Stress-response hormesis and aging: "that which does not kill us makes us stronger"

Hormesis refers to the beneficial effects of a treatment that at a higher intensity is harmful. In one form of hormesis, sublethal exposure to stressors induces a response that results in stress resistance. The principle of stress-response hormesis is increasingly finding application in studies of aging, where hormetic increases in life span have been seen in several animal models.     

Heat-induced hormesis in longevity as correlated response to thermal-stress selection in Drosophila buzzatii

Hormesis in longevity is a widespread phenomenon across the animal kingdom. It takes place when longevity is improved as an indirect effect of mild stress. We explored some possible evolutionary trajectories of hormesis in longevity in artificially selected lines of Drosophila buzzatii. The lines were bi-directionally selected for either knockdown resistance to heat stress (K⁻, K⁺) or chill-coma recovery (CCR⁻, CCR⁺, with the + and – signs indicating selection for decreased and increased tolerance, respectively). All K and CCR lines successfully diverged due to thermal-stress selection. The heat-inducible hormesis in longevity was substantial in both K⁻ and CCR⁻ females, whereas no hormesis was apparent for females in CCR⁺, K⁺ and control lines. Among-line differences in longevity of non-heat-treated females disappeared after a heat-hardening treatment. Hormesis effects on the demographic senescence rate were sex-specific and consistently higher in the shorter-lived than in the longer-lived lines. Hormesis is an adaptive response, as its magnitude can evolutionary increase with stress-sensitivity.     

Sex hormonal regulation and hormesis in aging and longevity: role of vitagenes

Aging process is accompanied by hormonal changes characterized by an imbalance between catabolic hormones, such as cortisol and thyroid hormones which remain stable and hormones with anabolic effects (testosterone, insulin like growth factor-1 (IGF-1) and dehydroepiandrosterone sulphate (DHEAS), that decrease with age. Deficiencies in multiple anabolic hormones have been shown to predict health status and longevity in older persons.Unlike female menopause, which is accompanied by an abrupt and permanent cessation of ovarian function (both folliculogenesis and estradiol production), male aging does not result in either cessation of testosterone production nor infertility. Although the circulating serum testosterone concentration does decline with aging, in most men this decrease is small, resulting in levels that are generally within the normal range. Hormone therapy (HT) trials have caused both apprehension and confusion about the overall risks and benefits associated with HT treatment. Stress-response hormesis from a molecular genetic perspective corresponds to the induction by stressors of an adaptive, defensive response, particularly through alteration of gene expression. Increased longevity can be associated with greater resistance to a range of stressors. During aging, a gradual decline in potency of the heat shock response occur and this may prevent repair of protein damage. Conversely, thermal stress or pharmacological agents capable of inducing stress responses, by promoting increased expression of heat-shock proteins, confer protection against denaturation of proteins and restoration of proteome function. If induction of stress resistance increases life span and hormesis induces stress resistance, hormesis most likely result in increased life span. Hormesis describes an adaptive response to continuous cellular stresses, representing a phenomenon where exposure to a mild stressor confers resistance to subsequent, otherwise harmful, conditions of increased stress. This biphasic dose–response relationship, displaying low-dose stimulation and a high-dose inhibition, as adaptive response to detrimental lifestyle factors determines the extent of protection from progression to metabolic diseases such as diabetes and more in general to hormonal dysregulation and age-related pathologies. Integrated responses exist to detect and control diverse forms of stress. This is accomplished by a complex network of the so-called longevity assurance processes, which are composed of several genes termed vitagenes. Vitagenes encode for heat shock proteins (Hsps), thioredoxin and sirtuin protein systems. Nutritional antioxidants, have recently been demonstrated to be neuroprotective through the activation of hormetic pathways under control of Vitagene protein network. Here we focus on possible signaling mechanisms involved in the activation of vitagenes resulting in enhanced defense against functional defects leading to degeneration and cell death with consequent impact on longevity processes.     

陆地生态系统中低剂量毒物刺激作用及拟合模型研究进展

低剂量毒物刺激作用(hormesis)是在毒物剂量/效应关系中低剂量毒物可能表现出对生物生长的一种刺激作用.大量的实验数据表明毒物刺激作用发生的剂量低于未观察到毒性效应的剂量(NOAEL),毒物刺激作用的最大刺激效应一般是对照的130%～160%,是一种客观存在的剂量/反应现象.就毒物刺激作用的概念、机理、毒物刺激作用剂量/反应曲线的一些定量特点和模型的拟合等方面进行了综述,并用实例说明毒物刺激作用模型的最新拟合方法的应用,最后提出了目前毒物刺激作用研究中存在的问题及今后的研究方向.     

Oxidative stress adaptation with acute,chronic, and repeated stress

Oxidative stress adaptation, or hormesis, is an important mechanism by which cells and organisms respond to, and cope with, environmental and physiological shifts in the level of oxidative stress. Most studies of oxidative stress adaption have been limited to adaptation induced by acute stress. In contrast, many if not most environmental and physiological stresses are either repeated or chronic. In this study we find that both cultured mammalian cells and the fruit fly Drosophila melanogaster are capable of adapting to chronic or repeated stress by upregulating protective systems, such as their proteasomal proteolytic capacity to remove oxidized proteins. Repeated stress adaptation resulted in significant extension of adaptive responses. Repeated stresses must occur at sufficiently long intervals, however (12-h or more for MEF cells and 7 days or more for flies), for adaptation to be successful, and the levels of both repeated and chronic stress must be lower than is optimal for adaptation to acute stress. Regrettably, regimens of adaptation to both repeated and chronic stress that were successful for short-term survival in Drosophila nevertheless also caused significant reductions in life span for the flies. Thus, although both repeated and chronic stress can be tolerated, they may result in a shorter life.     

Transcription‐blocking DNA damage in aging: a mechanism for hormesis

Recent evidence from studies on DNA repair systems that are implicated in accelerated aging syndromes, have revealed a mechanism through which low levels of persistent damage might exert beneficial effects for both cancer prevention and longevity assurance. Beneficial effects of adaptive responses to low doses of insults that in higher concentrations show adverse effects are generally referred to as hormesis. There are numerous examples of hormetic effects ranging from mild stresses of irradiation to heat stress, hypergravity, pro‐oxidants, or food restriction. Although the notion of hormesis is supported by many observations in various organisms, at least two major caveats have thus far prevented the application of hormesis for disease prevention in humans. First, the very nature of hormesis using toxins as a treatment regimen harbors the inherent danger of detrimental consequences. Second, the molecular mechanisms through which insults might exert beneficial effects have thus far remained elusive. Here, I discuss a mechanistic basis for hormesis and its implications for cancer prevention and healthy aging.     

Hormesis and ecological risk assessment: Fact or fantasy?

Hormesis is a widespread phenomenon across occurring many taxa and chemicals, and, at the single species level, issues regarding the application of hormesis to human health and ecological risk assessment are similar. However, interpreting the significance of hormesis for even a single species in an ecological risk assessment can be complicated by competition with other species, predation effects, etc. In addition, ecological risk assessments may involve communities of hundreds or thousands of species as well as a range of ecological processes. Applying hormetic adjustments to threshold effect levels for chemicals derived from sensitivity distributions for a large number of species is impractical. For ecological risks, chemical stressors are frequently of lessor concern than physical stressors (e.g., habitat alteration) or biological stressors (e.g., introduced species), but the relevance of hormesis to non‐chemical stressors is unclear. Although ecological theories such as the intermediate disturbance hypothesis offer some intriguing similarities between chemical hormesis and hormetic‐like responses resulting from physical disturbances, mechanistic explanations are lacking. While further exploration of the relevance of hormesis to ecological risk assessment is desirable, it is unlikely that hormesis is a critical factor in most ecological risk assessments, given the magnitude of other uncertainties inherent in the process.     

Extending life span by increasing oxidative stress

Various nutritional, behavioral, and pharmacological interventions have been previously shown to extend life span in diverse model organisms, including Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, mice, and rats, as well as possibly monkeys and humans. This review aims to summarize published evidence that several longevity-promoting interventions may converge by causing an activation of mitochondrial oxygen consumption to promote increased formation of reactive oxygen species (ROS). These serve as molecular signals to exert downstream effects to ultimately induce endogenous defense mechanisms culminating in increased stress resistance and longevity, an adaptive response more specifically named mitochondrial hormesis or mitohormesis. Consistently, we here summarize findings that antioxidant supplements that prevent these ROS signals interfere with the health-promoting and life-span-extending capabilities of calorie restriction and physical exercise. Taken together and consistent with ample published evidence, the findings summarized here question Harman's Free Radical Theory of Aging and rather suggest that ROS act as essential signaling molecules to promote metabolic health and longevity.     

Application of in silico and in vitro methods in the development of adverse outcome pathway constructs in wildlife

There is a long history of using both in silico and in vitro methods to predict adverse effects in humans and environmental species where toxicity data are lacking. Currently, there is a great deal of interest in applying these methods to the development of so-called ‘adverse outcome pathway’ (AOP) constructs. The AOP approach provides a framework for organizing information at the chemical and biological level, allowing evidence from both in silico and in vitro studies to be rationally combined to fill gaps in knowledge concerning toxicological events. Fundamental to this new paradigm is a greater understanding of the mechanisms of toxicity and, in particular, where these mechanisms may be conserved across taxa, such as between model animals and related wild species. This presents an opportunity to make predictions across diverse species, where empirical data are unlikely to become available as is the case for most species of wildlife.     

Age-dependent oxidative stress: toward an irreversible failure in endothelial maintenance

In order to maintain cellular homeostasis against endogenous and exogenous aggressions, different cellular mechanisms of defence, maintenance and repair are continuously activated throughout life. Hormesis, a concept based on the fact that mild stresses protect cells against subsequent stresses, amplifies the efficacy of the cellular mechanisms of defence and repair. Ageing, senescence and ultimately death, result from the exhaustion of these mechanisms maintaining cellular functions. One of the major sources of vascular endothelial damage is oxidative stress. The age-dependent shift in the redox environment towards pro-oxidation contributes to a progressive compensatory remodelling of the endothelium, an accumulation of damages, and its dysfunction, the premises for atherosclerosis. We propose that in agreement with the concept of hormesis, a moderate exposure during endothelial maturation to mild physiological oxidative stressors determines -vascular longevity.     

Mechanisms of Nrf2 Protection in Astrocytes as Identified by Quantitative Proteomics and siRNA Screening

The Nrf2 (NF-E2 related factor 2)-ARE (antioxidant response element) pathway controls a powerful array of endogenous cellular antioxidant systems and is an important pathway in the detoxification of reactive oxygen species (ROS) in the brain. Using a combination of quantitative proteomics and siRNA screening, we have identified novel protective mechanisms of the Nrf2-ARE pathway against oxidative stress in astrocytes. Studies from our lab and others have shown Nrf2 overexpression protects astrocytes from oxidative stress. However, the exact mechanisms by which Nrf2 elicits these effects are unknown. In this study, we show that induction of Nrf2 reduces levels of reactive oxygen species (ROS) produced by various oxidative stressors and results in robust cytoprotection. To identify the enzymes responsible for these effects, we used stable isotope labeling by amino acids in cell culture (SILAC) and quantitative shotgun proteomics to identify 72 Nrf2-regulated proteins in astrocytes. We hypothesized a subset of these proteins might play a critical role in Nrf2 protection. In order to identify these critical proteins, we used bioinformatics to narrow our target list of proteins and then systematically screened each candidate with siRNA to assess the role of each in Nrf2 protection. We screened each target against H₂O₂, tert-butyl hydroperoxide, and 4-hydroxynonenal and subsequently identified three enzymes–catalase, prostaglandin reductase-1, and peroxiredoxin-6–that are critical for Nrf2-mediated protection in astrocytes.     

A Proposed Working Definition for the Novel Concept of Neurobehavioral Hormesis

It is proposed that a novel concept, neurobehavioral hormesis, be considered for integration into the field of toxicology. Hormesis results in a non-linear dose response where low dose exposures to toxicants cause beneficial effects, and detrimental effects at higher doses. Hormesis has not been systematically incorporated into traditional risk assessment methodologies, yet there is recent evidence that this pattern of results is relatively prevalent. In this paper, hormesis is applied to neurobehavioral toxicology, and an operational definition is proposed for application to putative examples of neurobehavioral hormesis. The two primary criteria used for the operational definition are: (1) performance is enhanced with low dose exposure and denigrated at higher doses, and (2) the change in behavior persists following a recovery period. In recent research from our laboratory it was reported that rats exposed to JP-8 jet fuel vapor demonstrated such a pattern of neurobehavioral performance on tests of learning and memory. Specifically, animals with long-term exposure to low concentrations of jet fuel demonstrated enhanced performance on specific operant tasks as compared both to controls and to animals exposed to higher concentrations. The effect was most apparent during complex versus simple operant tests, and was observed months following the last exposure to jet fuel. The effects meet both criteria for the proposed working definition of neurobehavioral hormesis, and thus provide evidence of the validity for considering neurobehavioral hormesis in published and future research, and suggests a more systematic investigation of existing literature may be warranted. Also, it provides additional support for the overall proposal to include hormetic effects in formal risk assessment paradigms.     

Influence of environmental factors in early ontogenesis on aging and life span

A possible dependence of aging and life span in man on specific features of early ontogenesis has been analyzed on the basis of published and author's data. It was shown that the life span depended on climatic factors acting during prenatal and/or early postnatal period. When analyzing a sample of 101,634 humans died in Kiev in 1990-2000, a reliable relationship was established between the age of death and month of birth. The lowest and highest death ages were observed in persons born in April-June and in the end of the year, respectively. The lowest and highest average monthly values of death age differed in men and women by 2.6 and 2.3 years, respectively. In persons survived for more than 60 years, a "birthday" effect was demonstrated: dependence of the mortality level on the month of individual annual cycle was the highest in its first and last month. It has been proposed that this effect is related imprinting of the "birth stress" in the structure of biological rhythms, which may lead to periodic changes in viability during the individual annual cycle. The mechanisms underlying long-term effects of stresses in early ontogenesis have been studied on Drosophila melanogaster. X-irradiation of eggs at 0.50 and 0.75 Gy led to an increased level of survival of imago. The described radiation hormesis was accompanied by an increased resistance of DNA to S1-nuclease, which could be due to a long-term activation of the repair system in irradiated insects. The results obtained suggest that long-term changes in the range of gene expression induced by mild stresses in early ontogenesis can be a key mechanism of early "programming" of the potential of longevity and hormesis for life span.     

Calories do not explain extension of life span by dietary restriction in Drosophila

Dietary restriction (DR) extends life span in diverse organisms, including mammals, and common mechanisms may be at work. DR is often known as calorie restriction, because it has been suggested that reduction of calories, rather than of particular nutrients in the diet, mediates extension of life span in rodents. We here demonstrate that extension of life span by DR in Drosophila is not attributable to the reduction in calorie intake. Reduction of either dietary yeast or sugar can reduce mortality and extend life span, but by an amount that is unrelated to the calorie content of the food, and with yeast having a much greater effect per calorie than does sugar. Calorie intake is therefore not the key factor in the reduction of mortality rate by DR in this species.     

Caloric restriction-induced life extension of rats and mice: A critique of proposed mechanisms

In 1935, Clive McCay and colleagues reported that decreasing the food intake of rats extends their life. This finding has been confirmed many times using rat and mouse models. The responsible dietary factor in rats is the reduced intake of energy; thus, this phenomenon is frequently referred to as caloric restriction. Although many hypotheses have been proposed during the past 74 years regarding the underlying mechanism, it is still not known. It is proposed that this lack of progress relates to the fact that most of these hypotheses have been based on a single underlying mechanism and that this is too narrow a focus. Rather, a broad framework is needed. Hormesis has been suggested as providing such a framework. Although it is likely that hormesis is involved in the actions of caloric restriction, it also is probably too narrowly focused. Based on currently available data, a provisional broad framework is presented depicting the complex of mechanisms that likely underlie the life-extending and other anti-aging actions of caloric restriction.     

When Stress Predicts a Shrinking Gene Pool,Trading Early Reproduction for Longevity Can Increase Fitness,Even with Lower Fecundity

Background

Stresses like dietary restriction or various toxins increase lifespan in taxa as diverse as yeast, Caenorhabditis elegans, Drosophila and rats, by triggering physiological responses that also tend to delay reproduction. Food odors can reverse the effects of dietary restriction, showing that key mechanisms respond to information, not just resources. Such environmental cues can predict population trends, not just individual prospects for survival and reproduction. When population size is increasing, each offspring produced earlier makes a larger proportional contribution to the gene pool, but the reverse is true when population size is declining.

Principal Findings

We show mathematically that natural selection can favor facultative delay in reproduction when environmental cues predict a decrease in total population size, even if lifetime fecundity decreases with delay. We also show that increased reproduction from waiting for better conditions does not increase fitness (proportional representation) when the whole population benefits similarly.

Conclusions

We conclude that the beneficial effects of stress on longevity (hormesis) in diverse taxa are a side-effect of delaying reproduction in response to environmental cues that population size is likely to decrease. The reversal by food odors of the effects of dietary restriction can be explained as a response to information that population size is less likely to decrease, reducing the chance that delaying reproduction will increase fitness.     

Hormetic Effect of Berberine Attenuates the Anticancer Activity of Chemotherapeutic Agents

Hormesis is a phenomenon of biphasic dose response characterized by exhibiting stimulatory or beneficial effects at low doses and inhibitory or toxic effects at high doses. Increasing numbers of chemicals of various types have been shown to induce apparent hormetic effect on cancer cells. However, the underlying significance and mechanisms remain to be elucidated. Berberine, one of the major active components of Rhizoma coptidis, has been manifested with notable anticancer activities. This study aims to investigate the hormetic effect of berberine and its influence on the anticancer activities of chemotherapeutic agents. Our results demonstrated that berberine at low dose range (1.25 ~ 5 μM) promoted cell proliferation to 112% ~170% of the untreated control in various cancer cells, while berberine at high dose rage (10 ~ 80 μM) inhibited cell proliferation. Further, we observed that co-treatment with low dose berberine could significantly attenuate the anticancer activity of chemotherapeutic agents, including fluorouracil (5-FU), camptothecin (CPT), and paclitaxel (TAX). The hormetic effect and thereby the attenuated anticancer activity of chemotherapeutic drugs by berberine may attributable to the activated protective stress response in cancer cells triggered by berberine, as evidenced by up-regulated MAPK/ERK1/2 and PI3K/AKT signaling pathways. These results provided important information to understand the potential side effects of hormesis, and suggested cautious application of natural compounds and relevant herbs in adjuvant treatment of cancer.