Implications of clonality for ageing research

Senescence, an organismal performance decline with age, has historically been considered a universal phenomenon by evolutionary biologists and zoologist. Yet, increasing fertility and survival with age are nothing new to plant ecologists, among whom it is common knowledge that senescence is not universal. Recently, these two realities have come into a confrontation, begging for the rephrasing of the classical question that has led ageing research for decades: “why do we senesce?” to a more practical “what are the mechanisms by which some organisms escape from senescence?” Plants are amenable to examining this question because of their rich repertoire of life history strategies. These include the existence of permanent seed banks, vegetative dormancy and ability to produce clones, among others. Here, I use a large number of high resolution demographic models from 181 species that reflect life history strategies and their trade-offs among herbaceous perennials, succulents and shrubs measured under field conditions worldwide to examine whether senescence rates of ramets from clonal plants differ from those of whole plants reproducing either strictly sexually, or with a combination of sexual and clonal mechanisms. Contrary to the initial expectation from the mutation accumulation theory of senescence, ramets of clonal plants were more likely to exhibit senescence than those species employing sexual reproduction. I discuss why these comparisons between ramets and genets are useful, as well as its implications and future directions for ageing research.     

EXPERIMENTAL EVOLUTION OF SENESCENCE: AN ANALYSIS USING A “HETEROGENEITY” MORTALITY MODEL

A long-term laboratory selection experiment has produced replicated populations of fruit flies that differ in mean life span by more than twofold. An analysis of age-specific mortality rates indicated that differences in mean life span have been achieved principally by evolution of patterns of senescence. These results provide empirical confirmation that senescence can be modified within species by appropriate forms of natural selection, which is a fundamental prediction of theories regarding the genetic basis and evolution of senescence. Mortality data were fit to a model that accounts for the leveling off of cohort mortality rates at older ages, but that does not necessarily imply that very old individuals cease to senesce.     

SENESCENCE IN NATURAL POPULATIONS OF MAMMALS: A COMPARATIVE STUDY

Here, I use published mortality data from 56 natural populations of mammals to examine evidence for senescence, an increase in the probability of mortality with age. Data on extent of senescence and life history characteristics are compared across taxa in an attempt to test theories for the evolution of senescence in natural populations. In accord with theoretical expectation, senescence is highest in short-lived species with short generation times. In contrast to theoretical expectation, however, senescent increases in mortality rate do not begin until well after age at maturity in most cases. I also present evidence in support of the hypothesis that senescence will be lower in large-brained taxa.     

Early life expenditure in sexual competition is associated with increased reproductive senescence in male red deer

The evolutionary theories of senescence predict that investment in reproduction in early life should come at the cost of reduced somatic maintenance, and thus earlier or more rapid senescence. There is now growing support for such trade-offs in wild vertebrates, but these exclusively come from females. Here, we test this prediction in male red deer (Cervus elaphus) using detailed longitudinal data collected over a 40-year field study. We show that males which had larger harems and thereby allocated more resources to reproduction during early adulthood experienced higher rates of senescence in both harem size and rut duration. Males that carried antlers with more points during early life did not show more pronounced declines in reproductive traits in later life. Overall, we demonstrate that sexual competition shapes male reproductive senescence in wild red deer populations and provide rare empirical support for the disposable soma theory of ageing in males of polygynous vertebrate species.     

The case for negative senescence

Negative senescence is characterized by a decline in mortality with age after reproductive maturity, generally accompanied by an increase in fecundity. Hamilton (1966) ruled out negative senescence: we adumbrate the deficiencies of his model. We review empirical studies of various plants and some kinds of animals that may experience negative senescence and conclude that negative senescence may be widespread, especially in indeterminate-growth species for which size and fertility increase with age. We develop optimization models of life-history strategies that demonstrate that negative senescence is theoretically possible. More generally, our models contribute to understanding of the evolutionary and demographic forces that mold the age-trajectories of mortality, fertility and growth.     

The Williams' legacy: A critical reappraisal of his nine predictions about the evolution of senescence

Williams' evolutionary theory of senescence based on antagonistic pleiotropy has become a landmark in evolutionary biology, and more recently in biogerontology and evolutionary medicine. In his original article, Williams launched a set of nine “testable deductions” from his theory. Although some of these predictions have been repeatedly discussed, most have been overlooked and no systematic evaluation of the whole set of Williams' original predictions has been performed. For the sixtieth anniversary of the publication of the Williams' article, we provide an updated evaluation of all these predictions. We present the pros and cons of each prediction based on recent accumulation of both theoretical and empirical studies performed in the laboratory and in the wild. From our viewpoint, six predictions are mostly supported by our current knowledge at least under some conditions (although Williams' theory cannot thoroughly explain why for some of them). Three predictions, all involving the timing of senescence, are not supported. Our critical review of Williams' predictions highlights the importance of William's contribution and clearly demonstrates that, 60 years after its publication, his article does not show any sign of senescence.     

K-selection, α-selection, effectiveness, and tolerance in competition: Density-dependent selection revisited

In the Drosophila literature, selection for faster development and selection for adapting to high density are often confounded, leading, for example, to the expectation that selection for faster development should also lead to higher competitive ability. At the same time, results from experimental studies on evolution at high density do not agree with many of the predictions from classical density-dependent selection theory. We put together a number of theoretical and empirical results from the literature, and some new experimental results on Drosophila populations successfully subjected to selection for faster development, to argue for a broader interpretation of density-dependent selection. We show that incorporating notions of alpha-selection, and the division of competitive ability into effectiveness and tolerance components, into the concept of density-dependent selection yields a formulation that allows for a better understanding of the empirical results. We also use this broader formulation to predict that selection for faster development in Drosophila should, in fact, lead to the correlated evolution of decreased competitive ability, even though it does lead to the evolution of greater efficiency and higher population growth rates at high density when in monotypic culture.     

Lessons from senescence: Chromatin maintenance in non-proliferating cells

Cellular senescence is an irreversible proliferation arrest, thought to contribute to tumor suppression, proper wound healing and, perhaps, tissue and organismal aging. Two classical tumor suppressors, p53 and pRB, control cell cycle arrest associated with senescence. Profound molecular changes occur in cells undergoing senescence. At the level of chromatin, for example, senescence associated heterochromatic foci (SAHF) form in some cell types. Chromatin is inherently dynamic and likely needs to be actively maintained to achieve a stable cell phenotype. In proliferating cells chromatin is maintained in conjunction with DNA replication, but how non-proliferating cells maintain chromatin structure is poorly understood. Some histone variants, such as H3.3 and macroH2A increase as cells undergo senescence, suggesting histone variants and their associated chaperones could be important in chromatin structure maintenance in senescent cells. Here, we discuss options available for senescent cells to maintain chromatin structure and the relative contribution of histone variants and chaperones in this process. This article is part of a Special Issue entitled: Histone chaperones and chromatin assembly.     

A Generic Equation for Nitrogen-limited Leaf Area Index and its Application in Crop Growth Models for Predicting Leaf Senescence

Appropriate quantification of leaf area index (LAI) is importantfor accurate prediction of photosynthetic productivity by cropgrowth models. Estimation of LAI requires accurate modellingof leaf senescence. Many models use empirical turnover coefficients,the relative leaf-death rate determined from frequent fieldsamplings, to describe senescence during growth. In this paper,we first derive a generic equation for nitrogen-determined photosyntheticallyactive LAI (LAI_N), and then describe a method of using thisequation in crop growth models to predict leaf senescence. Basedon the theory that leaf-nitrogen at different horizons of acanopy declines exponentially, LAI_N, which is counted from thetop of the canopy to the depth at which leaf-nitrogen equalsthe minimum value for leaf photosynthesis, is calculated analyticallyas a function of canopy leaf-nitrogen content. At each time-stepof crop growth modelling, LAI_Nis compared to an independentcalculation of the non-nitrogen-limited LAI assuming no leafdeath during that time-step (LAI_NLD). In early stages, LAI_Nishigher than LAI_NLD; but with the advancement of crop growth,LAI_Nwill become smaller than LAI_NLD. The difference betweenLAI_NLDand LAI_N, whenever LAI_Nis smaller than LAI_NLD, gives theestimate of leaf area senesced at the time-step; the senescedleaf area divided by specific leaf area (SLA) gives the estimateof senesced leaf mass. The method was incorporated into twocrop models and the models adequately accounted for the LAIobserved in field experiments for rice and barley. The novelfeatures of the approach are that: (1) it suggests a coherent,biologically reasonable picture of leaf senescence based onthe link with photosynthesis and leaf nitrogen content; (2)it avoids the use of empirical leaf-turnover coefficients; (3)it avoids over-sensitivity of LAI prediction to SLA; and (4)it is presumably of sufficient generality as to be applicableto plant types other than crops. The method can be applied tomodels where leaf-nitrogen is used as an input variable or issimulated explicitly. Copyright 2000 Annals of Botany Company Leaf area index, leaf senescence, canopy nitrogen, modelling     

Two stochastic processes shape diverse senescence patterns in a single‐cell organism

Despite advances in aging research, a multitude of aging models, and empirical evidence for diverse senescence patterns, understanding of the biological processes that shape senescence is lacking. We show that senescence of an isogenic Escherichia coli bacterial population results from two stochastic processes. The first process is a random deterioration process within the cell, such as generated by random accumulation of damage. This primary process leads to an exponential increase in mortality early in life followed by a late age mortality plateau. The second process relates to the stochastic asymmetric transmission at cell fission of an unknown factor that influences mortality. This secondary process explains the difference between the classical mortality plateaus detected for young mothers’ offspring and the near nonsenescence of old mothers’ offspring as well as the lack of a mother–offspring correlation in age at death. We observed that lifespan is predominantly determined by underlying stochastic stage dynamics. Surprisingly, our findings support models developed for metazoans that base their arguments on stage‐specific actions of alleles to understand the evolution of senescence. We call for exploration of similar stochastic influences that shape aging patterns beyond simple organisms.     

Reports of the Death of Extrinsic Mortality Moulding Senescence Have Been Greatly Exaggerated

The classic evolutionary theory of aging posits that senescence evolves because the weakening of selection with age allows mutations with late-acting deleterious effects to accumulate. Because extrinsic mortality is an important cause of weakening selection, the central prediction of the theory has been that higher extrinsic mortality should lead to the evolution of a higher rate of senescence. However, the validity of this prediction has been questioned, even to the extent of suggesting that it is not a prediction of the theory at all, primarily on the basis that changes in population growth rate will compensate for changes in extrinsic mortality. The implication is that empiricists have been using the wrong prediction to test the theory. This claim is misleading, however, because it does not apply on an evolutionary timescale, when population size must be roughly constant. With a constant population size, Hamilton’s fitness sensitivities show that extrinsic mortality determines the rate at which the strength of selection declines with age, and thus determines the rate of senescence. The central prediction has been confirmed in the few controlled experiments with model organisms that have been conducted, but clearly this is an area ripe for further investigation.     

Age-specific fitness components and their temporal variation in the barn owl

Theory predicts that temporal variability plays an important role in the evolution of life histories, but empirical studies evaluating this prediction are rare. In constant environments, fitness can be measured by the population growth rate lambda, and the sensitivity of lambda to changes in fitness components estimates selection on these traits. In variable environments, fitness is measured by the stochastic growth rate lambda(S), and stochastic sensitivities estimate selection pressure. Here we examine age-specific schedules for reproduction and survival in a barn owl population (Tyto alba). We estimated how temporal variability affected fitness and selection, accounting for sampling variance. Despite large sample sizes of old individuals, we found no strong evidence for senescence. The most variable fitness components were associated with reproduction. Survival was less variable. Stochastic simulations showed that the observed variation decreased fitness by about 30%, but the sensitivities of lambda and lambda(S) to changes in all fitness components were almost equal, suggesting that temporal variation had negligible effects on selection. We obtained these results despite high observed variability in the fitness components and relatively short generation time of the study organism, a situation in which temporal variability should be particularly important for natural selection and early senescence is expected.     

Rural populations of the red fox Vulpes vulpes show little evidence of reproductive senescence

The ageing theory predicts fast and early senescence for fast-living species. We investigated whether the pattern of senescence of a medium-sized, fast-living and heavily-culled mammal, the red fox (Vulpes vulpes), fits this theoretical prediction. We used cross-sectional data from a large-scale culling experiment of red fox conducted over six years in five study sites located in two regions of France to explore the age-related variation in reproductive output. We used both placental scars and embryos counts from 755 vixens’ carcasses aged by the tooth cementum method (age range: 1–10), as proxies for litter size. Mean litter size per vixen was 4.7 ± 1.4. Results from Generalized Additive Mixed Models revealed a significant variation of litter size with age. Litter size peaked at age 4 with 5.0 ± 0.2 placental scars and decreased thereafter by 0.5 cubs per year. Interestingly, we found a different age-specific variation when counting embryos which reached a plateau at age 5–6 (5.5 ± 0.2) and decreased slower than placental scars across older ages, pointing out embryo resorption as a potential physiological mechanism of reproductive senescence in the red fox. Contrary to our expectation, reproductive senescence is weak, occurs late in life and takes place at an age reached by less than 11.7% of the population such that very few females exhibit senescence in these heavily culled populations.     

Extrinsic Mortality Can Shape Life-History Traits,Including Senescence

The Williams’ hypothesis is one of the most widely known ideas in life history evolution. It states that higher adult mortality should lead to faster and/or earlier senescence. Theoretically derived gradients, however, do not support this prediction. Increased awareness of this fact has caused a crisis of misinformation among theorists and empirical ecologists. We resolve this crisis by outlining key issues in the measurement of fitness, assumptions of density dependence, and their effect on extrinsic mortality. The classic gradients apply only to a narrow range of ecological contexts where density-dependence is either absent or present but with unrealistic stipulations. Re-deriving the classic gradients, using a more appropriate measure of fitness and incorporating density, shows that broad ecological contexts exist where Williams’ hypothesis is supported.     

Strategies to ameliorate abiotic stress-induced plant senescence

The plant senescence syndrome resembles, in many molecular and phenotypic aspects, plant responses to abiotic stresses. Both processes have an enormous negative global agro-economic impact and endanger food security worldwide. Premature plant senescence is the main cause of losses in grain filling and biomass yield due to leaf yellowing and deteriorated photosynthesis, and is also responsible for the losses resulting from the short shelf life of many vegetables and fruits. Under abiotic stress conditions the yield losses are often even greater. The primary challenge in agricultural sciences today is to develop technologies that will increase food production and sustainability of agriculture especially under environmentally limiting conditions. In this chapter, some of the mechanisms involved in abiotic stress-induced plant senescence are discussed. Recent studies have shown that crop yield and nutritional values can be altered as well as plant stress tolerance through manipulating the timing of senescence. It is often difficult to separate the effects of age-dependent senescence from stress-induced senescence since both share many biochemical processes and ultimately result in plant death. The focus of this review is on abiotic stress-induced senescence. Here, a number of the major approaches that have been developed to ameliorate some of the effects of abiotic stress-induced plant senescence are considered and discussed. Some approaches mimic the mechanisms already used by some plants and soil bacteria whereas others are based on development of new improved transgenic plants. While there may not be one simple strategy that can effectively decrease all losses of crop yield that accrue as a consequence of abiotic stress-induced plant senescence, some of the strategies that are discussed already show great promise.     

Antagonistic pleiotropy,mortality source interactions,and the evolutionary theory of senescence

Abstract.— Most theoretical work on the evolution of senescence has assumed that all individuals within a population are equally susceptible to extrinsic sources of mortality. An influential qualitative prediction based on this assumption is Williams's hypothesis, which states that more rapid senescence is expected to evolve when the magnitude of such extrinsic mortality sources is increased. Much evidence suggests, however, that for many groups of organisms externally imposed mortality risk is a function of an organism's internal condition and hence susceptibility to such hazards. Here we use a model of antagonistic pleiotropy to investigate the consequences that such interactions (between environmental hazard and internal condition) can have for Williams's hypothesis. As with some previous theory examining nonin-teractive extrinsic mortality sources, we find that an increase in interactive extrinsic sources of mortality makes it less likely that an individual will survive from birth to any given age, weakening selection against physiological deterioration at all ages and thus favoring more rapid senescence. However, an increase in interactive mortality sources also typically strengthens selection against physiological deterioration at any age, given an individual has survived to that age, because it reduces the fitness of poor-condition individuals more than good-condition individuals. These opposing effects are not felt equally at all ages, with the latter predominating at early ages. The combined effects can therefore result in the novel prediction that an increase in interactive extrinsic mortality sources can select for slower senescent deterioration early in life but more rapid deterioration late in life.     

Reproductive senescence: new perspectives in the wild

According to recent empirical studies, reproductive senescence, the decline in reproductive success with increasing age, seems to be nearly ubiquitous in the wild. However, a clear understanding of the evolutionary causes and consequences of reproductive senescence is still lacking and requires new and integrative approaches. After identifying the sequential and complex nature of female reproductive senescence, we show that the relative contributions of physiological decline and alterations in the efficiency of parental care to reproductive senescence remain unknown and need to be assessed in the light of current evolutionary theories of ageing. We demonstrate that, although reproductive senescence is generally studied only from the female viewpoint, age‐specific female reproductive success strongly depends on male–female interactions. Thus, a reduction in male fertilization efficiency with increasing age has detrimental consequences for female fitness. Lastly, we call for investigations of the role of environmental conditions on reproductive senescence, which could provide salient insights into the underlying sex‐specific mechanisms of reproductive success. We suggest that embracing such directions should allow building new bridges between reproductive senescence and the study of sperm competition, parental care, mate choice and environmental conditions.     

How strongly do sequence conservation patterns and empirical scales correlate with exposure patterns of transmembrane helices of membrane proteins?

Given the difficulty in determining high-resolution structures of helical membrane proteins, sequence-based prediction methods can be useful in elucidating diverse physiological processes mediated by this important class of proteins. Predicting the angular orientations of transmembrane (TM) helices about the helix axes, based on the helix parameters from electron microscopy data, is a classical problem in this regard. This problem has triggered the development of a number of different empirical scales. Recently, sequence conservation patterns were also made use of for improved predictions. Empirical scales and sequence conservation patterns (collectively termed as "prediction scales") have also found frequent applications in other research areas of membrane proteins: for example, in structure modeling and in prediction of buried TM helices. This trend is expected to grow in the near future unless there are revolutionary developments in the experimental characterization of membrane proteins. Thus, it is timely and imperative to carry out a comprehensive benchmark test over the prediction scales proposed so far to determine their pros and cons. In the current analysis, we use exposure patterns of TM helices as a golden standard, because if one develops a prediction scale that correlates perfectly with exposure patterns of TM helices, it will enable one to predict buried residues (or buried faces) of TM helices with an accuracy of 100%. Our analysis reveals several important points. (1) It demonstrates that sequence conservation patterns are much more strongly correlated with exposure patterns of TM helices than empirical scales. (2) Scales that were specifically parameterized using structure data (structure-based scales) display stronger correlation than hydrophobicity-based scales, as expected. (3) A nonnegligible difference is observed among the structure-based scales in their correlational property, suggesting that not every learning algorithm is equally effective. (4) A straightforward framework of optimally combining sequence conservation patterns and empirical scales is proposed, which reveals that improvements gained from combining the two sources of information are not dramatic in almost all cases. In turn, this calls for the development of fundamentally different scales that capture the essentials of membrane protein folding for substantial improvements.     

The Length of the Shortest Telomere as the Major Determinant of the Onset of Replicative Senescence

The absence of telomerase in many eukaryotes leads to the gradual shortening of telomeres, causing replicative senescence. In humans, this proliferation barrier constitutes a tumor suppressor mechanism and may be involved in cellular aging. Yet the heterogeneity of the senescence phenotype has hindered the understanding of its onset. Here we investigated the regulation of telomere length and its control of senescence heterogeneity. Because the length of the shortest telomeres can potentially regulate cell fate, we focus on their dynamics in Saccharomyces cerevisiae. We developed a stochastic model of telomere dynamics built on the protein-counting model, where an increasing number of protein-bound telomeric repeats shift telomeres into a nonextendable state by telomerase. Using numerical simulations, we found that the length of the shortest telomere is well separated from the length of the others, suggesting a prominent role in triggering senescence. We evaluated this possibility using classical genetic analyses of tetrads, combined with a quantitative and sensitive assay for senescence. In contrast to mitosis of telomerase-negative cells, which produces two cells with identical senescence onset, meiosis is able to segregate a determinant of senescence onset among the telomerase-negative spores. The frequency of such segregation is in accordance with this determinant being the length of the shortest telomere. Taken together, our results substantiate the length of the shortest telomere as being the key genetic marker determining senescence onset in S. cerevisiae.