Sirt1 protects the heart from aging and stress

The prevalence of heart diseases, such as coronary artery disease and congestive heart failure, increases with age. Optimal therapeutic interventions that antagonize aging may reduce the occurrence and mortality of adult heart diseases. We discuss here how molecular mechanisms mediating life span extension affect aging of the heart and its resistance to pathological insults. In particular, we review our recent findings obtained from transgenic mice with cardiac-specific overexpression of Sirt1, which demonstrated delayed aging and protection against oxidative stress in the heart. We propose that activation of known longevity mechanisms in the heart may represent a novel cardioprotection strategy against aging and certain types of cardiac stress, such as oxidative stress.     

Do large dogs die young?

In most animal taxa, longevity increases with body size across species, as predicted by the oxidative stress theory of aging. In contrast, in within-species comparisons of mammals and especially domestic dogs (e.g. Patronek et al., '97; Michell, '99; Egenvall et al., 2000; Speakman et al., 2003), longevity decreases with body size.We explore two datasets for dogs and find support for a negative relationship between size and longevity if we consider variation across breeds. Within breeds, however, the relationship is not negative and is slightly, but significantly, positive in the larger of the two datasets. The negative across-breed relationship is probably the consequence of short life spans in large breeds. Artificial selection for extremely high growth rates in large breeds appears to have led to developmental diseases that seriously diminish longevity.     

A Genetic Pathway Conferring Life Extension and Resistance to Uv Stress in Caenorhabditis Elegans

A variety of mechanisms have been proposed to explain the extension of adult life span (Age) seen in several mutants in Caenorhabditis elegans (age-1: an altered aging rate; daf-2 and daf-23: activation of a dauer-specific longevity program; spe-26: reduced fertility; clk-1: an altered biological clock). Using an assay for ultraviolet (UV) resistance in young adult hermaphrodites (survival after UV irradiation), we observed that all these Age mutants show increased resistance to UV. Moreover, mutations in daf-16 suppressed the UV resistance as well as the increased longevity of all the Age mutants. In contrast to the multiple mechanisms initially proposed, these results suggest that a single, daf-16-dependent pathway, specifies both extended life span and increased UV resistance. The mutations in daf-16 did not alter the reduced fertility of spe-26 and interestingly a daf-16 mutant is more fertile than wild type. We propose that life span and some aspects of stress resistance are jointly negatively regulated by a set of gerontogenes (genes whose alteration causes life extension) in C. elegans.     

Life history consequences of developing in anthropogenic noise

When environments change rapidly, adaptive phenotypic plasticity can ameliorate negative effects of environmental change on survival and reproduction. Recent evidence suggests, however, that plastic responses to human‐induced environmental change are often maladaptive or insufficient to overcome novel selection pressures. Anthropogenic noise is a ubiquitous and expanding disturbance with demonstrated effects on fitness‐related traits of animals like stress responses, foraging, vigilance, and pairing success. Elucidating the lifetime fitness effects of noise has been challenging because longer‐lived vertebrate systems are typically studied in this context. Here, we follow noise‐stressed invertebrates throughout their lives, assessing a comprehensive suite of life history traits, and ultimately, lifetime number of surviving offspring. We reared field crickets, Teleogryllus oceanicus, in masking traffic noise, traffic noise from which we removed frequencies that spectrally overlap with the crickets’ mate location song and peak hearing (nonmasking), or silence. We found that exposure to masking noise delayed maturity and reduced adult lifespan; crickets exposed to masking noise spent 23% more time in juvenile stages and 13% less time as reproductive adults than those exposed to no traffic noise. Chronic lifetime exposure to noise, however, did not affect lifetime reproductive output (number of eggs or surviving offspring), perhaps because mating provided females a substantial longevity benefit. Nevertheless, these results are concerning as they highlight multiple ways in which traffic noise may reduce invertebrate fitness. We encourage researchers to consider effects of anthropogenic disturbance on growth, survival, and reproductive traits simultaneously because changes in these traits may amplify or nullify one another.     

Heat Stress-Induced Life Span Extension in Yeast

The yeastSaccharomyces cerevisiaehas a limited life span that can be measured by the number of times individual cells divide. Several genetic manipulations have been shown to prolong the yeast life span. However, environmental effects that extend longevity have been largely ignored. We have found that mild, nonlethal heat stress extended yeast life span when it was administered transiently early in life. The increased longevity was due to a reduction in the mortality rate that persisted over many cell divisions (generations) but was not permanent. The genesRAS1andRAS2were necessary to observe this effect of heat stress. TheRAS2gene is consistently required for maintenance of life span when heat stress is chronic or in its extension when heat stress is transient or absent altogether.RAS1,on the other hand, appears to have a role in signaling life extension induced by transient, mild heat stress, which is distinct from its life-span-curtailing effect in the absence of stress and its lack of involvement in the response to chronic heat stress. This distinction between theRASgenes may be partially related to their different effects on growth-promoting genes and stress-responsive genes. Theras2mutation clearly hindered resumption of growth and recovery from stress, while theras1mutation did not. TheHSP104gene, which is largely responsible for induced thermotolerance in yeast, was necessary for life extension induced by transient heat stress. An interaction between mitochondrial petite mutations and heat stress was found, suggesting that mitochondria may be necessary for life extension by transient heat stress. The results raise the possibility that theRASgenes and mitochondria may play a role in the epigenetic inheritance of reduced mortality rate afforded by transient, mild heat stress.     

Life history,ecology and longevity in bats

The evolutionary theory of aging predicts that life span should decrease in response to the amount of mortality caused by extrinsic sources. Using this prediction, we selected six life history and ecological factors to use in a comparative analysis of longevity among 64 bat species. On average, the maximum recorded life span of a bat is 3.5 times greater than a non-flying placental mammal of similar size. Records of individuals surviving more than 30 years in the wild now exist for five species. Univariate and multivariate analyses of species data, as well as of phylogenetically independent contrasts obtained using a supertree of Chiroptera, reveal that bat life span significantly increases with hibernation, body mass and occasional cave use, but decreases with reproductive rate and is not influenced by diet, colony size or the source of the record. These results are largely consistent with extrinsic mortality risk acting as a determinant of bat longevity. Nevertheless, the strong association between life span and both reproductive rate and hibernation also suggests that bat longevity is strongly influenced by seasonal allocation of non-renewable resources to reproduction. We speculate that hibernation may provide a natural example of caloric restriction, which is known to increase longevity in other mammals.     

Growth negatively impacts the life span of mammals

A negative intraspecific relationship between growth and longevity was proposed in the early 20th century. Indeed, stunting the growth of rodents by restricting their food dramatically extended life span. Subsequently, however, the hypothesis that growth exacerbates aging rates fell into disfavor. Contributing to this was (a) the establishment of a positive relationship between body size and longevity interspecifically, (b) purported antiaging impacts of growth hormone, and (c) the fact that the longevity of even mature rodents that had completed growth was extended by dietary restriction. Furthermore, intraspecific analytical studies failed to provide any clear resolution. This article presents the first global analyses of maximal longevity versus maximum mature mass for laboratory rats and mice, based on a relatively comprehensive compilation of research across the 20th century. Peak body mass (which reflects juvenile growth rates) was negatively associated with longevity within both species. Proximal mechanisms for impacts of growth on longevity appear congruent with the free radical and immunological theories of aging.     

Artificial selection on male longevity influences age-dependent reproductive effort in the black field cricket Teleogryllus commodus

Although the trade-off between reproductive effort and longevity is central to both sexual selection and evolutionary theories of aging, there has been little synthesis between these fields. Here, we selected directly on adult longevity of male field crickets Teleogryllus commodus and measured the correlated responses of age-dependent male reproductive effort, female lifetime fecundity, and several other life-history traits. Male longevity responded significantly to five generations of divergent selection. Males from downward-selected lines commenced calling sooner and reached their peak calling effort at a younger age. They called more per night and, despite living less than half as long, called more overall than males selected for increased longevity. Females from the downward-selected lines lived significantly shorter lives than females from the upward-selected lines but still produced the same number of offspring. Nymph survival, development time, and body size and weight at eclosion did not show significant correlated response to selection on male longevity, despite evidence for substantial genetic variation in each of these traits. Collectively, our findings directly support the antagonistic pleiotropy model of aging and suggest an important role for sexual selection in the aging process.     

The effect of different light regimes on adult life span in Drosophila melanogaster is partly mediated through reproductive output

The effects of different light regimes on the fitness of organisms have typically been studied using mean or median adult life span as the sole index of physiological well-being. It is, however, known that life span is inversely related to reproductive output in many species. Moreover, the effects of a given environmental treatment on life span can be due to effects on either age-independent mortality or the "rate of aging," or a combination of both. Drawing evolutionary inferences from the effects of light regime on mean or median adult life span alone is difficult and, at best, speculative. We examined the effects of constant light (LL), alternating light-dark cycles (LD 12:12 h), and constant darkness (DD) on the life span of reproducing and virgin flies in four populations of Drosophila melanogaster and also estimated lifetime fecundity in the three light regimes. The light regime effects on life span were further dissected by examining the age-independent mortality and the Gompertz rate of aging under the three light regimes. While mean adult life span of reproducing males and females and virgin females was significantly shorter in LL compared to LD 12:12 h and DD, life-time egg production was highest in LL. Life span of virgin males was not significantly affected by light regime. The rate of aging in reproducing females was higher in LL as compared to DD, whereas age-independent mortality was higher in DD. As reproductive output, especially early in life, is a far more significant contributor to fitness than is life span, our results suggest that the earlier reported deleterious effects of LL on fitness are partly an artifact of examining life span alone, without considering other components of adult fitness that trade off with life span. Our results suggest that detailed investigation of the effects of light regime on the physiological and behavioral processes that accompany reproduction is necessary to fully understand the effects of different light regimes on adult fitness in Drosophila.     

灰飞虱与褐飞虱种内和种间密度效应比较

在人工气候室内比较研究了灰飞虱和褐飞虱在汕优63和秀水11上的种内和种间密度效应对其主要生物学参数的影响,结果表明两种稻飞虱均存在显著的种内竞争,主要表现为随着密度增加,若虫发育历期延长、若虫羽化率下降、雌成虫寿命缩短、每雌产卵量下降。种内密度效应与稻飞虱种类和寄主品种有显著互作关系,灰飞虱种内竞争较褐飞虱明显,二者在适宜寄主上种内竞争更为明显。同时,两种稻飞虱存在着显著的种间密度效应,主要表现为异种存在时的促进作用,即异种共存时若虫历期缩短、若虫羽化率提高、雌虫寿命延长、每雌产卵量增加。种间密度效应也与稻飞虱种类和寄主品种有显著互作关系,两种共存对灰飞虱的有利作用显著大于对褐飞虱的有利作用,在欠适宜寄主上种间互利效应更为明显。最后,本文对稻飞虱种内和种间密度效应的机制和进化意义进行了讨论。     

Higher respiratory activity decreases mitochondrial reactive oxygen release and increases life span in Saccharomyces cerevisiae

Increased replicative longevity in Saccharomyces cerevisiae because of calorie restriction has been linked to enhanced mitochondrial respiratory activity. Here we have further investigated how mitochondrial respiration affects yeast life span. We found that calorie restriction by growth in low glucose increased respiration but decreased mitochondrial reactive oxygen species production relative to oxygen consumption. Calorie restriction also enhanced chronological life span. The beneficial effects of calorie restriction on mitochondrial respiration, reactive oxygen species release, and replicative and chronological life span could be mimicked by uncoupling agents such as dinitrophenol. Conversely, chronological life span decreased in cells treated with antimycin (which strongly increases mitochondrial reactive oxygen species generation) or in yeast mutants null for mitochondrial superoxide dismutase (which removes superoxide radicals) and for RTG2 (which participates in retrograde feedback signaling between mitochondria and the nucleus). These results suggest that yeast aging is linked to changes in mitochondrial metabolism and oxidative stress and that mild mitochondrial uncoupling can increase both chronological and replicative life span.     

Metabolism and longevity: is there a role for membrane fatty acids?

More than 100 years ago, Max Rubner combined the fact that both metabolic rate and longevity of mammals varies with body size to calculate that "life energy potential" (lifetime energy turnover per kilogram) was relatively constant. This calculation linked longevity to aerobic metabolism which in turn led to the "rate-of-living" and ultimately the "oxidative stress" theories of aging. However, the link between metabolic rate and longevity is imperfect. Although unknown in Rubner's time, one aspect of body composition of mammals also varies with body size, namely the fatty acid composition of membranes. Fatty acids vary dramatically in their susceptibility to peroxidation and the products of lipid peroxidation are very powerful reactive molecules that damage other cellular molecules. The "membrane pacemaker" modification of the "oxidative stress" theory of aging proposes that fatty acid composition of membranes, via its influence on peroxidation of lipids, is an important determinant of lifespan (and a link between metabolism and longevity). The relationship between membrane fatty acid composition and longevity is discussed for (1) mammals of different body size, (2) birds of different body size, (3) mammals and birds that are exceptionally long-living for their size, (4) strains of mice that vary in longevity, (5) calorie-restriction extension of longevity in rodents, (6) differences in longevity between queen and worker honeybees, and (7) variation in longevity among humans. Most of these comparisons support an important role for membrane fatty acid composition in the determination of longevity. It is apparent that membrane composition is regulated for each species. Provided the diet is not deficient in polyunsaturated fat, it has minimal influence on a species' membrane fatty acid composition and likely also on it's maximum longevity. The exceptional longevity of Homo sapiens combined with the limited knowledge of the fatty acid composition of human tissues support the potential importance of mitochondrial membranes in determination of longevity.     

Longevity pathways converge on autophagy genes to regulate life span in Caenorhabditis elegans

Aging is a multifactorial process with many mechanisms contributing to the decline. Mutations decreasing insulin/IGF-1 (insulin-like growth factor-1) or TOR (target of rapamycin) kinase-mediated signaling, mitochondrial activity and food intake each extend life span in divergent animal phyla. Understanding how these genetically distinct mechanisms interact to control longevity is a fundamental and fascinating problem in biology. Here we show that mutational inactivation of autophagy genes, which are involved in the degradation of aberrant, damaged cytoplasmic constituents accumulating in all aging cells, accelerates the rate at which the tissues age in the nematode Caenorhabditis elegans. According to our results Drosophila flies deficient in autophagy are also short-lived. We further demonstrate that reduced activity of autophagy genes suppresses life span extension in mutant nematodes with inherent dietary restriction, aberrant insulin/IGF-1 or TOR signaling, and lowered mitochondrial respiration. These findings suggest that the autophagy gene cascade functions downstream of and is inhibited by different longevity pathways in C. elegans, therefore, their effects converge on autophagy genes to slow down aging and lengthen life span. Thus, autophagy may act as a central regulatory mechanism of animal aging.     

Saccharomyces cerevisiae SSD1-V confers longevity by a Sir2p-independent mechanism

The SSD1 gene of Saccharomyces cerevisiae is a polymorphic locus that affects diverse cellular processes including cell integrity, cell cycle progression, and growth at high temperature. We show here that the SSD1-V allele is necessary for cells to achieve extremely long life span. Furthermore, addition of SSD1-V to cells can increase longevity independently of SIR2, although SIR2 is necessary for SSD1-V cells to attain maximal life span. Past studies of yeast aging have been performed in short-lived ssd1-d strain backgrounds. We propose that SSD1-V defines a previously undescribed pathway affecting cellular longevity and suggest that future studies on longevity-promoting genes should be carried out in long-lived SSD1-V strains.     

Mitochondrial longevity pathways

Average lifespan has increased over the last centuries, as a consequence of medical and environmental factors, but maximal life span remains unchanged. Better understanding of the underlying mechanisms of aging and determinants of life span will help to reduce age-related morbidity and facilitate healthy aging. 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 oxidative damage. Reactive oxygen species (ROS) have been proposed to cause deleterious effects on DNA, proteins, and lipids, and generation of these highly reactive molecules takes place in the mitochondria. But ROS is positively implicated in cellular stress defense mechanisms and formation of ROS a highly regulated process controlled by a complex network of intracellular signaling pathways. There are endogenous anti-oxidant defense systems that have the potential to partially counteract ROS impact. In this review, we will describe pathways contributing to the regulation of the age-related decline in mitochondrial function and their impact on longevity. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.     

Longevity pathways converge on autophagy genes to regulate life span in Caenorhabditis elegans

Aging is a multifactorial process with many mechanisms contributing to the decline. Mutations decreasing insulin/IGF-1 (insulin-like growth factor-1) or TOR (target of rapamycin) kinase-mediated signaling, mitochondrial activity and food intake each extend life span in divergent animal phyla. Understanding how these genetically distinct mechanisms interact to control longevity is a fundamental and fascinating problem in biology. Here we show that mutational inactivation of autophagy genes, which are involved in the degradation of aberrant, damaged cytoplasmic constituents accumulating in all aging cells, accelerates the rate at which the tissues age in the nematode Caenorhabditis elegans. According to our results Drosophila flies deficient in autophagy are also short-lived. We further demonstrate that reduced activity of autophagy genes suppresses life span extension in mutant nematodes with inherent dietary restriction, aberrant insulin/IGF-1 or TOR signaling, and lowered mitochondrial respiration. These findings suggest that the autophagy gene cascade functions downstream of and is inhibited by different longevity pathways in C. elegans, therefore, their effects converge on autophagy genes to slow down aging and lengthen life span. Thus, autophagy may act as a central regulatory mechanism of animal aging.     

Sir2-independent life span extension by calorie restriction in yeast

Calorie restriction slows aging and increases life span in many organisms. In yeast, a mechanistic explanation has been proposed whereby calorie restriction slows aging by activating Sir2. Here we report the identification of a Sir2-independent pathway responsible for a majority of the longevity benefit associated with calorie restriction. Deletion of FOB1 and overexpression of SIR2 have been previously found to increase life span by reducing the levels of toxic rDNA circles in aged mother cells. We find that combining calorie restriction with either of these genetic interventions dramatically enhances longevity, resulting in the longest-lived yeast strain reported thus far. Further, calorie restriction results in a greater life span extension in cells lacking both Sir2 and Fob1 than in cells where Sir2 is present. These findings indicate that Sir2 and calorie restriction act in parallel pathways to promote longevity in yeast and, perhaps, higher eukaryotes.     

Independent chemical regulation of health and senescent spans in Drosophila

Curcumin feeding of Drosophila larvae or young adults inhibits TOR and other known longevity genes and induces an extended health span in a normal-lived Ra strain adult. Combining larval curcumin feeding with an adult dietary restriction (DR) diet does not yield an additive effect. The age-specific mortality rate is decreased and is comparable with that of genetically selected long-lived La animals. Feeding Ra adults with the drug their whole life, or only during the senescent span, results in a weak negative effect on median longevity with no increase in maximum lifespan. The La strain shows no response to this DR mimetic. Thus, curcumin acts in a life stage-specific manner to extend the health span. Histone deacetylase inhibitors decrease the longevity of Ra animals if administered over the health span only or over the entire adult lifespan, but these inhibitors increase longevity when administered in the transition or senescent spans. Their major effect is a reduction in the mortality rate of older flies, raising the possibility of reducing frailty in older organisms. Their life stage-specific effects are complementary to that of curcumin. Use of stage-specific drugs may enable targeted increases in health or senescent spans, and thus selectively increase the quality of life.