Aging intervention, prevention, and therapy through hormesis

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.     

Hormetic action of mild heat stress decreases the inducibility of protein oxidation and glycoxidation in human fibroblasts

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. This revised version was published online in July 2006 with corrections to the Cover Date.     

Repeat mild heat shock increases dermal fibroblast activity and collagen production

Repeat mild heat shock (RMHS) has been shown to have anti-aging effects on cellular and biological processes within human dermal fibroblasts. We have investigated the potential of an abridged mild heat shock regime to impact upon the functional properties of human dermal fibroblasts derived from three donors (male, 12 years; female, 22 years; female, 65 years). For each donor mild heat shock increased the rate of contraction of fibroblast-containing collagen gels and increased the de novo synthesis of collagen. Thus, hormetic mechanisms are proposed to provide functional anti-aging benefits to skin cells.     

Hormesis and intervention of aging

The concept of hormesis has recently been introduced into the gerontological field. The tenet of this concept embraces the notion that the aging process has been evolved through the organism's physiologic adaptation to the ever-changing stressful environmental conditions for survival. The hormetic phenomenon is exhibited by a biphasic bell-shape curve response that is the characteristic biological reaction, rather than a linear response. The beneficial effect of hormesis is due to a mild and low stress inductive to stimulated response, while high stress resulting in inhibitory or harmful results.
The adaptive response to a mild stress induces the organism's ability to maximize the metabolic efficiency to cope with a new challenging environment. Evidence strongly suggests that most of stresses under sub-lethal levels can in fact to be beneficial for the survival of the organism, as exhibited by a growth stimulation of bacteria treated by sub-lethal pesticides or the life-span extension of mice by a low dose of irradiation. The anti-aging action of calorie restriction stimulated by the mild nutritional deprivation considered being another good example of this hormetic phenomenon. For the future intervention of the aging and age-related diseases based on hormesis concept, one could conceive experimental models in which the endogenous defense systems and certain immune components may be strengthened by selective stimulatory measures. In this review, discussion is presented for further development of this hormetic concept on the premise as the potential anti-aging strategies.     

毒物兴奋效应与抗衰老研究

某些毒物在低剂量时对生物体的刺激导致反馈改善的现象,简称“毒物兴奋效应”。是一个近年发展兴起的生物细胞及生物体抗应激、抗衰老研究的新领域,其分子机制正在被逐步阐明。某些轻微的生物应激如：热应激、重力应激、运动应激、损伤应激及限食应激等,也能在生物体内产生一连串的级联放大效应,进而诱发多种协同的和多效的分子作用,从而对机体健康产生反馈保护的效果。由于导致机体防御能力的增加和大分子损伤的减少,毒物兴奋效应在生命平衡系统中起到了重要的“疫苗样”作用。同时,毒物兴奋效应理论也为生物体代谢及平衡的波动范围,机体的抗应激能力,细胞的适应性和存活率提供了更为广泛合理的科学解释。换言之,毒物兴奋效应减少了某些环境伤害时“人仆平衡态区域”的压缩,而这种平衡态区域的压缩就是引起衰老、疾病甚至死亡的最基本原因。因此,健康老龄化也许可以通过这种温和的周期性毒物兴奋效应刺激来实现。     

Life extension and the position of the hormetic zone depends on sex and genetic background in <Emphasis Type="Italic">Drosophila melanogaster</Emphasis>

Hormesis, the beneficial effect of a mild stress, has been proposed as a means to prolong the period of healthy ageing as it can increase the average lifespan of a cohort. However, if we want to use hormesis therapeutically it is important that the treatment is beneficial on the individual level and not just on average at the population level. Long lived lines have been shown not to benefit from a, in other lines, hormesis inducing heat treatment in Drosophila melanogaster, D. buzzatii and mice. Also in many experiments hormesis has been reported to occur in one sex only, usually males but not in females. Here we investigated the interaction between the hormetic response and genetic background, sex and duration of a mild heat stress in D. melanogaster, using three replicate lines that have been selected for increased longevity and their respective control lines. We found that genetic background influences the position of the hormetic zone. The implication of this result could be that in a genetically diverse populations a treatment that is life prolonging in one individual could be life shortening in other individuals. However, we did find a hormetic response in all combinations of line and sex in at least one of the experiments which suggests that if it is possible to identify the optimal hormetic dose individually hormesis might become a therapeutic treatment.     

Clinical anti-aging hormetic strategies

Hormesis is a term describing the beneficial effects of mild and repeated stimulation or stress, which ultimately bolsters defences against deleterious processes. Although hormetic influences are clearly encountered at the cellular and molecular level, little is known about the effects of hormesis at a clinical level. This paper examines the suggestion that mild stimulation or appropriately timed challenges may be used clinically in order to influence the impact of age-related disease and dysfunction. Examples of stimulation or challenges that may exhibit hormetic effects include dietary restriction, physical and mental exercise, and even social and spiritual stimulation. Dietary restriction places the organism under nutritional stress, stimulating several biochemical repair pathways that may counteract certain age-related changes. Physical and mental challenges, if appropriately timed and sufficiently varied, are directed at increasing the complexity and integration of interacting muscular, cardiovascular, and neural stimuli. Social and spiritual stimulation aimed at reversing age-related loss of dynamical complexity acts upon even higher levels to ensure a reduced risk of social problems in aging.     

Hormetic effects of repeated exposures to cold at young age on longevity,aging and resistance to heat or cold shocks in <Emphasis Type="Italic">Drosophila melanogaster</Emphasis>

Exposing young flies to hypergravity has hormetic effects on aging, longevity and resistance to heat stress. The present experiments tested whether cold shocks at young age could also have hormetic effects. Flies were cold-shocked at 0°C daily for 60 min during two periods of 5 days separated by 2 days, starting at 5 days of age. This cold stress increased longevity, resistance to a lethal heat stress or to cold up to 6 weeks of age, resistance to a non-lethal heat stress at middle age, and delayed behavioral aging. Cold and hypergravity exposure at young age have thus similar effects, excepting on resistance to cold stress, which is not increased after exposure to hypergravity. Mild heat stress has also been shown to slightly increase longevity and resistance to a lethal heat stress, but not to delay behavioral aging. Since there are thus at least two mild stresses with large hormetic effects at old age in flies, i.e. cold and hypergravity, hormetic effects in flies are not stress-specific. Therefore, it could be hypothetized that hormetic effects of mild stress on aging and longevity are a general phenomenon and that they could also be observed in other species such as rodents.     

Hormesis and aging in Caenorhabditis elegans

Hormesis has emerged as an important manipulation for the study of aging. Although hormesis is manifested in manifold combinations of stress and model organism, the mechanisms of hormesis are only partly understood. The increased stress resistance and extended survival caused by hormesis can be manipulated to further our understanding of the roles of intrinsic and induced stress resistance in aging. Genes of the dauer/insulin/insulin-like signaling (IIS) pathway have well-established roles in aging in Caenorhabditis elegans. Here, we discuss the role of some of those genes in the induced stress resistance and induced life extension attributable to hormesis. Mutations in three genes (daf-16, daf-18, and daf-12) block hormetically induced life extension. However, of these three, only daf-18 appears to be required for a full induction of thermotolerance induced by hormesis, illustrating possible separation of the genetic requirements for stress resistance and life extension. Mutations in three other genes of this pathway (daf-3, daf-5, and age-1) do not block induced life extension or induced thermotolerance; daf-5 mutants may be unusually sensitive to hormetic conditions.     

Modulating cellular aging in vitro: hormetic effects of repeated mild heat stress on protein oxidation and glycation

Intracellular and extracellular proteins are subject to a variety of spontaneous non-enzymatic modifications which affect their structure, function and stability. Protein oxidation and glycation are tightly linked and are implicated in the development of many pathological consequences of aging. Although multiple endogenous pathways in the cell can prevent the formation of oxidized and glycated proteins, and repair and degrade abnormal proteins, such abnormal proteins do accumulate during aging. The heat shock response involving the family of stress-proteins or the so-called heat shock proteins (HSP), represents the quickest and highly conserved response to proteotoxic insults. Since repeated mild heat stress is able to prevent the onset of various age-related changes during cellular aging in vitro, we suggest that treatments which increase HSP expression should reduce the extent of accumulation of abnormal proteins during aging. Such modulation of aging is an example of hormesis, which is characterized by the beneficial effects resulting from the cellular responses to mild repeated stress.     

Mild heat treatments induce long-term changes in metabolites associated with energy metabolism in <Emphasis Type="Italic">Drosophila melanogaster</Emphasis>

Heat-induced hormesis, the beneficial effect of mild heat-induced stress, increases the average lifespan of many organisms. Yet little is known about the mechanisms underlying this effect. We used nuclear magnetic resonance spectroscopy to investigate the long-term effects of repeated mild heat treatments on the metabolome of male Drosophila melanogaster. 10 days after the heat treatment, metabolic aging appears to be slowed down, and a treatment response with 40 % higher levels of alanine and lactate and lower levels of aspartate and glutamate were measured. All treatment effects had disappeared 16 days later. Metabolic reprogramming has been associated with the life extending effects of dietary restriction. The metabolite changes induced by the hormetic treatment suggest that the positive effects might not be limited to the repair pathways induced, but that there also is a change in energy metabolism. A possible direct link between changes in energy metabolism and heat induced increase in Hsp70 expression is discussed.     

Multiple mild heat-shocks decrease the Gompertz component of mortality in Caenorhabditis elegans

Exposure to mild heat-stress (heat-shock) can significantly increase the life expectancy of the nematode Caenorhabditis elegans. A single heat-shock early in life extends longevity by 20% or more and affects life-long mortality by decreasing initial mortality only; the rate of increase in subsequent mortality (Gompertz component) is unchanged. Repeated mild heat-shocks throughout life have a larger effect on life span than does a single heat-shock early in life. Here, we ask how multiple heat-shocks affect the mortality trajectory in nematodes and find increases of life expectancy of close to 50% and of maximum longevity as well. We examined mortality using large numbers of animals and found that multiple heat-shocks not only decrease initial mortality, but also slow the Gompertz rate of increase in mortality. Thus, multiple heat-shocks have anti-aging hormetic effects and represent an effective approach for modulating aging.     

Oxidative stress,antioxidants, hormesis and calorie restriction: The current perspective in the biology of aging

Aging, in a large measure, has long been defined as the resultant of oxidative stress acting on the cells. The cellular machinery eventually malfunctions at the basic level by the damage from the processes of oxidation and the system starts slowing down because of intrinsic eroding. To understand the initial destruction at the cellular level spreading outward to affect tissues, organs and the organism, the relationship between molecular damage and oxidative stress is required to understand. Retarding the aging process is a matter of cumulatively decreasing the rate of oxidative damage to the cellular machinery. Along with the genetic reasons, the decrease of oxidative stress is somehow a matter of lifestyle and importantly of diet. In the current review, the theories of aging and the understanding of various levels of molecular damage by oxidative stress have been emphasized. A broader understanding of mechanisms of aging have been elaborated in terms of effects of oxidative at molecular, mitochondrial, cellular and organ levels. The antioxidants supplementation, hormesis and calorie restriction as the prominent anti-aging strategies have also been discussed. The relevance and the efficacy of the antiaging strategies at system level have also been presented.     

Elevated extension of longevity by cyclically heat stressing a set of recombinant inbred lines of <Emphasis Type="Italic">Drosophila melanogaster</Emphasis> throughout their adult life

An extremely high (about 100 %) increase in longevity is reported for a subset of recombinant inbred lines (RILs) of Drosophila melanogaster subjected to a cyclic heat stress throughout the adult life. Previous work showed that both longevity and heat sensitivity highly differed among RILs. The novel heat stress treatment used in this study consisted of 5 min at 38 °C applicated approximately every 125 min throughout the adult life starting at the age of 2 days. In spite of the exceptionally high increase in longevity in a set of RILs, the same heat stress treatment reduced rather than increased longevity in other RILs, suggesting that heat-induced hormesis is dependent on the genotype and/or the genetic background. Further, one quantitative trait locus (QTL) was identified for heat-induced hormesis on chromosome 2 (bands 28A1-34D2) in one RIL panel (RIL-D48) but it was not significant in its reciprocal panel (RIL-SH2). The level of heat-induced hormesis showed a sexual dimorphism, with a higher number of lines exhibiting higher hormesis effects in males than in females. The new heat stress treatment in this study suggests that longevity can be further extended than previously suggested by applying a cyclic and mild stress throughout the life, depending on the genotype.     

Lifespan extension of Caenorhabditis elegans following repeated mild hormetic heat treatments

Mild hormetic heat treatments early in life can significantly increase the lifespan of the nematode C. elegans. We have examined the effects of heat treatments at different ages and show that treatments early in life cause the largest increases in lifespan. We also find that repeated mild heat treatments throughout life have a larger effect on lifespan compared to a single mild heat treatment early in life. We hypothesize that the magnitude of the hormetic effect is related to the levels of heat shock protein expression. Following heat treatment young worms show a dramatic increase in the levels of the small heat shock protein HSP-16 whereas old worms are a 100-fold less responsive. The levels of the heat shock proteins HSP-4 and HSP-16 correlate well with the effects on lifespan by the hormetic treatments.     

Hormesis does not make sense except in the light of TOR-driven aging

Weak stresses (including weak oxidative stress, cytostatic agents, heat shock, hypoxia, calorie restriction) may extend lifespan. Known as hormesis, this is the most controversial notion in gerontology. For one, it is believed that aging is caused by accumulation of molecular damage. If so, hormetic stresses (by causing damage) must shorten lifespan. To solve the paradox, it was suggested that, by activating repair, hormetic stresses eventually decrease damage. Similarly, Baron Munchausen escaped from a swamp by pulling himself up by his own hair. Instead, I discuss that aging is not caused by accumulation of molecular damage. Although molecular damage accumulates, organisms do not live long enough to age from this accumulation. Instead, aging is driven by overactivated signal-transduction pathways including the TOR (Target of Rapamycin) pathway. A diverse group of hormetic conditions can be divided into two groups. "Hormesis A" inhibits the TOR pathway. "Hormesis B" increases aging-tolerance, defined as the ability to survive catastrophic complications of aging. Hormesis A includes calorie restriction, resveratrol, rapamycin, p53-inducing agents and, in part, physical exercise, heat shock and hypoxia. Hormesis B includes ischemic preconditioning and, in part, physical exercise, heat shock, hypoxia and medical interventions.