Senescence Is More Important in the Natural Lives of Long- Than Short-Lived Mammals

Background

Senescence has been widely detected among mammals, but its importance to fitness in wild populations remains controversial. According to evolutionary theories, senescence occurs at an age when selection is relatively weak, which in mammals can be predicted by adult survival rates. However, a recent analysis of senescence rates found more age-dependent mortalities in natural populations of longer lived mammal species. This has important implications to ageing research and for understanding the ecological relevance of senescence, yet so far these have not been widely appreciated. We re-address this question by comparing the mean and maximum life span of 125 mammal species. Specifically, we test the hypothesis that senescence occurs at a younger age relative to the mean natural life span in longer lived species.

Methodology/Principal Findings

We show, using phylogenetically-informed generalised least squares models, a significant log-log relationship between mean life span, as calculated from estimates of adult survival for natural populations, and maximum recorded life span among mammals (R² = 0.57, p<0.0001). This provides further support for a key prediction of evolutionary theories of ageing. The slope of this relationship (0.353±0.052 s.e.m.), however, indicated that mammals with higher survival rates have a mean life span representing a greater fraction of their potential maximum life span: the ratio of maximum to mean life span decreased significantly from >10 in short-lived to ∼1.5 in long-lived mammal species.

Conclusions/Significance

We interpret the ratio of maximum to mean life span to be an index of the likelihood an individual will experience senescence, which largely determines maximum life span. Our results suggest that senescence occurs at an earlier age relative to the mean life span, and therefore is experienced by more individuals and remains under selection pressure, in long- compared to short-lived mammals. A minimum rate of somatic degradation may ultimately limit the natural life span of mammals. Our results also indicate that senescence and modulating factors like oxidative stress are increasingly important to the fitness of longer lived mammals (and vice versa).     

Environmental effects on the expression of life span and aging: an extreme contrast between wild and captive cohorts of Telostylinus angusticollis (Diptera: Neriidae)

Most research on life span and aging has been based on captive populations of short-lived animals; however, we know very little about the expression of these traits in wild populations of such organisms. Because life span and aging are major components of fitness, the extent to which the results of many evolutionary studies in the laboratory can be generalized to natural settings depends on the degree to which the expression of life span and aging differ in natural environments versus laboratory environments and whether such environmental effects interact with phenotypic variation. We investigated life span and aging in Telostylinus angusticollis in the wild while simultaneously estimating these parameters under a range of conditions in a laboratory stock that was recently established from the same wild population. We found that males live less than one-fifth as long and age at least twice as rapidly in the wild as do their captive counterparts. In contrast, we found no evidence of aging in wild females. These striking sex-specific differences between captive and wild flies support the emerging view that environment exerts a profound influence on the expression of life span and aging. These findings have important implications for evolutionary gerontology and, more generally, for the interpretation of fitness estimates in captive populations.     

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.     

An explanation for negligible senescence in animals

Negligible or negative senescence occurs when mortality risk is stable or decreases with age, and has been observed in some wild animals. Age‐independent mortality in animals may lead to an abnormally long maximum individual lifespans and be incompatible with evolutionary theories of senescence. The reason why there is no evidence of senescence in these animals has not been fully understood. Recovery rates are usually very low for wild animals with high dispersal ability and/or small body size (e.g., bats, rodents, and most birds). The only information concerning senescence for most of these species is the reported lifespan when individuals are last seen or caught. We deduced the probability density function of the reported lifespan based on the assumption that the real lifespan corresponding to Weibull or Gompertz distribution. We show that the magnitude of the increase in mortality risk is largely underestimated based on the reported lifespans with low recovery probability. The risk of mortality can aberrantly appear to have a negative correlation with age when it actually increases with increasing lifespan. We demonstrated that the underestimated aging rate for wild animals with low recovery probability can be generalizable to any aging models. Our work provides an explanation for the appearance of negligible senescence in many wild animals. Humans attempt to obtain insights from other creatures to better understand our own biology and its gain insight into how to enhance and extended human health. Our advice is to take a second glance before admiring the negligible senescence in other animals. This ability to escape from senescence is possibly only as beautiful illusion in animals.     

Anecdotal, Historical and Critical Commentaries on Genetics: The Szilard Hypothesis on the Nature of Aging Revisited

This year marks the 50th anniversary of a nearly forgotten hypothesis on aging by Leo Szilard, best known for his pioneering work in nuclear physics, his participation in the Manhattan Project during World War II, his opposition to the nuclear arms race in the postwar era, and his pioneering ideas in biology. Given a specific set of assumptions, Szilard hypothesized that the major reason for the phenomenon of aging was aging hits, e.g., by ionizing radiation, to the gene-bearing chromosomes and presented a mathematical target-hit model enabling the calculation of the average and maximum life span of a species, as well as the influence of increased exposure to DNA-damaging factors on life expectancy. While many new findings have cast doubt on the specific features of the model, this was the first serious effort to posit accumulated genetic damage as a cause of senescence. Here, we review Szilard's assumptions in the light of current knowledge on aging and reassess his mathematical model in an attempt to reach a conclusion on the relevance of Szilard's aging hypothesis today.     

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.     

Mammalian growth and development parameters, cell proliferation in culture and the maximal life span]

The maximum life span of mammals is known to be proportional to the pregnancy duration and to the age at puberty. We found that the maximum life span of mammals was also proportional to the number of cell doublings, and inversely proportional to the rate of duplication of these cells, during embryogenesis or for the time from zygote formation to growth termination. We found also that the life span of "stationary phase aging" transformed Chinese hamster cells (time from subcultivation until culture "death", i.e., until the moment when the number of live cells is less than 10% of their number at saturation density) was proportional to the duration of their growth and number of cell doublings during the period from subcultivation to saturation density, and inversely proportional to the rate of cell culture duplication during the same period. The dependencies for cell cultures and mammals proved to be analogous to each other. An approximately twofold decrease in the cell duplication rate, as a result of a decrease of the growth medium temperature from 37 to 27 degrees C or the introduction of ethanol to a final concentration 2%, increased the life span of "stationary phase aging" cultures more than twofold. The data obtained suggest that influences resulting in optimized delay of the rate of cell duplication, and correspondingly the mean rate of proliferation during the period of growth in mammals, may increase their maximum life span.     

The rate of free radical production as a determinant of the rate of aging: evidence from the comparative approach

The relationship of oxidative stress with maximum life span (MLSP) in different vertebrate species is reviewed. In all animal groups the endogenous levels of enzymatic and non-enzymatic antioxidants in tissues negatively correlate with MLSP and the most longevous animals studied in each group, pigeon or man, show the minimum levels of antioxidants. A possible evolutionary reason for this is that longevous animals produce oxygen radicals at a low rate. This has been analysed at the place where more than 90% of oxygen is consumed in the cell, the mitochondria. All available work agrees that, across species, the longer the life span, the lower the rate of mitochondrial oxygen radical production. This is true even in animal groups that do not conform to the rate of living theory of aging, such as birds. Birds have low rates of mitochondrial oxygen radical production, frequently due to a low free radical leak in their respiratory chain. Possibly the low rate of mitochondrial oxygen radical production of longevous species can decrease oxidative damage at targets important for aging (like mitochondrial DNA) that are situated near the places of free radical generation. A low rate of free radical production can contribute to a low aging rate both in animals that conform to the rate of living (metabolic) theory of aging and in animals with exceptional longevities, like birds and primates. Available research indicates there are at least two main characteristics of longevous species: a high rate of DNA repair together with a low rate of free radical production near DNA. Simultaneous consideration of these two characteristics can explain part of the quantitative differences in longevity between animal species. Accepted: 12 December 1997     

Positive correlation between mammalian life span and cellular resistance to stress

Identifying the mechanisms determining species-specific life spans is a central challenge in understanding the biology of aging. Cellular stresses produce damage, that may accumulate and cause aging. Evolution theory predicts that long-lived species secure their longevity through investment in a more durable soma, including enhanced cellular resistance to stress. To investigate whether cells from long-lived species have better mechanisms to cope with oxidative and non-oxidative stress, we compared cellular resistance of primary skin fibroblasts from eight mammalian species with a range of life spans. Cell survival was measured by the thymidine incorporation assay following stresses induced by paraquat, hydrogen peroxide, tert-butyl hydroperoxide, sodium arsenite and alkaline pH (sodium hydroxide). Significant positive correlations between cell LD90 and maximum life span were found for all these stresses. Similar results were obtained when cell survival was measured by the MTT assay, and when lymphocytes from different species were compared. Cellular resistance to a variety of oxidative and non-oxidative stresses was positively correlated with mammalian longevity. Our results support the concept that the gene network regulating the cellular response to stress is functionally important in aging and longevity.     

Cats, "rats," and bats: the comparative biology of aging in the 21st century

Laboratory models have suggested a link between metabolism and life span in vertebrates, and it is well known that the evolution of specific life histories can be driven by metabolic factors. However, little is known regarding how the adoption of specific life-history strategies can shape aging and life span in populations facing different energetic demands from either a theoretical or a mechanistic viewpoint but significant insight can be gained by using a comparative approach. Comparative biology plays several roles in our understanding of the virtually ubiquitous phenomenon of aging in animals. First, it provides a critical evaluation of broad hypotheses concerning the evolutionary forces underlying the modulation of aging rate. Second, it suggests mechanistic hypotheses about processes of aging. Third, it illuminates particularly informative species because of their exceptionally slow or rapid aging rates to be interrogated about potentially novel mechanisms of aging. Although comparative biology has played a significant role in research on aging for more than a century, the new comparative biology of aging is poised to dwarf those earlier contributions, because: (1) new cellular and molecular techniques for investigating novel species are in place and more are being continually generated, (2) molecular systematics has resolved the phylogenetic relationships among a wide range of species, which allow for the implementation of analytic tools specialized for comparative biology, and (3) in addition to facilitating the construction of accurate phylogenies, the dramatic acceleration in DNA-sequencing technology is providing us with new tools for a comparative genomic approach to understanding aging.     

Extension of life span of Drosophila melanogaster by the inhibitors of tryptophan-kynurenine metabolism

Upregulation of kynurenine (KYN) formation from tryptophan (TRY) was associated with aging in animal and human studies. TRY-KYN metabolism is affected by the activities of TRY 2,3-dioxygenase 2 (TDO) and AT P-binding cassette (ABC) transporter regulating TRY access to intracellular TDO. We studied the effects of TDO inhibitor, alpha-methyl tryptophan (aMT) and ABC transported inhibitor, 5-methyl tryptophan (5MT), on the life span of wild strain female Drosophila flies (Oregon-R). aMT and 5MT prolonged mean and maximum life span (by 27% and 43%, and 21% and 23%, resp.). The present results are the first observation of the extension of life span of Drosophila melanogaster by inhibitors of TRY-KYN metabolism, and in line with literature and previous studies on prolonged life span of TDO- and ABC-deficient female Drosophila mutants. Inhibition of TDO and ABC transporter activity might offer the new target for anti-aging interventions.     

Pro-Aging Effects of Glucose Signaling through a G Protein-Coupled Glucose Receptor in Fission Yeast

Glucose is the preferred carbon and energy source in prokaryotes, unicellular eukaryotes, and metazoans. However, excess of glucose has been associated with several diseases, including diabetes and the less understood process of aging. On the contrary, limiting glucose (i.e., calorie restriction) slows aging and age-related diseases in most species. Understanding the mechanism by which glucose limits life span is therefore important for any attempt to control aging and age-related diseases. Here, we use the yeast Schizosaccharomyces pombe as a model to study the regulation of chronological life span by glucose. Growth of S. pombe at a reduced concentration of glucose increased life span and oxidative stress resistance as reported before for many other organisms. Surprisingly, loss of the Git3 glucose receptor, a G protein-coupled receptor, also increased life span in conditions where glucose consumption was not affected. These results suggest a role for glucose-signaling pathways in life span regulation. In agreement, constitutive activation of the Gα subunit acting downstream of Git3 accelerated aging in S. pombe and inhibited the effects of calorie restriction. A similar pro-aging effect of glucose was documented in mutants of hexokinase, which cannot metabolize glucose and, therefore, are exposed to constitutive glucose signaling. The pro-aging effect of glucose signaling on life span correlated with an increase in reactive oxygen species and a decrease in oxidative stress resistance and respiration rate. Likewise, the anti-aging effect of both calorie restriction and the Δgit3 mutation was accompanied by increased respiration and lower reactive oxygen species production. Altogether, our data suggest an important role for glucose signaling through the Git3/PKA pathway to regulate S. pombe life span.     

Seasonal comparisons of Barn Owl diets in an agricultural and natural area in central South Africa

Longevity and displacement records aid in the understanding of animal senescence and the possible range of a species. Within wild populations this information is infrequent with most longevity reports being based on captive individuals and displacements being calculated from few monitored individuals within the population. Ringing offers a means of calculating these values and for avian species SAFRING and other bird ringing schemes are critically important. As many vulture populations are under threat, it has become ever more important to analyse all aspects of their demography to understand what can be done to aid the conservation of these species. Southern Africa’s eight vulture species are almost all listed as globally threatened and as a result many studies incorporate this ringing information. This has allowed for longevity records to be calculated for most of the species with the Cape Vulture obtaining the greatest reported longevity of 31 years 2 months and 14 days. In addition to the longevity records, ringing also produces maximum displacement records with the greatest vulture displacement being 2 530 km (White-backed Vulture). Although vulture ringing effort has improved in recent years very few new longevity records appear to be produced with most recent recoveries being under 10 years.     

A molecular marker confirms that the rate of adult maturation is largely independent of the rate of pre-adult development in Drosophila melanogaster

The separation of adult from pre-adult life seen with animals such as Drosophila melanogaster, which are holometabolous and undergo complete metamorphosis, provides the opportunity to examine the contribution of pre-adult rate of development on the rate of maturation and aging of the adult. Recent work has shown that when ambient temperature is used to alter the rate of development there is little effect on adult life span. From this work it has been concluded that the rate of aging is largely independent of the rate of pre-adult development. However, the techniques used to examine life span did not allow for the examination of the earliest events of adult life. Our experimental design used a molecular marker linked to life span as a sensitive measure of determining physiological age. In this way, we were able to evaluate the effect of pre-adult rate of development on the earliest events of adult life. Using ambient temperature to alter both the rate of development in the pre-adult and the rate of aging in the adult independently, we were able to show that it is the ambient temperature at which the adults are living that is the principle determinant of the rate of maturation and aging of the adult. Little effect was seen on the rate of adult maturation in response to an acceleration or a slowing down of the rate of pre-adult development as measured by our molecular marker. These data support the conclusions drawn by others who examined the effect of the rate of development on adult life expectancy. The timing mechanisms at work during pre-adult and adult life appear to be largely regulated separately. If there is such a thing as a physiological clock, it appears to be reset upon eclosion. © 1996 Wiley-Liss, Inc.     

Effect of different fetal bovine serum concentrations on the replicative life span of cultured chick cells

The effect of Eagle's minimal essential medium, containing different fetal bovine serum (FBS) concentrations, on the proliferation and replicative life span of cultured chick cells has been studied. Our results showed that the rate of chick cell proliferation and the cell density at stationary phase increased as a function of serum concentration between 5 and 30% FBS. The replicative life span of cultured chick cells was dependent on the FBS concentration between 5 and 20% in a medium volume of 0.20 ml/cm2. The maximum replicative life span of chick cells was obtained by serially propagating cells in a medium volume of 0.20 ml/cm2 containing 20 or 30% FBS, or, alternatively, in 0.53 ml/cm2 containing 10, 20 or 30% FBS. Cells grown in medium containing 5% serum had a calendar life span of 35 days, whereas cells propagated in medium containing higher serum concentrations had a calendar life span of 50 days. These results reenforce the concept that, although the kinetics of cell population aging can be affected by the culture medium composition, the aging of cells in culture is controlled by alterations within the cell.     

Effects of overexpression of copper-zinc and manganese superoxide dismutases,catalase, and thioredoxin reductase genes on longevity in Drosophila melanogaster

The overexpression of antioxidative enzymes such as CuZn-superoxide dismutase (SOD), Mn-SOD, and catalase has previously been reported to extend life span in transgenic flies (Drosophila melanogaster). The purpose of this study was to determine whether life-extending effects persist if the recipient control strains of flies are relatively long-lived. Accordingly, the life spans of large numbers of replicate control and overexpressor lines were determined in two long-lived genetic backgrounds involving a combined total of >90,000 flies. Significant increases in the activities of both CuZn-SOD and catalase had no beneficial effect on survivorship in relatively long-lived y w mutant flies and were associated with slightly decreased life spans in wild type flies of the Oregon-R strain. The introduction of additional transgenes encoding Mn-SOD or thioredoxin reductase in the same genetic background also failed to cause life span extension. In conjunction with data from earlier studies, the results show that increasing the activities of these major antioxidative enzymes above wild type levels does not decrease the rate of aging in long-lived strains of Drosophila, although there may be some effect in relatively short-lived strains.     

Up-regulation of the Cdc42 GTPase limits the replicative life span of budding yeast

Cdc42, a conserved Rho GTPase, plays a central role in polarity establishment in yeast and animals. Cell polarity is critical for asymmetric cell division, and asymmetric cell division underlies replicative aging of budding yeast. Yet how Cdc42 and other polarity factors impact life span is largely unknown. Here we show by live-cell imaging that the active Cdc42 level is sporadically elevated in wild type during repeated cell divisions but rarely in the long-lived bud8 deletion cells. We find a novel Bud8 localization with cytokinesis remnants, which also recruit Rga1, a Cdc42 GTPase activating protein. Genetic analyses and live-cell imaging suggest that Rga1 and Bud8 oppositely impact life span likely by modulating active Cdc42 levels. An rga1 mutant, which has a shorter life span, dies at the unbudded state with a defect in polarity establishment. Remarkably, Cdc42 accumulates in old cells, and its mild overexpression accelerates aging with frequent symmetric cell divisions, despite no harmful effects on young cells. Our findings implicate that the interplay among these positive and negative polarity factors limits the life span of budding yeast.     

Age-specific metabolic rates and mortality rates in the genus Drosophila

Early theories of aging suggested that organisms with relatively high metabolic rates would live shorter lives. Despite widespread tests of this 'rate of living' theory of aging, there is little empirical evidence to support the idea. A more fine-grained approach that examined age-related changes in metabolic rate over the life span could provide valuable insight into the relationship between metabolic rate and aging. Here we compare age-related metabolic rate (measured as CO2 production per hour) and age-related mortality rate among five species in the genus Drosophila. We find no evidence that longer-lived species have lower metabolic rates. In all five species, there is no clear evidence of an age-related metabolic decline. Metabolic rates are strikingly constant throughout the life course, with the exception of females of D. hydei, in which metabolic rates show an increase over the first third of the life span and then decline. We argue that some physiological traits may have been shaped by such strong selection over evolutionary time that they are relatively resistant to the decline in the force of selection that occurs within the life time of a single individual. We suggest that comparisons of specific traits that do not show signs of aging with those traits that do decline with age could provide insight into the aging process.     

Invited review: Theories of aging.

Several factors (the lengthening of the average and, to a lesser extent, of the maximum human life span; the increase in percentage of elderly in the population and in the proportion of the national expenditure utilized by the elderly) have stimulated and continue to expand the study of aging. Recently, the view of aging as an extremely complex multifactorial process has replaced the earlier search for a distinct cause such as a single gene or the decline of a key body system. This minireview keeps in mind the multiplicity of mechanisms regulating aging; examines them at the molecular, cellular, and systemic levels; and explores the possibility of interactions at these three levels. The heterogeneity of the aging phenotype among individuals of the same species and differences in longevity among species underline the contribution of both genetic and environmental factors in shaping the life span. Thus, the presence of several trajectories of the life span, from incidence of disease and disability to absence of pathology and persistence of function, suggest that it is possible to experimentally (e.g., by calorie restriction) prolong functional plasticity and life span. In this minireview, several theories are identified only briefly; a few (evolutionary, gene regulation, cellular senescence, free radical, and neuro-endocrineimmuno theories) are discussed in more detail, at molecular, cellular, and systemic levels.     

Oxidative damage to mitochondrial DNA is inversely related to maximum life span in the heart and brain of mammals.

DNA damage is considered of paramount importance in aging. Among causes of this damage, free radical attack, particularly from mitochondrial origin, is receiving special attention. If oxidative damage to DNA is involved in aging, long-lived animals (which age slowly) should show lower levels of markers of this kind of damage than short-lived ones. However, this possibility has not heretofore been investigated. In this study, steady-state levels of 8-oxo-7, 8-dihydro-2'-deoxyguanosine (8-oxodG) referred to deoxyguanosine (dG) were measured by high performance liquid chromatography (HPLC) in the mitochondrial (mtDNA) and nuclear (nDNA) DNA from the heart of eight and the brain of six mammalian species ranging in maximum life span (MLSP) from 3.5 to 46 years. Exactly the same digestion of DNA to deoxynucleosides and HPLC protocols was used for mtDNA and nDNA. Significantly higher (three- to ninefold) 8-oxodG/dG values were found in mtDNA than in nDNA in all the species studied in both tissues. 8-oxodG/dG in nDNA did not correlate with MLSP across species either in the heart (r=-0.68; P<0.06) or brain (r = 0.53; P<0.27). However, 8-oxodG/dG in mtDNA was inversely correlated with MLSP both in heart (r=-0.92; P<0.001) and brain (r=-0.88; P<0.016) tissues following the power function y = a(.)x(b), where y is 8-oxodG/dG and x is the MLSP. This agrees with the consistent observation that mitochondrial free radical generation is also lower in long-lived than in short-lived species. The results obtained agree with the notion that oxygen radicals of mitochondrial origin oxidatively damage mtDNA in a way related to the aging rate of each species.-Barja, G., Herrero, A. Oxidative damage to mitochondrial DNA is inversely related to maximum life span in the heart and brain of mammals.