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.     

Epigenetic epidemiology: the rebirth of soft inheritance

Non-communicable diseases (NCDs), such as cardiovascular disease and type 2 diabetes, constitute the main cause of death worldwide. Eighty percent of these deaths occur in low- and middle-income countries, especially as these countries undergo socio-economic improvement following reductions in the burden of infectious disease. The World Health Organization predicts a substantial increase in the incidence of NCDs over the next decade globally. NCDs are generally preventable, but current approaches are clearly inadequate. New initiatives are needed to implement such prevention, and there needs to be greater recognition that early-life interventions are likely to be the most efficacious. Devising appropriate prevention strategies necessitates an understanding of how the developmental environment influences risk. Progress in this field has been slow due to an excessive emphasis on fixed genomic variations (hard inheritance) as the major determinants of disease susceptibility. However, new evidence demonstrates the much greater importance of early-life developmental factors, involving epigenetic processes and 'soft' inheritance in modulating an individual's vulnerability to NCD. This also offers opportunities for novel epigenetic biomarkers of risk or interventions targeting epigenetic pathways to be devised for use in early life. This may pave the way to much more effective, customised interventions to promote health across the life course.     

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.     

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.     

Maternal and In Utero Determinants of Type 2 Diabetes Risk in the Young

The global prevalence of diabetes mellitus has reached epidemic proportions. In 2010, it was estimated that 6.4 % of the adult population (285 million) have diabetes. In recent years, the incidence of type 2 diabetes (T2D), a condition traditionally associated with aging, has been steadily increasing among younger individuals. It is now a well-established notion that the early-life period is a critical window of development and that influences during this period can “developmentally prime” the metabolic status of the adult. This review discusses the role of maternal and in utero influences on the developmental priming of T2D risk. Both human epidemiological studies and experimental animal models are beginning to demonstrate that early dietary challenges can accelerate the onset of age-associated metabolic disturbances, including insulin resistance, T2D, obesity, hypertension, and cardiovascular disease. These findings show that poor maternal nutrition can prime a prediabetes phenotype, often manifest as insulin resistance, by very early stages of life. Thus, the maternal diet is a critical determinant of premature T2D risk. While the mechanisms that link early nutrition to age-associated metabolic decline are currently unclear, preliminary findings suggest perturbations in a number of processes involved in cellular aging, such as changes in longevity-associated Sirtuin activity, epigenetic regulation of key metabolic genes, and mitochondrial dysfunction. Preliminary studies show that pharmacological interventions in utero and dietary supplementation in early postnatal life may alleviate insulin resistance and reduce T2D risk. However, further studies are warranted to fully understand the relationship between the early environment and long-term effects on metabolism. Such mechanistic insights will facilitate strategic interventions that prevent accelerated metabolic decline and the premature onset of T2D in the current and future generations.     

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.     

Neonatal exposure to estradiol/bisphenol A alters promoter methylation and expression of Nsbp1 and Hpcal1 genes and transcriptional programs of Dnmt3a/b and Mbd2/4 in the rat prostate gland throughout life

Evidence supporting an early origin of prostate cancer is growing. We demonstrated previously that brief exposure of neonatal rats to estradiol or bisphenol A elevated their risk of developing precancerous lesions in the prostate upon androgen-supported treatment with estradiol as adults. Epigenetic reprogramming may be a mechanism underlying this inductive event in early life, because we observed overexpression of phosphodiesterase 4D variant 4 (Pde4d4) through induction of hypomethylation of its promoter. This epigenetic mark was invisible in early life (postnatal d 10), becoming apparent only after sexual maturation. Here, we asked whether other estrogen-reprogrammable epigenetic marks have similar or different patterns in gene methylation changes throughout life. We found that hypomethylation of the promoter of nucleosome binding protein-1 (Nsbp1), unlike Pde4d4, is an early and permanent epigenetic mark of neonatal exposure to estradiol/bisphenol A that persists throughout life, unaffected by events during adulthood. In contrast, hippocalcin-like 1 (Hpcal1) is a highly plastic epigenetic mark whose hypermethylation depends on both type of early-life exposure and adult-life events. Four of the eight genes involved in DNA methylation/demethylation showed early and persistent overexpression that was not a function of DNA methylation at their promoters, including genes encoding de novo DNA methyltransferases (Dnmt3a/b) and methyl-CpG binding domain proteins (Mbd2/4) that have demethylating activities. Their lifelong aberrant expression implicates them in early-life reprogramming and prostate carcinogenesis during adulthood. We speculate that the distinctly different fate of early-life epigenetic marks during adulthood reflects the complex nature of lifelong editing of early-life epigenetic reprogramming.     

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 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.     

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.     

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.     

Biological Versus Chronological Aging: JACC Focus Seminar

Aging is the main risk factor for vascular disease and ensuing cardiovascular and cerebrovascular events, the leading causes of death worldwide. In a progressively aging population, it is essential to develop early-life biomarkers that efficiently identify individuals who are at high risk of developing accelerated vascular damage, with the ultimate goal of improving primary prevention and reducing the health care and socioeconomic impact of age-related cardiovascular disease. Studies in experimental models and humans have identified 9 highly interconnected hallmark processes driving mammalian aging. However, strategies to extend health span and life span require understanding of interindividual differences in age-dependent functional decline, known as biological aging. This review summarizes the current knowledge on biological age biomarkers, factors influencing biological aging, and antiaging interventions, with a focus on vascular aspects of the aging process and its cardiovascular disease related manifestations.     

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.     

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.     

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.     

Perinatale Programmierung des Typ-2-Diabetes

Early metabolic influences in utero increase the risk for metabolic imbalances such as type 2 diabetes mellitus in the offspring’s later life, via mechanisms referred to as fetal programming. Important perinatal risk factors for metabolic alterations in later life are intrauterine growth restriction, preconception maternal obesity, and a diabetic intrauterine milieu. As shown in human studies and experimental animal models, maternal diabetes mellitus in pregnancy can induce various long-term consequences for organ function in the offspring. Underlying mechanisms of perinatal programming involve epigenetic processes. Consecutively, gene expression may be modified, and/or structural modifications can occur in the offspring. A more detailed understanding of the early-life origins of diabetes mellitus and prediabetes is required for the development of preventive concepts and early treatment strategies.     

Conditional tradeoffs between aging and organismal performance of Indy long-lived mutant flies

Alterations that extend the life span of animals and yeast typically involve decreases in metabolic rate, growth, physical activity, and/or early-life fecundity. This negative correlation between life span and the ability to assimilate and process energy, to move, grow, and reproduce, raises questions about the potential utility of life span extension. Tradeoffs between early-life fitness and longevity are central to theories of the evolution of aging, which suggests there is necessarily a price to be paid for reducing the rate of aging. It is not yet clear whether life span can be extended without undesirable effects on metabolism and fecundity. Here, we report that the long-lived Indy mutation in Drosophila causes a decrease in the slope of the mortality curve consistent with a slowing in the rate of aging without a concomitant reduction in resting metabolic rate, flight velocity, or age-specific fecundity under normal rearing conditions. However, Indy mutants on a decreased-calorie diet have reduced fecundity, suggesting that a tradeoff between longevity and this aspect of performance is conditional, i.e., the tradeoff can occur in a stressful environment while being absent in a more favorable environment. These results provide evidence that there do exist mechanisms, albeit conditional, that can extend life span without significant reduction in fecundity, metabolic rate, or locomotion.     

Functional characterization and immunolocalization of the transporter encoded by the life-extending gene Indy

Caloric restriction extends life span in a variety of species, highlighting the importance of energy balance in aging. A new longevity gene, Indy (for I'm not dead yet), which doubles the average life span of flies without a loss of fertility or physical activity, was postulated to extend life by affecting intermediary metabolism. We report that functional studies in Xenopus oocytes show INDY is a metabolite transporter that mediates the high-affinity, disulfonic stilbene-sensitive flux of dicarboxylates and citrate across the plasma membrane by a mechanism that is not coupled to Na(+), K(+), or Cl(-). Immunocytochemical studies localize INDY to the plasma membrane with most prominent expression in adult fat body, oenocytes, and the basolateral region of midgut cells and show that life-extending mutations in Indy reduce INDY expression. We conclude that INDY functions as a novel sodium-independent mechanism for transporting Krebs and citric acid cycle intermediates through the epithelium of the gut and across the plasma membranes of organs involved in intermediary metabolism and storage. The life-extending effect of mutations in Indy is likely caused by an alteration in energy balance caused by a decrease in INDY transport function.