Hormetic mechanisms of anti-aging and rejuvenating effects of repeated mild heat stress on human fibroblasts in vitro

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 hormetic 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 11S 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 hormetic 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.     

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.     

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.     

Molecular damage in cancer: an argument for mTOR-driven aging

Despite common belief, accumulation of molecular damage does not play a key role in aging. Still, cancer (an age-related disease) is initiated by molecular damage. Cancer and aging share a lot in common including the activation of the TOR pathway. But the role of molecular damage distinguishes cancer and aging. Furthermore, an analysis of the role of both damage and aging in cancer argues against "a decline, caused by accumulation of molecular damage" as a cause of aging. I also discuss how random molecular damage, via rounds of multiplication and selection, brings about non-random hallmarks of cancer.     

Multiple stressors in Caenorhabditis elegans induce stress hormesis and extended longevity

We demonstrate here that the nematode Caenorhabditis elegans displays broad hormetic abilities. Hormesis is the induction of beneficial effects by exposure to low doses of otherwise harmful chemical or physical agents. Heat as well as pretreatment with hyperbaric oxygen or juglone (a chemical that generates reactive oxygen species) significantly increased subsequent resistance to the same challenge. Cross-tolerance between juglone and oxygen was also observed. The same heat or oxygen pretreatment regimens that induced subsequent stress resistance also increased life expectancy and maximum life span of populations undergoing normal aging. Pretreatment with ultraviolet or ionizing radiation did not promote subsequent resistance or increased longevity. In dose-response studies, induced thermotolerance paralleled the induced increase in life expectancy, which is consistent with a common origin.     

Hormetic use of stress in gerontological interventions requires a cautious approach

Hormesis as a general principle is conceivable only for factors that are present in the natural environment. For such factors, existence of an optimal level can be assumed, which would correspond to the current environmental level or some average of historic levels. Theoretic basis of some hormetic mechanisms has been discussed within the scope of stress response pathways. Impacts of multiple stressing agents may produce combined effects larger than those expected from isolated impacts i.e. act synergistically. Adding the effect of a damaging stress to another damaging stress would possibly augment the damage; but if two mild stresses have positive hormetic effects, their combination can have additive positive effects. Potential adverse effects of excessive doses of hormetic agents should be pointed out particularly for senile age or a state close to decompensation when minor stimuli might be damaging. In conclusion, a hormetic use of stress in gerontological interventions requires a cautious approach.     

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。     

Mitochondria and cardiovascular aging

Old age is a major risk factor for cardiovascular diseases. Several lines of evidence in experimental animal models have indicated the central role of mitochondria both in lifespan determination and in cardiovascular aging. In this article we review the evidence supporting the role of mitochondrial oxidative stress, mitochondrial damage and biogenesis as well as the crosstalk between mitochondria and cellular signaling in cardiac and vascular aging. Intrinsic cardiac aging in the murine model closely recapitulates age-related cardiac changes in humans (left ventricular hypertrophy, fibrosis and diastolic dysfunction), while the phenotype of vascular aging include endothelial dysfunction, reduced vascular elasticity, and chronic vascular inflammation. Both cardiac and vascular aging involve neurohormonal signaling (eg, renin-angiotensin, adrenergic, insulin-IGF1 signaling) and cell-autonomous mechanisms. The potential therapeutic strategies to improve mitochondrial function in aging and cardiovascular diseases are also discussed, with a focus on mitochondrial-targeted antioxidants, calorie restriction, calorie restriction mimetics, and exercise training.     

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.     

A high throughput screening assay for determination of chronological lifespan of yeast

A high throughput screening assay was developed based on the yeast chronological aging model and applied in evaluating several factors that mediate lifespan, including inoculum size, cellular state in nutrient-rich medium, and calorie level. Using our assay, we confirmed the previously reported genetic mimics of calorie restriction, including deletion of TOR1, SCH9 or RAS2. In contrast, deletion of SIR2 had longevity effect but seemed to produce only small beneficial effect on the response to calorie restriction. Overall, this new high throughput screening assay may facilitate identification of calorie restriction mimetics with a rapid and simple protocol, uncomplicated data analysis, and high sensitivity. In addition, the assay also provides quantifiable data including lag-time, growth rate, doubling time, and survival percentage.     

Genetic and molecular characterization of CLK-1/mCLK1, a conserved determinant of the rate of aging

The clk-1 gene of the nematode Caenorhabditis elegans encodes an evolutionarily conserved enzyme that is necessary for ubiquinone biosynthesis. Loss-of-function mutations in clk-1, as well as in its mouse orthologue mclk1, increase lifespan in both organisms. In nematodes, clk-1 extends lifespan by a mechanism that is distinct from the insulin signaling-like pathway but might have similarities to calorie restriction. The evolutionary conservation of the effect of clk-1/mclk1 on lifespan suggests that the gene affects a fundamental mechanism of aging. The clk-1/mclk1 system could allow for the understanding of this mechanism by combining genetic and molecular investigations in worms with studies in mice, where age-dependent disease processes relevant to human health can be modeled.     

Protein oxidation associated with aging is reduced by dietary restriction of protein or calories.

The accumulation of unrepaired oxidative damage products may be a major factor in cellular aging. Both oxidative lesions in DNA and oxidatively damaged proteins have been shown to accumulate during aging. The accumulation of oxidized proteins in Fischer 344 rats was compared for animals consuming protein-restricted and calorically restricted diets--both of which have been shown to extend lifespan. Rats were fed diets restricted in either protein (5% or 10% of the diet as compared with the normal 20% casein), or calories (25% or 40% less than normal), or total diet (40% less than normal). In addition, some of the rats fed a diet providing 5% or 20% protein were irradiated twice weekly (125 rads per exposure; 1 rad = 0.01 Gy). The level of oxidative damage to proteins (protein carbonyls) was determined in rats sacrificed at various times. The oxidative damage to proteins increased with aging and with radiation. Either protein or calorie restriction markedly inhibited the accumulation of oxidatively damaged proteins. Protein restriction reduced the accumulation of oxidatively damaged proteins during the oxidative stress of chronic irradiation.     

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.     

Methionine sulfoxide reductase regulation of yeast lifespan reveals reactive oxygen species-dependent and -independent components of aging

Aging is thought to be caused by the accumulation of damage, primarily from oxidative modifications of cellular components by reactive oxygen species (ROS). Here we used yeast methionine sulfoxide reductases MsrA and MsrB to address this hypothesis. In the presence of oxygen, these antioxidants could increase yeast lifespan and did so independent of the lifespan extension offered by caloric restriction. However, under ROS-deficient, strictly anaerobic conditions, yeast lifespan was shorter, not affected by MsrA or MsrB, and further reduced by caloric restriction. In addition, we identified changes in the global gene expression associated with aging in yeast, and they did not include oxidative stress genes. Our findings suggest how the interplay between ROS, antioxidants, and efficiency of energy production regulates the lifespan. The data also suggest a model wherein factors implicated in aging (for example, ROS) may influence the lifespan yet not be the cause of aging.     

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.     

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.