Extension Of Maximal Life Span Research Articles

Identification of longevity compounds with minimized probabilities of side effects

It is hypothesized that treating the general aging population with compounds that slow aging, geroprotectors, could provide many benefits to society, including a reduction of age-related diseases. It is intuitive that such compounds should cause minimal side effects, since they would be distributed to otherwise healthy individuals for extended periods of time. The question therefore emerges of how we should prioritize geroprotectors discovered in model organisms for clinical testing in humans. In other words, which compounds are least likely to cause harm, while still potentially providing benefit? To systematically answer this question we queried the DrugAge database—containing hundreds of known geroprotectors—and cross-referenced this with a recently published repository of compound side effect predictions. In total, 124 geroprotectors were associated to 800 unique side effects. Geroprotectors with high risks of side effects, some even with risk for death, included lamotrigine and minocycline, while compounds with low side effect risks included spermidine and d-glucosamine. Despite their popularity as top geroprotector candidates for humans, sirolimus and metformin harbored greater risks of side effects than many other candidate geroprotectors, sirolimus being the more severe of the two. Furthermore, we found that a correlation existed between maximum lifespan extension in worms and the likelihood of causing a side effect, suggesting that extreme lifespan extension in model organisms should not necessarily be the priority when screening for novel geroprotectors. We discuss the implications of our findings for prioritizing geroprotectors, suggesting spermidine and d-glucosamine for clinical trials in humans.

Extension of Maximal Lifespan and High Bone Marrow Chimerism After Nonmyeloablative Syngeneic Transplantation of Bone Marrow From Young to Old Mice.

The goal of this work was to determine the effect of nonablative syngeneic transplantation of young bone marrow (BM) to laboratory animals (mice) of advanced age upon maximum duration of their lifespan. To do this, transplantation of 100 million nucleated cells from BM of young syngeneic donors to an old nonablated animal was performed at the time when half of the population had already died. As a result, the maximum lifespan (MLS) increased by 28 ± 5%, and the survival time from the beginning of the experiment increased 2.8 ± 0.3-fold. The chimerism of the BM 6 months after the transplantation was 28%.

Verminoside mediates life span extension and alleviates stress in Caenorhabditis elegans

The discovery of bioactive molecules modulating aging in living organism promotes development of natural therapeutics for curing age-related afflictions. The progression in age-related disorders can be attributed to increment in intracellular reactive oxygen species (ROS) and oxidative stress level. To this end, we isolated an iridoid verminoside (VMS) from Stereospermum suaveolens (Roxb.) DC. and evaluated its effect on Caenorhabditis elegans. The present study delineates VMS-mediated alteration of intracellular ROS, oxidative stress, and life span in C. elegans. The different tested doses of VMS (5 μM, 25 μM, and 50 μM) were able to enhance ROS scavenging and extend mean life span in C. elegans. The maximal life span extension was observed in 25 μM VMS, that is, 20.79% (P < 0.0001) followed by 9.84% (P < 0.0001) in 5 μM VMS and 8.54% (P < 0.0001) in 50 μM VMS. VMS was able to alleviate juglone-induced oxidative stress and enhanced thermotolerance in worms. The stress-modulating and ROS-scavenging potential of VMS was validated by increment in mean survival by 29.54% (P < 0.0001) in VMS-treated oxidative stress hypersensitive mev-1 mutant strain. Furthermore, VMS modulates expression of DAF-16 (a FoxO transcription factor) promoting stress resistance and longevity. Altogether, our results suggest that VMS attenuates intracellular ROS and stress (oxidative and thermal) level promoting longevity. The longevity and stress modulation can be attributed to VMS-mediated alterations in daf-16 expression which regulates insulin signaling pathway. This study opens doors for development of phytomolecule-based therapeutics for prolonging life span and managing age-related severe disorders.

Altered metabolism and resistance to obesity in long-lived mice producing reduced levels of IGF-I.

The extension of lifespan due to reduced insulin-like growth factor 1 (IGF-I) signaling in mice has been proposed to be mediated through alterations in metabolism. Previously, we showed that mice homozygous for an insertion in the Igf1 allele have reduced levels of IGF-I, are smaller, and have an extension of maximum lifespan. Here, we tested whether this specific reduction of IGF-I alters glucose metabolism both on normal rodent chow and in response to high-fat feeding. We found that female IGF-I-deficient mice were lean on a standard rodent diet but paradoxically displayed an insulin-resistant phenotype. However, these mice gained significantly less weight than normal controls when placed on a high-fat diet. In control animals, insulin response was significantly impaired by high-fat feeding, whereas IGF-I-deficient mice showed a much smaller shift in insulin response after high-fat feeding. Gluconeogenesis was also elevated in the IGF-I-deficient mice relative to controls on both normal and high-fat diet. An analysis of metabolism and respiratory quotient over 24 h indicated that the IGF-I-deficient mice preferentially utilized fatty acids as an energy source when placed on a high-fat diet. These results indicate that reduction in the circulating and tissue IGF-I levels can produce a metabolic phenotype in female mice that increases peripheral insulin resistance but renders animals resistant to the deleterious effects of high-fat feeding.

Stress responses, vitagenes and hormesis as critical determinants in aging and longevity: Mitochondria as a "chi".

Understanding mechanisms of aging and determinants of life span will help to reduce age-related morbidity and facilitate healthy aging. Average lifespan has increased over the last centuries, as a consequence of medical and environmental factors, but maximal life span remains unchanged. Extension of maximal life span is currently possible in animal models with measures such as genetic manipulations and caloric restriction (CR). CR appears to prolong life by reducing reactive oxygen species (ROS)-mediated oxidative damage. But ROS formation, which is positively implicated in cellular stress response mechanisms, is a highly regulated process controlled by a complex network of intracellular signaling pathways. By sensing the intracellular nutrient and energy status, the functional state of mitochondria, and the concentration of ROS produced in mitochondria, the longevity network regulates life span across species by coordinating information flow along its convergent, divergent and multiply branched signaling pathways, including vitagenes which are genes involved in preserving cellular homeostasis during stressful conditions. Vitagenes encode for heat shock proteins (Hsp) Hsp32, Hsp70, the thioredoxin and the sirtuin protein systems. Dietary antioxidants, have recently been demonstrated to be neuroprotective through the activation of hormetic pathways, including vitagenes. The hormetic dose–response, challenges long-standing beliefs about the nature of the dose–response in a lowdose zone, having the potential to affect significantly the design of pre-clinical studies and clinical trials as well as strategies for optimal patient dosing in the treatment of numerous diseases. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing stress responses. Here we focus on possible signaling mechanisms involved in the activation of vitagenes resulting in enhanced defense against energy and stress resistance homeostasis dysiruption with consequent impact on longevity processes.

Hormesis, cellular stress response and vitagenes as critical determinants in aging and longevity

Understanding mechanisms of aging and determinants of life span will help to reduce age-related morbidity and facilitate healthy aging. Average lifespan has increased over the last centuries, as a consequence of medical and environmental factors, but maximal life span remains unchanged. Extension of maximal life span is currently possible in animal models with measures such as genetic manipulations and caloric restriction (CR). CR appears to prolong life by reducing reactive oxygen species (ROS)-mediated oxidative damage. But ROS formation, which is positively implicated in cellular stress response mechanisms, is a highly regulated process controlled by a complex network of intracellular signaling pathways. By sensing the intracellular nutrient and energy status, the functional state of mitochondria, and the concentration of ROS produced in mitochondria, the longevity network regulates life span across species by co-ordinating information flow along its convergent, divergent and multiply branched signaling pathways, including vitagenes which are genes involved in preserving cellular homeostasis during stressful conditions. Vitagenes encode for heat shock proteins (Hsp) Hsp32, Hsp70, the thioredoxin and the sirtuin protein systems. Dietary antioxidants, such as carnosine, carnitines or polyphenols, have recently been demonstrated to be neuroprotective through the activation of hormetic pathways, including vitagenes. The hormetic dose–response, challenges long-standing beliefs about the nature of the dose–response in a lowdose zone, having the potential to affect significantly the design of pre-clinical studies and clinical trials as well as strategies for optimal patient dosing in the treatment of numerous diseases. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing stress responses. In this review we discuss the most current and up to date understanding of the possible signaling mechanisms by which caloric restriction, as well hormetic caloric restriction–mimetics compounds by activating vitagenes can enhance defensive systems involved in bioenergetic and stress resistance homeostasis with consequent impact on longevity processes.

Ubiquitin ligases join the field of dietary restriction in C.elegans

Ubiquitin ligases join the field of dietary restriction in C.elegans

Effects of dietary restriction on mortality and age‐related phenotypes in the short‐lived fish Nothobranchius furzeri

The short-lived annual fish Nothobranchius furzeri shows extremely short captive life span and accelerated expression of age markers, making it an interesting model system to investigate the effects of experimental manipulations on longevity and age-related pathologies. Here, we tested the effects of dietary restriction (DR) on mortality and age-related markers in N. furzeri. DR was induced by every other day feeding and the treatment was performed both in an inbred laboratory line and a longer-lived wild-derived line. In the inbred laboratory line, DR reduced age-related risk and prolonged maximum life span. In the wild-derived line, DR induced early mortality, did not reduce general age-related risk and caused a small but significant extension of maximum life span. Analysis of age-dependent mortality revealed that DR reduced demographic rate of aging, but increased baseline mortality in the wild-derived strain. In both inbred- and wild-derived lines, DR prevented the expression of the age markers lipofuscin in the liver and Fluoro-Jade B (neurodegeneration) in the brain. DR also improved performance in a learning test based on conditioning (active avoidance in a shuttle box). Finally, DR induced a paradoxical up-regulation of glial fibrillary acidic protein in the brain.

Nutrition, hormetic stress and health

Hormesis defines an effect where exposure to a low dose of a toxic agent results in a beneficial response. It has been described in organisms exposed to low-dose radiation, heat stress, and chemicals. The effect is characterised by a J-shaped dose-response as opposed to a linear dose-response. Confirmation of the general phenomena of hormesis has proved difficult due to the lack of appropriate methodology and the absence of well-defined mechanisms to support the experimental observations. In the nutritional field there are few reports of its existence. The clearest illustration of the effect is seen in animals that are energy restricted when there is a clear benefit in the reduction of age-related disease, and an extension of maximum lifespan. DNA microarray experiments have shown that there is a down regulation of the stress-response genes that are up regulated through the ageing process. Electrophilic phytochemicals, that have been shown to have beneficial health effects at low doses, up regulate the antioxidant-electrophile response element. This probably occurs through an alteration in the redox state of the target cells which causes activation of protein kinases, the activation of the Nrf2 transcription factor and the up regulation of the phase II enzymes, similar to responses that occur under mild chemical stress. This situation might enable organisms to adapt to stress such that the effects of a subsequent exposure to a harmful challenge are reduced. There may be a permanent alteration in cellular homeostasis, or redox state, if the low level exposure is maintained. It remains to be proven if such a situation occurs in response to chronic low-dose exposure to dietary phytochemicals such that the target cells are better able to respond to a subsequent stress challenge.

The patriarch hypothesis : An alternative explanation of menopause.

Menopause is puzzling because life-history theory predicts there should be no selection for outliving one's reproductive capacity. Adaptive explanations of menopause offered thus far turn on women's long-term investment in offspring and grandoffspring, all variations on the grandmother hypothesis. Here, I offer a very different explanation. The patriarch hypothesis proposes that once males became capable of maintaining high status and reproductive access beyond their peak physical condition, selection favored the extension of maximum life span in males. Because the relevant genes were not on the Y chromosome, life span increased in females as well. However, the female reproductive span was constrained by the depletion of viable oocytes, which resulted in menopause.

Noncorrelation Between Maximum Life Span and Antioxidant Enzyme Levels Among Homeotherms: Implications for Retarding Human Aging

A series of studies over many years has conclusively disproved the hypothesis that longevity in warm-blooded animals (homeotherms) correlates with high levels of antioxidant enzymes: in fact, these variables generally exhibit a strong negative cross-species correlation. In flies and nematodes, however, substantial extension of maximum life span has resulted from genetic manipulations that increase antioxidant enzyme levels; these manipulations have always been associated with increased resistance to oxidative challenge, indicating that the life span extension is directly caused by the raised antioxidant capacity. This stark contrast merits careful analysis because it casts doubt on the value of short-lived invertebrates as models for the investigation of mammalian aging. Here is it shown that these results imply the existence, in homeotherms but not in flies or worms, of life span-limiting pathways of oxidative damage that are impervious to enzymatic antioxidants. This is shown to lend weight to the currently controversial theory that somatic mitochondrial DNA mutations contribute significantly to determining the rate of aging of homeotherms, and thereby suggests a feasible intervention to retard human aging.

Author's Repsonse to Commentary on "Revisiting the Role of Fat Mass in the Life Extension Induced by Caloric Restriction"

DECENTLY, mutations in several genes in the nematode s worm (1) and in the drosphilla fly (2) resulted in a dra­ matie inerease in life span. These diseoveries support the eon­ eept that genes determine longevity. Are these diseoveries rele­ vant to humans? This year a published report showed that siblings of eentenarians live longer than siblings of the eente­ narian's eohort (3), supporting a major genetie eomponent for human longevity. On the other hand, the effeets of ealorie re­ strietion on the extension of maximallife span seem to suggest that the environment also plays an important role in mediating this effeet. Are the suggestions that longevity may be deter­ mined by genes as weIl as by the environment eontradieting eaeh other? We argue that they are not-rather the environment may eause a marked differenee in the expression of longevity related genes. Dur hypothesis article (4) may help us under­ stand the interaetion between the environment and genes, and may provide an insight into how modulation of gene expression may determine longevity. We suggest that the obvious eandi­ dates for genes that influenee longevity are those expressed in fat, or whose levels are ehanged with fat mass. As an example of the latter, insulin levels inerease with fat mass and, therefore, decrease in ealorie-restrieted animals. As reviewed (4), hyperin­ sulinemia is associated with diseases and early mortality in hu­ mans, whereas a mutation in the nematodes' insulin-signaling pathway is associated with extreme longevity. Thus, this is an example demonstrating environment modulation (ealorie re­ striction), gene mutation (in nematodes), and their relationship to longevity. Fat mass is increased by 2- to 5-fold in ad-libitum fed com­ pared with calorie-restrieted animals. If the plasma levels of certain fat-derived peptides chronically increase by that many folds, they should be considered as eandidates to affect longevity (just like insulin). Durhypothesis article focused on the example of leptin-a fat-derived hormone, whose expres­ sion is modulated by fat mass, and which has been shown to control the hypothalamic response to ealorie deprivation and energy expenditure. Moreover, while fat mass is increased by several fold, the plasma leptin levels change by -2 log scales in obese humans (5) and with nutrient access to ad libitum fed an­ imals (6). This chronic -100-fold increase in the expression of a gene product is similar to differences in expression designed by genetie manipulation. Thus, together with the known actions of

Mortality rate and longevity of food-restricted exercising male rats: a reevaluation.

Food restriction increases the maximal longevity of rats. Male rats do not increase their food intake to compensate for the increase in energy expenditure in response to exercise. However, a decrease in the availability of energy for growth and cell proliferation that induces an increase in maximal longevity in sedentary rats only results in an improvement in average survival, with no extension of maximal life span, when caused by exercise. In a previous study (J.O. Holloszy and K.B. Schechtman. J. Appl. Physiol. 70:1529-1535, 1991), to test the possibility that exercise prevents the extension of life span by food restriction, wheel running and food restriction were combined. The food-restricted runners showed the same increase in maximal life span as food-restricted sedentary rats but had an increased mortality rate during the first one-half of their mortality curve. The purpose of the present study was to determine the pathological cause of this increased early mortality. However, in contrast to our previous results, the food-restricted wheel-running rats in this study showed no increase in early mortality, and their survival curves were virtually identical to those of sedentary animals that were food restricted so as to keep their body weights the same as those of the runners. Thus it is possible that the rats in the previous study had a health problem that had no effect on longevity except when both food restriction and exercise were superimposed on it. Possibly of interest in this regard, the rats in this study did considerably more voluntary running than those in the previous study. It is concluded that 1) moderate caloric restriction combined with exercise does not normally increase the early mortality rate in male rats, 2) exercise does not interfere with the extension of maximal life span by food restriction, and 3) the beneficial effects of food restriction and exercise on survival are not additive or synergistic.

Exercise and Food Restriction in Rats ,

A number of studies have shown that exercised rats live longer than sedentary freely eating controls. There is disagreement regarding whether exercise results in extension of maximal life span. However, in two studies of the effect of voluntary wheel running on longevity of male specific-pathogen-free Long-Evans rats it was found that, although the runners had a longer average survival than sedentary freely eating controls, they did not have an increase in maximal life span. This is in contrast to the effect of food restriction. Sedentary rats that were food restricted to keep their body weights in the same range as those of the runners lived longer than the runners and showed an extension of life span. When exercise, in the form of voluntary wheel running was combined with food restriction (∼30% below ad libitum), the runners had an increased mortality rate over the first ∼50% of their mortality curve up to age ∼900 d. However, in those food-restricted runners that survived past ∼900 d survival became similar to that of food-restricted sedentary controls, with a similar increase in maximal life span. Thus, although exercise has a deleterious effect on food-restricted rats, it does not counteract the increase in maximal life span induced by food restriction.

Interaction between exercise and food restriction: effects on longevity of male rats

Male rats that exercise in running wheels have a longer average survival than freely eating sedentary controls but, in contrast to food-restricted sedentary controls of the same weight, show no extension of maximal life span (J. Appl. Physiol. 59: 826-831, 1985). To test the possibility that exercise may counteract a life-extending effect of decreased availability of energy for certain biological processes such as cell proliferation, we examined the combined effects of exercise and food restriction on longevity of male rats. As before, wheel running improved average length of life, 978 +/- 172 vs. 875 +/- 175 (SD) days, for the sedentary controls (P less than 0.01) without increasing maximal life span. Paired-weight controls, food restricted (approximately 30% below ad libitum) to weight the same as the runners, showed increases in both average (1,056 +/- 144 days) and maximal life span. Food-restricted runners, with intake restricted to the same extent (approximately 30%), had an increased mortality rate over the first approximately 50% of their survival curve up to approximately 900 days of age; their average life span (995 +/- 226) was similar to that of the control group of runners and shorter than that of their paired-weight food-restricted sedentary controls (1,088 +/- 159 days, P less than 0.05). However, after approximately 900 days of age the food-restricted runners' survival became similar to that of the food-restricted sedentary groups, with a comparable increase in maximal life span. Thus the exercise did not counteract the increase in maximal life span induced by food restriction.(ABSTRACT TRUNCATED AT 250 WORDS)