecular mechanisms
concerned within the altered immunologic response in obesity square measure poorly
illustrious. In fact, it’s been urged that obesity may be associate in inflammatory
condition within which totally different interleukins are also concerned (Das 2001).
It has been shown that energy restriction is often helpful to revive an antecedently
impaired immune performance in diet-induced overweight rats. During this context,
energy restriction junction rectified to higher CD4+ lymphocyte set, inflated spleno-
cyte proliferation upon stimulation with phytohemagglutinin (PHA) and concanavalin
A (Con A), and increased natural killer (NK) cell cytotoxic activity (Csiszar et al. 2014).
16.2 The Effect of Energy Restriction on Metabolism and Its

Relationship with Aging
By altering the body’s metabolism, ER reduces the risk of age-related diseases asso-
ciated with reduced body weight (Patterson and Sears 2017). A major source of
energy for many tissues, especially the brain when energy is restricted, is ketone
bodies, which are produced when fasting plasma glucose, insulin, glycogen stores,
and fatty acid mobilization are reduced in initially overweight as well as normal-
weight subjects (Nikolai et al. 2015; Lezcano et al. 2014; Gabel et al. 2018).
ADP-ribosyl cyclase (CD38), poly(adenosine diphosphate [ADP]–ribose) poly-
merase 1 (PARP1), and poly(adenosine diphosphate [ADP]–ribose) polymerase 1
(PdiP2) are a few of the many proteins and molecules affected by ketones but also
regulate health and aging (Veech et al. 2017; Ye et al. 2017; Imai and Guarente
2016). The ER induces gluconeogenesis from lipids and amino acids in order to
compensate for reduced glucose intake. Under ER, glycolysis is reduced, as shown
in rats. As a result of improved glucoregulation, advanced glycation endproducts
(AGEs) are produced in various tissues and bind to their receptors (receptors for
AGE, RAGEs), thereby causing renal, vascular, or neurological changes associated
with aging (Gabel et al. 2018; Imai and Guarente 2016). A limiting energy supply,
however, can be interpreted as a mild stressor that activates a stress response in an
organism, thereby improving stress resistance. It is consistent with this hypothesis
that heat shock proteins and antioxidant enzymes are enhanced under ER (Yu and
Chung 2001; Ristow and Zarse 2010).
It is important to know that mitochondria, the cellular energy supplier’s source of
ROS, are extremely sensitive to oxidative damage. As mitochondria age, leaking
electrons and molecular oxygen create superoxide radicals, decreasing mitochon-
drial ATP efficiency and forming superoxide radicals during oxidation steps of the
electron chain. Thus, it seems useful to promote mitochondrial turnover by enhanc-
ing biogenesis of new mitochondria and degradation of old and damaged ones
(Murphy 2009; Cadenas and Davies 2000; Chocron et al. 2019).
In this line, PPARγ coactivator 1α (PGC1α) is thought to be the key modulator
of mitochondrial biogenesis and function via affecting on nuclear respiratory fac-
tors 1 and 2, estrogen-related receptors, and mitochondrial transcription factor A
(Ye et al. 2017; Dominy and Puigserver 2013).
A state of energy restriction results in declining ATP ranges and an extent in
AMP/ATP ratios, which activate the nutrient sensor AMPK. As such, improved
stages of phosphorylated AMPK (p-AMPK) indicate inadequate energy supply.
SIRT1, PGC1, and some forkhead box O (FOXO) produces in mitochondrial bio-
genesis and stress protection mechanisms are activated via AMPK phosphorylation.
A deacetylation response initiated by using SIRT1 could lead to mitochondrial bio-
genesis while lowering ROS production. In addition to preventing mitochondrial
characteristic loss in muscles, protecting adipose tissue from distributional and
practical changes, and affecting energy metabolism, lipids are favored over carbo-
hydrates (Dominy and Puigserver 2013; Hardie 2007; Pimentel et al. 2013; Cantó
et al. 2010; Golbidi et al. 2017). In mice, SIRT1-mediated activation of PGC1α had
a high-quality effect on glucose production, glucose mobilization, and glycolysis by
means of affecting hypoxia-inducible factor1α (HIF-1α) (Houtkooper et al. 2012).
In a study, Marotta et al. indicated that concomitant treatment of human amnion-
derived epithelial cell line (FL cells) with Rhodiola rosea, an herb which has been
used in traditional medicine for several years, and LF, a class of lipoproteins, derived
from the fish Trachurus sp. (LF-T) increased expression of antiaging genes such as
SIRT1, KLOTHO, SERPINA 6, MMP 9, and MMP 2 (Mantello et al. 2017; Marotta
et al. 2021). AMPK activation also phosphorylates and inactivates acetyl-CoA car-
boxylase (ACC). ACC inactivation is accompanied by the suppression of fatty acid
synthase and blocking lipogenesis. Recent results also have shown that long-term ER
stimulate browning of white adipose tissue (WAT) (Omar et al. 2012). Stimulation of
“browning” in WAT by dietary means can influence body weight and the potential
Fig. 16.2 Cellular and molecular mechanisms of aging and energy restriction
success anti-obesity therapies during reduction of cholesterol, LDL, and triglyceride

(TAG). In this regard, different food constituents and intermediary metabolites such
as lactate, β-hydroxybutyrate, and L-arginine can induce browning of WAT
(Houtkooper et al. 2012). In this line, Marotta and colleagues have several successful
studies on antioxidant and antiaging properties of a specific fermented papaya prepa-
ration (ORI lab, Gifu, Japan) which proved at electron spin resonance to yield remark-
ably robust properties as compared to other generic fermented papaya extracts and
beyond the expected effects of vitamins (A and C) and amino acids (arginine among
all) (Marotta et al. 2020; Marotta et al. 2017; Barbagallo et al. 2015) (Fig. 16.2).
Moreover, cytochrome P450 enzymes especially catalyze mixed-function oxida-
tion reactions during interacting with flavoenzymes or iron-sulfur proteins to get
hold of electrons from NAD(P)H. So, cytochrome P450 (P450) enzymes have been
suggested to be a source of ROS. In a finding by means of Barbagallo et al., it was
once shown that functional foods, such as fermented papaya ORI, are antioxidants
and have an effect on cells via the NADH and P450 pathways (Barbagallo et al.
2012; Barbagallo et al. 2015).
16.2.1 Association of Energy Restriction with Endocrine

Glands, Growth Hormone, Insulin-Like Hormone,
and Diabetes
The levels of adiponectin and insulin sensitivity rise upon energy restriction,
whereas fasting plasma glucose and insulin are reduced. Therefore, ER is related
with a lowered hazard of getting age-related diseases such as T2DM. As insulin
secretion decreases, plasma glucocorticoids concentrations commonly rise (Imai
and Guarente 2016; Fontana et al. 2010; Pires et al. 2014). Several species of ani-
mals show off lower ranges of anabolic hormones such as leptin, insulin, testoster-
one, estradiol, and follicle-stimulating hormone upon ER, which is predicted
thinking about the reduced increase rates and the slow maturation process. In con-
trast, plasma concentrations of the catabolic adiponectin and of the steroid hormone-
binding protein tend to be improved that is inversely related to body weight,
adiposity, and insulin resistance. It is hypothesized that the propensity of adiponec-
tin to shift metabolism from glucose burning to fats burning reduces oxidative stress
and promotes toughness (Imai and Guarente 2016; Redman and Ravussin 2009;
Cangemi et al. 2010).
On the other hand, human subjects undergoing ER regimens report reduced
availability of gonadal steroids like testosterone and estradiol due to higher levels of
steroid hormone-binding proteins (Gagnon et al. 2018).
When fed ER, triiodothyronine (T3) declined consistently in rodents, primates,
and humans, similar to leptin, insulin, and testosterone. Since T3 and body tempera-
ture are positively correlated, the reduced T3 levels of ER-fed subjects seem to fit
well with the reduced body temperatures of these subjects (Imai and Guarente 2016;
Silva et al. 2021; Tonelu et al. 2021).
A deficit of thyroid-stimulating hormone causes hypothyroidism in dwarf mice,
resulting in decreased T3. The mice had increased lifespans due to reduced meta-
bolic rates and reduced reactive oxygen species (ROS) generation. As mitochon-
drial heat is utilized more efficiently due to increased signaling by mitochondrial
uncoupling proteins (UCPs), ROS production and damage to mitochondria could
potentially be reduced. Insulin-like growth factor 1 (IGF-1) signaling pathway is
also negatively affected under ER which is accompanied by lowered growth hor-
mone (GH) concentrations since GH promotes IGF expression (Yang et al. 2018;
Brown-Borg 1996). ER-induced reduction in plasma levels of free IGF-1 is related
to proapoptotic and antiproliferative effects and, consequently, survival in long-
lived humans. IGF-1 signaling also activates mammalian target of rapamycin
(mTOR) that influences cell growth, including proliferation, transcription, and pro-
tein synthesis, as well as cell survival (Brown-Borg 1996; Chesnokova et al. 2019;
Johnson 2018).
SIRT1 activation also upregulates pancreatic insulin secretion, leading to an
increase in hepatic insulin sensitivity. A decrease in the ratio of NAD+/NADH
under ER decreases the inhibitory effect of SIRT1 on UCP-2, increasing ATP pro-
duction and insulin release (Lee et al. 2021; Ghiasi et al. 2019). As well, SIRT1 is
capable of activating the transcription factors NeuroD and MafA, which contribute
to the secretion of insulin from the Ins2 gene (Nishimura et al. 2022; Avilkina et al.
2022). SIRT1 also repress lipid synthesis and promote lipolysis through downregu-
lation of SREBP-1, SREBP-2, and PPARγ genes during ER (Kyun 2021; Sun et al.
2021). Putative ER mimetics (ERM) are natural/synthetic substances that mimic
potential antiaging effects of ER. Metformin (activator of MAPK signaling),
rapamycin (inhibitor of mTOR), resveratrol (inhibitor of SIRT1, mainly found in
the lingonberry, skin of red grapes, red wine, and roots of the medical plant Japanese
knotweed), flavonoids such as quercetin, kaempferol and hesperetin found widely
in flowers and fruits as inhibitors of mTOR and HIF-1α or other undesirable signal-
ing pathways) and spermidine (rich in soya and other beans, green tea, and mush-
rooms and diets traditionally consumed in Asian and Mediterranean regions) with
anti-inflammatory properties, antioxidant functions, enhancement of mitochondrial
metabolic function and respiration, as well as improved proteostasis and chaperone
activity (Zalpoor et al. 2022; Ashrafizadeh et al. 2020; Choi et al. 2020; Kawamura
et al. 2021; Madeo et al. 2018).
16.2.2 The Effect of Energy Restriction on the Nervous System

and Its Relationship with Aging
One of the predominant purposes of growing older is postulated to be the contem-

porary accumulation of cell damage, what has been recently termed as “garbaging,”
owed to surpassed manufacturing of reactive oxygen species (ROS) from mitochon-
dria (Wang et al. 2019). Brain tissue is in particular sensitive to oxidative stress, the
make higher of free oxygen species is associated with neurodegenerative illnesses
with the reduction of antioxidant activity and the cut range of the effectivity of
restore mechanisms (Barbagallo et al. 2015).
As a cease result of mitochondrial dysfunction, energy is depleted, disrupting
neuronal processes, and main to neurodegenerative illnesses such as Alzheimer’s,
Parkinson’s, Huntington’s, and so on (Cagin and Enriquez 2015; Casajus Pelegay
et al. 2019). According to current research, CR advantages the intelligence via a
range of neuroprotective mechanisms, such as antioxidant effects, the formation of
ketone bodies, anti-inflammatory effects, and expanded C activities through the
expression of neurodevelopmental factors, such as brain-derived neurotrophic ele-
ment (BDNF), neurotrophin-3 (NT-3), glial cell line-derived neurotrophic element
(GDNF), and SIRTs and mTOR (Rubovitch et al. 2019; Mladenovic Djordjevic
et al. 2021). Calcium buffering is one of the necessary mechanisms through which
CR has the functionality to extensively have an impact on mitochondrial function.
Under CR conditions, this may want to suggest that SIRT3-mediated deacetylation
and inhibition of cyclophilin D promote mitochondrial permeability transition inhi-
bition by using an exceptional pathway. By doing so, larger calcium is retained in
mitochondria or buffered better, and cellular loss of life can be prevented due to
overwhelmed buffers (Amigo et al. 2017). In addition to affecting the amplification
and enhancement of the brain, sirtuins have an effect on the destiny of the neu-
rotransmitters in neurons thru axon elongation, neurite outgrowth, and branching
(Rubovitch et al. 2019; Ran et al. 2015). SIRTs, specifically SIRT1, regulate the
ubiquitin-proteasome pathway (UPP). Synaptic protein turnover, plasticity, and
long-term reminiscence formation are all due to the UPP, as properly as the ordinary
movement of neuronal synapses (Abdullah et al. 2020; Thibaudeau and Smith 2019).
As a target of SIRT1, PGC-1α regulates the enzyme BACE1, involved in Aβ that
its generation/expression has been diminished in Alzheimer’s patients. Interestingly,
it has been said that the downregulation of PGC-1α can be accountable for blunted
antioxidant responses (Casajus Pelegay et al. 2019; Vasconcelos et al. 2019).
As a member of Mediterranean diets, there is developing evidence that polyphe-

nols from olive oil (especially hydroxytyrosol) and additionally fisetin, curcumin,
sulforaphane, quercetin, and oleuropein induce the expression of SIRT1 (Mladenovic
Djordjevic et al. 2021; Bianchi et al. 2021; Vasconcelos et al. 2019). Moreover,
research indicates that sulforaphane impairs mitochondrial membrane potential,
and quercetin has been shown to stimulate mitochondrial biogenesis and upregu-
lates mitochondrial bioenergetics (Zalpoor et al. 2022; Selvaraji et al. 2019).
Menopausal women may additionally trip improved oxidative stress and reduced
antioxidant endeavor along with diminished neurosteroids, which is a chance factor
for Alzheimer’s. A pilot study used to be investigated the function of an actual
Japanese purposeful food (FPP-ORI, Osato Research Institute, Gifu, Japan) on
redox and mitochondrial efficiency in postmenopausal female (Marotta et al. 2020).
On the different hand, produced ketone bodies (KB) mediated via ER have been
had exceptional tiers of success to forestall neuronal damage, motor changes, and
cognitive decline through a number of neuroprotective mechanisms including meta-
bolic, anti-inflammatory, and antioxidant (Camberos-Luna and Massieu 2020;
Jensen et al. 2020). As an end result of increased oxidation of NADH and mitochon-
drial respiration, KB decreased glutamate excitability in remoted cortical neurons
(Camberos-Luna and Massieu 2020; Marosi et al. 2016).
An excitotoxic response occurs when glutamate receptors, particularly NMDA
receptors, are prolonged activated and intracellular Ca2 levels are increased, leading
to mitochondrial dysfunction and ROS production (Bano and Ankarcrona 2018).
Ketone therapy is therefore cautioned for the cure of AD, HD, PD, MS, malignant
glioma, migraine headache, and motor neuron disease (Ran et al. 2015; Fitzgerald
et al. 2018). A lack of oxygen and glucose additionally leads to an extent in the
charge of oxygen consumption and ATP synthesis in cultured neurons receiving
BHB. By activating the PGC1a-SIRT3-UCP2 pathway, ketone derivatives inhibit
oxidative stress and increase TCA intermediates and promote mitochondrial bio-
genesis (Camberos-Luna and Massieu 2020; Hasan-Olive et al. 2019). Study find-
ings propose that EGCG and coconut oil can enhance ketone bodies in the blood,
thereby reducing cardiac risks in human beings with multiple sclerosis (MS)
(Benlloch et al. 2020).
16.3 Cellular Senescence, Energy Restriction, and Aging
Aging of the body’s cells is precipitated by using various factors in the body, and in
addition, the incidence of these elements is most per chance the spark for the struc-
ture of this development. Under the have an impact on of therapy, the use of onco-
genes in proliferation, senescent cells acquire many characteristics. The cell cycle
of these cells is stopped through the stimulating aspects that appear, and it seems
that they be in no way successful in reentering the cell cycle. Also, these cells secrete
elements that stimulate the immune system, which in some instances is an attribute
of the senescence-associated secretory phenotype (SASP). In addition to the prefer-
ences mentioned, these cells have their nonpublic appearance, qualities, and
epigenetic expression. Apparently, these cells provoke the immune system’s opposi-
tion to itself. For example, we have a tendency to agree that these cells have SASP
properties. SASP can also additionally act as a neurostimulator at the site of secre-
tion of inflammatory cytokines and chemokines such as IL-6, IL-8, CCL2, and
CXCL1 in senescent cells, stimulating immune cells to senescent cells away from
the surrounding environment (Birch and Gil 2020) (Fig. 16.2).
16.3.1 Cellular Senescence Modulator: Energy Restriction
Caloric restriction (CR) like energy restriction (ER) is a wonderful way to limit age-
associated persistent diseases and increase lifespan that is typically involved in
reducing caloric intake while with maintaining sufficient diet in people CR can
counteract a number of the mechanisms involved in age-associated diseases.
Adequate intake of vitamins and minerals it has been demonstrated that by way of
interfering with the source of injury, CR is involved in protection toward cell senes-
cence these sources of harm include oxidative stress by using promotion the expres-
sion and undertaking of NrF2 that induces a number of anti-oxidative enzymes,
information, repairing, and disposing of existing destruction, raises autophagy
(downregulation of the IGF1 signaling pathway) (Pimentel et al. 2013).
16.3.2 Cellular Senescence Biomarkers
16.3.2.1 Oxidative Stress
The accumulation of reactive oxygen species (ROS) reasons oxidative stress. ROS
is originated from mitochondria or ultraviolet radiation damages. Destruction of
lipids, proteins, and nucleic acids, inter alia protein carbonylation, and the produc-
tion of 8-hydroxy-20-deoxyguanosine (8-OHdG) are the results of ROS activity. In
addition, regulation of the mitogen-activated protein kinase (MAPK) and nuclear
factor kappa-B (NF-ĸB) signaling pathway that consequences to the activation of
heterodimer activator protein 1 (AP-1) is the end stop end result of excessive ROS
accumulation in senescent cells. In the following, AP-1 degrades collagen and elas-
tin in pores and skin tissues through induction of matrix protein metalloenzymes
(MMPs) (Abdullah et al. 2020).
16.3.2.2 Tumor Suppressing and Cell Cycle Arrest
Interestingly, senescent cells are terminally increase arrested. So cell cycle regula-
tors such as p16INK4a, p21CIP1, and p53 are desirable choices for figuring out the
senescent cells. As simultaneously upregulation of p16INK4a, p21CIP1, and p53 in
human skin fibroblasts post-ultraviolet (UV) radiation have been shown. P16INK4a
is a key issue in cell cycle controlling that is upstream of the retinoblastoma tumor
suppressor protein. Several preneoplastic lesions which encompass melanocyte-rich
benign human nevi are full of p16INK4a-positive cells; this phenomenon resulted
from N-RAS mutation or its downstream goal BRAF. Generally, p16INK4a locus is
often mutated in a range of cancers, such as pores and skin epithelial tumors (Wang
and Dreesen 2018).
16.3.2.3 The SASP Regulatory Signaling Pathways
Importantly, the SASP response is related to guidelines at the transcriptional level.

Convergence of SASP regulators to the transcription elements CCAAT/B enhancer-
binding protein β (C/EBP-β) and nuclear aspect kappa-B (NF-ĸB) co-induces the
rules of SASP factors in a broad range of contexts of aging. The stable DNA damage
response (DDR) signal at as soon as prompts the SASP program; on the other hand
this activation is no longer at once associated with p53, p21, and p16. Interestingly,
NF-ĸB activation relies upon on ATM kinase, which interacts with and phosphory-
lates the regulatory NF-ĸB indispensable modulator (NEMO) in the nucleus. Then,
the nuclear export of the ATM/NEMO difficult to the cytoplasm and the activation
of α and β IĸB kinase (IKK) proteins through NEMO are among the posttransla-
tional changes that phosphorylate IĸB inhibitory proteins. Finally, the IĸB protein
launched from the elaborate is degraded with the aid of the proteasome. This degra-
dation reasons NF-ĸB to translocate to the nucleus and transactivates a number of
SASP genes. Notably, interleukin-1α (IL-1α) acts intracellularly or as a cell mem-
brane-bound protein. In the early stage of senescence, this cytokine enhancement
initiates a feedforward loop that leads to amplification of C/EBPβ, NF-ĸB activity,
and SASP signaling. Interestingly, upregulation of IL-6 and IL-8 through means of
IL-1α and IL-1 receptor engages a positive remarks loop resulting from amplifica-
tion of C/EBPβ activation (Roger et al. 2021). Energy restriction increases the AMP/
ATP ratio activating nutrient sensors such as phosphorylated AMPK (p-AMPK).
Elevated p-AMPK ratio causes activation of the nutrient sensor AMPK and its
downstream factors such as SIRT1, PGC1, and FOXO leading to a reduction of ROS
level to improve inadequate energy supply. Cellular senescence leads to cell cycle
arrest via elevation of p53, p16, and p21 which is in favor of aging. The wrong for-
mation of lamins in the nuclear envelope, which structurally modifies nuclear genes,
reasons laminopathy and lamin injury will make greater sensitivity to reactive oxy-
gen species, ensuing in oxidative damage and untimely aging
16.4 Aging Genomics and Energy Restriction
Caloric restriction (CR) is one of the novel hypotheses of organismal lifespan and
posits that getting older is the ordinary end result of entropy on the cells, tissues, and
organs of the animal. We now have proof that growing old is as a substitute at least
in partly genetically regulated. Cellular fitness is managed at a range difficulty in the
cell and starts off evolved in the nucleus through chromosome structure/organiza-
tion, transcriptional regulation, and nuclear export/import, ranging outward to pro-
tein translation and great control, autophagy recycling of organelles, suspension of
cytoskeletal structure, and subsequently suspension of the extracellular matrix and
extracellular signaling (Xiang and Guoqing 2011).
16.4.1 Multi-omics for the Discovery of Aging Biomarkers
Age correlation analyses consist of huge quantities of data acquired from specific
omics analyses, such as genomics (epigenomics), transcriptomics, proteomics,
metabolomics, and microbiomics (DiLoreto and Murphy 2015).
16.4.2 Aging Epigenomics
Epigenetics is regarded for about alteration in the natural phenotype in avoidance

of alternate alteration in the inherent genotype; these transformations are gener-
ally produced with the aid of way of the environment. The DNA methylation pat-
tern is the most studied epigenetic feature. The epigenetic getting older clock is in
fact an advocated predictor of age-related diseases. Most research on DNA meth-
ylation sample analyzed peripheral blood samples and examined that the over- and
under-methylation of CpG sites are associated with mortality. The total of 353
CpG sites can be used to estimate physiological aging. On the top notch hand, the
immune system station can be characterized through 73 CpG sites, and 10 CpG
sites can be used as predictors of most cancers and cardiovascular ailment mortal-
ity. DNA methylation GrimAge has been correlated with ailments and can predict
mortality. The warning signs and symptoms of epigenetic getting older are in addi-
tion related to neurodegenerative diseases. For example, Parkinson’s disease (PD)
is associated with the first acceleration of epigenetic growing older clock. Higher
epigenetic age corresponds with a massive hazard for most cancers and age-related
cartilage degenerative diseases. The epigenetic getting older clock will be increase
with BMIs in weight troubles and metabolic syndrome, indicating the relationship
between the epigenetic clock and style of living, additionally (DiLoreto and
Murphy 2015).
16.4.3 Aging Gene Expression
In addition, overexpression of the O3 (FOXO3) gene in organisms has been linked

to long lifespan. Polymorphism in the FOXO3 gene is associated with longevity in
humans. In addition, the apolipoprotein E (APOE) gene encodes an LDL
cholesterol transporter that helps manipulate LDL cholesterol and lipid metabolism
and cell repair. Furthermore, knocking out the tumor suppressor gene p53 in aged
mice promotes organ atrophy, osteoporosis, and an anti-stress response (DiLoreto
and Murphy 2015).
16.4.4 Telomere-Based Biomarkers
Telomeres are protective nuclear protein caps at the tails of eukaryotic chromo-
somes that are composed of TTAGGG repeats. They have smart amplify manage
factors. Telomere measurement is a general marker of aging, and telomerase is the
fundamental telomere-modulating enzyme. Cell division is accompanied through
skill of telomere shortening and the use of controllable factors that can cause chro-
mosomal instability with growing (DiLoreto and Murphy 2015). Motile cultures of
mammalian cells enter senescence after 40–60 divisions, which is referred to as
Hayflick senescence or replication (Xiang and Guoqing 2011). Research in a large
populace (n = 105,539) tested that women have longer telomeres than men and that
there are sex-related editions in growing older that may also prefer to be due to
hormonal differences, such as estrogen degrees and X chromosome characteristics.
Age-related decline in immunosurveillance and accelerated contamination with
telomere shortening and telomerase decline are related with long-term incidence of
many diseases that have been described (DiLoreto and Murphy 2015).
16.4.5 Transcriptional Regulation
Transcriptional regulation is key in coordinating the activation of many genes to

expand lifespan. Regulation with the IIS pathway in C. elegans consists of chiefly
the PQM-1 and DAF-16/FOXO transcription factors, which localize to the
nucleus in a requited restrained method and promote both growth/development
and stress response/longevity, respectively; their requited limited nuclear local-
ization breaks down with age. The downstream dreams of these pathways consist
of genes in manipulation of cell health. The heat shock factor HSF-1 is respon-
sible for control of cytoskeletal probity and heat stress resistance, all of which
promote to its effect on C. elegans longevity. The Nrf/SKN-1 transcription factor
makes longevity, as well as regulation of extracellular collagen matrices (Xiang
and Guoqing 2011).
Another ordinary example of agingomics is transcriptomics, which studies
mRNA groups together, including lncRNAome, circRNAome, and exosomal
RNAome. To emerge the total transcriptome also remains a challenge. Focus on
research may affect transcriptomics and assist doctors in selecting suitable biomark-
ers from various RNA types. The characteristics of six gene expression factors of
cell senescence have been identified by Frenk and Houseley. As a control of lipid
homeostasis, phospholipid transport, and macrophage activity, ABCG1 makes the

pathway of endothelial cholesterol efflux and protects blood vessels from chronic
inflammation. Such alleles usually dictate the human lifespan. A study of the human
whole-blood transcriptome including 1016 people aged 70–80 years showed that
BIRC2 is an apoptosis regulator of inflammation, cell proliferation, and mitotic
kinase signal transduction and was the most downregulated in old age. In another
study analyzing whole-blood samples, aging was positively correlated with the
expression of 11 genes, namely, AMZ1, MANEAL, PARP3, KIAA0408, ISM1,
CRIP1, NEFL, PHLDA3, DDB2, CHN1, and CAPN2, in the event that it was nega-
tively correlated with that of 4 genes, namely, MXRA8, SLC4A10, CD248, and
PLEKHA7, thereby demonstrating that transcriptomics can classify the aging. The
expression of age-related genes can be used to classify aging biomarkers (DiLoreto
and Murphy 2015).
16.4.6 miRNAs-, lncRNAs-, and circRNAs-Based Biomarkers
miRNAs are 21–25 nucleotides, and it performs a function in the vital regula-
tion processes of living organisms. To identify transcriptome-specific biomark-
ers, the relationship between microRNA expression profiles and chronological
age is analyzed. For example, the expressions of miR-22-3p and miR-28-3p are
positively associated with age and miR-425-3p, miR-182-5p, and miR-99b-5p
are negatively related. miRNA is related to many illnesses, such as cancer, car-
diovascular diseases, hypertension, weight problems, and diabetes. Studies on
monocytes and the serum of lifespan and aged people have decided age-related
miRNAs. In sarcopenia, biomarkers such as miR-181a, miR-434-3p, miR-431,
miR-29, and miR-126 are involved in IGF-1, senescence, and apoptosis signal-
ing in cells. miR-19a-3p is determined as a biomarker for ischemic stroke and
the gene pathways focused by using miRNAs associated with the production of
inflammation, coagulation, and platelet activation. Regarding the relationship
between stroke and age and that the aged human beings have a greater hazard
of stroke, the identification of miRNAs can be used for greater age-related ill-
nesses to in a while find out biomarkers for ailment therapy and prevention. For
example, human hearing loss is related to the expression of miR-34a and
miR-21 and may additionally be the important biological markers of
inflammation.
miR455-3p has been endorsed as a possibility peripheral biomarker for
Alzheimer’s disease. lncRNAs have ≥200 nucleotides size that are other type of
noncoding RNA and effect as signals and guides during transcription and gene
expression on special levels, which includes recombination, transcription regula-
tion, and posttranscriptional modification, as a result affecting the lifespan and
aging. The downregulation of lncRNA leads to reduced cell growth and senescence.
Telomere-lncRNA can control cell telomerase function in old age. Age-related

lncRNA expression illnesses can reason neurogenesis and synaptic ductility which
strengthen neuropathy by means of protein integration and neurodegeneration meg3
to be related to growing older cardiovascular ailments.
circRNAs are RNA transcripts produced by using the reverse splicing of protein-
coding exons. These transcripts may additionally serve as really helpful biomarkers
that are produced in the brain at aging period. circRNAs can be detected in the
blood, serum, and saliva, and they are larger crucial biomarkers of aging.
It has been reported in a latest research, in multiple machine atrophy (MSA)
patients, circRNAs are upregulated (Xiang and Guoqing 2011).
Recent research have proven that natural material such as resveratrol is a herbal
phytoalexin existing in countless plants, such as grapes, berries, plums, and peanuts.
Genistein is an isoflavone naturally located in several plants. The epigallocatechin-3-
gallate is the main polyphenol determined in green tea. The indole-3-carbinol (I3C)
is a natural glucosinolate located in the Brassica plants such as cabbage, broccoli,
cauliflower, kale, radish, turnip, and Brussels sprouts, and ellagitannin, a polyphe-
nolic compound extracted from Balanophora japonica, exerts their antiproliferative
and/or proapoptotic effects on the rules of one or greater miRNAs; each miRNA is
successful of regulating the expression of many genes, permitting them to simulta-
neously alter more than one cellular signaling pathway and with the mechanisms
such as cell proliferation, invasion, migration, angiogenesis, and inflammation, and
induces stop cell cycle and apoptosis and additionally has outcomes on number of
cancers (Shen et al. 2013).
16.4.7 Nuclear Trafficking and Organization
The eukaryotic nuclear pore complicated (NPC) is one of the most necessary
molecular devices of the cell, which performs an important function in the transfer
of messages and proteins into and out of the nucleus and is accountable for many
manipulate features and imperative functions associated with cell health, inclusive
of tumor suppression. mRNA is transported to the cytoplasm by using the NPC, and
nuclear trafficking reduced with senescence can cause hyporesponsiveness to cel-
lular stresses. Wrong formation of lamins in the nuclear envelope, which structur-
ally modify nuclear genes, reasons laminopathy, such as illnesses related to untimely
aging. For example, patients with Hutchinson-Gilford progeria show symptoms of
premature growing older when they are very young. The instability of cell genes due
to laminopathies affects DNA to detrimental elements and will expand the inci-
dence of breaks, translocations, and aneuploidies. Correct control of nuclear lamins
is quintessential to keep tissues healthful in adults, and lamin injury will make
greater sensitivity to reactive oxygen species, ensuing in oxidative injury (Xiang
and Guoqing 2011).
16.4.8 Protein Translation
Protein translation is a critical control mechanism in longevity regulation; down-

regulation of translation upon reduced nutrient availability extends lifespan in many
organisms, including worms and flies, via TOR signaling in dietary restriction (DR)
regimes and IIS/FOXO signaling. Loss of the C. elegans eukaryotic initiation factor
4F (eIF-4F)/ife-2 extends lifespan, as does loss of ribosomal protein S6 kinase
(S6K)/rsks-1. Loss of TOR signaling, eIF-4E/ife-2, or S6K/rsks-1 also increases
heat stress resistance (Xiang and Guoqing 2011).
16.4.9 Autophagy
Organelle or protein digestion and rebuilding (homeostasis) and also proteome

modulation (proteostasis) are carried out with the aid of autophagy.
Autophagy is required for senescence paradigms in many species, consisting of
DR and IIS mutants, and inhibition of autophagy all at once induces signs and
symptoms of senescence. Dependence on autophagy for sturdiness suggests that
autophagic clearing of destroyed proteins, protein aggregates, organelles, lipids,
and one-of-a-kind cargoes is required to put together new elements for a strong cell.
Autophagy performs a worrying attribute in neurodegenerative health problem as
right in Parkinson ailments brains, autophagy is downregulated and CMA deregu-
lated then as soon as more autophagy is upregulated in the brains of sufferers with
Alzheimer’s and ALS regulatory variations exhibit off up at exclusive steps in the
autophagy pathway suggesting a frustrating attribute of autophagy in maintaining
fitness (Xiang and Guoqing 2011).
There are signs and symptoms that autophagic common performance is dysfunc-
tional in age-related ailments. Autophagy declines with getting old. Triggering
NLRP3 activation and improving the irritation strategy diminished NLRP3 activa-
tion and extended autophagy can lengthen the lifespan.
In this understanding, the extraordinarily ideal attribute of autophagic uptake in
the clearance of dysfunctional mitochondria reduced oxidative stress and impaired
NLRP3 activation is vital to conserving cell homeostasis. Developing observations
indicate that some components containing natural compounds such as resveratrol,
catechins, EGCG, propolis extracts, creosol, and luteoloside are labeled as antiag-
ing molecules. There is advice that dietary consumption of these compounds can in
addition promote fitness and lengthen the lifespan with the ordinary overall perfor-
mance of a couple of mechanisms which consists of the limit of oxidative stress,
induction of autophagy, and suppression of NLRP3 activation. This can lead to a
greater health and longer lifespan (Phuah and Nagoor 2014). Energy restriction
(ER) is one of the new longevity hypotheses, which posits that aging is the normal
end result of entropy. Management of cellular fitness through chromosome struc-

ture/organization, transcriptional regulation, and nuclear export/import to protein
translation and great control, autophagy recycling of organelles, suspension of cyto-
skeletal structure, and subsequently suspension of the extracellular matrix and
extracellular signaling is included. Aging biomarkers age correlation analyses
include data obtained from omics analyses, such as genomics (epigenomics), tran-
scriptomics, proteomics, metabolomics, and microbiomics. DNA methylation pat-
tern is the most important epigenetic characteristic studied. The epigenetic aging
clock is actually a predictor of age-related diseases. CpG sites are associated with
mortality and it predicts cancers and cardiovascular diseases and is associated with
neurological diseases such as Parkinson. Overexpression of the senescence gene O3
(FOXO3) is associated with long life span in organisms. The Apolipoprotein E
(APOE) gene contributes to lipid metabolism and cell repair by encoding the LDL
cholesterol transporter. Knockdown of the tumor suppressor gene p53 in aged mice
causes limb atrophy, osteoporosis and anti-stress response. Telomere measurement
is a general indicator of aging. Heat shock factor HSF-1 is responsible for cytoskel-
eton control, resistance to heat stress, which affects life span. The transcription fac-
tor Nrf/SKN-1 causes longevity and also regulates extra cellular collagen matrices.
Another example of agingomics is transcriptomics, which studies groups of mRNA
together. ABCG1 as a control of lipid homeostasis, phospholipid transport and
macrophage activity, it creates an endothelial cholesterol efflux pathway and pro-
tects blood vessels against chronic inflammation. Aging is positively associated
with the expression of 11 genes namely AMZ1, MANEAL, PARP3, KIAA0408,
ISM1, CRIP1, NEFL, PHLDA3, DDB2, CHN1 and CAPN2. The expression of
miR-22-3p and miR-28-3p is positively correlated with age and diseases. Induction
of autophagy and suppression of NLRP3 activation induces signs and symptoms of
aging and neurodegenerative diseases.
316
Table 16.1 Important molecular biomarkers in agingomics and ER

Telomere- miRNAs-, lncRNAs-, Nuclear
Aging Aging gene based and circRNAs-based trafficking and Protein
epigenomics expression biomarkers Transcriptional regulation biomarkers organization translation Autophagy
DNA FOXO3 gene TTAGGG PQM-1 and DAF-16/FOXO, miR-22-3p, miR-28-3p, The eukaryotic eIF-4F/ife-2, Autophagy
methylation Apolipoprotein repeats HSF-1, Nrf/SKN-1, miR-181a, miR- nuclear pore loss of and
of CpG sites E, gene p53 lncRNAome, circRNAome, 434-3p, miR-431, complicated ribosomal suppression of
exosomal RNAome, ABCG1, miR-29, and miR-126. (NPC), lamins protein S6 NLRP3
BIRC2 AMZ1, MANEAL, miR-19a-3p. miR-34a kinase (S6K)/ activation
PARP3, KIAA0408, ISM1, and miR-21, rsks-1. Loss of
CRIP1, NEFL, PHLDA3, miR455-3p. lncRNAs. TOR signaling
DDB2, CHN1, and CAPN2 Telomere-lncRNA.
circRNAs
L. Haghshenas et al.
16.5 Conclusion
Nutritional intervention with maintenance of adequate intakes of essential nutrients

is the main role of ER. This causes longevity mediated by a variety of mechanisms,
such as changes in energy metabolism, oxidative damage, insulin sensitivity, and
structural alterations in the sympathetic and neuroendocrine systems. There is
accruing evidence that some diet regimens or natural products are associated with
increased lifespan in human and mice, via different pathways involved in regulation
of crucial hormones/factors related in normal cell function. Energy restriction (ER)
has been demonstrated as one of the most effective nutritional interventions for
extending lifespan and delaying age-related diseases, including cancer prevention
and chronic diseases such as neurodegenerative diseases, diabetes, and cardiovascu-
lar disease. In addition, ER and using a variety of natural products have shown
neuroprotection through modulation of mitochondrial biogenesis, increasing
autophagy and reducing oxidative stress. ER also exhibits beneficial effects on stem
cell maintenance, which improves tissue regeneration, self-renewal, and
differentiation.
Senescent cells have special characteristics and the most important is SASP, by
which they recruit immune cells by releasing inflammatory cytokines and chemo-
kines. On the other hand, CR as a calorie reduction method can prevent many mech-
anisms that induce cellular senescence. Cellular senescence has many characteristics.
For example, increased oxidative stress in senescent cells destroys proteins, lipids,
and nucleic acid. Another characteristic of cellular senescence is cell cycle arrest,
which is the result of increasing factors such as p53, p16, etc. We said that SASP is
one of the most obvious features of cellular senescence. This phenomenon in the
cell is driven by NF-ĸB, whose stability is dependent on ATM kinase.
Regarding the genomics of aging and its relationship with energy restriction, we
stated that entropy changes in cells cause changes in lifespan. Cell health is man-
aged by regulating transcription and maintaining chromosomal structure, messen-
ger RNAs, protein translation, and autophagy.
The environment causes epigenetic changes and the phenotype of organisms.
The epigenetic aging clock is related to age-related diseases such as osteoporosis,
Alzheimer’s, Parkinson’s, cardiovascular diseases, and cancers. These changes are
caused by DNA methylation and mutations in genes, such as o3, APOE, and p53.
Obesity and body mass and metabolic diseases that are related to lifestyle are related
to epigenetic changes.
Regarding the role of telomeres in relation to aging, it was said that cell division
causes telomere shortening and shortening lifespan and the occurrence of aging and
age-related diseases.
Transcription of many genes by mRNAs plays a role in cell health, material and
signal transmission, macrophage activity, and apoptosis. We mentioned plant and
natural substances that have antiaging and proapoptotic compounds such as phenols
and participate in the regulation of cell cycle activities and aging signaling and age-
related diseases through the expression of genes with the help of miRNAs.
Autophagy causes the digestion of harmful cell organelles and proteins, which
decreases during aging, and diseases such as Alzheimer’s and Parkinson’s are
related to the decrease of autophagy; compounds such as resveratrol, catechin,
papaya, propolis extract, creosol, and luteoloside have autophagic properties, are
proapoptotic, reduce oxidative stress, and play a role in reducing aging and increas-
ing cellular health and related diseases.
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Zalpoor H, Bakhtiyari M, Liaghat M, Nabi-Afjadi M, Ganjalikhani-Hakemi M (2022) Quercetin
potential effects against SARS-CoV-2 infection and COVID-19-associated cancer progression
by inhibiting mTOR and hypoxia-inducible factor-1α (HIF-1α). Phytother Res 36(7):2679–2682
Chapter 17
Age-Related Neurodegenerative Diseases
Aging and Neurodegeneration
Narmadhaa Sivagurunathan and Latchoumycandane Calivarathan
Abstract Aging is one of the major risk factors for several neurodegenerative dis-
eases, the most common being Alzheimer’s and Parkinson’s diseases. Besides
increasing the lifespan, poor lifestyle, exposure to environmental contaminants, and
comorbidities directly or indirectly increase the prevalence of neurodegenerative
diseases in the elderly population. Even though several factors contribute to neuro-
degeneration, oxidative stress and neuroinflammation are critical factors that trigger
neuronal cell death. Since various nutraceuticals have anti-inflammatory and anti-
oxidative properties, they slow the progression of neurodegeneration and neuroin-
flammation, thereby preventing neurodegenerative diseases. This chapter discusses
various functional foods and their components that help relieve the symptoms or
prevent the progression of neurodegeneration in aging and age-related neurodegen-
erative diseases, including Alzheimer’s and Parkinson’s. Functional food contains
physiologically active components from either plants or animal sources and has
essential nutritional functions such as decreasing the risk of many chronic diseases
and providing some physiological benefits. Functional foods contain various thera-
peutic bioactive components such as carotenoids, flavonoids, polyphenols, miner-
als, and vitamins, which prevent several diseases, including neurodegenerative
diseases. The morbidity, mortality, and cognitive impairment caused by neurode-
generative disorders remain the primary health concern for society, and various
studies are focused on preventing and suppressing the symptoms of these diseases,
such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease.
Keywords Alzheimer’s disease · Functional foods · Neurodegeneration

Nutraceuticals · Parkinson’s disease
N. Sivagurunathan · L. Calivarathan (*)

Molecular Pharmacology and Toxicology Laboratory, Department of Biotechnology, School
of Integrative Biology, Central University of Tamil Nadu, Thiruvarur, Tamil Nadu, India
e-mail: latchoumycandane@cutn.ac.in
Ltd. 2023
326 N. Sivagurunathan and L. Calivarathan
Abbreviations
6-OHDA 6-Hydroxydopamine
AChE Acetylcholinesterase
ALA α-Lipoic acid
AMPK AMP-activated protein kinase
APOE Apolipoprotein E
APP Amyloid precursor protein
ATP Adenosine triphosphate
Aβ Amyloid-β
BACE1 Beta-secretase 1
BAG2 Bcl-2-associated athanogene 2
BBB Blood-brain barrier
BChE Butyrylcholinesterase
BDNF Brain-derived neurotrophic factor
COX-2 Cyclooxygenase 2
DNA Deoxyribonucleic acid
EGCG Epigallocatechin gallate
ER Endoplasmic reticulum
EVOO Extra virgin olive oil
GPx Glutathione peroxidase
GSH Glutathione
GSK3 Glycogen synthase kinase-3
IL Interleukins
iNOS Inducible nitric oxide synthase
LPS Lipopolysaccharide
MCFA Medium-chain fatty acid
MCP Monocyte chemoattractant protein 1
MPP+ 1-Methyl-4-phenylpyridinium
MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
NFκB Nuclear factor-kappa B
NO Nitric oxide
PARP Poly(ADP-ribose) polymerase
PI3k Phosphoinositide 3-kinase
SIRT1/2 Sirtuin 1/2
SNpc Substantia nigra pars compacta
TNF Tumor necrosis factor
17 Age-Related Neurodegenerative Diseases 327
17.1 Introduction
Age-related neurodegenerative diseases are the major problems in the aging popu-
lation that occur due to the progressive loss of structure and function of neuronal
cells during aging. Aging is a crucial factor that increases the risk of pathogenesis
and progression of several neurodegenerative diseases. Aging is an irreversible
process that alters genomic stability, telomere attrition, epigenetic changes, loss of
proteostasis, mitochondrial dysfunction, cellular senescence, deregulated nutri-
ent-sensing stem cell exhaustion, and altered intercellular communication (Hou
et al. 2019). Under pathological conditions, several factors contribute to increased
neuronal aging at the cellular and molecular levels, including mitochondrial dys-
function, dysregulated metabolism, accumulation of oxidatively damaged biomol-
ecules, compromised DNA repair, aberrant Ca2+ homeostasis, activation of
inflammasome signaling, and neuroinflammation (Fig. 17.1). Neuroinflammation,
a significant contributor to neurodegeneration, occurs due to the activation of
inflammasomes that increase the release of proinflammatory cytokines, including
pro-IL-18 and pro-ILβ, from the microglial cells (Brahadeeswaran et al. 2022).
The formation of abnormal proteins and aggregates are the two most common
characteristic features of neurodegenerative diseases that promote cytotoxic pro-
cesses by enhancing ROS production, excitotoxicity, synaptic dysfunction, ER
Fig. 17.1 Factors contributing to neuronal aging and neurodegeneration. Genomic instability, loss
of proteostasis, stem cell exhaustion, cellular senescence, deregulated nutrient sensing, mitochon-
drial dysfunction, telomere attrition, activation of inflammasomes, epigenetic alterations, and
altered intercellular communication are the major contributing factors for premature neuronal
aging and age-related neurodegenerative diseases. AD, PD, HD, and ALS stand for Alzheimer’s
disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, respectively
stress, DNA damage, mitochondrial dysfunction, and neuroinflammation. Some

key proteins commonly involved in the pathogenesis of neurodegenerative disor-
ders include amyloid-β, tau, α-synuclein, and prion protein, and deposition of
these proteins alters the physicochemical properties of the central nervous system,
which is associated with the development of various age-related neurodegenera-
tive diseases. Although currently, there is no treatment to cure or halt the progres-
sion of such diseases, researchers are focused on the neuroprotective and
anti-inflammatory activities of natural food products with low toxicity and high
efficacy.
17.2 Age-Related Neurodegenerative Diseases
Alzheimer’s and Parkinson’s are the two most common age-related neurodegenera-
tive diseases affecting thousands of people worldwide. Alzheimer’s disease (AD) is
caused due to the degeneration of neuronal cells, resulting in a decline in their cog-
nition, whereas the same results in the deterioration of motor activity in PD patients.
AD is the most common form of dementia, and the primary characteristic features
of AD include the accumulation of intracellular neurofibrillary tangles and extracel-
lular amyloid-β protein, which contributes to the formation of Aβ plaques. Aging,
family history, genetic factors, infections, traumatic brain injury, obesity, hyperten-
sion, depression, cardiovascular and cerebrovascular disease, APOE e4 allele,
smoking, and diabetes are some risk factors for AD (Cummings et al. 2019). The
major clinical manifestations of AD include cognitive impairment, dementia, and
impairment of comprehension, language, attention, reasoning, judgment, and mem-
ory. AD symptoms depend on the stage of disease, such as preclinical/presymptom-
atic, mild, and dementia stages. In the initial stage, the most common symptom is
short-term memory loss, followed by cognitive impairment, language disorders, and
problems in visuospatial skills. In the mid-stages of AD, symptoms like social with-
drawal, agitation, psychosis, and apathy are also observed. In the later stages,
patients exhibit olfactory dysfunction, motor disturbances, sleeping problems, and
parkinsonian symptoms (Tang et al. 2019).
The neuropathological changes in AD include the accumulation of amyloid
plaques, neurofibrillary tangles, dystrophic neurites, and neuropil threads in the
brain. Amyloid plaques are spherical microscopic lesions composed of β-amyloid
peptides derived from the amyloid precursor protein (APP). APP is cleaved by
α-secretase, β-secretase, and γ-secretase to form β-amyloid 42 peptide, which,
when accumulated, forms aggregates and causes neuronal toxicity. Another patho-
physiological hallmark of AD is the formation of neurofibrillary tangles from the
tau protein. Due to the extracellular aggregation of β-amyloid, tau hyperphos-
phorylation occurs, followed by tau aggregation within neurons, which further
leads to the formation of twisted helical fragments of neurofibrillary tangles

(Vik-Mo et al. 2019). Similarly, neuroinflammation, oxidative stress, loss of cho-
linergic neurons, and synaptic functions also contribute to the changes in the AD
brain (Serrano-Pozo et al. 2011). Currently, the treatment for AD focuses only on
controlling the symptoms with cholinesterase inhibitors and N-methyl D-aspartate
antagonists.
PD is the second most common neurodegenerative disease, following AD. This
progressive neurodegenerative disease affects the dopaminergic neurons in the
region of the brain, the substantia nigra pars compacta, and 50–70% of the neurons
have already degenerated when clinical symptoms arise. The risk factor for PD
includes aging, brain injury, and exposure to toxic chemicals, pesticides, and drugs.
The significant PD symptoms are categorized into motor and non-motor, and the
motor symptoms include bradykinesia, rigidity, gait disturbances, and postural
instability. The non-motor symptoms include behavioral deficits, cognitive changes,
and sensory and sleep disturbances, which affect the quality of day-to-day life. The
neuropathological changes in PD include the accumulation of abnormal proteins in
Lewy bodies, which contributes to the neurodegeneration of specific dopaminergic
neurons. Lewy bodies are cytoplasmic inclusions found in the neurons, mainly com-
posed of filamentous α-synuclein and other abnormal proteins such as ubiquitin,
parkin, tau, heat shock proteins, cytoskeletal proteins, etc. Factors such as
α-synuclein aggregation, mitochondrial dysfunction, neuroinflammation, and
abnormal protein homeostasis play a significant role in the onset and progression of
the disease (Kouli et al. 2018). Parkinson’s disease is currently diagnosed based on
clinical features from the patient’s history and examination and, over time, depend-
ing on how the patient reacts to dopamine-boosting drugs and the emergence of
motor fluctuations. PD is currently treated with dopaminergic drugs, stopping the
disease’s rapid progression by targeting motor symptoms. Levodopa is the most
common drug used to treat patients with PD at the initial stage of the disease. Other
medications prescribed for PD patients include monoamine oxidase type B inhibi-
tors and antagonists of NMDA receptors (Sveinbjornsdottir 2016). However, no
drugs are currently available to prevent the development of neurodegenerative dis-
eases or halt their progression.
17.3 Functional Food and Neurodegeneration
Functional foods include the nutrients from fruits, vegetables, fibers, and probiotics
taken along with diets; apart from providing beneficial effects, they also lower the
risk of developing diseases. Functional foods provide health benefits by improving
antioxidants, anti-inflammatory, and anti-lipidomic activities and have been reported
to prevent or improve insulin resistance, diabetes, and cardiovascular and
neurodegenerative diseases. Because of its positive impact on health and preventive

effects against the onset of several diseases, functional food is now widely accepted
by people for a healthy lifestyle. The loss of neurons in a particular brain area is the
primary distinguishing feature of neurodegenerative disorders like Alzheimer’s and
Parkinson’s diseases. Neurodegeneration is also accompanied by chronic neuroin-
flammation and mitochondrial oxidative stress, which are considered critical patho-
logical features in the progression of the diseases. However, one can induce the
other, and both are interlinked to contribute to developing neurodegenerative dis-
eases. Hence, functional food with specific compounds is also proposed to play a
significant role in slowing down the rate of neurodegeneration by inhibiting oxida-
tive stress and neuroinflammation. Various functional food compounds with anti-
oxidative and anti-inflammatory properties from various fruits and vegetables have
been identified to prevent disease progression (Griffiths et al. 2016).
Along with this functional food, other dietary supplements like vitamins effec-
tively prevent neuronal cell death (Fig. 17.2). Resveratrol, lycopene, carotenoids,
curcumin, quercetin, and epigallocatechin-3-gallate are some compounds that can
actively reduce neuroinflammation and oxidative stress in the central nervous sys-
tem (Table 17.1). Hence, consuming functional food as an effective component in
the patient’s diet will also be beneficial in slowing down the symptoms of diseases
(Abuajah et al. 2015). Since functional foods have therapeutic potential, they can be
further studied and modified for drug development by improving their bioavailabil-
ity and efficacy. This review summarizes the role of functional foods in age-related
Functional food Normal Brain Under pathological condition

constituents
Carvacrol
Astaxanthin Cerebral cortex
Genistein shrinkage
Resveratrol Activated
Curcumin microglia
Lycopene
Extra virgin olive
oil/ Coconut oil Enlarged
Coenzyme Q10 ventricles
Antioxidants
Hippocampus
Vitamins
shrinkage
Lutein
Fig. 17.2 Diagrammatic representations of the brain under normal and pathological conditions.
The left half of the brain shows the usual pattern, but the right side shows the brain under patho-
logical conditions. The functional foods’ constituents prevent or partially ameliorate pathological
shrinkage of the cerebrum and hippocampus, enlarged ventricles, and microglial activation, ulti-
mately preventing age-related neuroinflammation and neurodegeneration
Table 17.1 List of chemical compounds from food sources and their biological functions and
possible neuroprotective mechanisms in aging and age-related neurodegenerative diseases
Name of the compound
and its biological
functions Mechanism of neuroprotection References
Genistein • Blocks the binding of NFκB to the DNA Shi et al. (2012), Wang
Anti-apoptotic • Inhibits acetylcholinesterase et al. (2016)
Anti-inflammatory • Reduces H2O2 levels
Antioxidative • Inhibits cytochrome c release and
neuronal cell apoptosis
Resveratrol • Alters the soluble and fibrillar Aβ into Ge et al. (2012),
Anti-apoptotic nontoxic forms Ladiwala et al. (2010),
Anti-inflammatory • Inhibits ROS, ILs, NO, MCP-1, TNFα, Palle and Neerati (2018)
Antioxidative iNOS, and NFκB and prevents
Prevents Aβ mitochondrial damage
accumulation • Depletion of glutathione
Curcumin • Inhibits AChE, BChE, β-secretase, Di Martino et al. (2016),
Anti-apoptotic BACE1, and GSK3β Fan et al. (2017)
Anti-inflammatory • Scavenges free radicals and upregulates
Antioxidative antioxidant enzymes
• Inhibits apoptosis through the Bcl-2-
mitochondria-ROS-iNOS pathway
• Prevents tau phosphorylation
Carotenoids— • Reduces ROS production and promotes Chang et al. (2010)
astaxanthin the activity of antioxidant enzymes
Anti-apoptotic • Prevents apoptosis
Antioxidative
Carotenoids—lutein • Increases the activity of antioxidant Hadad and Levy (2012),
Antioxidative enzymes Katayama et al. (2011)
Prevents Aβ • Destabilizes the Aβ fibrils
accumulation
Lycopene • Inhibits cytochrome C release and Liu et al. (2018), Qu
Anti-apoptotic reduces the level of apoptotic proteins et al. (2016)
Anti-inflammatory • Inhibits NFκB signaling and decreases
Antioxidative the expression of proinflammatory
cytokines such as TNFα, IL-1β, and IL-6
Extra virgin olive oil • Reduces ROS and inhibits mitochondrial Gambino et al. (2018),
(EVOO) impairment Leri et al. (2019)
Antioxidative
Prevents Aβ
accumulation
Epigallocatechin-3- • Inhibits tau phosphorylation and Liu et al. (2014)
gallate (EGCG) neuronal apoptosis
Anti-apoptotic • Inhibits the fibril formation of Aβ and
Prevents Aβ and α-synuclein proteins
α-synuclein and
accumulation
(continued)

Name of the compound
and its biological
functions Mechanism of neuroprotection References
Coconut oil • Inhibits tau phosphorylation Bansal et al. (2019),
Anti-inflammatory • Reduces the BACE 1 expression and Mirzaei et al. (2018),
Antioxidative expression of genes regulating Nafar et al. (2017)
Prevents Aβ inflammation and oxidative stress
accumulation
Ubiquinone/coenzyme • Free radical scavenger Shults (2005)
Q10 • Inhibits release of IL-6, IL-8, and TNFα
Anti-inflammatory
Antioxidative
α-Lipoic acid • Free radical scavenger Jalali-Nadoushan and
Anti-inflammatory • Inhibits NFκB Roghani (2013), Suzuki
Antioxidative • Increases glutathione activity et al. (1992)
Prevents α-synuclein
accumulation
Carvacrol • Reduces ROS Dati et al. (2017),
Anti-inflammatory • Increases the activity of antioxidant Hamzehloei et al. (2019)
Antioxidative enzymes
Anti-apoptotic • Prevents neuronal apoptosis
Quercetin • Free radical scavenger and inhibits NO Magalingam et al.
Anti-inflammatory synthase, xanthine oxidase (2014, 2016), Zhu et al.
Antioxidative • Increases the activity of antioxidant (2013)
Prevents α-synuclein enzymes
accumulation • Inhibits α-synuclein fibrillization
17.4 Effective Functional Food for Alzheimer’s Disease
Several studies have shown that functional food improves the cognitive functions of
patients with AD (Atlante et al. 2020). AD is characterized by dysfunctional cholin-
ergic neurons and a lack of acetylcholine, a neurotransmitter, resulting in decreased
cognitive ability in the patients (Duan et al. 2021). Genistein is an active natural
isoflavone in soybeans that antagonizes Aβ by inhibiting the β-site of the amyloid
precursor protein (APP)-cleaving enzyme, BACE1 (Li et al. 2013; Youn et al. 2018).
Genistein has an anti-inflammatory effect on the neurons as it blocks the binding of
NFκB to the DNA (Jantaratnotai et al. 2013). Genistein protects neuronal cells from
DNA damage, apoptosis, endoplasmic reticulum stress, and tau hyperphosphoryla-
tion (Park et al. 2010). In the AD rat model, genistein pretreatment reduces tau
hyperphosphorylation by regulating calcium/calmodulin-dependent protein kinase
IV (Ye et al. 2017). Genistein possesses potent antioxidant properties and alleviates
Aβ-induced mitochondrial toxicity by reducing the levels of reactive oxygen spe-
cies in neurons (Vina et al. 2007).
Resveratrol, a polyphenolic compound, belongs to the class of plant secondary
metabolites known as stilbenes. This compound is extracted from medicinal plants
and grapevine leaves and is also found in peanuts, pistachios, grapes, and berries
such as blueberries, cranberries, bilberries, lingonberries, partridgeberries, mulber-

ries, strawberries, and their products. Resveratrol inhibits Aβ aggregation by directly
binding to the Aβ proteins, specifically in the medial cortex, striatum, and hypo-
thalamus (Ghobeh et al. 2014). Resveratrol binds to fibrillar and monomeric forms
of Aβ with varying binding affinity and specificity and alters the soluble fibrillar Aβ
into nontoxic compounds. When incubated with Aβ fragments, resveratrol reduces
the length and number of the fibrillar Aβ and thus slows down the progression of the
disease (Ge et al. 2012; Ladiwala et al. 2010). Resveratrol also ameliorates hippo-
campal injury, restoring memory, spatial memory, and cognition in rats, suggesting
that this polyphenolic compound has the potential to treat neurodegenerative dis-
eases (Moorthi et al. 2015; Sharma et al. 2005). Resveratrol also inhibits molecules
that contribute to inflammation, such as ROS, interleukins, nitric oxide (NO),
monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNFα),
inducible nitric oxide synthase (iNOS), and nuclear factor-κB (NFκB) (Ahmed
et al. 2017). Sirtuins (SIRTs) are a group of enzymes that regulate various biological
processes, including aging and inflammation. SIRT1 has a neuroprotective function,
but in contrast, SIRT2 promotes neurodegeneration in neurons. Oral administration
of resveratrol increases the levels of SIRT1 in the neurons and prevents the binding
of endogenous SIRT1 inhibitors to the SIRT1, preventing the cells from neurotoxic-
ity (Ahmed et al. 2017; Calliari et al. 2014). Resveratrol also has antioxidative prop-
erties, preventing the loss of mitochondrial membrane potential due to
ROS. Resveratrol downregulates the proteins that induce oxidative stress, such as
glycogen synthase kinase-3β and AMP-activated protein kinase (AMPK) (Kwon
et al. 2010). Hence, resveratrol is a potential phytomolecule for treating and manag-
ing various neurodegenerative diseases, including AD.
Curcumin, a natural phenolic phytochemical extracted from the plant Curcuma
longa, has anti-inflammatory and antioxidant properties and ameliorates the patho-
physiological changes in patients with AD (Tang and Taghibiglou 2017). Curcumin
inhibits AChE, butyrylcholinesterase (BChE), β-secretase, and glycogen synthase
kinase-3β (GSK3β), which significantly induce the pathological changes in
AD. Curcumin also inhibits Aβ formation and accumulation in the brain, thus reduc-
ing the oxidative stress induced by Aβ (Chainoglou and Hadjipavlou-Litina 2020).
Aβ formation is prevented by downregulating the BACE1 expression in the AD
mice model, alleviating synaptic degradation and improving memory (Zheng et al.
2017). Curcumin also inhibits the BACE1 enzyme in vitro, thus resulting in
decreased formation and accumulation of amyloid-β (Di Martino et al. 2016). In AD
rat models, curcumin shows a reduced accumulation of Aβ in the hippocampus and
improved cognition, spatial learning, and memory (Ge et al. 2012). Curcumin also
prevents tau hyperphosphorylation by inhibiting the GSK-3, which regulates the
phosphorylation of tau (Samy et al. 2016). In primary cortical neurons, curcumin
upregulates BAG2, a molecular chaperone involved in tau clearance through protea-
somal degradation (Carrettiero et al. 2009). Oxidative stress plays a significant role
in the development and progression of the disease due to increased accumulation of
Aβ and tau phosphorylation. Curcumin acts as an antioxidant by scavenging free
radicals and upregulating genes encoding antioxidant proteins, including heme
oxygenase-1, catalase, and superoxide dismutase (Gibellini et al. 2015). Curcumin

inhibits intrinsic apoptosis by regulating the anti-apoptotic proteins and blocking
the cleavage of poly(ADP-ribose) polymerase, activation of caspases, and ROS-
mediated DNA damage (Fan et al. 2017).
Carotenoids are secondary metabolites that play an essential role in various bio-
logical functions and show therapeutic potential in preventing neurodegenerative
diseases. Astaxanthin, a member of this family, reduces ROS production and plays
a beneficial role against oxidative stress by promoting the activities of antioxidant
enzymes, catalase, and superoxide dismutase (Zhang et al. 2014). Astaxanthin pre-
vents the neuronal cells from the damaging effects of Aβ25-35 by downregulating
apoptotic factors and suppressing IL-1β and TNFα (Chang et al. 2010). Lutein, a
type of carotenoid, has anti-inflammatory and antioxidant potential, inhibits NFκB
activity, reduces the production of proinflammatory molecules, increases the activ-
ity of antioxidant enzymes (Hadad and Levy 2012), and destabilizes the Aβ fibrils
formed in the AD brain (Katayama et al. 2011). Food sources containing high carot-
enoids act as a functional food to prevent the development and progression of neu-
rodegenerative diseases. Lycopene is also a carotenoid widely present in tomatoes,
watermelons, and papayas, and they have strong antioxidative, anti-inflammatory,
and antiproliferative properties. Lycopene improves memory retention, reduces
mitochondrial oxidative stress and damage, restores BDNF levels, and reduces neu-
roinflammation in Aβ1-42-treated rats (Prakash and Kumar 2014). Lycopene improves
the mitochondrial complex activities and ameliorates the Aβ-induced opening of
mitochondrial pores and release of cytochrome c (Qu et al. 2016). Lycopene also
reduces the neuroinflammation induced by Aβ by inhibiting the NFκB signaling and
decreasing proinflammatory cytokines, including TNFα, IL-1β, and IL-6, in the hip-
pocampus, cerebral cortex, and choroid plexus in the rat AD model (Liu et al. 2018).
Lycopene also reduces LPS-induced neuroinflammation, oxidative stress, Aβ accu-
mulation, and cognitive impairments (Wang et al. 2018), suggesting that lycopene
has neuroprotective effects.
Extra virgin olive oil (EVOO) is considered a nutraceutical as they have more
than 200 bioactive constituents. EVOO is commonly present in the Mediterranean
diet and modulates various physiological processes for beneficial health. Oleuropein,
hydroxytyrosol, and oleocanthal are phenolic compounds in EVOO, which have
antioxidative properties, reducing ROS and preventing amyloid plaque formation
and accumulation (Gambino et al. 2018; Leri et al. 2019; Rigacci 2015). EVOO
polyphenols also prevent the cell damage induced by Aβ1-42 by reducing ROS and
inhibiting mitochondrial impairment (Leri et al. 2021). Epigallocatechin-3-gallate
(EGCG) is a polyphenol mainly found in tea leaves, which has been shown to slow
down cell death, reduce the Aβ aggregation, and inhibit tau aggregation in the cel-
lular model of neurodegeneration (Chan et al. 2016; Walker et al. 2015; Wobst et al.
2015). EGCG ameliorates cognitive impairments and suppresses APP and Aβ accu-
mulation, inhibiting neuronal apoptosis in APP/PS1 transgenic mice (Liu et al.
2014). Coconut oil has a high percentage of polyphenols and medium-chain fatty
acids (MCFAs) and is involved in Aβ degradation by increasing the secretion of the
insulin-degrading enzyme, which is critical in maintaining Aβ homeostasis (Mett
et al. 2021). Para-coumaric acid, ferulic acid, caffeic acid, and catechin are the pow-
erful polyphenols in coconut oil, and a coconut oil-enriched Mediterranean diet
improves cognitive functions (De La Rubia Orti et al. 2018, 2017; Hu Yang et al.
2015). Coconut oil provides neuroprotection via antioxidant and anti-inflammatory
pathways and reduces the expression of the BACE-1 enzyme in AD rat models.
Virgin coconut oil significantly improves memory and learning, normalizes the
expression of genes regulating inflammasomes and oxidative stress, and reduces the
Aβ accumulation and tau hyperphosphorylation in AD models (Mirzaei et al. 2018).
17.5 Effective Functional Food for Parkinson’s Disease
CoQ10 is an electron transport chain component involved in cellular respiration and

acts as a free radical scavenger, protecting neuronal cells against toxicants. Patients
with PD show low levels of CoQ10 in platelet mitochondria that correlate with
reduced activities of complex I and complex II/III in the ETC in the brain and plate-
lets (Shults 2005). CoQ10 attenuates the MPTP-induced loss of striatal dopamine
and dopaminergic axons in an animal model of PD (Beal et al. 1998; Shults et al.
1997). Phase II clinical trial shows various dosages of CoQ10 reduce disability in
the patients and slow down the progression of symptoms of PD (Shults et al. 2002).
CoQ10 supplementation reduces oxidative stress and inflammation by inhibiting
NFκB transcription and the release of proinflammatory cytokines, including IL-6,
IL-8, and TNFα, by the endothelial cells (Maiuolo et al. 2019). α-Lipoic acid, also
known as thioic acid, is synthesized within the human body and is a natural antioxi-
dant, as they act as a free radical scavenger and cofactor of mitochondrial pyruvate
dehydrogenase, which prevents the neuronal damage induced by ROS in various
neurodegenerative diseases (De Araujo et al. 2011). As an anti-inflammatory mole-
cule, α-lipoic acid inhibits the NFκB transcription factor (Suzuki et al. 1992). α
Lipoic acid is also beneficial when administered along with L-DOPA to an in vivo
mouse PD model in the early stages, reducing the L-DOPA-induced dyskinesia
(Zhang et al. 2018). As an antioxidant, α-lipoic acid reduces malonaldehyde levels,
a lipid peroxidation product, and increases glutathione levels (Zhang et al. 2018).
ALA pretreatment attenuates rotations on behavioral testing and prevention of loss
of SNpc neurons in a 6-OHDA-induced PD mouse model (Jalali-Nadoushan and
Roghani 2013). α-Lipoic acid also protects the dopaminergic neurons in the LPS-
induced inflammatory PD mouse model by improving motor dysfunctions, reducing
α-synuclein accumulation, and activating proinflammatory molecules (Li et al.
2015; Tancheva et al. 2020; Toth et al. 2021). Carvacrol is a phenolic monoterpene
compound in the plant Zataria multiflora Boiss, which has several biological prop-
erties, including antioxidant, anti-inflammatory, antibacterial, antifungal, antinoci-
ceptive, anti-apoptosis, and anticancer properties. In hemiparkinsonian rat models,
carvacrol improves rotational behavior, reduces memory deficits, and decreases
lipid peroxidation levels in the striatum and hippocampus (Dati et al. 2017;
Hamzehloei et al. 2019). Carvacrol also exerts neuroprotective effects through an
antioxidative mechanism in both in vitro and in vivo models of PD (Haddadi et al.

2018; Manouchehrabadi et al. 2020).
Curcumin has antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotec-
tive properties that protect the dopaminergic neurons in both in vitro and in vivo
models of PD. Curcumin also inhibits the formation of fibrils and has fibril-
destabilizing properties in vitro (Ono and Yamada 2006). Similarly, curcumin pre-
vents the aggregation of α-synuclein complexes and increases their solubility
(Pandey et al. 2008). Curcumin has the ability to cross the BBB and alleviate the
toxicity induced by α-synuclein in the neuronal cells by reducing ROS and prevent-
ing apoptosis (Wang et al. 2010). Curcumin targets BDNF/PI3k/Akt signaling and
c-Jun N-terminal kinase pathways to reduce inflammation and oxidative stress in
PD models (Jin et al. 2022; Yu et al. 2010). Curcumin also prevents apoptosis
through attenuating p53 phosphorylation and reducing the Bax/Bcl-2 ratio in a
6-OHDA-induced model of a human dopaminergic cell line (Jaisin et al. 2011).
Curcumin inhibits depletion of GSH, monoamine oxidase B activity, and lipid per-
oxidation in the striatum and midbrain (Rajeswari and Sabesan 2008), and chronic
administration of curcumin prevents degeneration of dopaminergic neurons in the
substantia nigra by inducing the γ-glutamyl cysteine ligase activity, increasing GSH
levels, and inhibiting protein nitration (Mythri et al. 2011).
Resveratrol is neuroprotective in various in vitro PD models and protects the
cells from oxidative stress and apoptosis by regulating the expression of pro- and
anti-apoptotic genes (Albani et al. 2009; Bournival et al. 2009; Zhang et al. 2015).
Resveratrol also prevents the mitochondrial damage induced by MPP+ via the Akt/
GSK-3β pathway by altering the Bcl-2/Bax ratio and increasing the levels of Bax
and caspase-3 and caspase-9 (Zeng et al. 2017). Resveratrol activates PI3K/Akt
pathway to ameliorate the neuronal damage induced by neurotoxins and delay PD’s
progression. Resveratrol also protects rodents from motor impairment and hydroxyl
radical overloading through free radical scavenging, increasing dopamine and GPx
activities and thereby reducing MPTP effects (Anandhan et al. 2010; Da Rocha
et al. 2015). Resveratrol restores the redox balance by suppressing xanthine oxidase
activity and activating glutathione peroxidase (Palle and Neerati 2018; Yu et al.
2010). Some studies report the anti-inflammatory activity of resveratrol, which also
prevents neurons from cell death. The COX-2 protein and TNFα are significantly
reduced in the SNpc of the 6-OHDA-induced PD model, demonstrating that resve-
ratrol reduced neurodegeneration by reducing inflammatory action (Jin et al. 2008).
This also significantly reduces the levels of myeloperoxidase enzyme in the glial
cells, which oxidizes the NO and inhibits NO-induced inflammation, thereby pro-
tecting the dopaminergic neurons from rotenone-induced neuronal injury (Chang
et al. 2013). Resveratrol administration and the L-DOPA also reduce the activation
of astroglial cells in the nigrostriatal pathway of mice in the MPTP PD model (Liu
et al. 2019). Resveratrol and its derivatives are shown to have neuroprotective effects
in the PD models and hence could be promising agents for treating PD.
Vitamin E and β-carotene protect the cells from oxidative stress and damage by
neutralizing the effects of ROS. Consumption of vegetables and fruits with such
vitamins reduces the risk of developing PD in Japan (Miyake et al. 2011).
Advanced-stage PD patients had considerably lower levels of α- and β-carotenes

and lycopene than early stage of PD (Kim et al. 2017). In an animal model, lyco-
pene prevents depletion of dopamine and its metabolites in the SNpc by reducing
TBARS and other pro-apoptotic proteins such as Bcl-2-associated X proteins (Bax),
caspase-3, caspase-8, and caspase-9 and also increasing the levels of GSH
(Suganuma et al. 2002). In the PD mouse model, lycopene ameliorates MPTP and
6-OHDA-induced behavioral deficits, oxidative stress, apoptosis, and other physi-
ological abnormalities (Prema et al. 2015). Epigallocatechin-3-gallate is a polyphe-
nolic compound in green tea, which binds to the naturally unfolded polypeptides of
α-synuclein and inhibits fibril formation, preventing their conversion to toxic forms
for aggregation. EGCG disaggregates the accumulated α-synuclein in the cellular
model of PD model (Ge et al. 2012) and alleviates motor impairments, dopaminer-
gic neuronal injury, and α-synuclein aggregation in MPTP-intoxicated parkinsonian
monkeys (Chen et al. 2015). Quercetin is a natural bioactive flavonoid studied for its
beneficial antioxidative and anti-inflammatory properties attenuating the neuronal
damage caused by oxidative stress by scavenging free radicals. Quercetin reduces
ROS generation by inhibiting NO synthase and xanthine oxidase (Echeverry et al.
2010; Yu et al. 2010). Isoquercetin attenuates the neuronal damage induced by
6-OHDA in neuronal cells by increasing the activity of antioxidant enzymes, such
as superoxide dismutase, catalase, and glutathione peroxidase (GPx) (Magalingam
et al. 2014, 2016). Quercetin and other oxidized quercetin species such as chal-
canthite, benzofuranone, quercetin quinone, and other derivatives inhibit the
α-synuclein fibrillization (Zhu et al. 2013). Quercetin upregulates the activity of
mitochondrial complex I in the electron transport chain to prevent neuronal cell
death in the rotenone-induced PD model (Islam et al. 2021; Karuppagounder et al.
2013), thereby acting as a potent, natural, antioxidative, and anti-inflammatory
compound.
17.6 Conclusion and Future Perspectives
The present review gives a comprehensive insight into the biological activities of
the components present in the functional foods, their involvement, and the mecha-
nism of action in preventing the most common age-related neurodegenerative dis-
eases such as Alzheimer’s and Parkinson’s diseases (Fig. 17.2). The biologically
active food exerts therapeutic activity through various mechanisms, including anti-
inflammation, antioxidant, antiproliferative, and antimicrobial properties
(Table 17.1). Some of these components, such as resveratrol, quercetin, curcumin,
and EGCG, play a significant role in managing oxidative stress and neuroinflamma-
tion, thereby preventing neurodegeneration. Compounds in functional foods are
associated with the low incidence and risk of chronic diseases; hence, these com-
pounds and their mechanism for preventing these diseases and promoting health are
discussed in this chapter. Over 8000 such compounds are identified in plants, and
more are yet to be discovered and should be focused on for their role in ameliorating
various diseases. Due to growing knowledge of health advantages of functional

foods, such as enhancing our well-being and simultaneously reducing the risk of
various diseases, there is a rising demand for them. Nutraceutical compounds can
also be considered for drug development due to their natural therapeutic potential
and require further studies on their source, efficacy, dose, safety, stability, delivery
methods, cost, and bioavailability. In addition, given the recent scientific develop-
ments in human nutrition and food science, functional foods still need to be investi-
gated from a technological and commercial perspective. New research should focus
more on the multidisciplinary view of functional foods and their impact on primary
metabolism.
Acknowledgments The authors acknowledge DST-FIST for supporting the Department of

Biotechnology (formerly Department of Life Sciences).
Ethics Approval and Consent to Participate Not applicable.
Consent for Publication All authors agree to publish.
Funding NS acknowledges SERB Govt. of India for the Junior Research

Fellowship; CL acknowledges UGC (Startup Grant), DST-SERB
(EMR/2017/002793), and ICMR (File No.36/14/2020/Toxi/BMS) for the financial
support in the form of research grants.
Conflict of Interest None to declare.
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Chapter 18
Preventive Role of Nutraceutical Agents
Against Aging
R. Jayasree, C. Thangam, Langeswaran Kulanthaivel,

and Gowtham Kumar Subbaraj
Abstract The biological process of aging is intricate and progressive, and it is

influenced by both environmental and hereditary variables. These days, eating a diet
that is unbalanced and weak in many vital nutrients is also connected to aging.
Nutraceuticals are now valued and regarded as a vital component in enhancing life
and supplying antioxidant-containing compounds. Numerous fruits and vegetables
include antioxidant molecules that have advantageous qualities that can slow down
the aging process. Additionally, these nutraceuticals have a positive effect on the
digestive system and do not manifest any undesirable effects. Therefore, the use of
nutraceuticals as food supplements holds great promise for slowing down and pre-
venting the aging process. The advantages of nutraceuticals encourage their inclu-
sion in the diet for better health and longevity. The anti-aging effects of plant-based
supplements and plant-derived metabolites are systematically summarized.
Keywords Aging · Nutraceuticals · Antioxidants · Free radical scavengers

DNA damage
R. Jayasree
Department of Pharmacology, Sri Venkateswaraa Medical College Hospital and Research
Institute, Chennai, Tamil Nadu, India
C. Thangam
Department of Pharmacology, KSR Institute of Dental Science and Research,
Tiruchengode, Tamil Nadu, India
L. Kulanthaivel
Department of Biotechnology, Alagappa University, Science Campus,
Karaikudi, Tamil Nadu, India
G. K. Subbaraj (*)
Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (Deemed
to be University), Kelambakkam, Tamil Nadu, India
Ltd. 2023
346 R. Jayasree et al.
18.1 Introduction
The biological process of aging impairs cells’ and tissues’ normal activities, putting
the person at risk for illness and mortality. It is the process of developing and aging
for the layperson. Aging is influenced by both internal and external influences. The
normal biological activities of the cell make up internal variables, whereas external
factors include things like smoking, pollution, prolonged sun exposure, hormone
imbalances, dietary inadequacies, and exposure to ultraviolet (UV) radiation. By
adopting the right preventive steps, such as eating a healthy diet, using skincare
products, and taking antioxidant-rich supplements, wrinkle-causing skin aging can
be lessened. These steps can be performed to reduce the potentially harmful effects
that free radicals may have (Fig. 18.1).
Numerous bioactive substances included in food are crucial for preserving
human health. Therefore, humans typically and regularly provide their bodies with
nutrients through dietary consumption. Although the hypothesis of aging has not yet
been established, it has long been hypothesized that some diets, or specific compo-
nents in foods, have therapeutic and preventive properties against diseases. Despite
the fact that no specific meals or minerals in foods have yet been linked to longevity,
it is important to note that some studies have revealed that consuming foods that are
relatively high in antioxidants can lower mortality.
Fig. 18.1 Represents the hallmark of aging

18 Preventive Role of Nutraceutical Agents Against Aging 347
The connection between aging and nutrition has been thoroughly investigated
in animals and people as well over the past few decades. With “nutra” standing
for food and “ceutical” meaning therapeutic properties, nutraceuticals are nutri-
tious components with medical properties. Nutraceuticals are “food and food
products” that have therapeutic properties and offer health advantages, particu-
larly in the prevention and treatment of aging-associated disorders, as per the
description of “Foundation for Innovation in Medicine (FIM)” (Derevyanko
et al. 2017). These goods, which can be added to the diet as supplements, include
functional foods, herbal extracts, and nutritional supplements that have long-
term health advantages. Antioxidants may benefit both chronic and age-related
illnesses, particularly cancer and neurological diseases, according to researchers.
Carotenoids, flavonoids, and vitamins, among other food supplements that have
antioxidant capacity, prevent and treat chronic illnesses linked to ROS, leading
to healthier and longer lifespans. Food supplements have favorable effects on the
immunological and digestive systems as well as antagonistic effects on the
body’s inflammatory and degenerative processes, thereby enhancing quality of
life (Fig. 18.2).
It is widely recognized that plants and their inborn components have antioxi-
dant properties, such as vitamins, carotenoids, and flavonoids, which help in the
inhibition and management of chronic illnesses linked to ROS (Kasote et al.
2015). These nutritional supplements have opposing effects on the body’s inflam-
matory and degenerative progressions while exhibiting positive effects on the
immunological and digestive systems, thereby enhancing quality of life (Chen
et al. 2018).
Fig. 18.2 An example of how food antioxidants affect the body’s redox balance
18.2 Vegetables and Fruits
The abundance of fruits and vegetables in the Mediterranean diet has also been linked
to aging in specific fruits and vegetables. Consuming vegetables and fruits may lower
the incidence of heart-related disease (Bazzano et al. 2002). Increased consumption
of vegetables and fruits has been linked to a decreased risk of mortality (Leenders
et al. 2013). Increased intake of vegetables and fruits was linked to lower mortality
among smokers and hypertensive patients (Stefler et al. 2016). Vegetable eating, as
noted in this section, appears to be linked to lifespan; nevertheless, consuming sim-
ply vegetables might not promote longevity. For example, the mortality rates from all
causes for vegetarians and nonvegetarians were nearly equal (Appleby et al. 2016).
18.3 Nuts
Worldwide, people eat nuts, which are prevalent in the Mediterranean intake. Eating
nuts altered inflammation, glucose metabolism, and plasma lipids and was associ-
ated with a lower risk of dying from heart-associated complications (Imran et al.
2021). Peanuts, almonds, hazelnuts, and walnuts were among the varieties of nuts
that were said to significantly lower cancer death rates (Bonaccio et al. 2015).
According to a Japanese cohort research, men’s all-cause mortality was inversely
correlated with total nut intake (chestnuts and peanuts) (Yamakawa et al. 2022). It’s
interesting to note that the Golestan Cohort Study, which was carried out in Iran,
provided evidence that eating nuts—including peanuts, tree nuts, and other types of
nuts—reduces mortality without requiring a healthy lifestyle (Eslamparast et al.
2017). Among nuts, walnuts have been the subject of a sizable number of research
looking at its connection to longevity. Consuming walnuts may lower mortality,
according to several cohort studies (Luo et al. 2014; Guasch-Ferré et al. 2013). On
the other hand, irrespective of the type of nut consumed, a cohort research in China
found that intake of nuts is dose-dependent and improved long-term survival in
breast cancer survivors (Wang et al. 2022). Therefore, additional research and sci-
entific data on the constituents of each variety of nut are necessary to determine the
crucial element in the decreased mortality caused by different types of nuts.
18.4 Beverages
The consumption of beverages on a daily basis is thought to affect aging. The drink-
ing of green tea has the prospective to lower the risk of mortality from cardiovascular-
associated disease, according to several cohort studies of Japanese people (Abe
et al. 2019; Unno and Nakamura 2021). Hao et al. (2016) evaluated the effects of
life expectancy and the consumption of minerals in food and drinking water. The
intake of Zn, Se, and Cu from water and food was positively connected with
lifespan, but Pb was adversely correlated. There is an opposite relationship between

total coffee consumption and the likelihood of dying (Navarro et al. 2018).
18.5 Aging-Accelerating Foods
While eating has been linked to a lengthier life expectation, some have claimed that it
may also hasten aging and increase death. Traditional diets, for instance, have been
shown to increase mortality under some circumstances. The idea of “ultra-processed
food (UPF)” has gained significance as food processing technology has advanced in
contemporary culture. It gradually became apparent that consuming UPF would make
people more likely to die (Gourd 2018). According to the NOVA classification, UPF
is defined as “formulations of ingredients, mostly of exclusive industrial use, typically
manufactured by a succession of industrial procedures and processes,” and is distin-
guished from unprocessed and lightly processed foods, processed culinary ingredi-
ents, and processed foods (Monteiro et al. 2019). UPF is a term used to describe
industrially produced, ready-to-eat foods that include a high concentration of chemi-
cals such as salt, sugar, solidified oil, flavorings, preservatives, and emulsifiers
(Monteiro et al. 2018). Eating a diet that is classified as UPF permitting to the NOVA
classification is linked to a higher risk of developing cancer (Fiolet et al. 2018). An
increase in UPF consumption was linked to a higher risk of total mortality in this adult
population (Schnabel et al. 2019). UPFs, particularly ones high in sugar, were associ-
ated with an increased risk of death, according to a cohort study of Italians (Bonaccio
et al. 2021). Despite being delicious and widely consumed, fried meals have been
shown to raise mortality risk conditions such as cardiovascular disease and type 2
diabetes. The consumption of fried foods, especially fried seafood and fried chicken,
was connected with risk of death among US women, including from heart-related
diseases (Sun et al. 2019). The intake of non-fried and fried potatoes also affects mor-
tality of senior individuals in the USA, and it was found that more than thrice weekly
consumption of fried potatoes raised mortality risk (Veronese et al. 2017).
18.6 Individual Food Antioxidants and Aging
It appears practically certain that the composition of the human food has a major
impact on aging based on the findings of the numerous investigations that studied
the effect of diet on the risk of aging and death reported in the previous chapter.
However, it is still unclear which cellular, molecular, and physiological alterations
contribute most to aging in different creatures and how they interact (da Costa et al.
2016). It appears challenging to evaluate the impact of “whole foods,” which are
made up of numerous components, on aging using present scientific methods. There
are few theories are there such as (Matsumaru and Motohashi 2021), cross-linking
theory (Kim et al. 2011), autoimmune theory (Jalel et al. 2009), and glycation the-
ory (Najjar et al. 2017).
S.
no. Theory Description
Program theory The program theory has a close relationship with telomeres and
telomerase. When DNA’s terminal bases are lost during replication, it
loses its capacity for replication. Mammals’ DNA ends in a TTAGGG
repeat structure known as a telomere, which safeguards the genetic
material and permits replication. Telomerase increases the length of
telomeres. As a result, it is thought that telomere length influences how
many cell divisions occur, which affects aging and longevity (Vidaček
et al. 2018). Telomeres, however, are shortened with aging and have an
impact on the aging process since they partially renew with each
replication. More recently, it has been demonstrated that decreased neural
development and neurogenesis can be seen in telomerase-deficient mice
(Ferrón et al. 2009). According to studies using mice, the restoration of
telomere length and function can prevent physical aging and increase
animal longevity (Derevyanko et al. 2017; Bernardes de Jesus et al. 2012)
Error theory According to the error theory, a buildup of mutant proteins results from
random mutation in DNA to RNA process and RNA to protein process,
which promote cellular malfunction and aging (Orgel 1963). There hasn’t
been any concrete proof of the age-dependent failure of translation
process documented as of yet (Troen 2003). Additionally, a different
investigation utilizing Escherichia coli has shown that the introduction of
gene mutation enhanced the mutation frequency but did not result in
death of bacteria (Edelmann and Gallant 1977). As a result, there have
been less recent reports that lend weight to this notion
Wear-and-tear According to Weismann’s wear-and-tear theory, which was put forth in
theory 1882, aging progresses when tissues and cells weaken over time as a
result of risk factors (Weismann 1891). However, a number of phenomena
ruled out this notion. For instance, hyperactive mice can live more than
typical mice (Hanson and Hakimi 2008), but their tissues are worn down
faster. Caterpillars can live longer when they are unable to express
antioxidant enzymes (Van Raamsdonk and Hekimi 2009). Recent
research suggests that the wearing down must be taken into account in
terms of natural selection from an evolutionary perspective and cannot
simply be explained as a physical inevitability of aging
Cross-linking According to the cross-linking theory, cross-linking of weakly degradable
theory protein, carbohydrate, and lipid molecules affects the function of the cell
and speeds up aging by accumulating molecules with multiple reactive
units. The extracellular environment becomes more viscous as a result of
decreased solubility, flexibility, and permeability brought on by the
cross-linking of molecules like collagen. Aging developments as a result
of the minimized nutrients circulation and waste products in the cells
(Bjorksten 1971). It is well-known that the Maillard reaction’s products,
which involve the cross-linking of collagen and glucose, increase with
aging in the body (Monnier et al. 2005). Because the body produces free
radicals that trigger cross-linking reactions with other molecules
including collagen, Bjorksten et al. observed that the free radical theory is
also a type of cross-linking hypothesis (Rockstein 2012). Even though
this notion has been supported by quantitative and qualitative evidence of
cross-linked molecules, it is still unclear if the molecules play a
significant role in biological aging
S.
Autoimmune It has been thought that the autoimmune system is at least loosely related
theory to aging. Innate immunity and acquired immunity are the two main
immune systems present in higher vertebrates. In terms of aging, the
failure of acquired immunity is very important. Aging is linked to both an
increase in self-reactive B cell populations and a loss in B cell generation
in the bone marrow. In the USA, one of the primary causes of death for
women under the age of 65 is aged adaptive immunity, which when
combined with other factors encourages development that leads to the
body’s own tissues being harmed (Shanley et al. 2009; Gs and Stroehla
2003)
Glycation Maillard first described the aminocarbonyl reaction (also known as the
theory Maillard reaction) in 1912; this phenomenon is regarded as a component
of biological body aging (Tessier 2010). At body temperature, a
condensation process between the lysine and glucose residues in proteins
produces advanced glycation end products (AGEs). The developed AGEs
accumulate in a variety of tissues, including the blood vessel walls, and
cause tissue stiffness, which results in vasodilator dysfunction and
hypertension, which are thought to be aging-related factors (Simm 2013)
Oxidative Reactive oxygen species (ROS) are created during the metabolic process
damage theory of aerobic organisms as a result of oxygen consumption for energy
metabolism. Harman postulated in 1956 that ROS causes aging by
harming cells and tissues (Harman 2002). Antioxidants have frequently
been emphasized as chemicals that inhibit ROS formation and help to
lengthen (Stadtman 1992; Agarwal and Sohal 1994; Miyazawa 2021),
whereas older people have higher amounts of oxidized products, such as
DNA, lipids, and proteins, than young aged individuals. In aging people,
there is a larger level of ROS in cellular organelles. Additionally, in
mammals, there is an opposite correlation between the ROS present in the
mitochondria and lifespan, indicating that impairment to the membrane
lipids and DNA of the mitochondria may possibly be a significant
contributor to aging (Cadenas and Davies 2000). However, ROS also
contributes to biological defense against intracellular pathogens in the
mammalian immune system (Kulinsky 2007). Therefore, it is well
accepted that redox balance disruption causes inflammatory reactions.
This is related to the notion of aging as it relates to innate defense, which
relates to (Colloca et al. 2020) persistently (Gladyshev and Gladyshev
2016) no interaction with intruders, etc., and (López-Otín et al. 2013)
impaired inflammation, which has given rise to the term “inflammaging”
(Franceschi et al. 2018). On the basis of the “inflammaging concept,” it
has recently been demonstrated that prolonged tissue inflammation
brought on by ROS significantly affects the immune and nervous
systems’ regulatory mechanisms, as well as on the aging process (Fülöp
et al. 2019; Santoro et al. 2020). Chronic tissue inflammation can also be
brought on by suppressing the immune system’s control of inflammatory
factors
S.
Other Growing interest among gerontologists has been focused on the concept
biological of “senescent cells,” which speed up aging process. Cells that are older
aging-related and no longer divide are often eliminated from the body by the process
theories called phagocytosis. Despite the fact that cell division has ceased,
senescent cells still build up in the tissues. Recent research has
demonstrated that the accumulating senescent cells emit inflammatory
chemicals that cause excessive inflammation, accelerate the senescence of
nearby cells, and cause tissue malfunction (Laberge et al. 2012).
Senescent cells cannot all be removed by the body’s immune system;
hence certain anti-aging strategies have started to evolve that specifically
target these cells (Gasek et al. 2021). Further clarification of the
physiological phenomenon may be required because the exact
information on the connection is still lacking between these senescent
cells and aging
There is a hypothesis that claims all factors have no effect on how quickly
people age, in contrast to the belief that certain factor(s) speed up the
process of aging. According to Colchero et al. (2021), there is a
significant linear relationship between lifespan equality and life
expectancy in a variety of primates, which is mostly related to mortality
of the newborn or the improvement of mortality irrespective of age and
has no bearing on the aging rate. This finding implies that longevity is
solely determined by the biological limit
The “oxidative damage theory,” which was discussed in the first half of this
review, is the foundation for the majority of these earlier investigations. With a lot
of experimentally based data being documented from the past period to the pres-
ent period, this theory has been one of the most well-liked theories in aging
research (Viña et al. 2007). There is mounting substantiation that ROS may func-
tion as signaling molecules that ultimately increase lifespan as well as cause oxi-
dative stress (Tapia 2006). These developments gave rise to the theory of
“mitohormesis,” according to which ROS accelerates aging but, at the right con-
centrations, can strengthen the body’s natural defenses (Miyazawa et al. 2019;
Ristow and Schmeisser 2014). Since the formation of ROS during ATP synthesis
in the mitochondria is essential for aerobic organisms to obtain energy, the man-
agement of redox equilibrium in the body is a crucial factor in aging. Additionally,
it is anticipated that each antioxidant found in food will help to control the redox
balance. The anti-aging benefits of antioxidants appear to depend on cell signaling
pathways associated with this equilibrium, including MAPKs, NF-B, and Nrf2
(Santos et al. 2021; Chen et al. 2022; Tian et al. 2019; Wang et al. 2019, 2020)
(Fig. 18.3).
Fig. 18.3 Represents the free radical-mediated DNA damage and aging
18.7 Adaptogens
Adaptogens are herbs and mushrooms that improve your body’s capacity to deal
with stress, anxiety, exhaustion, and other health-related issues. Adaptogens can be
consumed as tinctures, added to food or drinks or both. By controlling both physical
and emotional stressors, adaptogens help your body regain a stable balance (Liao
et al. 2018). These substances lessen cellular susceptibility to stress and boost the
body’s ability to protect itself from numerous risks (Bhatia et al. 2011). Additionally,
they support and aid in restoring typical physiological activity (Singh et al. 2017).
18.8
Ginkgo biloba
Gingko, sometimes referred to as Ginkgo biloba, is a functional food that increases the
tissues’ ability to absorb oxygen (Isah 2015). The glucose levels and blood flow in the
brain have been demonstrated to be significantly maintained by ginkgo leaves (Dhanjal
et al. 2020). Additionally, it enhances the brain’s capacity for thought (Zuo et al. 2017).
Some of the flavone glycosides that are produced from the ginkgo leaves extract and are
active scavengers of free radicals are lactone derivatives (ginkgolides), catechin, shi-
kimic acid, isorhamnetin, and ascorbic acid (Van Beek 2002). Huang carried out a study
to determine how Gingko biloba extract affected the functions of the liver in old rats. As
a result of the administration of Gingko biloba extract, liver metalloproteinase and
malondialdehyde levels were decreased, and SOD activity was increased to reduce oxi-
dative stress (Huang et al. 2005). According to a different study, giving old female rats
Ginkgo biloba extract improves their cognitive performance (Belviranlı and Okudan
2015). The effectiveness of Gingko biloba extract in the management of Alzheimer’s
disease was well documented. A thorough analysis has shown that taking Gingko biloba
extract helps people with moderate dementia operate more cognitively (Liu et al. 2020).
18.9 Ginseng Panax
Ginseng, or Panax ginseng, is well-known for its therapeutic properties (Rokot

et al. 2016). The roots of this plant are where the bioactive chemical ginsenoside is
found (Yu et al. 2019). This bioactive substance modifies immunological function
and increases the body’s tolerance to stress, tiredness, anxiety, and trauma (Kumar
et al. 2012). Additionally, it exhibits stress subsidence qualities and enhances learn-
ing and memory (Rokot et al. 2016). According to an investigation, giving juvenile
leukemia-affected mice ginseng extended their lives (Wee et al. 2011). By reducing
oxidative stress, a different study on Panax ginseng found that it can lower lipid
peroxidation and boost antioxidant potential (Lee et al. 2017). Additionally, ginseng
eating enhances a person’s psychomotor ability, according to double-blind clinical
research (Caldwell et al. 2018). Additionally, Panax ginseng has been linked to the
activation of foxo3a gene, known as the longevity gene, and has been claimed to
have anti-melanogenic properties (Kim et al. 2017). According to certain research,
Panax ginseng delays the aging process of the skin. Additionally, a study was car-
ried out to evaluate the effectiveness of ginsenosides and Panax ginseng in delaying
the aging process of the skin. The findings revealed a substantial decrease in wrin-
kle creation, and no participant experienced any side effects (Hwang et al. 2015).
18.10
Glycyrrhiza glabra
The Fabaceae family includes Glycyrrhiza glabra, widely known as licorice

(Pastorino et al. 2018). This plant’s rhizomes and roots act as a brain tonic that aids
in controlling blood sugar levels (Frattaruolo et al. 2019). The key bioactive com-
pound isolated from this antioxidant-rich plant is glycyrrhizin, which improves
memory, prevents oxidative damage to the brain, and maintains typical nervous sys-
tem function (Grodzicki and Dziendzikowska 2020). Licorice, a phenolic molecule
found in Glycyrrhiza glabra, has antioxidant potential, making it useful in scaveng-
ing free radicals and chelating metal ions (Ciganović et al. 2019). According to
reports, G. glabra improves memory in the scopolamine-induced dementia mouse
model (Balmus and Ciobica 2017). Additionally, Dhingra and associates noted
memory improvements in mice given Glycyrrhiza glabra. Various doses of
Glycyrrhiza glabra extracts 75, 150, and 300 mg/kg were given orally over the
course of 7 days. The outcomes indicated that the mouse model’s memory was
improved by a dose of 150 mg/kg (Chinkwo 2005).
18.11
Curcuma longa
The ginger family member Curcuma longa generates the substance known as cur-
cumin (Kocaadam and Şanlier 2017). It is well-known for a variety of biological
functions, including its antioxidant, anti-inflammatory, and anticancerous qualities
(Wachtel-Galor 2011). Curcumin is a possible therapeutics for many malignancies
because of its natural features (Tomeh et al. 2019). Numerous investigations have
shown that curcumin can inhibit the activity or expression of tumor necrosis factor
(TNF), prostaglandin E2 (PGE2), COX-2, and other pro-inflammatory cytokines
(Desai et al. 2018). Curcumin’s antioxidant capabilities can help to lower ROS gen-
eration, prevent lipid peroxidation, and scavenge free oxygen radicals (Engwa
2018). Oral ingestion of curcumin in mice has been proven to improve cystic fibro-
sis and stop tumor growth; however, studies in people are still being conducted
(Tomeh et al. 2019). According to a study, curcumin activates the phosphatidylino-
sitol 3-kinase/Akt pathway and redox signaling in human fibroblasts to cause a cel-
lular stress response. This demonstrates the potential efficacy of curcumin-triggered
cellular antioxidant defenses as an anti-aging therapeutic strategy (Lima et al. 2011).
Additionally, it has been observed to lengthen the lives of mice, nematodes, and
fruit flies (Soh et al. 2013; Shen et al. 2006; Lee et al. 2010). Curcumin has even
been reported to lessen and control the signs of age-related illnesses like diabetes,
cancer, and atherosclerosis (He et al. 2015; Olszanecki et al. 2005). In addition to
this, curcumin has been noted to exhibit defense against radiation- and chemotherapy-
induced dermatitis in patients with breast cancer (Swamy et al. 2012; Ryan et al.
2013). Due to its ability to postpone cellular senescence, curcumin has been sug-
gested in certain studies to have anti-aging properties (Hamidie et al. 2015). In a
trial involving healthy people between the ages of 60 and 85, Cox et al. evaluated
the impact of solid lipid curcumin on cognition and mood.
18.12
Emblica officinalis
The Phyllanthaceae family includes Emblica officinalis, widely known as amla

(Yadav et al. 2017). Amla churn is renowned for lowering cholesterol levels and
enhancing cognitive capacity (Kapoor et al. 2020). The use of amla as part of a diet
is effective in reducing blood and brain cholesterol levels (Wilson et al. 2017).
Additionally, it has been touted as an advantageous functional meal for the treat-
ment of Alzheimer’s disease (Hasan et al. 2016). In order to assess the skin-
lightening capability of a topical formulation containing E. officinalis extract, kojic
acid, and glycolic acid, Draelos and colleagues undertook a double-blind trial.
Because the topical formulation performed 4% stronger than hydroquinone in the
study, investigators suggested that it might work as a natural substitute for treating
facial dyschromia (Lauer et al. 2013). Free radical buildup in numerous tissues is
linked to a variety of stress-induced situations, which accelerate the aging process
(Bhattacharya et al. 2002). Due to their antioxidant activity, tannins derived from
E. officinalis also have a protective effect in a tardive dyskinesia (Bhattacharya et al.
2000a, b). Additionally, the E. officinalis extract has antidepressant characteristics
by reducing the activity of GABA and MAO-A in combination with antioxidant
activity (Dhingra et al. 2012).
18.13
Bacopa monnieri
A perennial herb with purple blooms and tiny oblong leaves is called Bacopa mon-
nieri, or brahmi (Singh and Dhawan 1997). This medicinal herb contains highly
useful nootropic compounds like bacosides (Jain et al. 2016). The two primary phy-
tochemicals that are primarily derived from this herb are brahmine and herpestine
(Tewari et al. 2014). The phytochemicals derived from brahmi help to shield the
brain from the effects of ROS while also enhancing learning and cognitive function
(Vollala et al. 2010). It is understood that frequent brahmi oil use lowers the risk of
a number of illnesses, including amnesia and Alzheimer’s disease (Simpson et al.
2015). In a dose-dependent manner, Bhattacharya et al. (2000a, b) discovered that
extracts of Bacopa monnieri increase antioxidant enzymes activity such as superox-
ide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT). After 14
and 21 days, the results of this investigation in rats’ brain regions were examined
(Bhattacharya et al. 2000a, b). Using Bacopa monnieri extract and 3-nitropropionic
acid (NPA), a fungal toxin that causes neurotoxicity in both animals and humans,
Shinomol and associates conducted an in vitro and in vivo investigation. The results
revealed that NPA was effective in causing oxidative stress in the mitochondria and
dopaminergic (N27) cells of the striatum of rats, whereas Bacopa monnieri extract
was found to be beneficial in controlling the NPA-induced oxidative damage and
lowering the thiol and glutathione (GSH) levels (Shinomol and Bharath 2012). A
study was conducted by Kumar and his associates to determine the impact of
Bacopa monnieri extract on the cognitive abilities of medical professionals. The
study’s findings revealed a sizable improvement in the pupils’ cognitive perfor-
mance (Kumar et al. 2016).
18.14 Polyphenols
Secondary metabolites, particularly polyphenolic chemicals, are prevalent in vege-

tables, fruits, grains, and drinks and are mostly produced by plants (Fereidon and
Ambigaipalan 2015). Due to their natural qualities, such as antioxidant potential
and anti-inflammatory and anticarcinogenic effects, polyphenols have drawn the
attention in recent days (Quero et al. 2020). Due to these properties, polyphenolic
substances can help treat conditions like diabetes, asthma, cardiovascular disorders,
microbial infections, and cancer (Pandey 2009). Numerous polyphenolic
substances, including silymarin, proanthocyanins, and resveratrol, have been the

subject of studies. Their effectiveness on animal models exposed to oxidative stress,
DNA damage, and UV-mediated skin irritation has been examined (Dunaway et al.
2018). Additionally, these polyphenols can effectively protect the skin from UV
radiation-related skin issues and help lower the risk of skin cancer when combined
with sun protection cosmetics (D’Orazio et al. 2013). Below are several polyphe-
nols that have medicinal qualities.
The skin of grapes and peanuts contains resveratrol (also known as stilbenes), a
naturally occurring polyphenolic molecule with possible antioxidant properties
(Adhikari et al. 2019). Due to its use as an anti-aging component, it has been a
focus of intensive research for the past 20 years (Camins et al. 2009). It also has
anti-inflammatory effects, has the ability to scavenge free radicals, and can operate
as a chelating agent (De Vries et al. 2018). It is showing prospective in the treat-
ment of a number of illnesses, including cardiovascular and Alzheimer’s disease,
according to studies (Gomes et al. 2018). Additionally, resveratrol has the potential
to be a cancer chemopreventive, according to Bhat and Pezzuto (2002). According
to a study done on HaCat cells exposed to sodium nitroprusside, it also has a pro-
tective effect (Bastianetto et al. 2010). To evaluate the effectiveness of resveratrol
on the proliferation and inhibition of collagen activity, Giardina and associates
carried out an in vitro study on skin fibroblast. The outcome revealed a significant
suppression of collagenase activity and a dose-related increase in cell proliferation
rate (Giardina et al. 2010). Resveratrol is said to have the ability to slow down cel-
lular aging and may represent a breakthrough in geriatric and anti-aging treatment;
however there is no evidence to back up this claim in the human population
(Demidenko and Blagosklonny 2009; Xia et al. 2008; Giovannelli et al. 2011). The
biogenesis receptor gamma coactivator 1-alpha (PGC-1) through activating the
peroxisome was controlled by resveratrol (López-Lluch et al. 2008; Lagouge
et al. 2006).
Phlorizin is a kind of flavonoid that is only synthesized by a small number of
plants (Wang et al. 2018). For more than a century, the pharmaceutical industry has
greatly benefited from it and used it as a stage to assess physiological function
assessment (Dunaway et al. 2018). The advantages of phlorizin in terms of nutrition
have been the subject of numerous investigations. In a latest investigation, the anti-
aging benefits of phloretin and phlorizin were investigated on senile osteoporosis
mouse models. According to the study, phlorizin assisted in controlling the ratio of
osteoprotegerin (OPG), a biochemical marker of osteoporosis, to receptor activator
of nuclear factor kappa-B ligand (RANKL), a nuclear factor kappa-B ligand. The
quantity of osteoclast cells that express tartrate-resistant acid phosphatase (TRAP)
was likewise decreased by phlorizin (Antika et al. 2017). Unripe apples contain
significant quantities of phlorizin. Unripe apples containing phlorizin have been
shown to be helpful in reducing postprandial hyperglycemia, according to a prelimi-
nary study on human volunteers. The study, which involved six healthy participants,
found that eating unripe apples decreased postprandial glucose response and raised
urine glucose levels statistically significantly (Makarova et al. 2015). In a study by
Mela and colleagues reported that, the effects of eight plant extracts and their
combinations apple, mulberry fruit, elderberry, mulberry leaf, turmeric, white bean
on postprandial insulin (PPI) and glucose (PPG). According to the study’s findings,
PPI and PPG response might be decreased by using extracts of apple, mulberry
fruit, and mulberry leaf extracts (Mela et al. 2020). Phlorizin may be able to slow
down the effects of aging and hence improve quality of life because hyperglycemia
has been shown to speed up the aging process (Laiteerapong et al. 2011). Numerous
more plant extracts have shown to be rich sources of substances with antioxidant
activity (Ayaz et al. 2019). It has been discovered that metabolites such silymarin,
genistein, and apigenin have a favorable effect on the signs of skin aging (Isah
2015). The true anti-aging potential of phlorizin has yet to be revealed through clini-
cal or human research.
18.15 Apple
Apple is rich in phytochemicals, particularly polyphenols, which have an impor-

tant antioxidant potential (Zhang et al. 2015). Apples contain a variety of poly-
phenolic substances, including rutin, epicatechin, catechin phloretin, chlorogenic
acid, and proanthocyanidin B2 (Kschonsek et al. 2018). According to certain
studies, eating apples every day can lower your risk of developing hypercholes-
terolemia and cardiovascular disease (Boyer and Liu 2004). Consuming apples
may significantly reduce the risk of developing lung cancer, especially in
women, according to research (Vafa et al. 2011). Numerous investigations have
proved that apple is efficient in preventing oxidation of low-density lipoprotein
(LDL) (Boyer and Liu 2004). In order to determine how apple polyphenols
affect the gene expression of the SOD, CAT (catalase), Rpn11, Mth (methuse-
lah), and CcO (cytochrome c oxidase) subunits III and VIb, a study was carried
out. The study’s findings showed that apple polyphenols gave fruit flies a 10%
longer lifespan. Additionally, fruit flies showed downregulation of Mth; overex-
pression of SOD1, SOD2, and CAT; and no appreciable change in the gene
expression of VIb, Rpn11, or CcO subunits (Peng et al. 2011). Furthermore,
research on both normally aging mice and animals with genetic flaws demon-
strated the neuroprotective potential of concentrated apple juice. However, the
anti-aging properties of apples and the processes underlying them are yet
unknown (Peng et al. 2014).
18.16 Blueberry Extract
Compared to other fruits and vegetables, blueberries contain a higher concentration

of polyphenols (Cory et al. 2018). The reduction of signs of aging has been linked
to the strong antioxidant potential of blueberry extracts (Kalt et al. 2020). According
to studies, regular eating of blueberries may make senior populations more
susceptible to memory-related problems (Shukitt-Hale et al. 2019). Consuming

blueberry extract has been said to delay age-related functional and physiological
decline (Joseph et al. 2005). Blueberry extract administration was observed to
restore the age-related reduction in the hippocampus heat shock protein (HSP) by
Galli et al. (2006). In older rat models, blueberries have also been shown to effec-
tively improve motor and cognitive performance (Goyarzu et al. 2004). To compre-
hend the underlying mechanism, fruit flies have also been used to study the ability
of blueberry extracts to prolong life. The study’s findings demonstrated that adding
5 mg/mL of blueberry extract to the meal considerably extended fruit flies’ longev-
ity by 10% (Peng et al. 2012).
18.17 Theaflavins and Catechins from Tea
Tea has become the most popular beverage in Asia (Su et al. 2003). Theaflavins and
catechins, two of tea’s inherently beneficial components, are responsible for these
health benefits (Musial et al. 2020). Studies have indicated that drinking green or
black tea regularly can prevent DNA molecule oxidation (Yan et al. 2020).
Theaflavins and catechins have been shown to extend the average lifespan in other
in vivo investigations on Drosophila (Li et al. 2007). According to numerous pub-
lished studies, oral tea polyphenol ingestion and topical green tea application both
prevent UV radiation- or chemical-mediated skin carcinogenesis in a variety of ani-
mal models (Oyetakin et al. 2012). Theaflavins and catechins from tea are anti-
inflammatory and anticarcinogenic (Musial et al. 2020). To determine the impact of
tea polyphenol extract on variables related to acute UV harm, Elmets and his team
carried out a study. For this, volunteers’ skin was initially treated with extract of
green tea or its components, and then the treated areas were exposed to two low
doses of solar-simulated radiation to cause erythema. The biochemical, clinical, and
histologic signs of UV-induced DNA damage were subsequently studied in the skin.
The outcomes showed that tea extract had an inhibitory effect on the erythema
response brought on by UV irradiation in a concentration-dependent fashion. The
results of the histologic analysis also revealed less Langerhans and sunburn cells
(Elmets et al. 2001).
Additionally, tea polyphenol extracts also lessened DNA deterioration in the
skin. As a result, scientists claimed that tea polyphenol extract might work as a
healthy substitute for photoprotection (Elmets et al. 2001). Chiu and colleagues
studied the histological and clinical aspects of photoaging to determine the impact
of a combination therapy course of topical and oral green tea. In this trial, 40 women
with reasonable photoaging were randomly assigned to receive either a placebo or a
regimen of 300 mg of tea oral supplements (to be taken twice daily) and 10% green
tea cream for 8 weeks. The study’s findings did not reveal any appreciable variations
in the clinical signs of photoaging between the green tea treatment group and the
placebo group. However, the treated participants showed a histologic advancement
in the amount of elastic tissue (Chiu et al. 2005).
18.18 Anthocyanins in Black Rice
Black rice is rich in antioxidants, and it has been shown that taking antioxidant sup-
plements helps Alzheimer’s patients feel better (Liu et al. 2018). Additionally, it has
an anti-inflammatory and anticarcinogenic activity (Shaikh et al. 2014). Peonidin-3-
glucoside and cyanidin-3-o glucoside are two anthocyanins that are abundant in it as
well (Azevedo et al. 2010). Black rice may be able to increase the lifetime of fruit
flies, according to research done by Zuo and colleagues. The impacts on the SOD1,
SOD2, CAT, MTH, and Rpn11 gene expressions were assessed for determination.
The study’s findings showed that fruit flies’ lifespans were increased by 14% by
consuming 30 mg/dL of black rice anthocyanins. Additionally, Mth’s gene expres-
sion was downregulated, whereas SOD1, SOD2, CAT, and Rpn11 gene expression
was elevated (Zuo et al. 2012). To evaluate the impact of black rice anthocyanins,
Huang et al. used a subacute aging mouse model. They discovered that these antho-
cyanins have anti-aging, anti-fatigue, and anti-hypoxic effects (Huang et al. 2006).
18.19 Carotenoids
Lycopene and -carotene are examples of carotenoids, which are vitamin A deri-
vates with significant antioxidant potential and photoprotective properties
(National Research Council 2000). Skin texture can be slightly improved by lyco-
pene and -carotene (St Stahl and Sies 2012). Carotene can be found in a variety of
plants, including carrots, mangoes, papaya, and pumpkins (Pritwani and Mathur
2017). Due to its features, including lipid radical scavenging activity, pro-vitamin
A activity, and single oxygen-quenching qualities, it has become an important
carotenoid (Jaswir et al. 2011). According to studies, -carotene has great photopro-
tective capabilities and can prevent erythema brought on by UV radiation (Parrado
et al. 2018). There have been reports linking low plasma levels of -carotene to
cellular aging. The telomerase activity of older persons may be modulated by -car-
otene, according to a study (Boccardi et al. 2020) that involved 68 elderly partici-
pants. The adverse effects of more beta-carotene for smokers, on the other hand,
are well-known and can hasten the development of lung cancer. The α-tocopherol,
β-carotene cancer prevention study group released a groundbreaking report;
according to this study, men who received supplemental β-carotene had an unex-
pectedly higher occurrence of lung cancer than those who did not (Cockcroft
et al. 1994).
Various vegetables and fruits, including carrots, watermelons, papayas, toma-
toes, and others, contain lycopene, a red carotene, carotenoid, and phytochemical
(Schagen et al. 2012). Although it lacks vitamin A action, it has a great potential for
quenching single oxygen (Evans and Johnson 2010). A study further supported the
function of lycopene in tissues by preventing oxidative stress. It was shown that
more skin lycopene was damaged after exposure to UV light than -carotene (Ascenso
et al. 2016). In addition to having the capacity to drastically lower MMP-1 activity,
which is known to destroy collagen, products of lycopene have also been demon-
strated to be effective against malignant cells (Przybylska 2020). The major carot-
enoids present in human blood and tissues, lycopene and carotene, are both known
to control skin characteristics (Johnson 2002). Cheng and colleagues found that
lycopene promotes the base excision repair pathway in vitro in A549 cells in a pub-
lication that was just published. A molecular pathway has been revealed by this
study and needs to be further investigated in vivo and using animal models (Cheng
et al. 2020).
Ascorbic acid, the name by which vitamin C is frequently referred to, is a highly
water-soluble vitamin (Singh et al. 2020). Due to its intense reducing nature, this
colorless molecule possesses excellent antioxidant potential (Carr and Melcher
2017). The hydrophilic environment is ideal for the photosensitive ascorbic acid to
function (Hemila 2017). Humans cannot produce this crystalline substance; as a
result, it must be consumed as part of a normal diet (Souyoul et al. 2018). To prevent
the health issues linked to vitamin C deficiency, such as cardiovascular illnesses,
scurvy, and others, diets should be supplemented with vitamin C-rich sources, such
as grapefruit broccoli, strawberries, green peppers, Brussels sprouts, kiwifruit, and
oranges (Brickley et al. 2020). The elevated antioxidant potential and scavenging of
free radical capabilities of ascorbic acid aid in preventing free radicals from oxidiz-
ing macromolecules (DNA and proteins), cell membranes, and tissues diet (Souyoul
et al. 2018).
Vitamin E is a fat-soluble, membrane-bound substance with significant free radi-
cal scavenger (Galli et al. 2017). Vegetables, nuts, corn, almonds, soy, peanuts,
meat, sunflower oil, safflower oil, and wheat germ oil all contain this nonenzymatic
antioxidant (Sivakanesan 2018). Infants may have a variety of health issues, includ-
ing edema, depigmentation, papular erythema, and dryness if their bodies have vita-
min E deficiencies (Leonard et al. 1966). Due to its effectiveness in preventing the
peroxidation of lipids and the cross-connection of collagen fibers, vitamin E con-
sumption aids in the prevention of skin aging signs (Schagen et al. 2012). Sunburn
and UV-related skin damage can both be treated with vitamin E, according to
research (Abid Keen and Hassan 2016).
The two vitamins C and E complement one another. For instance, a chain reac-
tion of lipid peroxidation begins in the membrane rich in polyunsaturated fatty acids
when UV-induced molecules oxidize the components of the cell. During this pro-
cess, the antioxidant d-tocopherol is converted to the tocopheroxyl radical, which
then regenerates through ascorbic acid (Fryer 1993; Chan et al. 1991). Tocopherol
is abundant in a variety of foods, including corn, seeds, vegetable oils (sunflower oil
and safflower oil), and soy (Schagen et al. 2012). Vitamin E from natural sources
also protects against lipid peroxidation and collagen cross-linking, two processes
linked to skin aging. Additionally, vitamin E administered topically has been shown
to lessen photocarcinogenesis, erythema, burnt cells, and persistent UVB-induced
skin damage (Makrantonaki and Zouboulis 2008; McVean and Liebler 1999).
Depigmentation and dryness in premature newborns are also linked to vitamin E
insufficiency, along with a condition of edema with seborrheic alterations (Passi
et al. 1991). After reviewing their work, Ekanayake-Mudiyanselage and Thiele con-
cluded that the quantity of sebaceous glands in the skin affects the level of vitamin
E. It has been demonstrated that taking tocopherol orally for 3 weeks significantly
raises the levels of vitamin E in sebaceous glands, particularly those on the face
(Ekanayake-Mudiyanselage and Thiele 2006). Oral vitamin C and E supplementa-
tion has been demonstrated in a comparative study to enhance the photoprotective
efficacy in comparison to monotherapies (Eberlein-König and Ring 2005). Another
trial involved 33 volunteers who received either a placebo or 100 or 180 mg of vita-
min C daily for 4 weeks. According to the study’s findings, taking vitamin C orally
increased the skin’s capacity to scavenge free radicals by 22% for 100 mg and 37%
for 180 mg when compared to the baseline (Lauer et al. 2013). It was discovered
that vitamin E had negligible impact on the prevention of lung cancer in the study
of the alpha-tocopherol and beta-carotene cancer prevention study group (Cockcroft
et al. 1994). Several different groups of substances that are well-known to enhance
health are included in nutraceuticals, functional foods, and dietary supplements
(Shahidi 2012). Due to its ability to reduce the signs of aging skin, functional foods
have attracted interest on a global scale (Dhandevi and Jeewon 2015). Notably,
fruits are an important source of the active metabolites that are used to reduce the
signs of aging skin because they are rich in phenolic compounds, carotenoids, and
ascorbic acid and have a strong antioxidant potential (Petruk et al. 2018).
18.20 Conclusion
Dietary supplements are both nutraceuticals and nutrition supplements that are
meant to be used orally. Supplement use is advised, but does not guarantee the diag-
nosis, treatment, mitigation, or prevention of disease. Adopting low-carbohydrate
diets or eating a diet high in fruits, vegetables, nuts, grains, fish, and unsaturated fats
that are rich in antioxidants, potassium, and omega-3 fatty acids decreased the risk
of obesity and cardiovascular disease, protected the brain from aging, decreased the
risk of shortening of telomere, and encouraged a healthier lifestyle. The prevalence
of cancer, cardiovascular diseases, diabetes, and telomere attrition may be reduced
as a result of a low-fat diet that is also high in antioxidants, which also helps to mini-
mize DNA oxidation and oxidative stress. These diets can extend the life and
improve one’s quality of life.
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Evidence-based

ISBN 978-981-99-0533-1 ISBN 978-981-99-0534-8 (eBook)

This book, Evidence-Based Functional Foods for Prevention of Age-Related

the latest developments to food scientists, biochemists, medical doctors, nutrition-

Chennai, Tamil Nadu, India Surajit Pathak

1 Cellular Aging: An Introduction, Principle, Hallmarks,

11 Importance of Functional Foods Against Aging of Adult

Audinarayana N Department of Sociology and Population Studies, Bharathiar

Akiko Kuwabara Osaka Metropolitan University, Osaka, Japan

Gowtham Kumar Subbaraj Faculty of Allied Health Sciences, Chettinad

Meenu Bhatiya, Asim K. Duttaroy, Surajit Pathak, and Antara Banerjee

Abstract Aging is a complex natural biological process that shows progressive

Keywords Cellular senescence · Epigenetics · Telomeres · Hallmarks of aging

M. Bhatiya · S. Pathak · A. Banerjee (*)

© The Author(s), under exclusive license to Springer Nature Singapore Pte 1

Aging is a complicated biological process that, eventually leads to a time-depen-

1.2.1 Cellular and Metabolic Aging

Fig. 1.1 Hallmarks of aging

Epigenetic alterations such as DNA methylation, alterations in Histone protein,

the structure of chromatin. The epi-genome understanding and manipulation hold

1.3.2.1 Deregulated Nutrient Sensing

Deregulated nutrient sensing is an important hallmark of aging. Nutrient sensing is

Mitochondrial activity has a major effect on aging and Mitochondrial dysfunction

rises because of the aging-related increasing mitochondrial malfunction, which fur-

1.3.3.1 Stem Cell Exhaustion

1.3.3.2 Altered Intercellular Communication

Aging is involved both cell-autonomic as well as intercellular communication

Oxidative stress can be defined as a modification or imbalance of pro-oxidants and

1.5 Reactive Oxygen Species (ROS)

Fig. 1.2 Impact of reactive

Fig. 1.3 Role of ROS in normal, cancer, and senescent cells

mitochondria are considered the primary source. Superoxide dismutase, an enzyme

1.6 Molecular Mechanism of Cellular Aging

As the burden of aging-associated disorders is increasing, our understanding of cel-

Fig. 1.4 Mechanism of aging and age-associated diseases

Apoptosis, a programmed cell death, is a life-long regulated cycle that helps to

“Inflammation” is a notable intercellular connection modification linked to aging.

Aging is an irreversible time-dependent deterioration in functional organ activity,

Cognitive deterioration is a common problem of age-related brain changes

The most prevalent form of dementia is Alzheimer’s disease. it affects approxi-

1.8 Alternative Treatment Strategies for Aging

Many natural compounds were proposed for supplementation treatments. Among

Rutin, a quercetin glycoside is a member of a class of bioflavonoids believed to pos-

of inhibiting collagen-stimulated human platelet aggregation, reducing capillary

Curcumin is phenol derived lipophilic bioactive compound extracted from the

Phytoalexin compound, resveratrol is a bioactive compound belonging to the stil-

Aging is a complex biological phenomenon. Aging is a multifactorial process com-

components, cellular dynamics, cellular communication, and progressive deterio-

Conflict of Interest The authors declare no conflict of interest, financial or otherwise.

Availability of Data Not applicable.

Ethical Approval and Consent to Participate Not applicable.

Diptimayee Das, Amit Dey, Asim K. Duttaroy, Antara Banerjee,

Abstract Ageing is the multifaceted reduction in physiological function of all living

D. Das · A. Dey · A. Banerjee · S. Pathak (*)

© The Author(s), under exclusive license to Springer Nature Singapore Pte 19

Keywords Ageing · Epigenetic dysregulation · Oxidative stress · Ageing-related

Ageing is a natural process defined by increasing degradation of physiological

2.1.2 Epigenetics and Ageing

A reversible heritable mechanism called epigenetics changes gene expression

2.1.2.1 DNA Methylation and Ageing

Chennai, Tamil Nadu, India Surajit Pathak

1 Cellular Aging: An Introduction, Principle, Hallmarks,

11 Importance of Functional Foods Against Aging of Adult

1.2.1 Cellular and Metabolic Aging

1.3.2.1 Deregulated Nutrient Sensing

1.3.3.1 Stem Cell Exhaustion

1.3.3.2 Altered Intercellular Communication

1.5 Reactive Oxygen Species (ROS)

1.6 Molecular Mechanism of Cellular Aging

1.8 Alternative Treatment Strategies for Aging

2.1.2 Epigenetics and Ageing

2.1.2.1 DNA Methylation and Ageing

2.1.2.2 Histone Modifications and Ageing

2.1.2.3 Non-coding RNA and Ageing

2.2 Oxidative Stress-Induced Ageing

2.3 Ageing-Related Diseases (ARDs)

2.4 Modern Therapies Related to Ageing

2.5 Currently Proposed Treatments Involving Bioactive

2.5.1.1 Effects of Rhodiola on Ageing-Related Diseases

2.5.2.1 Effects of Curcumin on Ageing-Related Diseases

2.5.3.1 Effects of Quercetin on Ageing-Related Diseases

2.6 Conclusions and Perspectives

3.2 Dietary Composition and Aging (for More Details, Refer

3.3 Diet-Gene Interactions Modulating Aging and Disease

2 ↓↓↓ tryptophan • Sterility nhr-114 Gracida and

4 ↓↓↓ • Lifespan extension nmur-1 Maier et al.

3.3.1 Serine Threonine Kinase Gene (flr-4)

3.3.2 Nuclear Hormone Receptor Gene (nhr-114)

3.3.3 S-Adenosyl Methionine (SAM)-Dependent

3.3.4 Kinesin Motor Protein (osm-3) and Neuromedin U

3.3.5 Mechanistic Target of Rapamycin Complex 2 Subunit

3.3.6 Aldehyde Dehydrogenase Gene (alh-6)

3.3.7 Enoyl-CoA Hydratase Gene (ech-6)

3.3.8 Mitochondrial Ribosomal Protein Gene (mrpl-2)

3.3.9 NAD+ -Dependent Deacetylase Gene (Sirt6)

3.3.10 Myocyte Enhancer Factor Gene (Mef2)

3.3.11 Putative Glucose Transporter Gene (CG4607)

3.3.12 Neuropeptide CCHamide-2 Receptor Gene (CCHa2R)

3.3.13 ATP Synthase Subunit Gene (ATPsynD)

3.3.14 RNA-Binding Protein Split Ends Gene (Spen)

3.3.15 Pyridox(am)ine 5-Phosphate Oxidase Gene (PNPO)

3.3.16 Genes Associated with Age-Related