Evolutionary Theories Of Aging Research Articles

Aging: Evolution of Life Span Revisited

A new study reports that high rates of extrinsic mortality can lead to the evolution of a longer life - a pattern opposite to that expected under the classic predictions of the evolutionary theory of aging.

The stress of aging

Although the evolutionary theories of aging are quite well established, our knowledge about how we age is still very limited. The abundance and heterogeneity of available mechanistic theories of aging implicitly suggest that this phenomenon is overly complex and unlikely to be explained by a single pathway. Moreover, although aging remains a unique process, it is characterized by heterogeneous manifestations, not only determining inter-individual variations, but even intra-individual diversities. Such heterogeneity renders the inner nature of the aging process of difficult evaluation in older persons due to the potential biases introduced by multiple age-related social, biological, and clinical factors (and responsible for the evidence-based issue in geriatrics). Moving from the difficulties in translating anti-aging preclinical interventions into clinical trials, an alternative approach is illustrated. We encourage moving to a holistic evaluation of aging by adopting specific and consequent modifications in the design and conduction of clinical research. Such approach is today commonly applied in the clinical setting where the complexity of older patients often requires multidimensional interventions to adequately target the geriatric syndromes. Consistently, interventions targeting the aging process may result ineffective if too focused on a single underlying causal mechanism and/or failing to capture the complexity of the phenomenon. In this context, frailty (a geriatric syndrome characterized by age-related declines occurring across multiple physiologic systems) may indeed represent a clinically relevant threshold throughout the continuum of the aging process and a promising benchmark to test multidomain interventions against age-related conditions.

Fertility/longevity trade‐offs under limiting-male conditions in mating populations of Caenorhabditis elegans

Evolutionary theories of aging suggest that trade-offs between longevity and fitness should be found under certain conditions. In C. elegans, there is little evidence for the existence of such trade-offs. We asked if fertility/longevity trade-offs exist in populations of randomly mating males and hermaphrodites. We set up a large population of young males and 5-day-old hermaphrodites that were no longer self-fertile. We then allowed them to mate for one day with an equal number young males and then separated hermaphrodites to individual plates and determined daily fertility of individual hermaphrodites. There was a significant negative relationship between late-life fertility and individual longevity.

How the evolutionary theory of aging can guide us in the search for aging genes

It is a stroke of irony that lifespan — the principal phenotype used to search for aging genes — is a terrible phenotype for genetic analysis. Lifespan has relatively low heritability under most conditions, and it is affected by chronic, age-related diseases that confound its use as a biomarker of aging. If the majority of aging genes are pleiotropic, as proposed by the evolutionary theory of aging, an opportunity is provided to identify these genes through the “back door,” using phenotypes that are more amenable to genetic analysis. To choose the pleiotropic phenotype for our studies, we went back more than 50 years to Williams [1], who, in his seminal paper, specified four “physiological expectations that follow from the theory,” two of which we applied: “Rapid individual development should be correlated with rapid senescence,” and, to specify a particular developmental phenotype, “The time of reproductive maturation should mark the onset of senescence.” Therefore, to search for genes that regulate lifespan, we looked in the other direction — for genes that govern reproductive maturation. We started our search for pleiotropic aging genes by evaluating the age of female sexual maturity in the highly diverse, 32-inbred strain panel provided by The Jackson Laboratory Nathan Shock Center. As predicted by the evolutionary theory of aging, age of vaginal patency (VP) correlated positively with lifespan across strains. Interestingly, it also correlated negatively with circulating IGF1. And, because, in the same 32 strains of mice, 6-month IGF1 levels also correlate negatively with lifespan [2], it is likely that IGF1 mediates a significant portion of the linkage of reproductive maturation with aging and lifespan. We tested this idea in a congenic C57BL/6J (B6) mouse that carries a portion of Chr 10 from the C3H/HeJ strain. In congenic females, circulating IGF1 was elevated and as predicted, age of VP was accelerated and lifespan was shortened. (In males, IGF1 was not elevated and lifespan was not shortened.) Thus, the stage was set to begin a search for pleiotropic genes that influence both female reproductive maturation and lifespan in the strain panel. Using haplotype association mapping, we identified three loci (Vpq1 [Chr 4], Vpq2 and Vpq3 [both on Chr 16]) that accounted for 76% of the variance in age of VP across strains. Again, IGF1 may be involved. Age of VP was delayed and circulating IGF1 was diminished in the B6.PWD–Chr 16 consomic strain, in which the PWD/PhJ Chr 16, carrying the late age of VP haplotype at Vpq3, replaces the B6 Chr 16, carrying an intermediate age of VP haplotype. Haplotypes of Vpq 3 also associated with differences in lifespan, strongly supporting the hypothesis that a gene at Vpq3 mediates an antagonistic relationship between age of VP and lifespan. We then used an arsenal of bioinformatic and genetic strategies to query Vpq3 for candidate genes, which ultimately designated nuclear receptor interacting protein 1 (Nrip1) as a strong candidate. NRIP1 is a regulator of nuclear receptors that have broad functions in regulating cell growth, cell death, and metabolism. Nrip1, as a transcriptional repressor of PGC-1α and β, could promote senescence by suppressing mitochondrial biogenesis [3]. Nrip1 null (−/−) mice are smaller and leaner, are resistant to high-fat diet-induced obesity, and show increased glucose tolerance and insulin sensitivity [4,5] — mimicking characteristics found in calorierestricted mice. We compared Nrip1 null mice with their normal littermates. Results verified the hypothesis — generated by genetic and bioinformatic analyses — that knocking out Nrip1 could significantly decrease IGF1 level and delay age of VP. Lifespan studies of Nrip1 null mice are in process. Additional work is necessary to verify Nrip1 as an aging gene that mediates an antagonistic relationship between female reproductive maturation and lifespan. But our present analysis does provide direct support for the hypothesis that genes that regulate IGF1 constitute an entire category of pleiotropic genes that influence both reproductive maturation and aging. Our results also suggest that genes such as Nrip1 — with highly pleiotropic effects on metabolism and cell turnover as well as on cell signaling and life history traits — are the types of genes that have the greatest impact on aging. Our work demonstrates that the utilization of pleiotropy in strategies informed by evolutionary theory is an effective approach in the search for genes that regulate aging.

Aging brains and social behavior in an invertebrate model: neuromodulation and neuroanatomy of task attendance across the worker lifespan of the ant Pheidole dentata

Aging brains and social behavior in an invertebrate model: neuromodulation and neuroanatomy of task attendance across the worker lifespan of the ant Pheidole dentata

Sexually extravagant males age more rapidly

Evolutionary theories of ageing posit that increased reproductive investment occurs at the expense of physiological declines in later life. Males typically invest heavily in costly sexual ornaments and behaviour, but evidence that the expression of these traits can cause senescence is lacking. Long-lived houbara bustards (Chlamydotis undulata) engage in extravagant sexual displays to attract mates and here we show that males investing most in these displays experience a rapid senescent deterioration of spermatogenic function at a younger age. This effect is sufficiently large that the expected links between male 'showiness' and fertility reverse in later life, despite 'showy' males continuing to display at near maximal levels. We show that our results cannot be explained by the selective disappearance of competitive phenotypes and that they are instead consistent with an early vs. late life trade-off in male reproductive competence, highlighting the potential significance of sexual selection in explaining rates of ageing.

Helen Small, The Long LifeThe Long Life. HelenSmall. Oxford and New York: Oxford University Press, 2007. Pp. viii+346.

<i>Helen Small,</i> The Long Life<i>The Long Life</i>. HelenSmall. Oxford and New York: Oxford University Press, 2007. Pp. viii+346.

Social influence on age and reproduction: reduced lifespan and fecundity in multi‐queen ant colonies

Evolutionary theories of ageing predict that life span increases with decreasing extrinsic mortality, and life span variation among queens in ant species seems to corroborate this prediction: queens, which are the only reproductive in a colony, live much longer than queens in multi-queen colonies. The latter often inhabit ephemeral nest sites and accordingly are assumed to experience a higher mortality risk. Yet, all prior studies compared queens from different single- and multi-queen species. Here, we demonstrate an effect of queen number on longevity and fecundity within a single, socially plastic species, where queens experience the similar level of extrinsic mortality. Queens from single- and two-queen colonies had significantly longer lifespan and higher fecundity than queens living in associations of eight queens. As queens also differ neither in morphology nor the mode of colony foundation, our study shows that the social environment itself strongly affects ageing rate.

Human lifespan: what determines the intrinsic length of human lives?

SummaryHumans have an intrinsic lifespan of approximately 120 years. Classic evolutionary theories of ageing explain the limit as a response to inevitable cellular damage. The theories share the notion that natural selection acts less strongly to purge deleterious genes that are expressed after reproduction. Reproduction schedules are influenced by a species' ecology and so it is ecological factors which explain interspecies variation in lifespan. Human ecology has favoured the selection of an unusually large brain that both confers advantages that promote longevity and requires longevity to make it a worthwhile investment. The relatively long human lifespan therefore co-evolved with the large human brain.

The relationship between fertility and lifespan in humans

Evolutionary theories of aging predict a trade-off between fertility and lifespan, where increased lifespan comes at the cost of reduced fertility. Support for this prediction has been obtained from various sources. However, which genes underlie this relationship is unknown. To assess it, we first analyzed the association of fertility with age at menarche and menopause, and with mortality in 3,575 married female participants of the Rotterdam Study. In addition, we conducted a candidate gene study where 1,664 single nucleotide polymorphisms (SNPs) in 25 candidate genes were analyzed in relation to number of children as a measure of fertility. SNPs that associated with fertility were analyzed for association with mortality. We observed no associations between fertility and age at menarche (p = 0.38) and menopause (p = 0.07). In contrast, fertility was associated with mortality. Women with two to three children had significantly lower mortality (hazard ratio (HR), 0.82; 95% confidence interval (95% CI), 0.69–0.97) compared to women with no children. No such benefit was observed for women with four or more children, who had a similar mortality risk (HR, 0.93; 95% CI, 0.76–1.13) as women with no children. The analysis of candidate genes revealed four genes that influence fertility after correction for multiple testing: CGB/LHB gene cluster (p = 0.0036), FSHR (p = 0.023), FST (p = 0.023), and INHBA (p = 0.021). However, none of the independent SNPs in these genes predicted mortality. In conclusion, women who bear two to three children live longer than those who bear none or many children, but this relationship was not mediated by the candidate genes analyzed in this study.Electronic supplementary materialThe online version of this article (doi:10.1007/s11357-010-9202-4) contains supplementary material, which is available to authorized users.

Heritability Analysis of Life Span in a Semi-isolated Population Followed Across Four Centuries Reveals the Presence of Pleiotropy Between Life Span and Reproduction

Although genetic factors are known to influence the human aging process, the proportion of life span and longevity variation explained by them is still controversial. We evaluated the genetic contribution to life span using historical data from three Alpine communities in South Tyrol, Italy. We estimated the heritability of life span and survival to old age (longevity), and we assessed the hypothesis of a common genetic background between life span and reproduction. The heritability of life span was 0.15 (SE = 0.02), whereas the heritability of longevity increased from 0.20 to 0.35 as the longevity threshold increased. Heritability estimates were little influenced by shared environment, most likely due to the homogeneity of lifestyle and environmental factors in our study population. Life span showed both positive association and genetic correlation with reproductive history factors. Our study demonstrates a general low inheritance of human life span, but which increases substantially when considering long-living individuals, and a common genetic background of life span and reproduction, in agreement with evolutionary theories of aging.

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

BackgroundSenescence 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 FindingsWe 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/SignificanceWe 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).

Aging as a result of the implementation of the phenoptosis program

There are two main points of view on the driving force of aging: destructive action of free radicals generated by mitochondria and implementation of the genetic program. The free-radical theory dominating now asserts that there are no specific genes of aging, as the evolutionary theory proves inability of natural selection to differentiate separate individuals by longevity. The concept of programmed aging, named phenoptosis, has no wide recognition, since it contradicts postulates of the evolutionary theory of aging and, moreover, has no mechanism for the implementation of the program. The present review shows the following: (1) contrary to the statement of the evolutionary theory of aging, the species-specific longevity is controlled by selection but the interpopulation one rather than individual; hence, there are specific genes of aging; (2) primarily programmed process causing aging is a decrease in the bioenergetics level; and (3) this causes age-related increase of the level of free radicals. Hence, the free-radical theory should be incorporated into the theory of programmed aging as one of the components. The key diagram of the mechanism of programmed aging is presented.

Suitability of the clonal marbled crayfish for biogerontological research: a review and perspective, with remarks on some further crustaceans

This article examines the suitability of the parthenogenetic marbled crayfish for research on ageing and longevity. The marbled crayfish is an emerging laboratory model for development, epigenetics and toxicology that produces up to 400 genetically identical siblings per batch. It is easily cultured, has an adult size of 4-9 cm, a generation time of 6-7 months and a life span of 2-3 years. Experimental data and biological peculiarities like isogenicity, direct development, indeterminate growth, high regeneration capacity and negligible senescence suggest that the marbled crayfish is particularly suitable to investigate the dependency of ageing and longevity from non-genetic factors such as stochastic developmental variation, allocation of metabolic resources, damage and repair, caloric restriction and social stress. It is also well applicable to examine alterations of the epigenetic code with increasing age and to identify mechanisms that keep stem cells active until old age. As a representative of the sparsely investigated crustaceans and of animals with indeterminate growth and extended brood care the marbled crayfish may even contribute to evolutionary theories of ageing and longevity. Some relatives are recommended as substitutes for investigation of topics, for which the marbled crayfish is less suitable like genetics of ageing and achievement of life spans of decades under conditions of low food and low temperature. Research on ageing in the marbled crayfish and its relatives is of practical relevance for crustacean fisheries and aquaculture and may offer starting points for the development of novel anti-ageing interventions in humans.

Evolution: Aging Up a Tree?

Evolutionary theories of aging predict that species in low-risk habitats will evolve longer lifespans. A new study comparing lifespan in arboreal and terrestrial mammals provides further support for this prediction. But is the prediction valid?

Age at the onset of senescence in birds and mammals is predicted by early-life performance

Life-history theory predicts that traits involved in maturity, reproduction and survival correlate along a fast-slow continuum of life histories. Evolutionary theories and empirical results indicate that senescence-related traits vary along this continuum, with slow species senescing later and at a slower pace than fast species. Because senescence patterns are typically difficult to estimate from studies in the wild, here we propose to predict the associated trait values in the frame of life-history theory. From a comparative analysis based on 81 free-ranging populations of 72 species of birds and mammals, we find that a nonlinear combination of fecundity, age at first reproduction and survival over the immature stage can account for ca two-thirds of the variance in the age at the onset of actuarial senescence. Our life-history model performs better than a model predicting the onset based on generation time, and it only includes life-history traits during early life as explanatory variables, i.e. parameters that are both theoretically expected to shape senescence and are measurable within relatively short studies. We discuss the good-fit of our life-history model to the available data in the light of current evolutionary theories of senescence. We further use it to evaluate whether studies that provided no evidence for senescence lasted long enough to include the onset of senescence.

Transgenerational memory effect of ageing in Drosophila

Children born to older parents tend to have lower intelligence and are at higher risk for disorders such as schizophrenia and autism. Such observations of ageing damage being passed on from parents to offspring are not often considered within the evolutionary theory of ageing. Here, we show the 25% memory impairment in Drosophila melanogaster offspring solely dependent on the age of the parents and also passed on to the F2 generation. Furthermore, this parental age effect was not attributed to a generalized reduction in condition of the offspring but was specific to short-term memory. We also provide evidence implicating oxidative stress as a causal factor by showing that lines selected for resistance to oxidative stress did not display a memory impairment in offspring of old parents. The identification of the parental age-related memory impairment in a model system should stimulate integration between mechanistic studies of age-related mortality risk and functional studies of parental age effects on the fitness of future generations.

Arboreality has allowed for the evolution of increased longevity in mammals.

The evolutionary theory of aging predicts that species will experience delayed senescence and increased longevity when rates of extrinsic mortality are reduced. It has long been recognized that birds and bats are characterized by lower rates of extrinsic mortality and greater longevities than nonvolant endotherms, presumably because flight reduces exposure to terrestrial predators, disease, and environmental hazards. Like flight, arboreality may act to reduce extrinsic mortality, delay senescence, and increase longevity and has been suggested as an explanation for the long lifespans of primates. However, this hypothesis has yet to be tested in mammals in general. We analyze a large dataset of mammalian longevity records to test whether arboreal mammals are characterized by greater longevities than terrestrial mammals. Here, we show that arboreal mammals are longer lived than terrestrial mammals at common body sizes, independent of phylogeny. Subclade analyses demonstrate that this trend holds true in nearly every mammalian subgroup, with two notable exceptions-metatherians (marsupials) and euarchontans (primates and their close relatives). These subgroups are unique in that each has experienced a long and persistent arboreal evolutionary history, with subsequent transitions to terrestriality occurring multiple times within each group. In all other clades examined, terrestriality appears to be the primitive condition, and species that become arboreal tend to experience increased longevity, often independently in multiple lineages within each clade. Adoption of an arboreal lifestyle may have allowed for increased longevity in these lineages and in primates in general. Overall, these results confirm the fundamental predictions of the evolutionary theory of aging.

The Promise of Slow Down Ageing May Come from Curcumin

No genes exist that have been selected to promote aging. The evolutionary theory of aging tells us that there is a trade-off between body maintenance and investment in reproduction. It is commonly acceptable that the ageing process is driven by the lifelong accumulation of molecular damages mainly due to reactive oxygen species (ROS) produced by mitochondria as well as random errors in DNA replication. Although ageing itself is not a disease, numerous diseases are age-related, such as cancer, Alzheimer's disease, atherosclerosis, metabolic disorders and others, likely caused by low grade inflammation driven by oxygen stress and manifested by increased level of pro-inflammatory cytokines such as IL-1, IL-6 and TNF-alpha, encoded by genes activated by the transcription factor NF-kappaB. It is believed that ageing is plastic and can be slowed down by caloric restriction as well as by some nutraceuticals. As the low grade inflammatory process is believed substantially to contribute to ageing, slowing ageing and postponing the onset of age-related diseases may be achieved by blocking the NF-kappaB-dependent inflammation. In this review we consider the possibility of the natural spice curcumin, a powerful antioxidant, anti-inflammatory agent and efficient inhibitor of NF-kappaB and the mTOR signaling pathway which overlaps that of NF-kappaB, to slow down ageing.

Evolution of Senescence in Nature: Physiological Evolution in Populations of Garter Snake with Divergent Life Histories

Evolutionary theories of aging are linked to life-history theory in that age-specific schedules of reproduction and survival determine the trajectory of age-specific mutation/selection balances across the life span and thus the rate of senescence. This is predicted to manifest at the organismal level in the evolution of energy allocation strategies of investing in somatic maintenance and robust stress responses in less hazardous environments in exchange for energy spent on growth and reproduction. Here we report experiments from long-studied populations of western terrestrial garter snakes (Thamnophis elegans) that reside in low and high extrinsic mortality environments, with evolved long and short life spans, respectively. Laboratory common-environment colonies of these two ecotypes were tested for a suite of physiological traits after control and stressed gestations. In offspring derived from control and corticosterone-treated dams, we measured resting metabolism; mitochondrial oxygen consumption, ATP and free radical production rates; and erythrocyte DNA damage and repair ability. We evaluated whether these aging biomarkers mirrored the evolution of life span and whether they were sensitive to stress. Neonates from the long-lived ecotype (1) were smaller, (2) consumed equal amounts of oxygen when corrected for body mass, (3) had DNA that damaged more readily but repaired more efficiently, and (4) had more efficient mitochondria and more efficient cellular antioxidant defenses than short-lived snakes. Many ecotype differences were enhanced in offspring derived from stress-treated dams, which supports the conclusion that nongenetic maternal effects may further impact the cellular stress defenses of offspring. Our findings reveal that physiological evolution underpins reptilian life histories and sheds light on the connectedness between stress response and aging pathways in wild-dwelling organisms.