Senescence in the worker honey bee Apis Mellifera

Honey bees are social insects that exhibit striking caste-specific differences in longevity. Queen honey bees live on average 1-2 years, whereas workers live 2-6 weeks in the summer and about 20 weeks in the winter. It is not clear whether queen-worker differences in longevity are due to intrinsic physiological differences in the rate of senescence, to differential exposure to extrinsic factors such as predation and adverse environmental conditions, or both. To determine if the relatively short lifespan of worker bees involves senescence, we measured age-specific resistance to three different physiological stressors (starvation, thermal, and oxidative stress) while eliminating age-related differences in foraging activity and minimizing age-related differences in energy expenditure. Despite these manipulations, older worker bees were still significantly less resistant to all three stressors than were younger bees. These results indicate that the regulation of worker bee lifespan involves senescence, in addition to extrinsic factors.     

Cellular and molecular mechanisms of negligible senescence: insight from the sea urchin

Sea urchins exhibit a very different life history from humans and short-lived model animals and therefore provide the opportunity to gain new insight into the complex process of aging. Sea urchins grow indeterminately, regenerate damaged appendages, and reproduce throughout their lifespan. Some species show no increase in mortality rate at advanced ages. Nevertheless, different species of sea urchins have very different reported lifespans ranging from 4 to more than 100?years, thus providing a unique model to investigate the molecular, cellular, and physiological mechanisms underlying both lifespan determination and negligible senescence. Studies to date have demonstrated maintenance of telomeres, maintenance of antioxidant and proteasome enzyme activities, and little accumulation of oxidative cellular damage with age in tissues of sea urchin species with different lifespans. Gene expression studies indicate that key cellular pathways involved in energy metabolism, protein homeostasis, and tissue regeneration are maintained with age. Taken together, these studies suggest that long-term maintenance of mechanisms that sustain tissue homeostasis and regenerative capacity is essential for indeterminate growth and negligible senescence, and a better understanding of these processes may suggest effective strategies to mitigate the degenerative decline in human tissues with age.     

Successful aging and sustained good health in the naked mole rat: a long-lived mammalian model for biogerontology and biomedical research

Naked mole rats (NMRs; Heterocephalus glaber) are the longest-living rodents known, with a maximum lifespan of 30 years--5 times longer than expected on the basis of body size. These highly social mouse-sized rodents, naturally found in subterranean burrows in the arid and semiarid regions of the horn of Africa, are commonly used in behavioral, neurological, and ecophysiological research. Very old NMRs (>28 years), like humans, show signs of age-associated pathologies (e.g., muscle loss) as well as the accumulation of lipofuscin pigments, but no signs of tumorigenesis. Indeed, for at least 80% of their lives NMRs maintain normal activity, body composition, and reproductive and physiological functions with no obvious age-related increases in morbidity or mortality rate. Their long lifespan is attributed to sustained good health and pronounced cancer resistance. Clearly physiological and biochemical processes in this species have evolved to dramatically extend both their good health- and lifespan. We and others have tested various current theories using this species as an exceptionally long-lived animal model of successful abrogated aging. Surprisingly, NMRs have high levels of oxidative stress and relatively short telomeres, yet they are extremely resilient when subjected to cellular stressors and appear capable of sustaining both their genomic and protein integrity under hostile conditions. The challenge is to understand how these animals are able to do this. Elucidating these mechanisms will provide useful information for enhancing human life- and healthspan, making the naked mole rat a true "supermodel" for aging research and resistance to chronic age-associated diseases.     

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.     

Programmed ageing: decline of stem cell renewal,immunosenescence, and Alzheimer's disease

The characteristic maximum lifespan varies enormously across animal species from a few hours to hundreds of years. This argues that maximum lifespan, and the ageing process that itself dictates lifespan, are to a large extent genetically determined. Although controversial, this is supported by firm evidence that semelparous species display evolutionarily programmed ageing in response to reproductive and environmental cues. Parabiosis experiments reveal that ageing is orchestrated systemically through the circulation, accompanied by programmed changes in hormone levels across a lifetime. This implies that, like the circadian and circannual clocks, there is a master ‘clock of age’ (circavital clock) located in the limbic brain of mammals that modulates systemic changes in growth factor and hormone secretion over the lifespan, as well as systemic alterations in gene expression as revealed by genomic methylation analysis. Studies on accelerated ageing in mice, as well as human longevity genes, converge on evolutionarily conserved fibroblast growth factors (FGFs) and their receptors, including KLOTHO, as well as insulin-like growth factors (IGFs) and steroid hormones, as key players mediating the systemic effects of ageing. Age-related changes in these and multiple other factors are inferred to cause a progressive decline in tissue maintenance through failure of stem cell replenishment. This most severely affects the immune system, which requires constant renewal from bone marrow stem cells. Age-related immune decline increases risk of infection whereas lifespan can be extended in germfree animals. This and other evidence suggests that infection is the major cause of death in higher organisms. Immune decline is also associated with age-related diseases. Taking the example of Alzheimer's disease (AD), we assess the evidence that AD is caused by immunosenescence and infection. The signature protein of AD brain, Aβ, is now known to be an antimicrobial peptide, and Aβ deposits in AD brain may be a response to infection rather than a cause of disease. Because some cognitively normal elderly individuals show extensive neuropathology, we argue that the location of the pathology is crucial – specifically, lesions to limbic brain are likely to accentuate immunosenescence, and could thus underlie a vicious cycle of accelerated immune decline and microbial proliferation that culminates in AD. This general model may extend to other age-related diseases, and we propose a general paradigm of organismal senescence in which declining stem cell proliferation leads to programmed immunosenescence and mortality.     

Dietary restriction alters demographic but not behavioral aging in Drosophila

Dietary restriction extends lifespan substantially in numerous species including Drosophila. However, it is unclear whether dietary restriction in flies impacts age-related functional declines in conjunction with its effects on lifespan. Here, we address this issue by assessing the effect of dietary restriction on lifespan and behavioral senescence in two wild-type strains, in our standard white laboratory stock, and in short-lived flies with reduced expression of superoxide dismutase 2. As expected, dietary restriction extended lifespan in all of these strains. The effect of dietary restriction on lifespan varied with genetic background, ranging from 40 to 90% extension of median lifespan in the seven strains tested. Interestingly, despite its robust positive effects on lifespan, dietary restriction had no substantive effects on senescence of behavior in any of the strains in our studies. Our results suggest that dietary restriction does not have a global impact on aging in Drosophila and support the hypothesis that lifespan and behavioral senescence are not driven by identical mechanisms.     

Do age‐specific survival patterns of wild boar fit current evolutionary theories of senescence?

Actuarial senescence is widespread in age‐structured populations. In growing populations, the progressive decline of Hamiltonian forces of selection with age leads to decreasing survival. As actuarial senescence is overcompensated by a high fertility, actuarial senescence should be more intense in species with high reproductive effort, a theoretical prediction that has not been yet explicitly tested across species. Wild boar (Sus scrofa) females have an unusual life‐history strategy among large mammals by associating both early and high reproductive effort with potentially long lifespan. Therefore, wild boar females should show stronger actuarial senescence than similar‐sized related mammals. Moreover, being polygynous and much larger than females, males should display higher senescence rates than females. Using a long‐term monitoring (18 years) of a wild boar population, we tested these predictions. We provided clear evidence of actuarial senescence in both sexes. Wild boar females had earlier but not stronger actuarial senescence than similar‐sized ungulates. Both sexes displayed similar senescence rates. Our study indicates that the timing of senescence, not the rate, is associated with the magnitude of fertility in ungulates. This demonstrates the importance of including the timing of senescence in addition to its rate to understand variation in senescence patterns in wild populations.     

Why men matter: mating patterns drive evolution of human lifespan

Evolutionary theory predicts that senescence, a decline in survival rates with age, is the consequence of stronger selection on alleles that affect fertility or mortality earlier rather than later in life. Hamilton quantified this argument by showing that a rare mutation reducing survival is opposed by a selective force that declines with age over reproductive life. He used a female-only demographic model, predicting that female menopause at age ca. 50 yrs should be followed by a sharp increase in mortality, a "wall of death." Human lives obviously do not display such a wall. Explanations of the evolution of lifespan beyond the age of female menopause have proven difficult to describe as explicit genetic models. Here we argue that the inclusion of males and mating patterns extends Hamilton's theory and predicts the pattern of human senescence. We analyze a general two-sex model to show that selection favors survival for as long as men reproduce. Male fertility can only result from matings with fertile females, and we present a range of data showing that males much older than 50 yrs have substantial realized fertility through matings with younger females, a pattern that was likely typical among early humans. Thus old-age male fertility provides a selective force against autosomal deleterious mutations at ages far past female menopause with no sharp upper age limit, eliminating the wall of death. Our findings illustrate the evolutionary importance of males and mating preferences, and show that one-sex demographic models are insufficient to describe the forces that shape human senescence.     

Predicting all‐cause mortality from basic physiology in the Framingham Heart Study

Using longitudinal data from a cohort of 1349 participants in the Framingham Heart Study, we show that as early as 28–38 years of age, almost 10% of variation in future lifespan can be predicted from simple clinical parameters. Specifically, we found diastolic and systolic blood pressure, blood glucose, weight, and body mass index (BMI) to be relevant to lifespan. These and similar parameters have been well‐characterized as risk factors in the relatively narrow context of cardiovascular disease and mortality in middle to old age. In contrast, we demonstrate here that such measures can be used to predict all‐cause mortality from mid‐adulthood onward. Further, we find that different clinical measurements are predictive of lifespan in different age regimes. Specifically, blood pressure and BMI are predictive of all‐cause mortality from ages 35 to 60, while blood glucose is predictive from ages 57 to 73. Moreover, we find that several of these parameters are best considered as measures of a rate of ‘damage accrual’, such that total historical exposure, rather than current measurement values, is the most relevant risk factor (as with pack‐years of cigarette smoking). In short, we show that simple physiological measurements have broader lifespan‐predictive value than indicated by previous work and that incorporating information from multiple time points can significantly increase that predictive capacity. In general, our results apply equally to both men and women, although some differences exist.     

The impact of dietary restriction, intermittent feeding and compensatory growth on reproductive investment and lifespan in a short-lived fish

While dietary restriction usually increases lifespan, an intermittent feeding regime, where periods of deprivation alternate with times when food is available, has been found to reduce lifespan in some studies but prolong it in others. We suggest that these disparities arise because in some situations lifespan is reduced by the costs of catch-up growth (following the deprivation) and reproductive investment, a factor that has rarely been measured in studies of lifespan. Using three-spined sticklebacks, we show for the first time that while animals subjected to an intermittent feeding regime can grow as large as continuously fed controls that receive the same total amount of food, and can maintain reproductive investment, they have a shorter lifespan. Furthermore, we show that this reduction in lifespan is linked to rapid skeletal growth rate and is due to an increase in the instantaneous risk of mortality rather than in the rate of senescence. By contrast, dietary restriction caused a reduction in reproductive investment in females but no corresponding increase in longevity. This suggests that in short-lived species where reproduction is size dependent, selection pressures may lead to an increase in intrinsic mortality risk when resources are diverted from somatic maintenance to both growth and reproductive investment.     

Senescence or selective disappearance? Age trajectories of body mass in wild and captive populations of a small-bodied primate

Classic theories of ageing consider extrinsic mortality (EM) a major factor in shaping longevity and ageing, yet most studies of functional ageing focus on species with low EM. This bias may cause overestimation of the influence of senescent declines in performance over condition-dependent mortality on demographic processes across taxa. To simultaneously investigate the roles of functional senescence (FS) and intrinsic, extrinsic and condition-dependent mortality in a species with a high predation risk in nature, we compared age trajectories of body mass (BM) in wild and captive grey mouse lemurs (Microcebus murinus) using longitudinal data (853 individuals followed through adulthood). We found evidence of non-random mortality in both settings. In captivity, the oldest animals showed senescence in their ability to regain lost BM, whereas no evidence of FS was found in the wild. Overall, captive animals lived longer, but a reversed sex bias in lifespan was observed between wild and captive populations. We suggest that even moderately condition-dependent EM may lead to negligible FS in the wild. While high EM may act to reduce the average lifespan, this evolutionary process may be counteracted by the increased fitness of the long-lived, high-quality individuals.     

Retarded senescence in an insular population of Virginia opossums (Didelphis virginiana)

Evolutionary senescence theory predicts that genetically isolated populations historically subjected to low rates of environmentally-imposed mortality will ultimately evolve senescence that is retarded in relation to that of populations historically subjected to higher mortality rates. This prediction was evaluated in the field by comparing three general measures of senescence—age-specific mortality rate acceleration, age-related reproductive output and tail tendon collagen denaturation rate—in two radiocollared Virginia opossum ( Didelphis virginiana ) populations, one a mainland control and the other an insular population having a four-to five-thousand-year history of reduced exposure to predators. In comparison with those on the mainland, insular female opossums were found to exhibit greater survivorship and reduced litter sizes at all ages, as well as slower acceleration of age-specific mortality. Also, island females in their second reproductive year failed to show the senescent reduction in pouch young growth rate seen in mainland animals. Island opossums also manifested slower 'ageing' of tail tendon fibres, a generalized measure of physiological ageing. All these results are consistent with evolutionary senescence theory. Various environmental explanations (parasitism, disease, lessened food availability) for this populational difference are evaluated by physiological measures. No evidence for an environmental explanation is found.     

Extreme lifespan of the human fish (Proteus anguinus): a challenge for ageing mechanisms

Theories of extreme lifespan evolution in vertebrates commonly implicate large size and predator-free environments together with physiological characteristics like low metabolism and high protection against oxidative damages. Here, we show that the ‘human fish’ (olm, Proteus anguinus), a small cave salamander (weighing 15–20 g), has evolved an extreme life-history strategy with a predicted maximum lifespan of over 100 years, an adult average lifespan of 68.5 years, an age at sexual maturity of 15.6 years and lays, on average, 35 eggs every 12.5 years. Surprisingly, neither its basal metabolism nor antioxidant activities explain why this animal sits as an outlier in the amphibian size/longevity relationship. This species thus raises questions regarding ageing processes and constitutes a promising model for discovering mechanisms preventing senescence in vertebrates.     

Depth-selection behavior and longevity in Daphnia: an evolutionary test for the predation-avoidance hypothesis

The classic evolutionary theory of senescence predicts that long lifespan evolves under low risk of extrinsic mortality. As lakes present planktonic animals with vertical gradients of mortality risk associated with fish predation, we expected the individual lifespan of Daphnia of the “hypolymnetic” clones to be longer than that of “epilimnetic” Daphnia. In order to test this prediction, we performed a laboratory study on 14 clones from the D. longispina species complex, taken during the daytime either from epilimnion or hypolimnion of three mesotrophic lakes. “Epilimnetic” Daphnia started reproduction earlier, aged faster, and lived shorter than their “hypolimnetic” conspecifics. Our results indirectly support the predation-avoidance hypothesis as the ultimate explanation for depth-selection behavior in Daphnia.     

Parental age and lifespan influence offspring recruitment: a long-term study in a seabird

Recent studies of wild populations provide compelling evidence that survival and reproduction decrease with age because of senescence, a decline in functional capacities at old ages. However, in the wild, little is known about effects of parental senescence on offspring quality. We used data from a 21-year study to examine the role of parental age on offspring probability of recruitment in a long-lived bird, the blue-footed booby (Sula nebouxii). Offspring probability of recruiting into the breeding population varied over the life of parents and effects age were similar in mothers and fathers. Offspring recruitment was high when parents were roughly 6-12 years old and low before and after then. Effects of parental age on offspring recruitment varied with lifespan (parental age at last reproduction) and previous breeding experience. Offspring recruitment from young and old parents with long reproductive lifespans was greater than that of offspring from parents with short lifespans at young and old ages. For parents with little previous breeding experience recruitment of offspring decreased with their hatch date, but experienced parents were no similarly affected. We found evidence of terminal effects on offspring recruitment in young parents but not in older parents, suggesting that senescence is more likely a gradual process of deterioration than a process of terminal illness. Failure to recruit probably reflects mortality during the first years after independence but also during the fledgling transition to full independence. Our results show effects of parental age and quality on offspring viability in a long-lived wild vertebrate and support the idea that wild populations are composed of individuals of different quality, and that this individual heterogeneity can influence the dynamics of age-structured populations.     

Evolution of multiple components of virulence in Drosophila-nematode associations

Abstract.— Virulence is of central importance in host-parasite interactions, yet little is known about how it changes over extended evolutionary periods. In this study, all four species in the testacea species group of Drosophila were experimentally infected with sympatric and allopatric nematodes in the Howardula aoronymphium species complex, and the effect of parasite infection on three components of host fitness was determined. The Drosophila species show striking differences in their responses to infection, with reductions reaching 80% in adult lifespan, 100% in female fertility, and 90% in male fertility. Female sterility appears to be determined by the host; species that are sterilized by their local nematodes are also sterilized by the other allopatric nematodes in the H. aoronymphium complex. Host species that are not sterilized by their local parasite are not sterilized by other nematodes in the complex. In contrast, reductions in host adult lifespan and male fertility depend on both the host and the parasite. Whereas all nematodes reduced the survival of their local host species equally (about 40–45%), survival of two host species was drastically reduced (about 80%) when infected with an allopatric parasite. Thus, virulence is evolutionarily labile in associations between Drosophila testacea group species and their Howardula parasites. The data suggest that changes in the sterility component of virulence are due primarily to host evolution, whereas changes in the host mortality component are due in large part to parasite evolution.     

Senescence, aging, and disease

All over the world people are surviving into their seventh and later decades of life more frequently today than ever before in human history. Some remain in good health, while others show chronic degenerative conditions (CDCs), frailty, and relatively rapid mortality. Thereafter, multiple factors promoting health and well-being become ever more complex as we age. After attainment of reproductive maturation, many physiological decrements occurring in concert with age reflect both senescent and disease processes, not simply the passage of time. Senescence is a process that begins with DNA, molecules and cells and ultimately terminates in cellular death, loss of organ function, and somatic frailty. These changes are different from benign changes with age that do not alter function. Both differ from the pathological processes represented by disease. Either disease or senescence may be age-related, but neither is age-determined. Disease results from pathological alterations and it affects all age groups. Diseases need not be related to senescence, which includes alterations due to inherent aspects of organismal biology. Distinctions among senescence, aging, and disease blur for the late-life CDCs because, in addition to disease processes, many CDCs are phenotypic manifestations of senescing DNA, organelles, cells, and organs. During earlier epochs of human evolution, greater environmental exposures and fewer cultural buffers likely lead to greater frailty and mortality before senescence progressed greatly, as they still do for most animals. In modern-day settings, culturally patterned behaviors have allowed human frailty to become disconnected somewhat from mortality, unlike non-human species.     

Effects of Aging and Mate Retention on Reproductive Success of Captive Female Peregrine Falcons

SYNOPSIS. Separating ecological (extrinsic) factors affectingreproduction from physiological and experiential (intrinsic)factors can be problematic in free-ranging animals. This studyexamined age-related changes in six measures of reproductivesuccess (clutch size, fertility, hatchability, brood size athatching, survivorship of nestlings, and brood size at fledging)for captive female peregrine falcons (Falco peregrinus) whereecological factors (i.e., access to mates, nesting sites, andfood) were not limiting and were similar across years and betweenindividuals. Mean nestling survivorship increased throughoutthe lifespan of the female while all other measures of reproductionpeaked at about seven years of age and decreased thereafter.Birds with prior breeding experience had higher productivitythan inexperienced birds of the same age. Productivity increasedwith increasing experience of the pair. Productivity droppedby an average of 53% when females experienced a change of mate,and then subsequently increased over a period of several years.Productivity was not affected when birds were moved to differentbreeding sites. There was no evidence that early improvementsin reproduction were related to chronological aging in the absenceof experiential differences. Birds that began breeding earlierproduced more fledglings during their lifetimes as a resultof higher annual productivity. Lifetime reproduction was notcorrelated with longevity because birds with higher maximalegg production had shorter breeding lifespans. Birds retainingmates produced more fledglings during their lifetime than birdsthat changed mates, but birds that changed mates more than oncedid not have lower lifetime reproduction than birds that hadonly one mate change. These results suggest that 1) age-relatedchanges in reproduction are not necessarily resource-mediated,2) in the absence of resource limitation, experience of thepair is a primary factor determining annual reproductive success,3) benefits of increasing experience may be offset by the onsetof senescence, 4) the cost of present egg production on futurereproductive potential supports a "pleiotropic" theory of aging,and 5) costs associated with mate changes may encourage selectionfor low "divorce" rates (i.e., lifetime monogamy) in this species.     

Neuroendocrine and immune characteristics of aging in avian species

Avian species show a remarkable diversity in lifespan. The differing lifespan patterns are found across a number of birds, in spite of higher body temperature and apparent increased metabolic rate. These characteristics make study of age-related changes of great interest, especially for understanding the biology of aging associated with surprisingly long lifespan in some birds. Our studies have focused on a short-lived avian model, the Japanese quail in order to describe reproductive aging and the neuroendocrine characteristics leading to reproductive senescence. Biomarkers of aging used in mammalian species include telomere length, oxidative damage, and selected metabolic indicators. These markers provide confirming evidence that the long-lived birds appear to age more slowly. A corollary area of interest is that of immune function and aging. Immune responses have been studied in selected wild birds and there has been a range of studies that have considered the effects of stress in wild and domestic species. Our laboratory studies have specifically tested response to immune challenge relative to aging in the quail model and these studies indicate that there is an age-related change in the qualitative aspects of the response. However, there are also intriguing differences in the ability of the aging quail to respond that differ from mammalian data. Finally, another approach to understanding aging is to attempt to develop or test strategies that may extend lifespan and presumably health. One area of great interest has been to consider the effect of calorie restriction, which is a treatment shown to extend lifespan in a variety of species. This approach is routinely used in domestic poultry as a means for extending reproductive function and enhancing health. Our data indicate that moderate calorie restriction has beneficial effects, and that physiological and endocrine responses reflect these benefits.