Comparative biology and non-traditional approaches for basic aging research for facilitating translational studies.

As humans, we aspire to healthy aging and ideally reaching our maximal lifespan. That, however, requires optimizing resilience to stressors and minimizing exposure to factors that accelerate aging. Understanding the complexities of aging processes involves characterizing the causal bases of physical, physiological, and cognitive deficits that accumulate over time, eventually culminating in reduced functionality and decreased resistance to disease and environmental stressors. Both the progression of age-related conditions and onset of diseases are affected by environmental stressors; however, the basis for increased susceptibility remains poorly understood. Furthermore, the actions of some environmental stressors, such as endocrine disruptors, can alter both developmental and aging processes, contributing to lifelong issues with inflammatory and neurodegenerative conditions. This manuscript focuses on the comparative biology and evolution of aging and longevity. The status of an array of animal models and potential for specific geroscience translational applications is addressed by asking these questions. What animal models are currently available for aging and translational geroscience? What are the key roadblocks and barriers for studies of healthy aging, and how might specific animal models be useful? Are research tools available? Which vertebrate animal models can specifically address targeted questions in human aging processes? Can information be synthesized for a range of vertebrate species to identify suitable animal models for addressing specific research questions in geroscience, especially relative to basic physiological function, timing and trajectory of disease progression, effects of environmental stressors, and potential for regenerative medicine?

New Perspectives on Avian Models for Studies of Basic Aging Processes.

Avian models have the potential to elucidate basic cellular and molecular mechanisms underlying the slow aging rates and exceptional longevity typical of this group of vertebrates. To date, most studies of avian aging have focused on relatively few of the phenomena now thought to be intrinsic to the aging process, but primarily on responses to oxidative stress and telomere dynamics. But a variety of whole-animal and cell-based approaches to avian aging and stress resistance have been developed-especially the use of primary cell lines and isolated erythrocytes-which permit other processes to be investigated. In this review, we highlight newer studies using these approaches. We also discuss recent research on age-related changes in neural function in birds in the context of sensory changes relevant to homing and navigation, as well as the maintenance of song. More recently, with the advent of "-omic" methodologies, including whole-genome studies, new approaches have gained momentum for investigating the mechanistic basis of aging in birds. Overall, current research suggests that birds exhibit an enhanced resistance to the detrimental effects of oxidative damage and maintain higher than expected levels of cellular function as they age. There is also evidence that genetic signatures associated with cellular defenses, as well as metabolic and immune function, are enhanced in birds but data are still lacking relative to that available from more conventional model organisms. We are optimistic that continued development of avian models in geroscience, especially under controlled laboratory conditions, will provide novel insights into the exceptional longevity of this animal taxon.

Embryonic exposure to maternal testosterone influences age-specific mortality patterns in a captive passerine bird.

Hormones are potent mediators of developmental programming and maternal epigenetic effects. In vertebrates, developmental exposure to maternal androgen hormones has been shown to impact multiple behavioral and physiological traits of progeny, but the possible consequences of this early exposure in terms of aging-related changes in mortality and fitness remain largely unexplored. Avian eggs naturally contain variable doses of maternal hormones-in particular, androgens-which have documented effects on embryo growth and differentiation as well as adult behavior and physiology. Here, we report that injections of a physiological dose of testosterone (T) into yolks of freshly laid eggs of a small, seasonally breeding songbird, the house sparrow (Passer domesticus), increased survivorship in a semi-natural aviary environment. In addition, survival effects of developmental T exposure were sex-dependent, with males generally having a higher risk of death. Separate analyses for young birds in their first year of life (from hatching up to the first reproductive period the following calendar year) and in adulthood (after the first breeding season) showed similar effects. For first-year birds, mortality risk was higher during the winter than during the period after fledging; for adults, mortality risk was higher during the reproductive than the non-reproductive phase (post-breeding molt and winter). T treatment did not affect nestling body mass, but resulted in higher body mass at 3-4 months of age; T and body mass at this age interacted to influence mortality risk. Embryonic exposure to maternal testosterone may result in lower adult mortality by modifying intrinsic physiological processes involved in health or aging over the lifespan of adult birds.

Ovarian aging in developmental and evolutionary contexts.

Evolutionary theory predicts that aging-related fertility declines result from tradeoffs between reproduction and somatic maintenance. Developmental programs for oogenesis also contribute to variation in aging-related reproductive declines among female vertebrates. Documented reproductive aging patterns in female vertebrates, including humans, are consistent with canonical aging patterns determined developmentally and require no special adaptive explanation. Here we discuss patterns of aging-related ovarian decline in diverse female vertebrates, and place human ovarian aging in comparative context. Depletion of finite oocyte stores accompanied by fertility loss occurs in a variety of nonhuman mammals and vertebrates, including short-lived rodents, birds, and some fishes; moreover, postreproductive lifespans of considerable length clearly are not limited to long-lived, social species with well-developed kin networks. We argue for a more rigorous comparative approach for understanding the evolutionary and developmental bases of ovarian aging in vertebrates with a wider range of aging patterns and social structures.

Concomitant mutations in the P450 oxidoreductase and androgen receptor genes presenting with 46,XY disordered sex development and androgenization at adrenarche.

CONTEXT: Undervirilization in males, i.e. 46,XY disordered sex development (46,XY DSD), is commonly caused by either lack of androgen action due to mutant androgen receptor (AR) or deficient androgen synthesis, e.g. due to mutations in 17alpha-hydroxylase (CYP17A1). Like all other microsomal cytochrome P450 (CYP) enzymes, CYP17A1 requires electron transfer from P450 oxidoreductase (POR). OBJECTIVE: The objective of the study was to analyze the clinical and biochemical phenotype in a 46,XY individual carrying concomitant POR and AR mutations and to dissect their impact on phenotypic expression. METHODS: We characterized the clinical and biochemical phenotype, genetic identification, and functional analysis of POR missense mutation by yeast micrososomal coexpression assays for CYP17A1, CYP21A2 and CYP19A1 activities. RESULTS: The patient presented neonatally with 46,XY DSD and was diagnosed as partial androgen insensitivity syndrome carrying a disease causing AR mutation (p.Q798E). She was raised as a girl and gonadectomized at the age of 4 yr. At 9 yr progressive clitoral enlargement prompted reassessment. Urinary steroid analysis was indicative of POR deficiency, but surprisingly androgen production was normal. Genetic analysis identified compound heterozygous POR mutations (p.601fsX12/p.Y607C). In vitro analysis confirmed p.Y607C as a pathogenic mutation with differential inhibition of steroidogenic CYP enzymes. CONCLUSION: Both mutant AR and POR are likely to contribute to the neonatal presentation with 46,XY DSD. Virilization at the time of adrenarche appears to suggest an age-dependent, diminishing disruptive effect of both mutant proteins. This case further highlights the importance to assess both gonadal and adrenal function in patients with 46,XY DSD.

The evolution of senescence and post-reproductive lifespan in guppies (Poecilia reticulata).

The study of post-reproductive lifespan has been of interest primarily with regard to the extended post-menopausal lifespan seen in humans. This unusual feature of human demography has been hypothesized to have evolved because of the "grandmother" effect, or the contributions that post-reproductive females make to the fitness of their children and grandchildren. While some correlative analyses of human populations support this hypothesis, few formal, experimental studies have addressed the evolution of post-reproductive lifespan. As part of an ongoing study of life history evolution in guppies, we compared lifespans of individual guppies derived from populations that differ in their extrinsic mortality rates. Some of these populations co-occur with predators that increase mortality rate, whereas other nearby populations above barrier waterfalls are relatively free from predation. Theory predicts that such differences in extrinsic mortality will select for differences in the age at maturity, allocation of resources to reproduction, and patterns of senescence, including reproductive declines. As part of our evaluation of these predictions, we quantified differences among populations in post-reproductive lifespan. We present here the first formal, comparative study of the evolution of post-reproductive lifespan as a component of the evolution of the entire life history. Guppies that evolved with predators and that experienced high extrinsic mortality mature at an earlier age but also have longer lifespans. We divided the lifespan into three non-overlapping components: birth to age at first reproduction, age at first reproduction to age at last reproduction (reproductive lifespan), and age at last reproduction to age at death (post-reproductive lifespan). Guppies from high-predation environments live longer because they have a longer reproductive lifespan, which is the component of the life history that can make a direct contribution to individual fitness. We found no differences among populations in post-reproductive lifespan, which is as predicted since there can be no contribution of this segment of the life history to an individual's fitness. Prior work on the evolution of post-reproductive lifespan has been dominated by speculation and correlative analyses. We show here that this component of the life history is accessible to formal study as part of experiments that quantify the different segments of an individual's life history. Populations of guppies subject to different mortality pressures from predation evolved differences in total lifespan, but not in post-reproductive lifespan. Rather than showing the direct effects of selection characterizing other life-history traits, post-reproductive lifespan in these fish appears to be a random add-on at the end of the life history. These findings support the hypothesis that differences in lifespan evolving in response to selection are confined to the reproductive lifespan, or those segments of the life history that make a direct contribution to fitness. We also show, for the first time, that fish can have reproductive senescence and extended post-reproductive lifespans despite the general observation that they are capable of producing new primary oocytes throughout their lives.

Naturally long-lived animal models for the study of slow aging and longevity.

Judicious selection of new animal models for the study of basic aging processes must combine feasibility and good use of the comparative method with evidence of antiaging adaptations, like the ability to combat oxidative damage to cells and tissues. A number of vertebrate species already in use or being developed as new biomedical models lend themselves very well to laboratory studies of aging, including small birds, bats, and mole-rats.

Declining immunity with age in the wild.

Despite their higher metabolic rates and lifetime energy expenditures, birds generally outlive similar-sized mammals even in the wild, often reaching maturity and aging considerably more slowly. Wild populations of many bird species have been monitored for years using banding-and-recapture methods, allowing field ornithologists to document age-related declines in survival and reproductive success. Although elderly birds rarely reach advanced stages of senescence in nature, many show other signs of physiological deterioration. In this Perspective, we review recent reports of aging-related changes in the immune response of two small European songbirds, the barn swallow and the collared flycatcher. Researchers in both studies challenged birds' humoral immune response by administering antigen to free-ranging adults during the breeding season. Older barn swallows--particularly breeding females--showed lower antibody responses (both primary and secondary) to vaccination with Newcastle disease virus, an avian pathogen. In flycatchers, older females raised lower antibody titers than younger breeders did in response to an injection of sheep red blood cells, a nonpathogenic antigen, and produced offspring with lower average body masses. Although the relevance of such measures of "immunosenescence" to actual fitness, reproductive success, and mortality is still unclear, studies of wild vertebrate populations may ultimately provide an important link between laboratory research and our understanding of the natural history and evolution of basic mechanisms of aging.

Reproductive aging in female birds.

Birds are underutilized as animal models for studying the basis of longevity, cellular adaptations for resisting oxidative damage, and delayed reproductive senescence. Reproductive aging patterns in female birds range from slightly slower than those in rodents of similar size to extremely slow or even negligible. The best-studied laboratory bird model of female reproductive aging is the relatively short-lived, rapidly aging domestic laying hen. Promising long-lived avian models for the prolongation of fertility include cage birds, like the budgerigar, and wild seabirds, like the Common Tern, many of which show no reproductive aging in nature. Preliminary comparisons of ovarian aging patterns in Japanese quail and budgerigars suggest that declining stores of primary oocytes may play different roles in fertility declines in these two species, as they do among mammals.

Is postmenopausal life-span a gift of modern health or a product of natural selection?

The author discusses how researchers from various scientific disciplines view the origins of and mechanisms (evolutionary as well as physiological) underlying menopause in humans. She describes presentations from a symposium centered around interdisciplinary perspectives on female reproductive aging. Comparative zoology, primatology, and anthropology have much to contribute to our understanding of human menopause; hence the symposium contained speakers representing these subdisciplines, as well as the more typical disciplines of endocrinology and neurobiology.