Cloning of differentially expressed genes in skin fibroblasts from centenarians

Normal human fibroblasts undergoing serial passaging have been extensively used to identify genes linked with aging. Most of the isolated genes relate to growth retardation signals and the failure of homeostasis that accompanies aging and senescence. In contrast, there is still limited knowledge regarding the nature of the genes that influence positively the rate of aging and longevity. Healthy centenarians represent the best example of successful aging and longevity. Studies using samples from these individuals have proved very valuable for identifying a variety of factors that contribute to successful aging. The aim of the current work was to take advantage of skin fibroblast cultures established from healthy donors including centenarians in order to clone differentially expressed genes in centenarians. First, we demonstrate that centenarian derived cultures follow the typical Hayflick curve and they enter senescence after serial passaging. Application of differential screening techniques in minimally passaged cultures of four control donors of different ages (18–80 years old) and four centenarians has resulted in the cloning of six differentially expressed genes in centenarians. Four of the cloned genes, namely adlican, KBL, EST 38 and EST 39, were over-expressed in centenarians, while VDUP1 and OCIF were down-regulated in the same samples. We have also compared the expression levels of two representative cloned genes in cultures of human embryonic and adult fibroblasts to establish potential links with replicative senescence. Interestingly, VDUP1 was found over-expressed in late passage cells, while EST 39 was down-regulated in the same cultures. Thus our work demonstrates that a combination of the use of both biopsies derived cells and classical in vitro cells passaging will facilitate the better understanding of the biology of aging and longevity.Normal human fibroblasts undergoing serial passaging have been extensively used to identify genes linked with aging. Most of the isolated genes relate to growth retardation signals and the failure of homeostasis that accompanies aging and senescence. In contrast, there is still limited knowledge regarding the nature of the genes that influence positively the rate of aging and longevity. Healthy centenarians represent the best example of successful aging and longevity. Studies using samples from these individuals have proved very valuable for identifying a variety of factors that contribute to successful aging. The aim of the current work was to take advantage of skin fibroblast cultures established from healthy donors including centenarians in order to clone differentially expressed genes in centenarians. First, we demonstrate that centenarian derived cultures follow the typical Hayflick curve and they enter senescence after serial passaging. Application of differential screening techniques in minimally passaged cultures of four control donors of different ages (18–l80 years old) and four centenarians has resulted in the cloning of six differentially expressed genes in centenarians. Four of the cloned genes, namely adlican, KBL, EST 38 and EST 39, were over-expressed in centenarians, while VDUP1 and OCIF were down-regulated in the same samples. We have also compared the expression levels of two representative cloned genes in cultures of human embryonic and adult fibroblasts to establish potential links with replicative senescence. Interestingly, VDUP1 was found over-expressed in late passage cells, while EST 39 was down-regulated in the same cultures. Thus our work demonstrates that a combination of the use of both biopsies derived cells and classical in vitro cells passaging will facilitate the better understanding of the biology of aging and longevity.     

Heritable variation in telomere length predicts mortality in Soay sheep

Telomere length (TL) is considered an important biomarker of whole-organism health and aging. Across humans and other vertebrates, short telomeres are associated with increased subsequent mortality risk, but the processes responsible for this correlation remain uncertain. A key unanswered question is whether TL–mortality associations arise due to positive effects of genes or early-life environment on both an individual’s average lifetime TL and their longevity, or due to more immediate effects of environmental stressors on within-individual TL loss and increased mortality risk. Addressing this question requires longitudinal TL and life history data across the entire lifetimes of many individuals, which are difficult to obtain for long-lived species like humans. Using longitudinal data and samples collected over nearly two decades, as part of a long-term study of wild Soay sheep, we dissected an observed positive association between TL and subsequent survival using multivariate quantitative genetic models. We found no evidence that telomere attrition was associated with increased mortality risk, suggesting that TL is not an important marker of biological aging or exposure to environmental stress in our study system. Instead, we find that among-individual differences in average TL are associated with increased lifespan. Our analyses suggest that this correlation between an individual’s average TL and lifespan has a genetic basis. This demonstrates that TL has the potential to evolve under natural conditions, and suggests an important role of genetics underlying the widespread observation that short telomeres predict mortality.

Telomeres are repetitive sequences of noncoding DNA found at the terminal ends of linear chromosomes, and they play an important role in maintaining DNA stability and integrity (1–3). Telomeres shorten during cell replication and in response to oxidative stress (4, 5), and cellular senescence and apoptosis is triggered once telomeres reach a critically short threshold (2). The important role of telomeres in cellular senescence has led to telomere shortening being considered as one of nine “hallmarks of aging,” and average telomere length (TL) as an important biomarker of whole-organism health and biological aging (6). In humans, relatively short leukocyte telomeres have been linked to a range of age-related diseases such as diabetes, cancer, and cardiovascular disease (7–9) and increased subsequent mortality risk (10–12). A recent metaanalysis suggests this pattern may generalize beyond humans: Across studies from 20 nonmodel vertebrate species (predominantly birds), there was an overall positive association between TL and subsequent survival (13). Although evidence for a causal role for telomeres in whole-organism aging and longevity remains weak (14), these findings highlight the potential significance of TL as a biomarker of human and animal health (15, 16) and for our understanding of life history evolution (17, 18).Studies in humans and other vertebrates have found evidence for consistent differences in TL among individuals over multiple measurements (19, 20). Such repeatable among-individual differences in any trait may result from the trait being under genetic influence, from long-term effects of the early-life environment, and/or environmental conditions that persist across the lifetime. There is good evidence that variation in average TL in blood cells has a genetic basis in humans and other vertebrates, although estimates of the heritability (the proportion of variation attributed to additive genetic effects) of TL are variable (21, 22). Recent studies of wild vertebrates have also revealed considerable variation in adult TL among birth cohorts, suggesting persistent impacts of early-life environment (23, 24). At the same time, there is growing evidence that TL is highly dynamic across an individual’s lifetime, and metaanalyses of human and nonhuman animal studies show that experience of diverse forms of environmental stress are predictive of shorter TL (25–27). Indeed, some studies using longitudinal TL data have found that telomere shortening over successive measurements rather than TL per se is predictive of mortality (28–30). Thus, the emerging picture from studies in humans and other vertebrates is that shorter TL generally predicts increased risk of subsequent mortality, and that variation in TL is under the influence of both genetics and environmental stressors.The observation that shorter TL measurements predict increased mortality risk could be underpinned by two nonmutually exclusive processes operating across the lifetimes of individuals. Firstly, individuals may differ in their average TL across life, and individuals with shorter TL may be shorter lived. This pattern is referred to as the “selective disappearance” of individuals with shorter telomeres, and it implies that TL reflects constitutive differences among individuals (for example, due to genetics or differences in early-life environment) which shape their longevity (31, 32). Secondly, individuals may differ in their pattern of TL change over time, and individuals showing the greatest telomere loss across successive measurements are more likely to die subsequently. This pattern is consistent with the idea that within-individual telomere dynamics reflect recent and cumulative experiences of environmental stress and physiological deterioration that also predict mortality. Neither pattern necessarily implies a causal role for telomeres in driving the mortality risk of an organism, because associations between TL and survival could result from both traits being correlated with underlying, unmeasured variables which causally impact survival (14, 18). Nevertheless, unraveling the contribution of genetics, early-life environment, and more immediate telomere shortening to the observed association between TL and survival is essential for our understanding of TL as a biomarker of health and aging (19).To our knowledge, no study to date has assessed the relative importance of the different processes underlying the relationship between TL and mortality risk across the entire lifespan. To do so demands repeated measurements from across life to characterize among- and within-individual variation in TL, a population pedigree or genomic information to separate genetic and environmental sources of variation, and detailed information on individual health and fitness outcomes over the lifetime. Here, we use a multivariate mixed-effects modeling approach to analyze extensive, longitudinal data from a long-term study of wild Soay sheep living on St Kilda, Scotland, to distinguish between possible models of why shorter TL predicts increased mortality risk. We find that the observed positive association between TL and mortality in this system is underpinned by selective disappearance of individuals with shorter average TL. Importantly, our results suggest this is largely driven by genetically based differences in both TL and longevity.     

Rejuvenation of the disposable soma: Repeated injury extends lifespan in an asexual annelid

The disposable soma theory of senescence proposes that aging is the result of the accumulation of somatic damage with age resulting from insufficient somatic maintenance and repair. Comparative studies that show a positive correlation between longevity and DNA excision repair efficiency in mammals provide support for the theory but their validity has been questioned. A more satisfactory approach to investigate the role of somatic damage accumulation in aging would be to manipulate experimentally the levels of somatic repair and observe its effect on longevity. Here I report the results of studies in the asexual annelid Paranais litoralis where I have experimentally extended the worms' lifespan by subjecting them to repeated injury. I propose that repeated injury enhanced the normal level of repair of the worms, resulting in a rejuvenation of the soma. These results provide experimental support for the disposable soma theory of senescence.     

Experimental and empirical approaches in the study of aging

Two approaches to the study of aging are contrasted. The results and implications of the gene-by-gene, hypothetico-deductive molecular genetic approach are compared with studies engendered by uniqueempirical findings. The former hypothesis-testingapproach examines the changing phenotype that resultsfrom alterations of the genome and measures therelevance of a gene by the effectiveness with which italters life-span. Investigations of empiricaldemographic and physiological puzzles that have cometo light in aging studies, examine these phenomena forthe broader understanding they bring rather than theknowledge of specific causative genetic elements.While the former hypothesis testing method requirescaution in interpretation of results and conclusions,it has been highly informative. Studies ofempirical phenomena have necessarily progressed moreslowly, but have also yielded substantial gains. Both approaches have advanced the understanding ofthe aging process from distinctly different butcomplementary viewpoints.     

Is mammalian aging genetically controlled?

The rate of aging is species-specific, indicating that aging has a strong genetic component. Amongst mammals, the synchronization of the aging process suggests the presence of genetic determinants. In addition, single gene manipulations can change the rate of aging and demonstrate how a few genetic factors can regulate aging. Therefore, I propose that aging is regulated by a small set of genetic mechanisms, a single clock. If we can find what these regulatory mechanisms are, then instead of trying to delay age-related pathologies one by one we may be able to discover how to delay the entire aging process and most, if not all, of its pathologies. This revised version was published online in July 2006 with corrections to the Cover Date.     

Recent discoveries in the cycling,growing and aging of the p53 field

The P53 gene and it product p53 protein is the most studied tumor suppressor, which was considered as oncogene for two decades until 1990. More than 60 thousand papers on the topic of p53 has been abstracted in Pubmed. What yet could be discovered about its role in cell death, growth arrest and apoptosis, as well as a mediator of the therapeutic effect of anticancer drugs. Still during recent few years even more amazing discoveries have been done. Here we review such topics as suppression of epigenetic silencing of a large number of non-coding RNAs, role of p53 in suppression of the senescence phenotype, inhibition of oncogenic metabolism, protection of normal cells from chemotherapy and even tumor suppression without apoptosis and cell cycle arrest.     

Organ- and Tissue-specific Alterations in the Anti-apoptotic Protein Bcl-2 in CD1 Female Mice of Different Ages

The anti-apoptotic protein Bcl-2, which also has cytoprotective and antioxidant functions might be one of the crucial factors that altogether, establish how a cell may deal with stress and damage, contributing to longevity. Among the controversial issues to understand Bcl-2 functions in vivo, is to establish its content and variation in tissues during an organismal lifespan. In this work we analyzed the changes of Bcl-2 levels in lung, liver, heart, kidney, spleen and brain homogenates obtained from CD1 mice throughout their lifespan (newborn to 24 months). A tendency of increment was observed in all the organs analyzed, except brain where Bcl-2 was not detected. Bcl-2 over-expression during aging could be interpreted as a protective mechanism preventing cell death, despite the overall accumulated cell damage.     

Aged keratinocyte phenotyping: morphology, biochemical markers and effects of Dead Sea minerals

The aging process and its characterization in keratinocytes have not been studied in depth until now. We have assessed the cellular and molecular characteristics of aged epidermal keratinocytes in monolayer cultures and in skin by measuring their morphological, fluorometric and biochemical properties. Light and electron microscopy, as well as flow cytometry, revealed increase in cell size, changes in cell shape, alterations in mitochondrial structure and cytoplasmic content with aging. We showed that the expression of 16 biochemical markers was altered in aged cultured cells and in tissues, including caspases 1 and 3 and beta-galactosidase activities, immunoreactivities of p16, Ki67, 20S proteasome and effectors of the Fas-dependent apoptotic pathway. Aged cells diversity, and individual variability of aging markers, call for a multifunctional assessment of the aging phenomenon, and of its modulation by drugs. As a test case, we have measured the effects of Dead Sea minerals on keratinocyte cultures and human skin, and found that they stimulate proliferation and mitochondrial activity, decrease the expression of some aging markers, and limit apoptotic damage after UVB irradiation.     

Reproductive fitness and longevity in Drosophila melanogaster

It has been suggested that senescence could have evolved by selection of genes with beneficial effects early in life and detrimental ones later in life (pleiotropy theory of the evolution of senescence). To test that theory, the egg production of 322 females of the Oregon strain of Drosophila melanogaster was recorded daily throughout their life. At the individual level, no relation could be detected between early components of fitness and longevity. For the time being it appears that there are no unequivocal reasons to accept the pleiotropy theory of the evolution of senescence.     

Inflammatory and non-invasive vascular markers: the multimarker approach for risk stratification in coronary artery disease

Current thinking supports the notion that several inflammatory proteins intervene with endothelium and haemostatic factors leading to plaque formation and rupture. Of these, C-reactive protein (CRP), monocyte/macrophage colony-stimulating factor (MCSF) and interleukin-6 (IL-6) promote atherogenesis by inducing monocyte-macrophage activation, foam cell formation, platelet activation, tissue factor expression, release of other procoagulant cytokines or downregulation of atheroprotective cytokines such as interleukin 10 and transforming growth factor b-1 (TGFb-1). CRP, MSCF and IL-6 are interrelated and have been found in increased blood concentrations in CAD. Increased levels of CRP and IL-6 predict a higher cardiovascular event rate in the general population and in addition to high MCSF or low TGFb-1 predict adverse outcome in CAD patients independently of traditional risk factors. Moreover, in CAD patients, the predictive value of MCSF is additive and beyond that of CRP suggesting the need of a “multimarker approach” in assessing cardiovascular risk. Accumulating evidence supports the utility of non-invasive markers of subclinical atherosclerosis, namely carotid intimal media thickness, flow mediated dilatation of the brachial artery, augmentation index or pulse wave velocity, in the prediction of cardiovascular risk particularly in primary prevention settings. The combination of these non-invasive tests has been shown to improve their prognostic accuracy compared to each other alone. Although several therapeutic strategies like vaccination against antigens promoting atherogenesis, cyclooxygenase inhibitors, statins, and ACE inhibitors may reduce the levels of these inflammatory markers and improve the non-invasive markers of subclinical atherosclerosis, the impact on cardiovascular risk resulting from these changes is unknown. The combination of an established inflammatory marker such as CRP or a vascular marker such as IMT with novel biochemical and vascular markers of cardiovascular disease may offer additive prognostic information for adverse outcome.     

Longevity and aging: beneficial effects ofexposure to mild stress

Every organism has to deal with exposure to stresses.Animals have developed various strategies to cope with stress. It appears that the developed resistanceto stress is often related to longevity. Somescientists have advanced the hypothesis that thestress response may also counteract the negativeeffects of aging, and that exposing organisms to amild, sublethal stress, inducing a stress response,may help them to live longer. Several mild stresseshave been reported to increase longevity (irradiation,heat and cold shock, hypergravity, exercise, etc.), andone of them, hypergravity, to decrease the rate ofbehavioral aging. The mechanisms whereby thesestresses increase longevity have not yet been elucidated.However, the studies conducted so far show that theymay involve metabolic regulation and stress protein(hsps) induction.     

Justice,insurance, and biomarkers of aging

Insurers will want to use biomarkers of aging to decide whom to insure and how much to charge. If insurers are allowed to use biomarker information, then people whose biomarkers indicate shorter or more afflicted lives will find insurance harder to get and more expensive, while the longer-lived and less afflicted will find it cheaper and easier to get. If insurers are forbidden to use such information, then these two groups will be in a more equal position with regards to insurance—as they are now, in the absence of such information. Does society have a moral responsibility to address such natural inequalities? If so, then insurers should be forbidden to use such information. I will discuss arguments on both sides of this issue, and argue that justice requires preventing insurers from obtaining and using biomarker information.     

Proteasome dysfunction in mammalian aging: steps and factors involved

Mammalian aging is a natural biological process, determined by both genetic and environmental/stochastic factors, that results in the gradual decline of physiological function and the eventual failure of organism homeostasis. The proteasome is one of the major proteolytic systems of mammalian cells. It is responsible for the degradation of normal proteins as well as of abnormal proteins (like misfolded and oxidized proteins) that tend to accumulate during aging. Impaired proteasome function has been tightly correlated with aging both in vivo and in vitro. Given the fundamental function of proteasome for retaining cellular homeostasis, this review article examines the steps and the factors involved in proteasome dysfunction during mammalian aging. We discuss the proteasome structural organization, its activities and biosynthesis during aging and senescence as well as the genetic and environmental causes of its age-dependent alterations. Finally, we provide insights on the possibilities of proteasome activation that may retard the appearance of the senescent phenotype.     

The diet restriction paradigm: a brief review of the effects of every-other-day feeding

It has been known since the early 1900s that restriction of dietary intake relative to the ad libitum (AL) level increases stress resistance, cancer resistance, and longevity in many species. Studies investigating these phenomena have used three paradigms for dietary restriction. In the first, the AL intake of a control group is measured, and an experimental group is fed less than that amount in a specified proportion, e.g., 40%. In the second, food is provided AL to both the control and experimental groups: however, the experimental group is subjected to periods of fasting. Recent studies using this paradigm provide food every other day (EOD). Both of these paradigms have been in use since the early 1900s. A third paradigm that combines them was developed in the early 1970s: one or more days of fasting separate the provision of a limited amount of food. It was assumed for many years that the physiological responses to these paradigms were due exclusively to a net decrease in energy intake. Recently, however, it was found that some species and strains of laboratory animals, when fed AL every other day, are capable of gorging so that their net weekly intake is not greatly decreased. Despite having only a small deficit in energy intake relative to control levels, however, these animals experience enhanced longevity and stress resistance is enhanced in comparison to AL controls as much in animals enduring daily restriction of diet. These observations warrant renewed interest in this paradigm and suggest that comparisons of the paradigms and their effects can be used to determine which factors are critical to the beneficial effects of caloric restriction.*R.M. Anson and B. Jones contributed equally to this review.     

Phenotypic adjustment of senescent cells: Replace or restore

The historical concept of aging as an irreversible, inevitable, and inefficient biologic status led to the deterministic view of aging, which resulted in the replacement principle of aging control. For this purpose, the replacements of genes, cells, tissues, or organs have been proposed, but without satisfactory results. The novel concept of aging as a responsive and adaptive response to survival has resulted in the development of a new hypothesis of aging; namely, the Gate Theory. The prerequisites of the new hypothesis are gatekeeper molecules and a responsive aging field. Based on this concept, the modulation of gatekeeper molecules affects the cellular aging field, and result in the adjustment of the senescent phenotype. As a candidate for such molecules, caveolin has been examined with respect to its association with the aging phenotype. This new concept proposes the possibility of a restoration principle, which changes our view of aging in the community from simple longevity to a functional longevity. Functional longevity engenders the notions of active participation, positive thinking, and responsible behavior by the elderly. Therefore, it can be suggested that now is the time to accept the restoration principle as a key approach to individual aging control as well as the long live community in substitution with replace principle.     

Dying of old age: an examination of death certificates of Minnesota centenarians

OBJECTIVES: To compare how causes of death are recorded on the death certificates of centenarians with those who die in their 70s, 80s, and 90s. We also examined direct and indirect acknowledgment of age as a cause of death. DESIGN: Retrospective review of death certificates. SETTING: State of Minnesota. PARTICIPANTS: The death certificates of 26,415 individuals aged 70 and over who died in Minnesota in 1998 were examined for underlying causes of death. Of these, 449 were for individuals who were aged 100 and older at the time of their death. MEASUREMENTS: Causes of death. RESULTS: Diabetes mellitus, chronic obstructive pulmonary disease, cirrhosis, myocardial infarction, and most cancers decreased in frequency as reported causes of death with advancing age. Conversely, congestive heart failure, atherosclerosis, and neurological/mental and poorly defined conditions increased in frequency with age. CONCLUSIONS: Centenarians appear to "outlive" the risks for many of the conditions that are common causes of death for those who die in their 70s, 80s, and 90s, such as cancer and myocardial infarction. Conditions associated with aging, such as congestive heart failure and degenerative neurological conditions become more prominent as reported causes of death in the oldest individuals. The guidelines for the completion of death certificates should be modified to facilitate direct acknowledgment of age-related frailty as a contributing cause of death.     

A unique life history among tetrapods: an annual chameleon living mostly as an egg

The approximately 28,300 species of tetrapods (four-limbed vertebrates) almost exclusively have perennial life spans. Here, we report the discovery of a remarkable annual tetrapod from the arid southwest of Madagascar: the chameleon Furcifer labordi, with a posthatching life span of just 4-5 months. At the start of the active season (November), an age cohort of hatchlings emerges; larger juveniles or adults are not present. These hatchlings grow rapidly, reach sexual maturity in less than 2 months, and reproduce in January-February. After reproduction, senescence appears, and the active season concludes with population-wide adult death. Consequently, during the dry season, the entire population is represented by developing eggs that incubate for 8-9 months before synchronously hatching at the onset of the following rainy season. Remarkably, this chameleon spends more of its short annual life cycle inside the egg than outside of it. Our review of tetrapod longevity (>1,700 species) finds no others with such a short life span. These findings suggest that the notorious rapid death of chameleons in captivity may, for some species, actually represent the natural adult life span. Consequently, a new appraisal may be warranted concerning the viability of chameleon breeding programs, which could have special significance for species of conservation concern. Additionally, because F. labordi is closely related to other perennial species, this chameleon group may prove also to be especially well suited for comparative studies that focus on life history evolution and the ecological, genetic, and/or hormonal determinants of aging, longevity, and senescence.     

INAUGURAL ARTICLE by a Recently Elected Academy Member:Female reproductive aging in seven primate species: Patterns and consequences

Age-related changes in fertility have increasingly been documented in wild animal populations: In many species the youngest and oldest reproducers are disadvantaged relative to prime adults. How do these effects evolve, and what explains their diversity across species? Tackling this question requires detailed data on patterns of age-related reproductive performance in multiple animal species. Here, we compare patterns and consequences of age-related changes in female reproductive performance in seven primate populations that have been subjects of long-term continuous study for 29 to 57 y. We document evidence of age effects on fertility and on offspring performance in most, but not all, of these primate species. Specifically, females of six species showed longer interbirth intervals in the oldest age classes, youngest age classes, or both, and the oldest females also showed relatively fewer completed interbirth intervals. In addition, five species showed markedly lower survival among offspring born to the oldest mothers, and two species showed reduced survival for offspring born to both the youngest and the oldest mothers. In contrast, we found mixed evidence that maternal age affects the age at which daughters first reproduce: Only in muriquis and to some extent in chimpanzees, the only two species with female-biased dispersal, did relatively young mothers produce daughters that tended to have earlier first reproduction. Our findings demonstrate shared patterns as well as contrasts in age-related changes in female fertility across species of nonhuman primates and highlight species-specific behavior and life-history patterns as possible explanations for species-level differences.

The effects of age on reproductive performance remain poorly understood in nonhuman animals, particularly in wild populations. This is true despite several decades of growth in research on age-related changes in fertility patterns in the wild (1–4), which has revealed a number of species in which either older parents or very young parents—or both—are compromised, relative to prime-aged parents, in their ability to produce healthy offspring. In wild mammals in particular, reproductive traits can often be reasonably approximated with a negative quadratic function: An initial increase in reproductive performance after sexual maturity is associated with increasing parental competence and enhanced body condition; this may then be followed by a period of prime reproductive performance and finally by a subsequent decline associated with general senescence (5–12). The effects of old versus young parental age on fertility and offspring performance are distinct, but they both have important implications for understanding the evolution of life-history traits and their correlates.Negative effects of old age on reproductive performance—reproductive senescence—are well-known in humans and also widespread among long-lived iteroparous animals (1, 2, 13). However, the details of which reproductive traits show senescence, and in what manner, vary between species. Age-related declines in reproductive performance (“fertility senescence”) and age-related reduction of offspring performance (“parental-effect senescence”) represent two distinct components of reproductive senescence (14). Fertility senescence is one of the best-documented aspects of aging in wild animal populations, although data are often restricted to females (15). Evolutionary explanations for age-related declines in fertility are strongly connected to theories of biological aging, which invoke the weakening influence of natural selection with advancing age (16, 17). Parental-effect senescence, also known as the Lansing effect (18), has been well-documented in humans and in laboratory animal models (19), and more recently in a small number of wild animals (20–22). It can affect any component of offspring fitness, including offspring health, survival, rate of sexual maturation, or fecundity. For example, in humans, delayed childbearing is associated with steep increases in the risks of infant mortality, miscarriage, polysomy, and other congenital abnormalities, reduced lifespan, and other negative health outcomes in offspring (23–26). The mechanisms that underpin parental-effect senescence in different species remain poorly understood, but may include epigenetic influences on offspring phenotypes or age-related declines in the ability to provision and care for eggs, embryos, or dependent offspring (9, 11, 13, 27). The limited evidence on parental-effect senescence in animals thus far highlights the heterogeneity of parental-effect senescence across species, not only in which offspring traits are affected by parental senescence, but in the magnitude of the effects (3, 4).Negative effects of very young maternal age are also frequently associated with reduced fertility and offspring performance, but as with parental-effect senescence, the effects of young maternal age on offspring performance are heterogeneous across species. For example, in Soay sheep the youngest mothers show reduced fertility, reduced offspring birth weight, and reduced offspring survival relative to prime-aged mothers (11). In contrast, in red deer, young females show reduced fertility and reduced offspring birthweight, but not reduced offspring survival relative to older mothers (28, 29). In many, but not all, nonhuman primate species, offspring of primiparous females experience higher mortality than those of multiparous females. This result has been attributed to the inexperience or relatively small body size of primiparous mothers (30–34). However, small body size and inexperience are common characteristics of primate primiparas, while a survival disadvantage for firstborn offspring is not universal, indicating that the relevance of this explanation varies across species (35).The evolution of parental-age effects may be linked to the evolution of longevity, fertility, parental care, and social behavior (3, 4). This broad importance of parental-age effects and their implications for multiple aspects of life history and behavior highlight an important emerging question in evolutionary biology: How do these effects evolve, how do they differ between the sexes, and what explains their diversity across species? Detailed data on patterns of reproductive senescence in multiple species are required to tackle this question effectively.In this study, we contribute data on patterns of age-related changes in fertility and age-related changes in maternal effects in wild nonhuman primates. Specifically, we compare patterns and consequences of female reproductive aging in seven primate populations that have been subjects of long-term continuous study for 29 to 57 y (36–39) (SI Appendix, Table S1). For example, previous studies on these populations have documented age-related changes in mortality, contributing to our understanding of the evolution of senescence (37, 40, 41), and species-specific patterns of age at last live birth, contributing to our understanding of the evolution of human menopause (38). High-quality individual-based datasets on aging in wild animals are uncommon and difficult to gather (42), making this dataset a unique and exceptionally valuable resource for examining female reproductive aging in our closest living relatives. Our cross-species approach provides a comparative landscape in which the evolution of human aging and reproduction can be situated and allows us to test for both components of reproductive senescence: fertility senescence and parental-effect senescence. First, we aimed to determine how variable are patterns of age-related changes in female fertility across primate species, focusing specifically on whether a cross-species signature of aging could be reliably detected as a lengthening of interbirth intervals (IBIs) after the birth of a surviving offspring with advancing maternal age. Second, we sought to determine whether maternal age effects could be observed in components of fitness in the next generation, focusing on offspring survival during infancy and age at first reproduction (AFR) in daughters. We chose to analyze these three components of female reproductive performance because they could be extracted and measured unambiguously for each of the seven primate populations from our comparative life-history dataset. In the aggregate, our results provide important insights into the extent of, and variability in, age-dependent reproductive performance in wild primates.     

Nanotechnology and Molecular Homeostasis

Molecular nanotechnology is a rapidly emerging field that will allow for the precise and purposeful arrangement of matter atom by atom and eventually the building of submicron-scale medical sensors and therapeutic devices. These tools will provide the means to analyze, understand, and precisely control the molecular machinery of the human body. This will allow for the detection and correction of any undesired structural changes (disease or aging) at the finest level of detail and the earliest possible time. Genuine rejuvenation followed by the indefinite maintenance of an optimal physiologic state, or molecular homeostasis, may ultimately become possible. Current progress is rapid and accelerating, with a wide array of early nanoscale medical technologies under active development at the present time.