Hormesis in Health and Disease: Molecular Mechanisms (Meiliana A, et al.

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DOI: 10.18585/inabj.v12i4.1315 Indones Biomed J. 2020; 12(4): 288-303

REVIEW ARTICLE

Hormesis in Health and Disease: Molecular Mechanisms

Anna Meiliana1,2,, Andi Wijaya1,2

1
Postgraduate Program in Clinical Pharmacy, Padjadjaran University, Jl. Eijkman No.38, Bandung, Indonesia
2
Prodia Clinical Laboratory, Jl. Cisangkuy No.2, Bandung, Indonesia


Corresponding author. E-mail: anna.meiliana@prodia.co.id

Received date: Jun 18, 2020; Revised date: Oct 5, 2020; Accepted date: Oct 7, 2020

homeostasis, which exemplifies how illness is the doorway

Abstract to health.

B
ACKGROUND: Hormesis was initially defined SUMMARY: Hormesis reconcile many paradoxical
as a phenomenon where a small dose of harmful phenomena exert opposite effects of the same substance,
agent exposure to living organisms gives beneficial either a xenobiotic or an endogenous substance, a hormone
effects. The dose and time of this ‘tress’ exposure has or a metabolite, a genetic manipulation or an epigenetic
become the object of investigation across the broad range alteration, an experimental intervention or a natural event.
of biomedical studies. Human bodies are highly adaptive. A resilient body
would be resulted after the ‘training’. In this review, we
CONTENT: Hormesis characterized by the biphasic dose- will elucidate the hormesis’ definition, mechanisms and
effect or time-effect relationship for any substance. Some pathways, and also how hormesis impacts in human health
hormetic mechanisms performed biological plasticity, and lifespan.
involve oxidative damage which instead induce antioxidant
enzyme production in various cells. Early-life stress can KEYWORDS: biphasic, cell signaling, dose response,
increase resilience in later life and lack of stress can lead to hormesis, preconditioning
vulnerability. Many stressors like dietary factors and natural
environmental toxins can be occupied for healthy growth or Indones Biomed J. 2020; 12(4): 288-303

The initial dose low-dose exposure may protect against

Introduction the following exposure of the same substrate in a higher
dose (‘single mode’ stress-response), against a different
‘What doesn’t kill you makes you stronger’. The ear-friendly substance (‘cross-mode’ stress-response), or may develop
aphorism illustrated the original idea of hormesis, which a process in the interval time (‘developmental’ stress-
involved an initial exposure to induce an adaptive response response).(2) A classic example of single-mode stress-
before it can be referred to as ‘stress-response’ hormesis.(1) response hormesis is priming the body with an initial low
At a glance hormesis seems like counterintuitive, but in a dose of xenobiotic chemical to induce the expression of
deeper philosophical thinking, if ‘too much of a good thing detoxification enzymes, which can confer protection against
is a bad thing’, a little bad thing can be good. At a precise subsequent exposures to the same chemical in a higher
dose and time, we can transform an adverse effect into a dose. Some xenobiotic chemicals serve directly as ligands
favorable effect, as articulated in the philosophy of Yin and for nuclear receptors such as the constitutive androstane
Yang that ‘illness is the doorway to health’. receptor (CAR) or pregnane X receptor (PXR). Some other
The hormesis scenario involves three factors: first, indirectly activate other transcription factors, for example
the initial stress exposure that ‘tries to kill you’; second, altering the intracellular stress-response signaling pathways
the following exposure which you are more resilient such as redox status, to activate the nuclear factor erythroid
against; and third, the time interval between those two. 2-related factor 2 (Nrf2). The transcription factors activation

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will upregulate the genes that encode the enzymes for studies involve brief stress exposure to induce mechanisms
xenobiotic metabolism in three phases. Phases I including that protect against stress. This form of hormesis refer as
cytochrome p450 family enzymes, phase II is glutathione- ‘stress-response hormesis’ to distinguish it from hormesis in
based conjugation enzymes, and phases III is adenosine the broader sense.(1) For example, a brief exposure to very
triphosphate (ATP)-binding cassette transporters. Those high levels of oxygen increase life span in the nematode
three phases collectively detox and secrete the xenobiotic Caenorhabditis elegans.(11)
from the body.(3) The most consistent and reliable character of the
The dose response concept is central to biology, hormetic dose-response is its biphasic feature, i.e., a low
medicine, and public health. It represents the biological dose stimulation zone, followed by a higher dose with
integration of how living systems at all levels of organization inhibitory response (Figure 1). The maximum magnitude
(from the cell, more complex organisms, human being) of the stimulatory response is typically modest, being only
respond, adapt or fail to adapt to endogenous agents, about 30-60% above that of the control response. The strong
metabolic stress, and externally dynamic threats/stressors. majority of stimulatory responses are less than twice the
(4-6) The substance’s dose–effect or time-effect relationship control value.(7) The Hormesis concept suggested that dose
was presented in a bell-like biphasic curve, either U-shape responses in the low dose zone were not only not linear but
or inverted U-shape (2,7), describe the portion of the dose- possibly not even a threshold but probably biphasic (i.e.,
response immediately below the threshold which is related J-shaped or inverted U-shaped depending on the endpoint
to performance, contrast to the portion of the dose-response graphed).
above the threshold, which have the potency of toxic Figure 2 proposed the nomenclature for hormesis
interactive effects. Hormetic dose-response can occur as that recognizes the classic hormetic-like biphasic
a direct stimulation response, a modest overcompensation dose±response relationships, and the temporal hormesis
response after an initial disruption in homeostasis, or as which also include the duration of exposure.(12,13) The
a response to an ‘adapting’ or ‘pre- conditioning’ dose classic definition of hormesis is more common in the
followed by an extensive challenging dose.(8) fields of radiation biology/health physics and ecological
In the broadest sense, everything can be hormesis. and human toxicology. Adaptive response of temporal
The term often used to describe a paradoxical low-dose hormesis could result from direct stimulation hormesis
beneficial effects of stressors. The paradox arises due to (DSH), or as the compensatory biological processes after
our own preconception about what is good and bad, and initial disruption in homeostasis or overcompensation
we often cognitively biased towards the monotonic cause- stimulation hormesis (OCSH)).(10)
effect relationships. The hormetic dose-response model is Calabrese and Baldwin (10,14) defined hormesis as
apparently the most fundamental and very common in the an adaptive biphasic response, i.e., OCSH. Therefore, the
biological and biomedical sciences, across biological model, adaptive response of hormesis can be low, no response
endpoint measured and chemical class and physical agent. at an intermediate level, then a second response at a high
(7) In this review, we will elucidate the hormesis definition, level of deviation from homeostasis, described in a U- or
mechanisms and pathways, and also how hormesis impacts J-shaped response.(10) In other words, a low to moderate
in human health and lifespan.

Defining Hormesis

The term hormesis first coined in 1943 by Chester Southam

and John Ehrlich after their observation on low concentration
Red Cedar tree extract benefit in enhancing the metabolism
of fungal species.(9) The definition later been revived by
Edward Calabrese.(10) Many variants have been grown of
its exact meaning. In general, the term hormesis related to
Figure 1. Dose-response curve showing the quantitative
the dose-response relationships of treatments, including
features of hormesis. NOAEL: No-observed-adverse-effect level;
chemical, thermal, or radiological which are beneficial at ZEP: Zero equivalent point.(7) (Adapted with permission from
a low level but harmful at a higher level. However, some John Wiley and Sons).

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 Hormesis in Health and Disease: Molecular Mechanisms (Meiliana A, et al.)
DOI: 10.18585/inabj.v12i4.1315 Indones Biomed J. 2020; 12(4): 288-303

Figure 2. Schematic of hormetic nomenclature.(10)

(Adapted with permission from SAGE Publication).

levels of acute stress alerts multicellular organisms, disrupt biphasic dose/concentration responses were identified since
and trigger a slight overcompensation before it return 1980s with many examples that conformed to the hormetic
to homeostasis. The natural explanation for the biphasic dose/concentration response quantitative features.(23,24)
response is either ignores the conventional dose response, The mechanism involving a complex and integrative array
or due to a different mechanism for the response.(10,15,16) of signal transduction pathways. A part of these pathways,
the relationship to the cell membrane and membrane
receptors, and the inter-connections among the signaling
Hormetic Mechanisms pathways described in Figure 3.(26) Hormesis employed
the same mechanisms to yield a response, either mediated
The hormetic dose/concentration response relationship by cell signaling or by any receptor. The experiment on
has attracted many researchers from a broad range in finding which pathway is mediating the hormesis response
biological and biomedical disciplines, seen from the performed by blocking a specific cell signaling pathway and
markedly increased peer-reviewed scientific literatures see if it prevents the hormetic stimulation.
over the past two decades (10,17,18), bring up hormesis as There are three types of hormetic dose/concentration
a highly generalizable, independent of biological model, response mechanisms for signaling pathways, based on their
endpoint measured, inducing agent and level of biological pathways for stimulation and inhibition. First, low dose
organization (e.g., cell, organ, organism).(19) stimulation and higher dose inhibition were mediated by
It’s not easy to provide one clear mechanism on the same receptor; second, the receptor only mediated the
hormesis, since more than 100 agents and signaling pathways stimulation and the inhibition mediated by another subtype
involved in almost 400 dose/concentration responses from of receptor; or third, the stimulation and inhibition do not
a wide range of chemical classes, with a broad range of share the same family of receptor, or happen in different
endpoints. However, a general mechanism must underlie mechanisms. Despite these differences in mechanistic
those all. Vast range of mechanisms mediate hormetic strategies the quantifiable features of the dose/concentration
responses 400 different hormetic dose response relationships responses are similar, suggesting a similar functional and
at the level of receptor and cell signaling pathways.(19,20) adaptive strategy.(19) A lot of hormetic dose response with
Hormetic-like biphasic dose/concentration responses occur end point of cell proliferation was mediated via mitogen
by a single agonist which act via two different receptor activated protein kinase (MAPK)-extracellular-signal-
subtypes, that antagonistic mediated the stimulatory and regulated kinase (ERK)1/2 cell signaling pathway (Figure
inhibitory pathways.(21) Receptor with high affinity to the 4), counted about 14 different cell types, except V79 cells
agonist but have lower capacity (fewer receptors) mediate in which p38 was essential whereas ERK1/2 involvement
the stimulation, and receptor with lower affinity but have was absent. Meanwhile, when the same cell type have the
a greater capacity mediate the inhibitory response.(22- hormetic dose responses for cell migration, it is typically
25) From this concept, numerous receptors that mediated mediated via a different cell signaling pathway such as p38

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Figure 3. Signal transduction pathways.(26) (Adapted from Wikimedia Commons).

(e.g., rat aortic smooth muscle), c-Jun N-terminal Kinase In the principals, hormesis represents a central
(JNK) or ovarian tumor cell lines (28), and microglia (29). evolutionary strategy that is constrained by the limits of
Thus, advance researches is needed focused on hormetic biological plasticity, where a high dose of stressors damaged
dose response quantitative features mechanisms, and how a biological system, while a low dose of the same substance
modifying dose could modulate it in a biological switching yield in a positive response in several physiologic functions
context. from cell growth to cognition, thus hormesis can be seen as
a component of biological plasticity.(35,36) Hormesis dose
response model is the quantitative features of plasticity.
Hormesis and Biological Plasticity
(34) Generally, the degree of phenotypic adaptive change
and type of phenotypic alternative can vary depends on
Phenotypic plasticity represents changes in an organism’s environmental conditions.(36) The phenotypic adjustments
observable properties such as behavior, morphology, induced by hormesis could be long lasting, and probably
and physiology, in response to the environment irreversible. This adjustment might regards as a mechanism
challenges. It is a fundamental adaptive feature, which of survival in organism, and one potential mechanism
has been extensively assessed within an ecological involving transmission of chromatin modifications through
evolutionary framework. Phenotypic plasticity is the mitosis (somatic memory) and meiosis (trans-generational
basic concept in biology, and applied in many broader memory.(37)
subjects including evolutionary biology, genetics, ecology, In many biomedical disciplines such as radiation
neurosciences, developmental biology, stem cell biology biology, toxicology and environmental mutagenesis, the
and biogerontology, among others which concern about phenomenon of preconditioning and adaptive responses
phenotypical adaptation to heterogeneous environments as involving a low dose exposures of numerous agents
described in Figure 5.(30-33) (radiation, heavy metals, hepatotoxins such as carbon

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 Hormesis in Health and Disease: Molecular Mechanisms (Meiliana A, et al.)
DOI: 10.18585/inabj.v12i4.1315 Indones Biomed J. 2020; 12(4): 288-303

Figure 4. Schematic representation of activation

of corneal epithelial wound healing by MAPK.(27)
(Adapted with permission from American Society for
Biochemistry and Molecular Biology).

tetrachloride, numerous oxidants, hypoxia) and stressful (ZEP) or threshold (Figure 1). The stimulatory response is
procedures to protect against a subsequent and more believed to be at the below threshold dose, i.e.., when the
massive exposure.(38) The prior exposure aims to produce organism acquired an altered/new adaptation phenotype.
an environmentally induced phenotype alteration with an Then, the quantitative features in hormetic stimulatory zone
enhanced adaptive response to the subsequent higher dose. represent a quantitative index of phenotypic plasticity, or
Different magnitude of the pre-conditioning dose result a measure of biological performance, usually in average
in altered phenotype created. When the higher dose was maximum response being about 30-60% greater than the
exposed, and the phenotype response generally follows an control.(39,40) The models are remarkable consistent
inverted U-shaped dose response, that indicates that the in different substances and endpoints, suggest a similar
change in plasticity is both qualitatively and quantitatively plasticity strategies and constraints are the rule throughout
described by the hormetic dose response. the biological sciences. Therefore, assessing the hormetic
The point where the dose response crossed from dose response could revealed the quantitative features of
stimulation to inhibition is called the Zero Equivalent Point biology plasticity and clarify the basic biological concepts.

Figure 5. Biological plasticity: A key to

survival.(34) (Adapted with permission from
Springer Nature).

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(34) The hormesis-induced phenotypic responses do not obscures the independent OSA contribution in metabolic
manifest only at the molecular level but even substantial for and vascular dysfunction.(51,52) OSA itself is recognized
life-history or demographic traits.(37) to be an independent risk factor for cardiovascular (53) and
One clear example is the macrophages polarization. liver diseases (54). Intermittent hypoxia (IH) is the major
Over the past two decades, studies recognize that component in OSA that is responsible to hepatic, glucose
macrophages can be reprogrammed toward pro-oxidative and lipid metabolism impairment, liver and vascular
(called M1 macrophages) or anti-inflammatory forms consequences of OSA.(54-57) In contrast, IH then proposed
(called M2 macrophages). A recent study hypothesized that as a technique to improve physiological performance by
macrophage reprogramming with polarization to M1 or utilizing the adaptation capability on ischemia-reperfusion
M2 macrophage forms may be mediated via concentration preconditioning mechanisms, and shown to improve
gradients of signaling agents utilizing many substances, and endothelial function in hypertension (58) and to limit
that conforms to an hormetic dose response.(41) infarct size (59). Thus, adaptation to IH could offer confer
cardiovascular protection against more severe and sustained
hypoxia, and other stresses such as ischemia. The results are
Signaling Pathways: Mechanisms of different depend on the diversity and duration of reduced
Protection in Pre- and Post-conditioning oxygen patterns applied, age, genotype variations, which
determine the homeostatic response and decompensation.
Preconditioning is an exposure of a sub-lethal physiologic (60) The direct and cross benefit of IH was used as treatment
stress to an organ, in order to confers subsequent protection and prevention of a variety of diseases, and to increase
from lethal injury by the prolonged exposure of same stressor. exercise training efficiency.
The term and concept of preconditioning later expanded Hypoxia may affect nitric oxide (NO) production
rapidly with various modifiers for specific application such (Figure 6), NO tissue concentration, and nitric oxide
as ischemic preconditioning (IPC), hypoxic preconditioning synthases (NOS) expression by several mechanisms: (i)
and remote preconditioning. Hence, preconditioning concept inadequate of O2 as NOS substrate, limit NO production; (ii)
developed into a different temporal exposure conditions O2 act as NOS feedback inhibition; (iii) modulation of NO
where a low dose of stress administered in order to enhance bioavailability; (iv) hypoxia inducible factor (HIF)-1 and
repair and recovery processes after exposure of a more other NOS transcription factors induced; (v) intracellular
challenging stress, resulting in the term post-conditioning. Ca2+ concentration and influx changed; (vi) NOS-regulating
(38,42-44). Both pre- and post-conditioning phenomena heat shock proteins (HSP) induced.(61) NO plays a
were biphasic dose responses with quantitative features pivotal role in adaptation to IH. It may be beneficial
similar to hormesis.(38,45) The adaptive phenomena as the by increasing efficiency of vascular oxygen transport and
specific manifestation to hormesis could present as an auto- energy supply (62,63), inducing protective antioxidant
protection, pre- and post-conditioning, and radiation- and enzymes such as catalase and superoxide dismutase (59),
chemical-induced adaptive responses.(46) and HSP (60), stabilizing cellular membranes, and restricting
Hypoxia is one of the most frequently encountered apoptosis (61).
stresses in health and disease. Previous studies demonstrated NO synthesis moderate stimulation and NO
that hypoxia could be beneficial or harmful depend on the overproduction restriction, either directly or via NO
duration, frequency, and severity of hypoxic episodes. negative feedback originating from NOS and alternative
Obesity has been a growing problem worldwide, due to its sources are the key of NO-dependent adaptation to IH.
cardiovascular morbidity and mortality.(47,48) Metabolic In adapted condition, NO synthesis and availability was
Syndrome (MS), a group of metabolism abnormality enhanced despite of the oxygen lack, and this will induce
including central obesity, hypertriglyceridemia, low levels the expression of other protective factors in robust and
of high-density lipoprotein (HDL) cholesterol, hypertension sustained way. Therefore, IH could represent an efficient
and hyperglycemia, is the most frequent clinical and and economic strategy to prevent and treat hypoxic or
metabolic consequence of obesity among others.(49,50) ischemic damage in organs and cells without drugs, with
Furthermore, overweight and obesity is the essential risk a similar protection resulted by physical training. In this
factor for obstructive sleep apnea (OSA). Indeed, two- respect strategic modulation of NO metabolism is of specific
thirds of MS patients experience moderate to severe OSA, interest.(61) Some protocols were developed utilizing IH
and the frequent association between OSA and obesity to improve cardio performance, induce neo-angiogenesis

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DOI: 10.18585/inabj.v12i4.1315 Indones Biomed J. 2020; 12(4): 288-303

occlusion, which was insufficient to cause myocardial

necrosis, and continue with a prolonged (40 minutes)
coronary occlusion and reperfusion which caused infarction.
This resulted in a substantial reduction (75%) in the area of
infarction in the subsequent exposure (66). The experiment
in cerebral did in 4 years later using a brief (2 minutes)
bilateral carotid occlusions, and could protect from neuronal
death due to the subsequent 5 minutes bilateral carotid in
gerbils.(67)
Ischemic pre- and postconditioning complex
signaling pathways involve ligands released from
ischemic myocardium, G-protein-linked receptors,
membrane growth factor receptors, phospholipids, signaling
kinases, NO, protein kinase C (PKC) and cGMP-dependent
protein kinase or protein kinase G (PKG), mitochondrial
ATP-sensitive potassium channels, reactive oxygen species
(ROS), tumor necrosis factor (TNF-α and sphingosine-
1-phosphate. The mitochondrial permeability transition
pore (mtPTP) is probably the final effector, together with
the signal to prevent pore formation. Many studies tried
to produce a roadmap of this signaling, hope to reveal a
point to intervene and could patients with acute myocardial
infarction whose hearts are being reperfused.(62)
Scientists acknowledged IPC as the most powerful
Figure 6. NO-dependent mechanisms in protective effects of cardioprotective intervention to salvage ischemic
adaptation to hypoxia.(60) (Adapted with permission from myocardium, reduce infarct size, and protect the cardiac.
SAGE Publications). Acute myocardial infarction (AMI) is caused by a coronary
thrombus, which could be dissolved with a thrombolytic
and resist to ischemia-reperfusion injury, mediates by agent. the size of a myocardial infarction is not only
the phosphatidylinositol 3-kinase (PI3K)-Akt signaling. determined by ischemic damage, but also by reperfusion
Such preconditioning maybe not reduce the incidence of itself which contribute up to 50% of the final infarct size.
myocardial ischemia-reperfusion injury, but at least reduce Current standard of treatment is revascularization therapy
the myocardial damage severity.(59,64) (62), such as mechanical postconditioning using short
Ischemic conditioning performed by induced periods of ischemia immediately after reperfusion. Oxygen
a transient, subcritical ischemia in a tissue to form re-introduction leads to sudden changes in myocardial
endogenous protection. It is promising to protect ischemia- viability, mediated by a burst of ROS produced in the
sensitive organs such as the heart, the brain, and spinal mitochondria. This led to membrane damage, ion pumps
cord. Both pre- and post-conditioning give a similar level interference, and volume dysregulation. Another
of neuroprotection. The effects can appear immediately hypothesis was the invasion of leucocyte to the
after the sublethal stress, or with a delay of days, termed as reperfused tissue and attack viable myocytes by releasing
early or late effects. The early effects may associate to post- free radicals.
translational modification of critical proteins (membrane Preconditioning and adaptive responses are the
receptors, mitochondrial respiratory chain), while the manifestation of hormesis. The constraints of biological
late effects come after gene up-or down- regulation. The plasticity may be an obstacle in enhancing the hormetic
transient ischemic attacks (TIA) could be relevant to brain stimulation amplitude. However, in the resilient phenotype,
ischemic preconditioning and may reduce the severity of the duration may be extended to resolve this.(68,69)
subsequent strokes.(65) It is expected that efforts will be directed in these
Ischemic preconditioning (IPC) was first described directions via metabolic engineering and other molecular
in 1986, implemented as four 5 minutes cycles of coronary approaches.(20)

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heat stress, the expression levels of the small heat-shock

Mitohormesis Promoting Health and protein gene hsp-16 in C. Elegans are predictive of both
Lifespan thermotolerance and life span.(72) Another study suggested
an extension of lifespan in C. Elegans after glucose
restriction, which induces hormesis via mitochondrial
The levels of molecular damage increase over time, respiration and oxidative stress enhancement.(73,74) Seems
contributes to the biological process of aging, and that increased stress resistance will increased life span.(1)
organism’s pathology and mortality. The precise ROS regards as toxic oxygen-containing molecules
mechanisms underlying aging process and how to control that induce molecular damage in the cell, and contribute
its rate to increase lifespan was investigated using models to aging.(75,76) In contrary, mildly elevated ROS alter
such as Saccharomyces cerevisiae, C. elegans, Drosophila physiologic rates (77-79) and contribute to longevity in
melanogaster, and Mus musculus. From a molecular some organisms including clk-1 worms (79-81). Treatment
genetic perspective, hormetic adaptive and defensive dose with the superoxide-generator paraquat induce oxidative
response involving an alteration of genes’ expression, and damage (77,80,82) and decreased the levels of protein
result in stress resistance. Utilizing the hormetic principal, carbonylation (83,84), decreased lipofuscin accumulation
longevity may be increased after achieving a greater (85), and decreased 4-Hydroxynonenal (4-HNE) (86,87),
resistance to a range of stressors. The treatments applied while increasing the levels of F3-isoprostanes (88) in the
in many studies involving insulin/IGF-1 signaling pathway worms. Measurement of ROS level in clk-1 worms using
manipulations, dietary restriction (food intake significant redox dyes showed increased level of ROS in whole worm
reduction without malnutrition), oxygen reduction, physical extracts and in the heads of whole worms (82), but not in
activity, etc (Figure 7).(70) The hormetic dose response has isolated mitochondria (80). This indicate that the worms
important implications for the fields of hazard assessment, have increased levels of ROS but decreased levels of at least
risk assessment for carcinogens, endocrine disruption, for some types of oxidative damage.
pharmaceuticals/natural products that enhance biological Oxidative damage is a result of the homeostasis
performance, and pre/post conditioning activities that between ROS production, ROS detoxification and repair,
upregulate adaptive mechanisms, enhancing resilience. thus the result suggested that antioxidant defense or damage
A brief thermal stress exposure is sufficient to repair may be increased in the worms. The elevated ROS
induce thermotolerance in C. Elegans and cause small, but in clk-1 worms upregulates multiple classes of antioxidant
statistically significant increases in life span.(71) Apparently, genes during adulthood, increased the level of catalase
the dose-response relationships for thermotolerance and activity (89), while the increasing of superoxide dismutase
longevity are very similar (68); after subjected to a mild (SOD) protein or mRNA showed different results (83,90-

Figure 7. A non-exhaustive overview on

lifespan-extending interventions linked to
mitohormetic ROS signalling.(70) (Adapted
with permission from SAGE Publication).

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92). Increased levels of ROS in the mitochondria further misinterpretation happened to the subsequent decrease in
increase clk-1 lifespan, while cytoplasmic ROS decrease ROS as being the primary result of CR, whereas it is an
it, but actually the specific compartment does not affect on adaptive detoxifying mechanism, and CR is the essential
lifespan. What counted to the longevity of clk-1 worms is trigger of mitohormetic mechanisms.(73,126)
both ROS-dependent and ROS-independent mechanisms on Thioredoxin is another important factor regarding the
stress resistance.(93) effects of CR. It extends C. elegans lifespan under dietary
Besides their responsibility in conversing the bulk deprivation and knockouts of eat-2, a genetic surrogate of
of nutritive energy, mitochondria play an important role in nematodal CR.(127) The oxidoreductase thioredoxin roles
aging processes and the related diseases. Over 90% of all in antioxidant response via Nrf2 binding at the antioxidants
intracellular ROS was produced as the inevitable by-product responsive elements (AREs), redox regulation, acts as
of mitochondria oxidative phosphorylation (OxPhos) electron donor for metabolic enzymes, and prevents
process, with conversion of 0.15-5 % of total oxygen aggregation of cytosolic proteins in the cell.(128,129) Nrf2
consumed by resting cells (89-92). Thus, mitochondria transcription factor activation from the leucine zipper family
are the main producers of energy and ROS within the is indeed a crucial pathway to mediate mitohormesis. Nrf2
cell, which majorly impact on cell’s physiological and in a normal condition is insulated by its specific repressor
pathophysiological processes. Mitochondrial dysfunction Kelch-like ECH-Associated Protein 1 (KEAP1) in the
increased oxidative stress and associated with many diseases cytoplasm. KEAP1 is an actin-binding protein, which also
such as diabetes, cancer and neurodegenerative disorders, targets Nrf2 for proteasomal degradation.(130) The redox-
including Alzheimer’s and Parkinson’s disease (94-97), and sensitive cysteine residues in KEAP-1 sensors oxidants and
of course aging (97-99), whereas the role of ROS in this electrophiles, leading to abrogation of the Nrf2/KEAP1
regard is still unclear. Hence, ROS in different levels may
exert opposite effects on biological outcomes. At a high dose,
ROS clearly induce detrimental effects on cellular integrity,
while in low amounts ROS may exert specific functions
in promoting general health, and specifically lifespan. By
today, a range of stressors provide hormetic effects on aging
process (10,11,18,100-102). The term of mitochondrial
hormesis or mitohormesis later specified in 2006 (103),
which used in setting for mitochondrial ROS (mtROS) as
sublethal stressors promoting lifespan in a lower doses (73).
Figure 8 showed how ROS transcriptionally influence stress
resistance and lifespan.
Calorie restriction (CR) has been applied in study
for aging since world war II, refers to dietary regimens
that reduce 10-50% calorie intake without incurring
malnutrition (104). CR induces metabolic adaptation and
reduces regenerative diseases including cardiovascular
diseases, cancer, and type 2 diabetes mellitus (T2DM) (105-
109) as well as the factors involved in the before-mentioned
diseases (110-112). CR is capable of inducing stress defense
mechanisms which reflect mitohormetic responses, notably
in ROS detoxification, involving radical-scavenging
enzymes and phase I and II biotransformation response
enzymes.(73,74,81,113-125)
Mitohormetic mechanism was showed in CR as
hypothesized in some independent observations. Initial
induction of mtROS by CR induces stress defense
Figure 8. Overview on how ROS transcriptionally influence
mechanisms and culminate in secondarily decreased of stress resistance and lifespan.(70) (Adapted with permission
mtROS levels, in a time-resolved manner.(81) Some from SAGE Publication).

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complex.(130,131) Nrf2 is shown to be activated by ROS of hormesis mechanisms, propose the beneficial effects of
(131,132), and binds to the DNA via AREs to coordinate the DER for health. HSP level was increase in several different
stress response by boosting the expression of antioxidant tissues, which serve a chaperone function that protects
proteins, and phase I and II detoxification enzymes.(133) proteins against damage. For example, HSP-70 levels are
Due to various interventions mechanisms, there increased in liver cells of rats treated on CR (151), while
are some other transcription factors which are important intermittent fasting increased HSP-70 and glucose-regulated
for lifespan extension including member of the Forkhead protein 78 in rat’s brain synapses (152).
transcription factors (FOX) and heat shock factor 1 (HSF-1). Another cytoprotective benefit of DER is the
FOXOs activate a number of target genes involved in cellular upregulation of antioxidants. Diabetic rodents demonstrated
stress response. Oxidative stress induce mitohormesis and increased levels of some antioxidant enzymes in their liver
upregulates superoxide dismutase and catalase in FOXO- after DER maintenance (153), and reduced calorie diet
dependent pathway (134-136), while stress-response result in increased vitamin E and coenzyme Q10, also higher
induced by CR is mediated by FOXAs (137,138). Overall, plasma membrane redox enzyme activities, in brain cell
a number of important lifespan-regulating molecular membranes compared to control rats fed ad libitum (154).
pathways were unified in mitohormesis, and prospectively The increased antioxidant levels are consistent with reduced
to become a common denominator in aging research.(70) oxidative damage to proteins, lipids and DNA in various
tissues of animals as a result of hormetic mechanisms on DER
(155), which involve system adaptation on cellular energy
Dietary Factors, Hormesis and Health regulation. For example, some proteins which involved in
mitochondrial oxidative phosphorylation (138), glycolysis
Many studies demonstrated different dietary factors effect on (148) and nicotinamide adenine dinucleotide (NAD)/NADH
health and longevity. Some of those showed incontrovertible metabolism (166) regulation were upregulated in some cell
evidences, while some other were inconclusive. Beyond of types as respond to DER.
the food variety, the amount of calories consumed firmly The current evidences for hormetic response due
showed an associated with the risk of many prominent to environmental toxins in biological systems raise the
age-related diseases.(139–141) Higher calories increase possibility that the same mechanism also occurs by the
the risks of such metabolic and even neurodegenerative induction from chemicals in foodstuffs (particularly plants),
disorders. Regarding the dietary components, diet high in resulting from chemicals ingestion in doses within the
saturated fats, cholesterol and trans-fats may promote age- hormetic range. Plants developed biosynthetic pathways
related disease (142,143), while simple sugars increase and generate more than 100 biotoxins in its evolution in
the risk of diabetes (144). Healthy diets recommendation order to prevent microorganisms and insects from eating
including lots of vegetables and fruits (145), fish (146) them.(164) The harmful chemicals usually concentrated
and nuts (147). in exposed vulnerable regions of the plant such as the skin
Oxidative stress is often be blamed for ageing process of fruits and the growing buds. The phytochemicals can
and mortality. Therefore, modifying dietary factors might be toxic to mammalian cells in high concentrations, but in
influence disease processes and longevity. Dietary energy subtoxic doses, it may induce adaptive stress responses.
restriction (DER), and substances contain in vegetables, Several studies performed on the hormetic actions of specific
fruits, nuts and fish oils exert anti-oxidative effects.(148) phytochemicals, such as high levels of isothocyanates in
Animal and in vitro studies found that dietary factor induced broccoli which induced the expression of cytoprotective
specific adaptive stress response signaling pathways, i.e., phase 2 proteins in liver, intestinal and stomach cells (167);
hormesis.(149) Another highly controlled studies on animals curcumin contains in curry spices induce adaptive stress
showed that DER either by controlled CR or intermittent responses genes and protect cells in animal models of
fasting can increased animal cells to various types of stress. cataract formation, pulmonary toxicity, multiple sclerosis
DER studies in human also resulted in counteract disease and Alzheimer’s disease (168); resveratrol found in grape
processes. Alternate day fasting reduced inflammation skin protect cells in models of myocardial infarction and
markers and oxidative stress and also improve symptoms in stroke (169). Nrf-2 is involved in the hormetic signal
asthma subjects.(150) transduction, by its binding to ARE upstream of genes and
DER regiment in animals change several biochemical encodes cytoprotective antioxidant enzymes and phase-2
and molecular which are consistent with the involvement proteins.(170) Other pathways such in resveratrol, involving

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 Hormesis in Health and Disease: Molecular Mechanisms (Meiliana A, et al.)
DOI: 10.18585/inabj.v12i4.1315 Indones Biomed J. 2020; 12(4): 288-303

Table 1. Summarized agents that induce hormesis-related to dietary and health.

Hormetin Agents Food in Diet Stress Pathway Effect
Phytochemicals Broccoli, curry spices Activation of nuclear factor Broccoli induced the expression of
(isothocyanates, curcumin) erythroid 2 (Nrf2) cytoprotective phase 2 proteins in liver,
intestinal and stomach cells. Curcumin
protects against cataract formation, pulmonary
toxicity, multiple sclerosis and Alzheimer’s
disease.

Resveratrol Grapes skin, red wine Regulation of redox Resveratrol protect cells in models of
homeostasis, Activation of myocardial infarction and stroke.
Nrf2 and sirtuin pathway,
Blocking of nuclear factor κB
(NF-κB)

Alcohol Alcoholic drinks Alterations in protein kinase C Moderate consumption of alcohol increase in
(PKC) HDL cholesterol, increased insulin sensitivity,
anti-inflammatory effect, increase adiponectin,
increase fibrinolysis, decrease in platelet
aggregation, and coagulation and improved
endothelial function.

activation of sirtuin – FOXO, and increase the expression of

antioxidant enzymes, and cell survival-promoting proteins. Conclusion
(162) Some other phytochemicals may activate the hormetic
transcription factors NF-κB and CREB and induce genes Human bodies are highly adaptive. Exposure to a stressor
encoding growth factors and anti- apoptotic proteins. in adequate dose evidently can induce stress responses that
(163,164) are protective against the same stress exposure in higher
Since the early recorded history, alcohol has been an levels. While constant high-level exposure induce tolerance
integral part of human culture. Moderate alcohol consumption to avoid overstressing the system. Our body needs to adjust
associated with beneficial health effects, but excess and to different functions from fecundity versus longevity until
binge drinking leads to increasing risk of cardiovascular energy conservation versus expenditure. These adaptations
diseases and mortlity.(165-170) Thus, moderate amount of are essential to protect us from unpredictable environmental
alcohol is protective against coronary artery disease (CAD), changes. Our endocrine, nervous, and immune systems are
and the higher amount exert different effect.(171) Multiple capable to adapt, since these systems directly sense the
studies observed a J- or U-shaped association between environmental changes and communicate the perceived
alcohol consumption and all-cause mortality.(169-175) The change to the rest of the body. A lot of adaptation occurred
benefit of moderate alcohol consumption include an increase during evolution and the training formed the body that is
in HDL cholesterol, increased insulin sensitivity, favorable more resistant to stress.
effects mediated by alterations in PKC, anti-inflammatory
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