SPECIALTY GRAND CHALLENGE

published: 16 November 2020

doi: 10.3389/fragi.2020.610406

The Promise of a Golden Era for

Exploring the Frontiers of Aging,
Metabolism and Redox Biology
Jianhua Zhang *
Department of Pathology, Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, United States

Keywords: autophgy, mitophagy, diet, exercise, omics, bioenergetics, oxidative stress, comparative biology

From ancient times to the modern day extending longevity or even finding the elixir for eternal life
has been a motivating quest for many civilizations. There are no shortage of Hollywood films and TV
series that feature long-lived creatures: some heroes and others villains. Many of the ancient Greeks
have what we would regard as a normal lifespan (Montagu, 1994; Batrinos, 2008). For example,
Socrates before his untimely demise was in his 70s. Physicians had been directed to concoct potions
to extend the life of emperors and the wealthy. In the Qin Dynasty, the emperor sent 500 young men
and 500 young women to find the elixir of life in the legendary Penglai, the miraculous place of the
immortals. Detailed descriptions of medicines for immortality were written in the book “Essential
Formulas of Danjing Classics”. Some of these concoctions we would regard as remarkably toxic as
they contain mercury or arsenic. Interestingly, this quest for longevity continues unabated and has
now become a central pillar for modern health care. However, the perils persist with the unverified
claims of a broad range of supplements or the off-target effects of therapeutics which maybe toxic or
otherwise decrease longevity. Clearly, then as now an understanding of the fundamental biology and
chemistry of aging is an essential goal for modern scientific research.
Despite the long history of the fascination of a long life, aging research as a systematic scientific
effort is a recent affair. In the United States, the Aging Related Unit in the National Institutes of
Edited and reviewed by: Health was formed in the 1940s, first in the NIH Division of chemotherapy, then moved to Baltimore
Changhan David Lee, City Hospital under the direction of Nathan Shock. In 1974 the National Institute of Aging (NIA)
University of Southern California, Los became an independent institute with a focus on aging biology and age related diseases. PubMed
Angeles, United States documents publications on aging as early as in 1925. In 1988, the first genetic locus age-1 that
*Correspondence:
modulates lifespan was identified in C. elegans (Friedman and Johnson, 1988), and 8 years later
Jianhua Zhang cloned and found to encode a PI3 kinase (Morris et al., 1996). Now there are a total of ∼487,000
JianhuaZhang@uabmc.edu articles using the search term “Aging” in PubMed, with ∼20,000 articles since 2020.
There has also been a long-standing interest associating aging with metabolism. Searching
Specialty section: PubMed with “Aging and Metabolism” results in ∼188,685 articles, with 3,219 since 2020. Dietary
This article was submitted to Aging, restriction has been shown to affect longevity and age related illnesses in several organisms and
Metabolism and Redox Biology, model systems, with the effects on longevity dependent on genetic background (Mair et al., 2003;
a section of the journal Liao et al., 2010; Cava and Fontana, 2013). At the molecular level, extended lifespan has been
Frontiers in Aging
associated with insulin and IGF-1 receptor function, as well as age-1/PI3 kinase activity (Kenyon
Received: 25 September 2020 et al., 1993; Kimura et al., 1997). Modulation of sirtuins, which are NAD+ (Nicotinamide adenine
Accepted: 23 October 2020 dinucleotide) dependent enzymes, was reported to extend lifespan in yeast (Kennedy et al., 1995;
Published: 16 November 2020
Kaeberlein et al., 1999). AMPK (AMP activated protein kinase), a key sensor of metabolism and
Citation: cellular energy, is required for lifespan extension in C. elegans in response to dietary restriction
Zhang J (2020) The Promise of a
(Greer et al., 2007). Targeting the nutrient sensing pathway, the mTOR (mechanistic target of
Golden Era for Exploring the Frontiers
of Aging, Metabolism and
rapamycin) signaling pathway, using the inhibitor rapamycin, has been used to enhance longevity in
Redox Biology. several organisms, and shows efficacy when administered to aged mice (Harrison et al., 2009; Miller
Front. Aging 1:610406. et al., 2011; Papadopoli et al., 2019). These studies suggest that the aging can be modified by changes
doi: 10.3389/fragi.2020.610406 in lifestyle or pharmacological intervention.

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Zhang Frontier Aging – Metabolism & Redox Biology

Observations that a deficit of mitochondrial function may cellular context, may have contrasting effects on aging-
result in energy shortage and accumulation of reactive species dependent processes.
that are damaging to cellular structure and function inspired the In many aging related phenomena, including cellular
“Mitochondrial dysfunction theory of aging” (Lemasters, 2005; senescence and perturbation circadian control, inadequacy in
Payne and Chinnery, 2015; Kauppila et al., 2017). Paradoxically, the autophagy and mitophagy pathways, also have strong
there are also observations that inhibition of mitochondrial connection to redox and metabolic regulation (Lopez-Otin
respiration can extend lifespan. Reconciliation of these et al., 2013). Autophagy is an intracellular degradation process
observations leads to the concept that the plasticity of that is highly regulated by a variety of signals including
metabolic pathways, which has a preprogrammed genetic availability of metabolic substrates, cellular and the
component, is central in adapting to the environment and in environmental redox landscape (Zhang, 2015; Klionsky et al.,
turn impacts longevity (Kayser et al., 2004; Lapointe and Hekimi, 2016). It is now clear that autophagy is a pathway that may
2008; Copeland et al., 2009; Yang and Hekimi, 2010). This is an remove and reverse cellular damage caused by oxidative stress
idea captured in the “Hormesis theory of aging” (Ristow and and as such it is important to understand whether it is sufficiently
Schmeisser, 2014; Yun and Finkel, 2014). Clearly, the term active at the right place and at the right time (Lee et al., 2012;
“mitochondrial dysfunction” is inadequate to describe the Giordano et al., 2014). Because of its central importance in health,
complexity of the adaptive capacity of the age regulated disease and aging, the specific autophagic degradation of the
metabolic pathways. Additionally, a judicious inhibition of mitochondria was identified as a specific process known as
mitochondrial respiration may be required for activation of mitophagy (Lemasters, 2005; Redmann et al., 2014; Ma et al.,
survival pathways (Chouchani et al., 2013). A better 2020). Autophagy and mitophagy then play a key role in the
understanding of the role of metabolism in aging calls for quality control and turnover of lipids, proteins, and organelles,
more insights into the specifics of regulation of bioenergetics and their regulation modulates the metabolic and redox
and metabolism which is now becoming feasible with the advent landscape (Dodson et al., 2013; Redmann et al., 2016). In
of sensitive and high precision technologies in these areas of aging tissues and age related diseases, these processes are
research (Hill et al., 2019). unable to clear excess or dysfunctional proteins and organelles
Although that “the Free Radical Theory of Aging” was (Wong et al., 2020). Damaged organelles including mitochondria
proposed in 1956 based on the idea that free radicals can together with the accumulation of toxic proteins may further
attack cellular constituents and thus may be a direct cause for propagate cellular damage and contribute to the progression of
aging (Harman, 1956), research linking aging to redox age related diseases (Chen et al., 2020).
modulation is still evolving. With the realization that “free Aging research has been gaining momentum as better tools are
radicals” have a signaling role, it is clear that this basic developed and systems biology approaches are adopted. CRISPR/
hypothesis needs refinement to encompass new advances in Cas techniques provide enhanced means of determining
redox biology and the recognition that all “free radicals” are experimentally the functional consequence of gene disruption
not the same. Searching “Aging and Free Radical” has total of or mutation (Ran et al., 2013; Charpentier et al., 2019). These
13,754 articles, “Aging and oxidative stress” 19,044, “Aging and approaches can give insights into the networks that sense
Redox” 9,139 articles. Many studies have challenged the idea that environmental signals that change cellular functions and
cellular oxidative damage due to “free radicals” or oxidative stress thereby contributing to healthy aging or age related
is a cause of aging. First, reactive oxygen species (or ROS) may be pathologies. Genomics, transcriptomics, proteomics, and
important in modulating aging, but the hypothesis lacks precision metabolomics, some even at the single cell level, will aid in the
since it fails to identify “which species” contribute to aging or the understanding of the aging process in complex organs including
mechanisms involved. This point is sometimes over-looked but the brain and the immune system (Aon et al., 2020; Zhang et al.,
similarly if we say “Genes” and “Proteins” are important in 2020). High throughput bioenergetics analyses are now available
modulating aging, most of us will ask which gene(s) and which use small quantities of materials and even frozen samples
which protein(s). Fortunately, technical advances are over- and thus greatly extend the current studies of metabolism and its
coming these barriers and allow specific hypotheses to be connection to aging (Dranka et al., 2011; Hill et al., 2012; Chacko
tested. Over the last 10 years the genetic regulation of redox et al., 2014; Redmann et al., 2018; Acin-Perez et al., 2020). For
related networks has also turned out to be remarkably complex. example, recent studies substantiated the connection of
For example, one of the key regulators of redox modulatory mitochondrial function, metabolism inflammation, and aging,
proteins is Nrf2, which is a transcription factor that regulates and revealed the potential for a better understanding of this
genes encoding a subset of redox regulatory proteins, and is also a integrated regulatory network in attenuating age related diseases
downstream target of insulin receptor and involved in lifespan and promoting healthy aging (Bernard et al., 2018; Dunham-
regulation in C. elegans (Tullet et al., 2008). What is not predicted Snary et al., 2018; Rangarajan et al., 2018). In addition, a better
from the “Free radical theory of aging” is that increased understanding of the fundamentals of redox biology, and the
expression of Nrf2 and its target antioxidant enzymes is improvement of techniques detecting and scavenging different
detrimental for health and disease (Rajasekaran et al., 2011; reactive species are resulting in a rapid evolution of redox biology
Levonen et al., 2014; Dodson et al., 2015; Schmidlin et al., research (Kalyanaraman et al., 2012; Kalyanaraman, 2013;
2019). This key finding indicates that both “oxidative” and Afonso and Spickett, 2019). Advanced informatics methods
“reductive” stress, depending on their specificity, levels and have been developed, including GWAS, NetWAS, the

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Zhang Frontier Aging – Metabolism & Redox Biology

transcriptome-metabolome-wide association study (TMWAS) involved in modifying lifespan are complex, and may be
and xMWAS platforms. These methods facilitate data dependent on genetic, environmental, age, and other as yet
integration, network visualization, clustering and differential unknown factors (Longo and Panda, 2016; Radak et al., 2019;
network analyses of data from two or more omics dataset of Kepp et al., 2020; Perez-Matos & Mair, 2020). Pharmacological
genetic phenotypic, biochemical, or cell biological assays, which reagents that target autophagy and mitophagy can be tested and
can reveal the whole organism changes that underlie the biology optimized against age related diseases and promote healthy
of aging (Beekman et al., 2013; Go et al., 2018; Uppal et al., 2018; aging (Galluzzi et al., 2017; Piskovatska et al., 2019).
Chacko et al., 2019; Roussarie et al., 2020; Smith et al., 2020). Compounds targeting the mitochondria, for example, MitoQ,
Integration of metabolism, redox biology with aging phenotypes and SS-31 have been explored for their potential for healthspan
will likely reveal novel nodes of regulation which can then identify enhancement (Tate et al., 2019; Young & Franklin, 2019;
new targets for healthspan extension interventions. Whitson et al., 2020). Senolytics have been shown to
It is important to recognize that aging is not a single organ attenuate cell-free mitochondrial DNA release, which then
disease, and is highly dependent on the fact that tissues decreases the detrimental immune responses associated with
functionally interact and cross modulate. The blood and aging (Iske et al., 2020). Mitochondria not only can be targeted
lymph circulate through the body and transport hormones, to improve metabolism and healthspan, but also can generate
nutrients, cytokines, myokines, cell-free mitochondrial DNA, the mitochondrial-derived peptides (MDPs) that can regulate
and other cellular metabolic products to other parts of the body metabolism and health (Reynolds et al., 2020).
(Barron and Pike, 2012; Coelho et al., 2019; Cunnane et al., Advancement of hygiene, food and environmental safety,
2020; Iske et al., 2020). Aging associated accumulation of the health care, and a better understanding of aging biology and
propionate metabolism product methylmalonic acid in the aging interventions are at such a stage that it has been suggest
serum, may reprogram cancer cells to become more that the individuals who will reach the age of 150 are already living
aggressive (Gomes et al., 2020). The microbiome contributes (https://www.stevenaustad.com/). It is still not clear why age is the
to a large portion of the total DNA/RNA in mammals and single most important risk factor for many diseases including but
controls metabolism through its interaction with the diet and not limited to: cancer, cardiovascular and neurodegenerative
other environmental factors (Bernard et al., 2018; Bana and diseases. This is a new exciting era in which enabling
Cabreiro, 2019; Buford, 2020). Bacterial and viral infection, technologies can provide exciting new insights into the
also alters the biology of the body and impact aging and age mechanisms and biology of aging. It is likely that research
related diseases (Szaniawski and Spivak, 2020). Thus linking aging to metabolism and redox regulation will feature
understanding the crosstalk between the gut, brain, liver, prominently in the next decade. The grand challenge is then to
heart and muscle via the circulation is of critical importance understand the networks linking metabolism, and redox biology to
to the understanding of aging biology (Lehallier et al., 2019). cell aging and organismal aging and to target specific metabolic and
Since we cannot view age related pathologies only in isolated redox networks for the promotion of a healthy lifespan.
cells or tissue, we can also learn by observing nature. The
existence of long-lived and short-lived species, for example, the
naked mole-rat, different varieties of fish, clams, turtles,
rodents, and centenarian humans, surely hold important
AUTHOR CONTRIBUTIONS
clues to understanding how longevity and healthy living The author confirms being the sole contributor of this work and
have been achieved (Austad, 2018). has approved it for publication.
An important contemporary research goal is to convert what
we understand about metabolism and redox regulation in the
context of aging into approaches to promote healthy aging. This
approach can be surprisingly straight forward. For example, it
ACKNOWLEDGMENTS
has been shown that supplementation of mitochondrial TCA The author thanks the UAB NSC P30 AG05886 and its faculties
cycle metabolites, malate, fumarate, alpha-ketoglutarate, and for discussions.
oxaloacetate, supplementation of NAD+ precursor
nicotinamide riboside extended lifespan in Drosophila and C.
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MitoQ inhibits memory loss, neuropathology, and extends lifespan in aged 3xTg- Conflict of Interest: The authors declare that the research was conducted in the
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1016/j.cmet.2014.01.011.
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1111/acel.13119. original author(s) and the copyright owner(s) are credited and that the
Zhang, H., Ryu, D., Wu, Y., Gariani, K., Wang, X., Luan, P., et al. (2016). NAD+ original publication in this journal is cited, in accordance with accepted
repletion improves mitochondrial and stem cell function and enhances life span academic practice. No use, distribution or reproduction is permitted which
in mice. Science 352 (6292), 1436–1443. doi:10.1126/science.aaf2693. does not comply with these terms.

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