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Unlike proteins, carbohydrates and fats as the main macromolecules necessary for biological structure and functions, numerous other chemicals present in the food have a paradoxical nature. Various dietary components in the food are actually toxins which induce molecular damages in a biphasic dose response. A successful handling of the damage, through a complex series of biochemical pathways of maintenance and repair can result in achieving health beneficial effects in the body. This is the phenomenon of mild stress-induced hormesis, and the conditions causing hormesis are known as hormetins. Food components, which induce one or more pathways of stress response in cells and organisms, are potential hormetins which can have health beneficial, anti-ageing and longevity promoting effects. Various dietary components present in spices, herbs, and numerous medicinal plants, and some vitamins, trace elements, minerals and others are such hormetins. These nutritional hormetins have almost no nutritional value in terms of providing proteins, carbohydrates and fats, but have pleiotropic biological effects in maintaining, recovering, and enhancing health and longevity.

The exposure of living organisms to environmental stress triggers defensive responses resulting in the activation of protective processes. Whenever the exposure occurs at low doses, defensive effects overwhelm the adverse effects of the exposure; this adaptive situation is referred to as “hormesis”. Environmental, physical, and nutritional hormetins lead to the stimulation and strengthening of the maintenance and repair systems in cells and tissues. Exercise, heat, and irradiation are examples of physical hormetins, which activate heat shock-, DNA repair-, and anti-oxidative-stress responses. The health promoting effect of many bio-actives in fruits and vegetables can be seen as the effect of mildly toxic compounds triggering this adaptive stimulus. Numerous studies indicate that living organisms possess the ability to adapt to adverse environmental conditions, as exemplified by the fact that DNA damage and gene expression profiling in populations living in the environment with high levels of air pollution do not correspond to the concentrations of pollutants. The molecular mechanisms of the hormetic response include modulation of (a) transcription factor Nrf2 activating the synthesis of glutathione and the subsequent protection of the cell; (b) DNA methylation; and (c) microRNA. These findings provide evidence that hormesis is a toxicological event, occurring at low exposure doses to environmental stressors, having the benefit for the maintenance of a healthy status.

Using data from Schink et al. (2018), a large number of herbal extracts were assessed for their capacity to inducepro- and anti-inflammatory effects based on TLR4 expression normalized for cell viability in two immune cellmodels (i.e., HeLa-TLR4 transfected reporter cell line, and THP-1 monocytes) applying seven concentrations(0.01–3.0%). The analysis revealed that 70–80% of the extracts satisfying the a priori entry criteria also satisfieda priori evaluative criteria for hormetic concentration responses. These findings demonstrate that a large proportionof herbal extracts display hormetic dose responses in immune cells, indicating that hormetic mechanismsmediate pro- and anti-inflammatory processes and may provide a means to guide optimal dosing strategies. Theidentification of doses eliciting only anti-inflammatory therapeutic activity as well as the use of dose-variableherbal extracts in the treatment of inflammatory diseases will be challenging.

Although high levels of stress hormones are associated with well-known negative health outcomes, their low levels can have health-promoting effects by virtue of the phenomenon of mild stress-induced hormesis. We have studied the effects of a wide range (between 100 nmol/L and 150 μmol/L) of hydrocortisone (HC) on human bone marrow stem cells in vitro. Telomerase-immortalized human mesenchymal stem cells (hTERT-MSCs) were exposed to various doses of HC for different durations (1-6 days) and analyzed for survival and metabolic activity by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, for cell migratory ability by a wound-healing assay and for osteoblastic and adipogenic differentiation abilities in vitro. Our findings indicate that hTERT-MSCs exposed to HC resulted in a biphasic hormetic dose–response in some measures but not all. Although the mitochondrial and metabolic MTT activity assay clearly showed low-level stimulatory (between 0.1 and 1 µmol/L) and high-level inhibitory effects (from about 10 µmol/L onward), the cytostatic and differentiation-inducing effects were mostly linear at concentrations between 1 and 100 µmol/L. Further long-term studies will elucidate whether chronic or intermittent exposure of human cells to stress hormones has physiologically beneficial hormetic effects.

Curcumin is shown to commonly induce biphasic dose responses in a broad range of cell types, with particular emphasis on neural cells, including neuronal stem cells. The quantitative features of these biphasic dose responses, with respect to the magnitude and width of the low dose stimulation, are similar to those reported for hormetic dose responses. These hormetic dose responses occur within the framework of direct stimulatory responses as well as in preconditioning experimental protocols, displaying acquired resistance within an adaptive homeodynamic framework. These findings have important implications for study design strategies involving dose selection and spacing, as well as sample size and statistical power considerations. These findings further reflect the broadly general occurrence of hormetic dose responses that consistently appear to be independent of biological model, endpoint, inducing agent and mechanism.

Evolutionary processes have developed in all organisms the intrinsic ability to counteract physiological and environmental stress as an essential tool for survival. The widely observed phenomenon, that a single or repeated exposure to mild stress can improve their biological performance and stress resistance including tolerance to severe stress, necessitates understanding the molecular mechanisms that underlie such effect. The focus of this chapter is to discuss the primary biochemical pathways that participate in stress response (SR), and form the basis of preconditioning and physiological hormesis. SR pathways are activated by a variety of stressors, such as intracellular denatured proteins, heat shock, free radicals, food deprivation, energy depletion, DNA lesions, inflammation-inducing pathogens/allergens, and unfolded proteins in the endoplasmic reticulum. Although SR pathways are generally stressor specific, different responses can be triggered depending on other factors, such as the time lapsed after stress exposure and the activation of further molecular responses by downstream modulators.

One of the aims of the EU-funded Research and Innovation Action (RIA), titled "Ageing with Elegans" (AwE) is to enhance better understanding of the factors causing health and disease in aging and develop evidence-based preventive, diagnostic, therapeutic, and other strategies. The work package-5 of this project is focused on testing the effects of phytochemicals of natural and synthetic origin on aging, longevity, and health of human cells in vitro, after the initial screening using the animal model systems of nematodes and rats and mice. Accordingly, the first series of three compounds, rosmarinic acid (ROSM), ampelopsin (AMPEL), and amorfrutin-A (AMOR), were selected to test for their short-term and long-term effects on human skin fibroblasts undergoing aging and senescence in vitro. The lifelong modulatory effects of these compounds were tested individually at two doses (0.5 and 1.0 mu M), selected after a short-term dose response check of a 20,000-fold range (0.01-200 mu M). The results show that these compounds do have some beneficial effects in terms of supporting the long-term lifelong growth and enhanced stress tolerance of serially passaged cells. These effects seem to be achieved by reducing the extent of loss of telomeres, of 5-methyl-cytosine (5-mC) and of 5-hydroxymethyl-cytosine (5-hmC), by reducing the accumulation of oxidative DNA damage product 8-OHdG. There is also some indication that these compounds induce at least one of the stress responses in terms of the increased synthesis of heat shock protein Hsp70. Thus, these phytochemicals may be potential hormetins, which bring about their health beneficial effects by the phenomenon of mild stress-induced hormesis.

Nanodiamonds (ND) and silica nanoparticles (SiO2-NP) have been much investigated for their toxicity at high doses, little is known about their biological activity at low concentrations. Here we report the biphasic dose response of ND and SiO2-NP in modulating normal human facial skin fibroblasts (FSF1) in culture. ND and SiO2-NP at low concentration (up to 0.5 μg/ml) had beneficial effects on FSF1 in terms of increasing their proliferation and metabolic activity. Exposure of FSF1 cells to low levels of NP enhanced their wound healing ability in vitro and slowed down aging during serial passaging as measured by maintenance of youthful morphology, reduction in the rate of loss of telomeres, and the over all proliferative characterisitics. Furthermore, NP treatment induced the activation of Nrf2- and FOXO3A mediated cellular stress responses, including an increased expression of heme oxygenease HO-1), sirtuin (SIRT1), and DNA methyltransferase II (DNMT2). These results imply that ND and SiO2-NP at low doses are potential hormetins, which exert mild stress-induced beneficial hormetic effects through improved survival, longevity, maintenance, repair andfunction of human cells

A promising strategy to slow down aging and to prevent or delay the onset of age-related diseases is that of repeated mild stress-induced hormesis. Any condition that causes low level damage in cells and leads to the activation of one or more stress response defence pathways is a potential hormetin. Physical, nutritional and mental hormetins initiate cellular stress responses and strengthen the homeodynamic space that determines the health and survival of an individual. Exercise, heat and irradiation are examples of physical hormetins, which activate heat shock-, DNA repair- and anti-oxidative-responses. Several non-nutritional chemical components in the food, such as flavonoids and polyphenols present in spices, herbs and other sources, are examples of nutritional hormetins, which induce anti-oxidative and anti-inflammatory stress responses. Calorie restriction and intermittent fasting are also hormetins, which activate the autophagic and sirtuin-mediated stress responses. Intense brain activity and focussed attention comprise mental hormetins, which also induce various stress responses. A successful strategy for discovering novel hormetins involves elucidating multiple stress responses of normal cells in culture. This requires establishing immediate and delayed stress response profiles, followed by cell type-specific functional assays, after exposure to natural or synthetic compounds and mixtures. A combination of physical and nutritional hormetins, combined with mental hormetins, can be the drugs for maintaining, improving and recovering health during aging.

Mild stress-induced activation of stress response (SR) pathways, such as autophagy, heat shock response, oxidative SR, DNA damage response, and inflammatory response, can be potentially health beneficial. Using the model system of cellular ageing and replicative senescence in vitro, we have studied the ageing modulatory effects of the two conditions, rapamycin and serum starvation. Chronic exposure to 0.1, 1 and 10 nM rapamycin positively modulated the survival, growth, morphology, telomere length, DNA methylation levels, 8-oxo-dG level in DNA, N6-methyl-adenosine level in RNA, and ethanol stress tolerance of serially passaged normal human skin fibroblasts. Furthermore, episodic (once a week) serum starvation of human skin fibroblasts extended their replicative lifespan by about 22%, along with the maintenance of early passage youthful morphology even in late passage cultures. Although the results of this study may be considered preliminary, it can be inferred that intermittent and episodic induction of SR, rather than chronic up-regulation of SR, is more effective and applicable in the practice of hormesis for healthy ageing and longevity.

Aging at the molecular and cellular levels is characterized by the occurrence and accumulation of damage in DNA, RNA, proteins, and other macromolecules. Increased molecular heterogeneity is the fundamental basis for the cellular and physiological changes that happen during aging. Specifically, imperfections of the maintenance and repair systems that comprise the homeodynamic space lead to a progressive failure of homeodynamics. Major age-related changes include genomic instability, mutations, dysregulated gene expression, cellular senescence, impaired intercellular communication, tissue disorganization, organ dysfunctions, increased vulnerability to stress, and reduced ability to adapt and remodel. Various approaches for intervention, prevention, and modulation of aging incorporate means to minimize the occurrence and accumulation of molecular damage. Mild stress-induced hormesis caused by physical, biological, and nutritional hormetins is a promising holistic strategy for strengthening the homeodynamics. Food components, which induce one or more pathways of stress response in cells and organisms, are potential nutritional hormetins, and can have health- and longevity-promoting effects.

Wound healing becomes impaired in several diseases and during ageing. A commonly used model for the study of wound healing is a scratched monolayer of cells in vitro, which is convenient for the analysis of the cellular and molecular changes occurring during the two phases of wound healing, namely cell migration and cell proliferation. Cell migration, which is the primary event to occur during initial wound healing, is inversely dependent on the number of focal adhesions (FA) that attach cells to the extracellular matrix. Here we report that the number of FA, measured by determining the levels of FA-proteins paxillin and talin, increase with increasing population doubling level of the serially passaged normal adult skin fibroblasts, and that this increase may account for the age-related slowing down of wound healing in vitro. We also report that curcumin, a component of the widely used spice turmeric, modulates wound healing in vitro in a biphasic dose response manner, being stimulatory at low doses (between 1 and 5 μM), and inhibitory at higher doses. Furthermore, our results show that the hormetic effects of low levels of curcumin are achieved by virtue of it being a hormetin in terms of the induction of stress response pathways, including Nrf2 and HO-1 in human cells.

Strategies for testing and developing effective means of intervention, prevention, and modulation of aging incorporate means to minimize the occurrence and accumulation of molecular damage, to reduce molecular heterogeneity, and to evaluate the relevance of the type and extent of damage with respect to its role in aging and age-related diseases. One such approach is that of mild stress-induced hormesis, which stimulates maintenance and repair systems and strengthens the homeodynamic space of cells and organisms. Hormesis through mild heat shock, natural and synthetic hormetins, and other stressors brings about several antiaging effects in human fibroblasts, keratinocytes, and telomerase-immortalized bone marrow stem cells. Depending on the cell type, these antiaging hormetic effects include extension of replicative life span, enhanced proteasomal activities, increased chaperone levels, and improved wound healing, angiogenesis, and differentiation. The main molecular pathways for achieving such hormetic effects are through targeting the processes for the repair and removal of molecular damage, which can slow aging.

Aging is amenable to intervention and prevention by mild stress-induced hormesis. Previously, we have reported that repeated mild heat stress has antiaging and other beneficial effects on growth and a range of cellular and biochemical characteristics of normal human skin fibroblasts and keratinocytes undergoing aging in vitro. We have also established a model system of sugar-induced premature senescence in human cells, which can be useful for monitoring the protective and hormetic effects of other treatments. We have now initiated studies on testing the hormetic effects of glyoxal and heat shock on the wound-healing capacity of skin fibroblasts and on the angiogenic ability of endothelial cells. The effects of glyoxal on the extent of wound closure in vitro showed a typical biphasic hormetic curve with 20-40% stimulation at lower doses (up to 0.125 mmol) and more than 50% inhibition at concentrations above 0.5 mmol. In the case of angiogenesis by endothelial cells, measured by the standard tube formation assay on Matrigel, a prior exposure to mild heat shock at 41 degrees C for 1 h increased the total tube length and total number of junctions by 30-60% and 10-14%, respectively. In contrast, a severe heat shock at 42.5 degrees C had slightly inhibitory effects on total tube length and the number of junctions. These data add to the ever-growing body of evidence in support of the view that mild stress-induced hormesis can be a useful approach for the modulation, intervention, and prevention of aging and age-related impairments.

Progressive accumulation of molecular damage is a hallmark of cellular aging, which is amenable to intervention and prevention by hormesis through mild stress. Our studies have shown that repeated mild heat stress (RMHS) has antiaging effects on growth and various other cellular and biochemical characteristics of normal human skin fibroblasts undergoing aging in vitro. RMHS at 41 degrees C, for 1 h twice a week, increased the basal levels of various chaperones, reduced the accumulation of oxidatively and glycoxidatively damaged proteins, stimulated proteasomal activities for the degradation of abnormal proteins, improved cellular resistance to ethanol, hydrogen peroxide, and UV-B rays, enhanced the levels of various antioxidant enzymes, and increased the phosphorylation-mediated activities of various stress kinases. RMHS-exposed human fibroblasts are also better protected against glucose- and glyoxal-induced growth inhibition and apoptosis. We have also observed various hormetic effects of RMHS on normal human epidermal keratinocytes, which include increased replicative life span, increased proteasomal activity, and enhanced levels of Na/K-ATPase pump. We are also testing the above effects of RMHS in combination with potential hormetic molecules, such as curcumin, on aging, longevity, and differentiation of human cells in culture.

Mild stress-induced hormesis is an effective strategy to intervene in the aging process. Repeated exposure of human skin fibroblasts to 41 degrees C heat shock for 1 h twice a week is an example of mild stress that has many hormetic effects, including improved resistance to other stressors. We are now developing an experimental model system of sugar-induced premature senescence, which can be useful to test the hormetic and antiaging effects of other stresses. Our present studies show that early-passage human skin fibroblasts treated with 1 mM glyoxal for 72 h undergo premature senescence in terms of enlarged cell size, inhibition of cell division, slowing down of cell growth, a decrease in the number of DNA synthesizing cells, and increased resistance to apoptosis.

The phenomenon of hormesis is represented by mild stress-induced stimulation of maintenance and repair pathways resulting in beneficial effects for the cells and organisms. Anti-aging and life-prolonging effects of a wide variety of the so-called stressors, such as pro-oxidants, aldehydes, calorie restriction, irradiation, heat shock, and hypergravity, have been reported. Molecular mechanisms of hormesis due to different stresses are yet to be elucidated, but there are indications that relatively small individual hormetic effects become biologically amplified resulting in the collective significant improvement of cellular and organismic functions and survival. Accepting that some important issues with respect to establishing the optimal hormetic conditions still need to be resolved by future research, hormesis appears to be a promising and effective approach for modulating aging, for preventing or delaying the onset of age-related diseases, and for improving quality of life in old age.

Udgivelsesdato: 2004-null Since aging is primarily the result of a failure of maintenance and repair mechanisms, various approaches are being developed in order to stimulate these pathways and modulate the process of aging. One such approach, termed hormesis, involves challenging cells and organisms by mild stress that often results in anti-aging and life prolonging effects. In a series of experimental studies, we have reported that repeated mild heat stress (RMHS) has anti-aging hormetic effects on growth and various cellular and biochemical characteristics of human skin fibroblasts undergoing aging in vitro. These beneficial effects of repeated challenge include the maintenance of stress protein profile, reduction in the accumulation of oxidatively and glycoxidatively damaged proteins, stimulation of the proteasomal activities for the degradation of abnormal proteins, improved cellular resistance to other stresses, and enhanced levels of cellular antioxidant ability. In order to elucidate the molecular mechanisms of hormetic effects of RMHS, we are now undertaking studies on signal transduction pathways, energy production and utilisation kinetics, and the proteomic analysis of patterns of proteins synthesised and their posttranslational modifications in various types of human cells undergoing cellular aging in vitro. Human applications of hormesis include early intervention and modulation of the aging process to prevent or delay the onset of age-related conditions, such as sarcopenia, Alzheimer's disease, Parkinson's disease, cataracts and osteoporosis.

The phenomenon of hormesis is represented by mild stress-induced stimulation of maintenance and repair pathways, resulting in beneficial effects for cells and organisms. We have reported that repeated mild heat stress (RMHS) has anti-aging hermetic effects on growth and various cellular and biochemical characteristics of human skin fibroblasts undergoing aging in vitro. These effects of RMHS include the maintenance of the stress protein profile, reduction in the accumulation of oxidatively and glycoxidatively damaged proteins, stimulation of the activities of the proteasome and its US activator, improvement in cellular resistance to ethanol, hydrogen peroxide, and ultraviolet rays, and increased antioxidative activity of the cells. We have also reported that RMHS prolongs the lifespan of Drosophila. Others have reported anti-aging and life prolonging effects of a wide variety of so-called stressors, such as pro-oxidants, aldehydes, calorie restriction, irradiation, heat shock, and hypergravity. Although molecular mechanisms of hormesis are yet to be elucidated, there are indications that relatively small hermetic effects become biologically amplified, resulting in significant improvement of cellular and organic functions and survival. Hormesis, therefore, can be an effective approach for modulating aging, for preventing or delaying the onset of age-related diseases, and for improving the quality of life in old age.

We assessed the impact of repeated episodes of a mild heat stress on lifespan, fecundity, heat stress resistance and Hsp70 expression in Drosophila melanogaster. There was a significant increase in lifespan of females repeatedly exposed to a mild heat stress when measured in both a pair and a group situation. There was no effect on fecundity when the flies were first exposed to the mild heat stress at an age later than 3 days old, but when it did occur on day 3, there was a significant effect on cumulative fecundity levels over 18 days. The negative fitness effect appears to be the result of a direct cessation or reduction of oviposition during the first bout of stress exposure, and is influenced by the age at which this first exposure occurs. The mild heat stress had no impact on egg viability. The mild heat stress exposures increased resistance to potentially lethal heat stress and levels of Hsp70 expression in heat-exposed flies were higher than those in controls.

Repeated mild heat shock (RMHS) has anti-aging effects on growth and various other cellular and biochemical characteristics of human skin fibroblasts undergoing aging in vitro. In this study, we have tested whether RMHS can reduce the accumulation of heavily damaged proteins, such as oxidized and glycoxidized proteins involved in the development of many pathological consequences of aging. Cultured human skin fibroblasts were subjected to RMHS and were subsequently incubated either with glyoxal (0.1–1 mM) generatingN∈-carboxymethyl-lysine (CML), or withtert-butyl-hydroperoxide (t-BHP 10–700 μM) producing oxidized proteins. About50% more carbonylated-proteins were producedin control cells treated with t-BHP than incells previously exposed to RMHS. More dramatically, a treatment with 0.1 mM glyoxal for 48 h generated CML only in control cells. Such modulation of the level of damaged proteins is most likely related to the beneficial effects of hormesis resulting from exposure to mild stress.

Repeated exposure to mild heat shock (HS) has been shown to induce a wide range of health promoting hormetic effects in various biological systems, including human cells undergoing aging in vitro. In order to understand how cells distinguish between mild and severe stress, we have investigated the extent of early and immediate HS response by analyzing the nuclear translocation of the transcription factor heat shock factor-1 (HSF1), in serially passaged normal adult human facial skin fibroblasts exposed to mild (41 °C) or severe (43 °C) HS. Cells respond differently when exposed to mild and severe HS at different passage levels in terms of the extent of HSF1 translocation. In early passage young cells there was a 5-fold difference between mild and severe HS in the extent of HSF1 translocation. However, in near senescent late passage cells, the difference between mild and severe stress in terms of the extent of HSF1 translocation was reduced to less than 2-fold. One of the reasons for this age-related attenuation of heat shock response is due to the fact there was a higher basal level of HSF1 in the nuclei of late passage cells, which is indicative of increased intrinsic stress during cellular aging. These observations are consistent with previously reported data that whereas repeated mild stress given at younger ages can slow down aging and increase the lifespan, the same level of stress given at older ages may not provide the same benefits. Therefore, elucidating the early and immediate steps in the induction of stress response can be useful in deciding whether a particular level of stress is potentially hormetically beneficial or not.

Biological aging research shows that there are no gerontogenes that have evolved with the specific function of causing aging and determining the time of our death. Genes determine our survival and our ability to live and maintain health, but for about 40-50 years only. This period of life is known as the essential lifespan (ELS), required by evolution for the assurance of life and the continuation of generations. In the presence of survival genes, we are able to live, and now we even expect to live, for much longer duration than our species’ ELS. However, a longer life beyond ELS also allows the emergence of aging together with all its physical, mental and social manifestations. That then requires lifestyle adjustments, and biomedical, aesthetic and psycho-social methods for maintaining health and identity in old age.

Single or multiple exposures to mild stress at younger ages often have positive health beneficial effects throughout life, indicating that rescue systems turned on at a young age can be effective even in old age (e.g. Le Bourg 2011). This seems to be at variance with the notion of the so-called trade-offs that due to a limitation of resources it is impossible for an organism to increase all aspects of fitness (see for example, Stearns 2000). Recently, this view has again been raised in an article by McClure et al. (2014), published in Evolution. These authors have reported that Drosophila melanogaster flies challenged by a pretreatment with dead spores of the fungus Metarhizium robertsii lived longer, survived better under heat stress, and had a higher fecundity. Thus, these flies displayed the well-established phenomenon of physiological hormesis (for hormesis terminology, see for example Calabrese et al. 2007; Wiegant 2014). However, McClure et al. (2014) also showed that the pretreatment by dead fungal spores decreased by 10% the survival time of the flies after infection by live spores of the same fungus, and concluded that “when it occurs, hormesis leads to trade-offs with other fitness traits” and that, if applied to human patients, “the consequences of hormetic treatments for infected patients could be dire”. Thus, the balance of positive and negative effects of hormesis on fitness traits could be definitely on the negative side, precluding relying on hormesis in therapy or health maintenance and improvement. In our opinion, this viewpoint is not completely accurate because several other studies performed with flies and other systems show that a mild stress can have positive, negative or no effects on fitness-related traits. For instance, Lints and Le Bourg (1989) showed that female D. melanogaster flies living continuously in hypergravity had a lower and delayed peak of egg-laying, but the total fecundity remained roughly the same. Similarly, Hercus et al. (2003) showed that four rounds of exposure to mild heat stress, which increased the average and maximum lifespan of D. melanogaster and their resistance to heat, slightly reduced egg-laying (about 5%). Growing in hypergravity or having parents living in hypergravity slightly decreased viability of the larvae (Le Bourg and Lints 1989) but, by contrast, living in hypergravity for two weeks, a treatment known to increase longevity of males and resistance to heat in both sexes, had no effect on the number of females inseminated by males (Le Bourg, unpublished results). Regarding resistance to infection by the entomopathogenic fungus Beauveria bassiana, two mild stresses had no effect on post-infection lifespan (hypergravity and heat, Le Bourg et al. 2009), while a pretreatment by cold increased survival in males and had no clear effect in females (e.g. Le Bourg et al. 2009), the result of males being opposite to that of McClure et al. (2014) on immunity. Therefore, these results on traits linked to fitness in a direct (fecundity and viability) or in an indirect way (survival to fungal infection, possibly encountered in the wild) show that mild stresses can have either positive, slightly negative or no effects on these traits. The negative effects, using dead spores of a fungus as a mild stress, reported by McClure et al. (2014), do not pose a serious challenge to the application of hormesis for human health and longevity. However, by pointing out the possible interactive, counteractive or synergistic effects of hormetic interventions, these authors surely address an important aspect of physiological hormesis. Indeed, not all mild stresses increase lifespan and resistance to severe stresses (Lagisz et al. 2013), because the effects on longevity can be sex-specific and mild stresses can decrease resistance to starvation (Le Bourg 2009). Therefore, using hormesis as a possible therapy or a preventive strategy requires, as for any new therapy, testing whether any deleterious consequences of the pretreatment do exist. To give an example in mammals, subjecting a pig to a pretreatment with 250 ppm of carbon monoxide (1000 ppm is lethal) before cardiopulmonary bypass decreases the number of defibrillations necessary to restart the heart (2 vs 6) and prevents cardiac edema (Lavitrano et al. 2004). Obviously, it is necessary to rule out possible deleterious effects of this pretreatment before routinely using it in human cardiac surgery. Other studies have shown that mild stress can mitigate the effects of cardiac and cerebral ischemia (reviews in Simm and Horstkorte 2014; Bejot and Garnier 2014). Since a wide variety of mild stresses, including exercise, have been shown to have health beneficial hormetic effects in various species, including mammals, there is a definitive hope that new strategies relying on hormetic effects could be used either as preventive or as therapeutic in human beings (reviews in Rattan and Le Bourg 2014, but see also, Pardon 2010; Sorensen et al. 2010). It seems that the balance between positive and possible negative effects of mild stress is clearly on the positive side, and any trade-offs in fitness are specific to the general health, robustness and resilience of the body.

Aging is well understood in evolutionary and biological terms, and a distinctive framework has been established upon which general principles of aging and longevity can be formulated. These principles of aging can be the basis for developing effective aging interventional strategies for prevention and therapies. Aging and longevity are not determined by any specific gerontogenes, but are the result of imperfect maintenance and repair. At the cellular and molecular levels aging is characterized by the progressive failure of homeodynamics, unregulated growth, accumulation of macromolecular damage, increased molecular heterogeneity, altered cellular functioning, and reduced stress tolerance and ability to adapt. Novel approaches for testing and developing effective means of intervention, prevention, and modulation of aging incorporate means to minimize the occurrence and accumulation of molecular damage, and to strengthen the homeodynamics of the organism. Gene therapy, stem cell therapy, hormonal replenishment, nutritional supplementation, and other natural and synthetic molecules demonstrate varying degrees of promise and success as aging interventions. Another powerful strategy for achieving healthy aging and for preventing age-related diseases is that of mild stress-induced hormesis by physical, mental, and nutritional hormetins including exercise, polyphenols, flavonoids, and oils and fatty acids. A combination of different approaches for aging interventions aims to extend the health span and improve the quality of life.

Ageing occurs in spite of complex pathways of maintenance and repair. There is no "enemy within", which has the specific evolution-selected function to cause ageing and death. This understanding of ageing should transform our approach towards interventions from therapeutic "anti-ageing" to maintaining health. But what is health? Ideally, health is a state of complete physical and mental independence in activities of daily living. But in pragmatic terms, health is a state of adequate physical and mental independence in activities of daily living. In order to identify a set of measurable, evidence-based and demonstratable parameters of health, robustness and resilience at various levels, the concept of homeodynamic space can be a useful one. Age-related health problems for which there are no clear-cut causative agents, except the complex process of ageing, may be better tackled by focusing on health mechanisms and their maintenance, rather than disease management and treatment. Continuing the disease-oriented research approaches are economically, socially and psychologically unsustainable as compared with health-oriented and preventive strategies, such as hormesis. Supporting health-oriented research is the urgency of our time.

The science and study of the biological basis of aging, biogerontology, is now a well-established field with solid scientific base. A paradigm-shift in gerontology has occurred by realising the fact that biological aging occurs in spite of the presence of complex homeodynamic pathways of maintenance, repair and defence, and there is no “enemy within”. This viewpoint separates the modulation of aging from the treatment of one or more age-related diseases. A promising strategy in biogerontology is to slow down aging and to extend healthspan by hormetin-mediated hormesis. Physical, nutritional and mental hormetins, which initiate stress responses and strengthen the homeodynamics, are potentially effective aging modulators. As a biomedical issue, the biological process of aging underlies all major diseases, and while the optimal treatment of every disease is a social and moral necessity, preventing the onset of age-related diseases by intervening in the basic process of aging is the best approach for designing novel pharmaceutical interventions.

Aging is the progressive shrinkage of the homeodynamic space. A crucial component of the homeodynamic space is the stress response (SR), by virtue of which a living system senses disturbance and initiates a series of events for maintenance, repair, adaptation, remodeling and survival. Here we discuss the main intracellular SR pathways in human cells, and argue for the need to define and establish the immediate and delayed stress response profiles (SRP) during aging. Such SRP are required to be established at several age-points, which can be the molecular biomarkers of homeodynamic space and the health status of cells and organisms. SRP can also be useful for testing potential protectors and stimulators of homeodynamics, and can be a standard for monitoring the efficacy of potential pro-survival, health-promoting and aging-modulating conditions, food components and other compounds. An effective strategy, which makes use of SRP for achieving healthy aging and extending the healthspan, is that of strengthening the homeodynamics through repeated mild stress-induced hormesis by physical, biological and nutritional hormetins. Furthermore, SRP can also be the basis for defining health as a state of having adequate physical and mental independence of activities of daily living, by identifying a set of measurable parameters at the most fundamental level of biological organization.

Ageing can be understood at various levels, from evolutionary and biological levels to psychological and sociological levels. At the molecular biological level ageing is characterized by the stochastic occurrence and progressive accumulation of molecular damage. Failure of homeodynamics, increased molecular heterogeneity, altered cellular functioning and reduced stress tolerance are the determinants of health status, probability of diseases and the duration of survival. The inefficiency and imperfection of the maintenance and repair systems underlie the biological basis of ageing. Two major issues yet to be resolved in bigerontology are determining the physiological relevance of various types of molecular damage, and establishing the nature of healthy and unhealthy gene-protein networks. Gene therapy, stem cells, and modulation through functional foods, nutriceuticals, cosmeceuticals and other life style alterations are examples of ageing interventions. A promising healthy-ageing approach is that of hormesis by strengthening the homeodynamic ability of self-maintenance through transient and repetitive mild stress-inducing hormetins. Achieving the goal of extended health-span will depend on elucidating and exploiting successful and dynamic interactions among biological, psycho-social and environmental factors.

Introduction: Mild stress-induced hormesis is becoming increasingly attractive as an aging interventional strategy, and is leading to the discovery of hormesis-inducing compounds called homretins. This review gives the background, rationale and approaches for screening, testing and developing novel hormetins.Areas covered: Almost fifty years of modern biogerontolgical research has established a clear framework regarding the biological basis of aging and longevity, and it is now generally accepted that aging occurs in spite of the presence of complex pathways of maintenance, repair and defence, and there is no “enemy within”. This viewpoint makes modulation of aging different from the treatment of one or more age-related diseases. A promising strategy to slow down aging and prevent or delay the onset of age-related diseases is that of mild stress-induced hormesis by using hormetins. Physical, nutritional and mental hormetins, which initiate stress responses and stimulate maintenance and repair pathways, are potentially effective aging modulators. The rationale and a strategy for discovering novel hormetins as potential drugs for aging intervention are presented, by elucidating multiple stress responses of normal human cells. Establishing immediate and delayed stress response profiles, followed by cell type-specific functional assays, after exposure to natural or synthetic compounds and mixtures, is the first step in identifying prospective hormetin drugs. A recent example of a successful product development based in the ideas of hormesis and by following the strategy described here is a skin care cosmetic.Expert opinion: As a biomedical issue, the biological process of aging underlies several major diseases, and although the optimal treatment of every disease, irrespective of age, is a social and moral necessity, preventing the onset of age-related diseases by intervening in the basic process of aging is the best approach for achieving healthy aging and for extending the health-span.

Application of hormesis in aging research and interventions is becoming increasingly attractive and successful. The reason for this is the realization that mild stress-induced activation of one or more stress response (SR) pathways, and its consequent stimulation of repair mechanisms, is effective in reducing the age-related accumulation of molecular damage. For example, repeated heat stress-induced synthesis of heat shock proteins has been shown to have a variety of anti-aging effects on growth and other cellular and biochemical characteristics of normal human skin fibroblasts, keratinocytes and endothelial cells undergoing aging in vitro. Therefore, searching for potential hormetins - conditions and compounds eliciting SR-mediated hormesis - is drawing attention of not only the researchers but also the industry involved in developing healthcare products, including nutriceuticals, functional foods and cosmeceuticals. Here we present the example of a skin care cosmetic as one of the first successful product developments incorporating the ideas of hormesis. This was based on the studies to analyse the molecular effects of active ingredients extracted from the roots of the Chinese herb Sanchi (Panax notoginseng) on gene expression at the level of mRNAs and proteins in human skin cells. The results showed that the ginsenosides extracted from Sanchi induced the transcription of stress genes and increased the synthesis of stress proteins, especially the heat shock protein HSP1A1 or Hsp70, in normal human keratinocytes and dermal fibroblasts. Furthermore, this extract also has significant positive effects against facial wrinkles and other symptoms of facial skin aging as tested clinically, which may be due to its hormetic mode of action by stress-induced synthesis of chaperones involved in protein repair and removal of abnormal proteins. Acceptance of such a hormesis-based product by the wider public could be instrumental in the social recognition of the concept of hormesis as the beneficial effects of mild stress of choice, and will encourage the development of novel health care products with physical, nutritional and mental hormetins.