Longevity and ageing: appraising the evolutionary consequences of growing old

Senescence or ageing is an increase in mortality and/or decline in fertility with increasing age. Evolutionary theories predict that ageing or longevity evolves in response to patterns of extrinsic mortality or intrinsic damage. If ageing is viewed as the outcome of the processes of behaviour, growth and reproduction then it should be possible to predict mortality rate. Recent developments have shown that it is now possible to integrate these ecological and physiological processes and predict the shape of mortality trajectories. By drawing on the key exciting developments in the cellular, physiological and ecological process of longevity the evolutionary consequences of ageing are reviewed. In presenting these ideas an evolutionary demographic framework is used to argue how trade-offs in life-history strategies are important in the maintenance of variation in longevity within and between species. Evolutionary processes associated with longevity have an important role in explaining levels of biological diversity and speciation. In particular, the effects of life-history trait trade-offs in maintaining and promoting species diversity are explored. Such trade-offs can alleviate the effects of intense competition between species and promote species coexistence and diversification. These results have important implications for understanding a number of core ecological processes such as how species are divided among niches, how closely related species co-occur and the rules by which species assemble into food-webs. Theoretical work reveals that the proximate physiological processes are as important as the ecological factors in explaining the variation in the evolution of longevity. Possible future research challenges integrating work on the evolution and mechanisms of growing old are briefly discussed.     

Understanding ageing.

A broad biological approach makes it possible to understand why ageing exists and also why different mammalian species have very different maximum longevities. The adult organism is maintained in a functional state by at least ten major mechanisms, which together comprise a substantial proportion of all biological processes. These maintenance mechanisms eventually fail, because the evolved physiological and anatomical design of higher animals is incompatible with continual survival. The lifespan of each mammalian species depends on the efficiency of maintenance of their cells, tissues and organisms, and there is much evidence that such maintenance is more effective in long-lived species, such as man, than in short-lived small mammals. It is also evident that there is an inverse relationship between reproductive potential and longevity, which would be expected if total metabolic resources are shared between investment in reproduction, and investment in the preservation of the adult body. It is proposed that the eventual failure of maintenance leads to the pathological changes seen in age-associated disease. Although we now have a biological understanding of the ageing process, much future research will be needed to uncover the cellular and molecular changes which give rise to age-associated diseases. The major aim of such research is to devise procedures to delay or prevent the onset of these diseases.     

Metabolism and aging in the nematode Caenorhabditis elegans

Research into the causes of aging has greatly increased in recent years. Much of this interest is due to the discovery of genes in a variety of model organisms that appear to modulate aging. Studies of long-lived mutants can potentially provide valuable insights into the fundamental mechanisms of aging. While there are many advantages to the use of model organisms to study aging it is also important to consider the limitations of these systems, particularly because ectothermic (poikilothermic) organisms can survive a far greater metabolic depression than humans. As such, the consideration of only chronological longevity when assaying for long-lived mutants provides a limited perspective on the mechanisms by which longevity is increased. Additional physiological processes, such as metabolic rate, must also be assayed to provide true insight into the aging process. This is especially true in the nematode Caenorhabditis elegans, which has the natural ability to enter into a metabolically reduced state in which it can survive many times longer than its normal lifetime. The extended longevity of at least some long-lived C. elegans mutants may be due to a reduction in metabolic rate, rather than an alteration of a metabolically independent genetic mechanism specific for aging.     

Insulin/IGF signalling and ageing: seeing the bigger picture

Although the underlying mechanisms of ageing are not understood, it is known that the longevity of the nematode Caenorhabditis elegans is modulated by an insulin/IGF-signalling pathway. The focus now is on how this pathway is regulated, how it controls nematode ageing, and how this relates to the ageing process in higher animals.     

Ageing, gerontogenes, and hormesis

Evolutionary theories of ageing and longevity argue against the existence of specific genes that cause ageing. However, genes whose altered activity influences ageing and longevity, may be termed gerontogenes. Several putative gerontogenes have been identified in various ageing systems, including the Drosophila, budding yeast, nematodes and cells in culture. Since ageing is characterized by a progressive failure of maintenance and repair, it is reasoned that genes involved in homeodynamic repair pathways are the most likely candidate gerontogenes. A promising approach for the identification of critical gerontogenic processes is hormesis-like positive effects of stress. Stimulation of various repair pathways by mild stress has significant effects on delaying the onset of various age-associated alterations in cells, tissues and organisms.     

The origins of human ageing.

The origins of human ageing are to be found in the origins and evolution of senescence as a general feature in the life histories of higher animals. Ageing is an intriguing problem in evolutionary biology because a trait that limits the duration of life, including the fertile period, has a negative impact on Darwinian fitness. Current theory suggests that senescence occurs because the force of natural selection declines with age and because longevity is only acquired at some metabolic cost. In effect, organisms may trade late survival for enhanced reproductive investments in earlier life. The comparative study of ageing supports the general evolutionary theory and reveals that human senescence, while broadly similar to senescence in other mammalian species, has distinct features, such as menopause, that may derive from the interplay of biological and social evolution.     

Genomics of human longevity

In animal models, single-gene mutations in genes involved in insulin/IGF and target of rapamycin signalling pathways extend lifespan to a considerable extent. The genetic, genomic and epigenetic influences on human longevity are expected to be much more complex. Strikingly however, beneficial metabolic and cellular features of long-lived families resemble those in animals for whom the lifespan is extended by applying genetic manipulation and, especially, dietary restriction. Candidate gene studies in humans support the notion that human orthologues from longevity genes identified in lower species do contribute to longevity but that the influence of the genetic variants involved is small. Here we discuss how an integration of novel study designs, labour-intensive biobanking, deep phenotyping and genomic research may provide insights into the mechanisms that drive human longevity and healthy ageing, beyond the associations usually provided by molecular and genetic epidemiology. Although prospective studies of humans from the cradle to the grave have never been performed, it is feasible to extract life histories from different cohorts jointly covering the molecular changes that occur with age from early development all the way up to the age at death. By the integration of research in different study cohorts, and with research in animal models, biological research into human longevity is thus making considerable progress.     

Endless paces of degeneration—applying comparative genomics to study evolution's moulding of longevity

Why do mice and humans have such different lifespans? Genome sequencing efforts are allowing researchers to pick apart the genetic foundations of longevity, with some promising results beginning to emerge.Why can mice not live more than five years and dogs not more than 30, yet bats can live over 40 years and humans over a century? Differences in longevity between closely related species are one of the greatest mysteries in biology, and identifying the processes responsible could ultimately presage the development of therapies against a multitude of age-related diseases. The variation in mammalian longevity must have a genomic basis, with recent genome sequencing efforts opening up exciting opportunities to decipher it; some promising results are beginning to emerge. Analysis of two bat genomes revealed that a high proportion of genes in the DNA damage checkpoint–DNA repair pathway, including ATM, TP53, RAD50 and KU80, are under selection in bats [1]. This finding is exciting because these genes have been directly associated with ageing in model systems and, therefore, it points towards a potential role for averting DNA damage in longevity assurance mechanisms; a notion dating back several decades that remains contentious. In addition, the report of a systematic scan for proteins with accelerated evolution in mammalian lineages in which longevity increased over the course of their evolution, hinted that some repair systems, such as the ubiquitin–proteasome pathway and a few proteins related to DNA damage repair, might have been selected for in long-lived lineages [2]. However, much work remains to improve the signal-to-noise ratio of this and similar methods.With decreasing costs of sequencing, the growing number of genomes of species with diverse lifespans is expected to facilitate studies in this area. As such, we can make an increasing number of comparisons such as those described above. Put simply, if we study long-lived species and find that they share genetic adaptations—for example in DNA damage response pathways—then we might assume that those adaptations are important to increase longevity. There are major intrinsic difficulties with this type of analysis, however, that one must keep in mind. Perhaps the best illustration is that despite the dramatic phenotypic divergence between humans and chimpanzees, only a relatively small number of genetic adaptations that are probably responsible for such divergence have thus far been identified [3]. One difficulty is that the genomic elements underlying species differences remain controversial. Possible processes include mutations in coding and non-coding sequences, gene family expansion and contraction, and copy number variation, all of which we think must be explored in the context of longevity adaptations. Whilst changes in regulatory regions might be important, standard methods are lacking for the detection of selection on functional non-coding sequences on a genome-wide scale and this, we think, is a limitation for progress in this area. Another limitation is that experimental validation of promising candidates is often extremely difficult to obtain.Applying comparative genomics to study the evolution of longevity also has unique challenges. For one, the force of natural selection weakens with age, indicating that, although under low-hazard conditions selection favours genes and pathways conferring longevity, selective pressure for longevity is significantly less than for other traits. Furthermore, we think that the integration of additional data—for example gene expression and age-related phenotypic data—is crucial to link genotypes to phenotypes and identify physiological adaptations that are required for extended longevity. Unfortunately, such data and even the necessary samples to generate it are as yet only available for a subset of species. In our opinion, another crucial issue is the extent to which common mechanisms underlie the extension of longevity by evolution in different species. Just as rare variants contribute to missing human heritability, taxa-specific adaptations might contribute to longevity. It can be assumed that the environment—for example, diet—of each species will influence the physiological and biochemical pathways that must be optimized to fend off ageing and age-related diseases. However, the ageing process, despite progressing at different rates, is remarkably similar across most mammals studied [4], hinting that retarding ageing might involve adaptations in similar pathways. The degree of overlap between longevity assurance mechanisms is, in our view, a crucial determinant of how much we can expect to learn about species differences in ageing in the foreseeable future. If common pathways do indeed underlie longevity evolution in multiple species, even if involving different genetic elements in different taxa, then it is reasonable to expect that they can be identified by using comparative genomics as more genomes of short- and long-lived species are sequenced. We hope to live long enough to help unravel this age-old problem.     

Systems biology of ageing and longevity

Ageing is intrinsically complex, being driven by multiple causal mechanisms. Each mechanism tends to be partially supported by data indicating that it has a role in the overall cellular and molecular pathways underlying the ageing process. However, the magnitude of this role is usually modest. The systems biology approach combines (i) data-driven modelling, often using the large volumes of data generated by functional genomics technologies, and (ii) hypothesis-driven experimental studies to investigate causal pathways and identify their parameter values in an unusually quantitative manner, which enables the contributions of individual mechanisms and their interactions to be better understood, and allows for the design of experiments explicitly to test the complex predictions arising from such models. A clear example of the success of the systems biology approach in unravelling the complexity of ageing can be seen in recent studies on cell replicative senescence, revealing interactions between mitochondrial dysfunction, telomere erosion and DNA damage. An important challenge also exists in connecting the network of (random) damage-driven proximate mechanisms of ageing with the higher level (genetically specified) signalling pathways that influence longevity. This connection is informed by actions of natural selection on the determinants of ageing and longevity.     

The influence of metabolic rate on longevity in the nematode Caenorhabditis elegans

Much of the recent interest in aging research is due to the discovery of genes in a variety of model organisms that appear to modulate aging. A large amount of research has focused on the use of such long-lived mutants to examine the fundamental causes of aging. While model organisms do offer many advantages for studying aging, it also critical to consider the limitations of these systems. In particular, ectothermic (poikilothermic) organisms can tolerate a much larger metabolic depression than humans. Thus, considering only chronological longevity when assaying for long-lived mutants provides a limited perspective on the mechanisms by which longevity is increased. In order to provide true insight into the aging process additional physiological processes, such as metabolic rate, must also be assayed. This is especially true in the nematode Caenorhabditis elegans, which can naturally enter into a metabolically reduced state in which it survives many times longer than its usual lifetime. Currently it is seen as controversial if long-lived C. elegans mutants retain normal metabolic function. Resolving this issue requires accurately measuring the metabolic rate of C. elegans under conditions that minimize environmental stress. Additionally, the relatively small size of C. elegans requires the use of sensitive methodologies when determining metabolic rates. Several studies indicating that long-lived C. elegans mutants have normal metabolic rates may be flawed due to the use of inappropriate measurement conditions and techniques. Comparisons of metabolic rate between long-lived and wild-type C. elegans under more optimized conditions indicate that the extended longevity of at least some long-lived C. elegans mutants may be due to a reduction in metabolic rate, rather than an alteration of a metabolically independent genetic mechanism specific to aging.     

The evolution of plant life span: facts and hypotheses

There are two different views on the evolution of life forms in Cormophyta: from woody plants to herbaceous ones or in opposite direction - from herbs to trees. In accordance with these views it is supposed that life span in plants changed in the course of evolution from many years (perennials) to few years (annuals, biennials), or went in reverse - from few years to many years. The author discusses the problems of senescence and longevity in Cormophyta in the context of various hypotheses of ageing (programmed death theory, mutation accumulation, antagonistic pleiotropy, disposable soma, genes of ageing, genes of longevity). Special attention is given to bio-morphological aspects of longevity and cases of non-ageing plants ("negative senescence", "potential immortality"). It is proposed to distinguish seven models of simple ontogenesis in Cormophyta that can exemplify the diversity of mechanisms of ageing and longevity. The evolution of life span in plants is considered as an indirect result of natural selection of other characteristics of organisms or as a consequence of fixation of modifications (episelectional evolution). It seems that short life span could emerge several times during evolution of one group of plants, thus favoring its adaptive radiation.     

Calorie restriction, SIRT1 and metabolism: understanding longevity

Calorie restriction (CR) is the only experimental manipulation that is known to extend the lifespan of a number of organisms including yeast, worms, flies, rodents and perhaps non-human primates. In addition, CR has been shown to reduce the incidence of age-related disorders (for example, diabetes, cancer and cardiovascular disorders) in mammals. The mechanisms through which this occurs have been unclear. CR induces metabolic changes, improves insulin sensitivity and alters neuroendocrine function in animals. In this review, we summarize recent findings that are beginning to clarify the mechanisms by which CR results in longevity and robust health, which might open new avenues of therapy for diseases of ageing.     

Normal brain ageing: models and mechanisms

Normal ageing is associated with a degree of decline in a number of cognitive functions. Apart from the issues raised by the current attempts to expand the lifespan, understanding the mechanisms and the detailed metabolic interactions involved in the process of normal neuronal ageing continues to be a challenge. One model, supported by a significant amount of experimental evidence, views the cellular ageing as a metabolic state characterized by an altered function of the metabolic triad: mitochondria-reactive oxygen species (ROS)-intracellular Ca2+. The perturbation in the relationship between the members of this metabolic triad generate a state of decreased homeostatic reserve, in which the aged neurons could maintain adequate function during normal activity, as demonstrated by the fact that normal ageing is not associated with widespread neuronal loss, but become increasingly vulnerable to the effects of excessive metabolic loads, usually associated with trauma, ischaemia or neurodegenerative processes. This review will concentrate on some of the evidence showing altered mitochondrial function with ageing and also discuss some of the functional consequences that would result from such events, such as alterations in mitochondrial Ca2+ homeostasis, ATP production and generation of ROS.     

Prospects for the genetics of human longevity

Longevity varies between and within species. The existence of species-specific limit to human life-span and its partial heritability indicate the existence of genetic factors that influence the ageing process. Insight into the nature of these genetic factors is provided by evolutionary studies, notably the disposable soma theory, which suggests a central role of energy metabolism in determining life-span. Energy is important in two ways. First, the disposable soma theory indicates that the optimum energy investment in cell maintenance and repair processes will be tuned through natural selection to provide adequate, but not excessive, protection against random molecular damages (e.g. to DNA, proteins). All that is required is that the organism remains in a sound condition through its natural expectation of life in the wild environment, where accidents are the predominant cause of mortality. Secondly, energy is implicated because of the intrinsic vulnerability of mitochondria to damage that may interfere with the normal supply of energy to the cell via the oxidative phosphorylation pathways. Oxidative phosphorylation produces ATP, and as a by-product also produces highly reactive oxygen radicals that can damage many cell structures, including the mitochondria themselves. Several lines of evidence link, on the one hand, oxidative damage to cell ageing, and on the other hand, energy-dependent antioxidant defences to the preservation of cellular homeostasis, and hence, longevity. Models of cellular ageing in vitro allow direct investigation of mechanisms, such as oxidative damage, that contribute to limiting human life-span. The genetic substratum of inter-individual differences in longevity may be unraveled by a two-pronged reverse genetics approach: sibling pair analysis applied to nonagenarian and centenarian siblings, combined with association studies of centenarians, may lead to the identification of genetic influences upon human longevity. These studies have become practicable thanks to recent progress in human genome mapping, especially to the development of microsatellite markers and the integration of genetic and physical maps.     

Male Reproductive Strategy and Decreased Longevity

An explanation of the inter-gender difference in longevity consistent with the 'disposable soma' theory of ageing is proposed. It is based on the concept of r-K selection as applied to the inter-gender situation. The concept predicts that the gender with a higher potential reproductive rate (males) should invest relatively less in somatic maintenance, which in its turn should result in a lower longevity according to the 'disposable soma' theory of ageing. In females, which are interpreted as K-selected organisms, the reproductive strategy strongly depends on steady, secure constitution designed for oocyte/embryo bearing and is therefore closely related to somatic maintenance, whereas in (r-selected) males it has a greater behavioural component - risky, variable, with a greater potential reproductive success at the expense of somatic maintenance. The higher metabolic and growth rates, a higher premature mortality and a longer period of sexual competence of males also find explanation as a complex of r-selected traits.     

Extending healthy ageing: nutrient sensitive pathway and centenarian population

Ageing is a challenge for any living organism and human longevity is a complex phenotype. With increasing life expectancy, maintaining long-term health, functionality and well-being during ageing has become an essential goal. To increase our understanding of how ageing works, it may be advantageous to analyze the phenotype of centenarians, perhaps one of the best examples of successful ageing. Healthy ageing involves the interaction between genes, the environment, and lifestyle factors, particularly diet. Besides evaluating specific gene-environment interactions in relation to exceptional longevity, it is important to focus attention on modifiable lifestyle factors such as diet and nutrition to achieve extension of health span. Furthermore, a better understanding of human longevity may assist in the design of strategies to extend the duration of optimal human health. In this article we briefly discuss relevant topics on ageing and longevity with particular focus on dietary patterns of centenarians and nutrient-sensing pathways that have a pivotal role in the regulation of life span. Finally, we also discuss the potential role of Nrf2 system in the pro-ageing signaling emphasizing its phytohormetic activation.     

Cancer and ageing: convergent and divergent mechanisms

Cancer and ageing are both fuelled by the accumulation of cellular damage. Consequently, those mechanisms that protect cells from damage simultaneously provide protection against cancer and ageing. By contrast, cancer and longevity require a durable cell proliferation potential and, therefore, those mechanisms that limit indefinite proliferation provide cancer protection but favour ageing. The overall balance between these convergent and divergent mechanisms guarantees fitness and a cancer-free life until late adulthood for most individuals.     

Having it all: historical energy intakes do not generate the anticipated trade-offs in fecundity

An axiom of life-history theory, and fundamental to our understanding of ageing, is that animals must trade-off their allocation of resources since energy and nutrients are limited. Therefore, animals cannot "have it all"--combine high rates of fecundity with extended lifespans. The idea of life-history trade-offs was recently challenged by the discovery that ageing may be governed by a small subset of molecular processes independent of fitness. We tested the "trade-off" and "having it all" theories by examining the fecundities of C57BL/6J mice placed onto four different dietary treatments that generated caloric intakes from -21 to +8.6% of controls. We predicted body fat would be deposited in relation to caloric intake. Excessive body fat is known to cause co-morbidities that shorten lifespan, while caloric restriction enhances somatic protection and increases longevity. The trade-off model predicts that increased fat would be tolerated because reproductive gain offsets shortened longevity, while animals on a restricted intake would sacrifice reproduction for lifespan extension. The responses of body fat to treatments followed our expectations, however, there was a negative relationship between reproductive performance (fecundity, litter mass) and historical intake/body fat. Our dietary restricted animals had lower protein oxidative damage and appeared able to combine life-history traits in a manner contrary to traditional expectations by having increased fecundity with the potential to have extended lifespans.