The genetic basis of aging: an evolutionary biologist's perspective

This Perspective discusses recent progress in the study of the genetic basis of aging from the viewpoint of an evolutionary biologist. Work in this area has revealed that homologous genes and pathways play a role in determining life span in many different species. Because life span is a complex polygenic trait, however, these findings provide information about only a small portion of the genetic basis of this trait. Additionally, because the model organisms used to study aging have been exposed to similar laboratory conditions that can lead to unintentional artificial selection, some of the similarities among these organisms might have resulted from such selection. It is not yet clear whether the results found in model organisms will extend to organisms in a natural environment. A few species are known for which there are natural populations that differ in life span and patterns of senescence, and they should be useful for assessing whether the genetic mechanisms identified in the laboratory also operate in the wild.     

Dieting dwarves live it up

Two longevity pathways affect growth and metabolism in similar ways, and researchers have wondered for years whether the two routes coincide. A new study hints that these roads might not even lie on the same page of the atlas. Calorie restriction further extends the lives of mice already renowned for longevity due to a mutation in the Prop-1 gene. The results, reported in the 22 November issue of Nature, suggest that the two pathways don't overlap and indicate that researchers could travel a long way before they reach the maximum life-span of mice and perhaps humans.     

Reactive oxygen species and aging: evolving questions

Over the past 50 years, reactive oxygen species (ROS) have been investigated as putative mediators of the process of aging. As specific genes and pathways that are involved with ROS homeostasis have been linked to aging in lower organisms, such as Caenorhabditis elegans and Drosophila, the questions of how ROS regulate aging in higher organisms, and whether they do so to the same extent as in lower organisms, have emerged.     

Epigenetic regulation of aging in honeybee workers

Aging and longevity are complex life history traits that are influenced by both genes and environment and exhibit significant phenotypic plasticity in a broad range of organisms. A striking example of this plasticity is seen in social insects, such as ants and bees, where different castes can have very different life spans. In particular, the honeybee worker offers an intriguing example of environmental control on aging rate, because workers are conditionally sterile and display very different aging patterns depending on which temporal caste they belong to (hive bee, forager, or a long-lived caste capable of surviving for several months on honey alone). The ubiquitous yolk protein vitellogenin appears to play a key role in the regulatory circuitry that controls this variation. Here we outline the current understanding of the relation between vitellogenin and somatic maintenance in honeybee workers, and how this relation can be understood in a life history context.     

Genes, culture, and aging flies--what the lab can and cannot tell us about natural genetic variation for senescence

Model organisms cultured in the lab provide a powerful way to explore basic biological processes. However, lab culture can select for high early fecundity and dramatically shorten the life-span of lab organisms. Studies that use these short-lived organisms to identify aging-related genes might identify genes that simply restore the organism's original life-span. These results might not be fully relevant to wild populations. Experiments that reduce selection for shorter life-span or seek genes in naturally long-lived cohorts should lead to a more accurate understanding of aging.     

Linking development and aging

Evolutionary theory predicts that the different life stages of organisms are coordinated to achieve maximal reproductive output. Moreover, aging can be seen as an evolutionary side effect of this selective process that applies to many living organisms. Hence, genetic, developmental, and physiological mechanisms resulting from this selection are expected to be conserved in diverse lineages. The insulin/insulin-like growth factor signaling (INS) pathway appears to be such a mechanism that regulates life span and reproduction in a variety of model organisms. Here I argue that the experimental tools of environmental manipulation and gene by environment interaction should be used more often both during the experimental organism's development and its adult life. This approach will help us to fully understand the functions of longevity-determining pathways and will determine the life stages during which these pathways exert their effects on adult life. These points are raised because of a recent Aging Cell publication by Tu and Tatar, in which the larval food environment was manipulated to determine the effects on adult reproduction, life span, aging, and INS. The results of this study are a promise of the usefulness of this approach for understanding the aging process.     

Meeting report--44th Annual Drosophila Research Conference

The ability to compare the genetics of aging in multiple model organisms is a powerful tool to dissect the biology of aging. Although the fruit fly has only about half again as many genes as the nematode worm, its tissue organization is much more complex. The emerging importance of tissue specificity and endocrine signaling in aging makes the fly a natural choice for many researchers interested in unraveling the next level of complexity of the aging process. This Perspective provides an overview of research related to aging that was described at the annual Drosophila conference held in Chicago in March 2003.     

Using yeast to discover the fountain of youth

The budding yeast Saccharomyces cerevisiae has long served as a model organism for the study of basic cellular processes. Its short generation time, well-established molecular genetics, and fully sequenced genome have made this organism a favorite of researchers in diverse fields. Much of the information obtained has been shown to apply to higher eukaryotes, including humans. Recently, researchers have begun using yeast to tackle one of the outstanding questions in science: How and why do organisms age? The identification of individual genes in yeast that can affect the aging process itself has elevated this single-celled fungus to full contender status in the aging field. In this Perspective, we present two fundamentally different measures of aging in yeast: replicative life-span and stationary phase survival (chronological life-span). We describe the benefits and limitations of each and present models that attempt to explain these "aging" phenomena. Finally, we present compelling evidence that the use of yeast as a model system will ultimately prove beneficial to the study of human aging.     

Narrative analysis in aging studies: A typology for consideration

This article seeks to expand our understanding on narrative and the analysis of stories researchers invite and collect in the domain of aging studies. To do so, we first offer an understanding of what narrative inquiry can be by laying out a theoretical basis for this kind of research, and making a case for the relevance of narrative as an alternative methodology. Painting with broad strokes, narrative analysis as a method is then considered before a typology of different ways in which stories can be analyzed is introduced. Illuminated by the typology are two contrasting standpoints toward narrative analysis—storyteller and story analyst—and three specific methods—structural, performative, and autoethnograpic creative analytic practices—that each standpoint might use to analyse the whats and hows of storytelling. The article closes by suggesting that in order to assist us to understand the complexities of aging researchers might consider using a variety of analyses.     

Does anti-aging equal anti-microbial?

Aging is the dominant risk factor for human disease in developed countries. Could it be that a wide variety of disease states all have their origins in a common mechanism? Major signaling pathways that determine the rate of aging, such as the insulin/insulin-like growth factor 1 (IGF-1) pathway, might give clues to the nature of this major disease risk factor. It has now been shown that insulin/IGF-1 signaling influences Caenorhabditis elegans resistance to bacteria in such a way that long-lived worms are stress-resistant and slow to succumb to infection. Perhaps enhanced innate immunity is a feature of genetically determined longevity.     

Ubiquitin,proteasomes, and the aging brain

Ubiquitinated proteinaceous inclusions are the hallmark of many neurodegenerative diseases. Inefficient proteolysis might lead to the accumulation and ultimate deposition of potentially toxic entities as inclusions within neurons or glial cells. This hypothesis is supported by genetic evidence both from patient populations and from engineered mutations in genes that encode ubiquitin/proteasome components in mice. The appearance of similar inclusions in the brains of elderly individuals of normal and subclinical conditions begs the question of whether there is a general age-related decline in the ability of the ubiquitin/proteasome pathway (UPP) to recognize and eliminate abnormal proteins, and whether such a decline would be reflected by changes in the abundance or activity of some or all components of the UPP. Here we describe alterations in the aging mammalian brain that correlate with a decline in the function of the UPP and review the evidence for age-related changes in specific UPP components. These alterations are discussed within the context of prevalent theories of aging.     

Is Akt the mastermind behind age-related heart disease?

Over the past several years, the insulin/insulin-like growth factor (IGF) signaling pathway has become a central figure in the study of organismal aging. Mutations in components of this pathway have led to enhanced longevity in several organisms, but it is still not clear whether and how this pathway contributes to human aging and aging-related diseases. In a new study, Miyauchi and colleagues propose that Akt, a member of the phosphatidylinositol 3-kinase family and a downstream component of the insulin/IGF pathway, plays a central role in the life span of endothelial cells. These findings implicate the insulin/IGF pathway in the development and progression of cardiovascular disease.     

Perspectives on the Biodemography of Longevity and Aging

Biodemography is a timely and exciting area of research that has been emerging over the past 15–20 years and might arguably be the most quickly growing area of demography. From the perspective of longevity and aging, questions arise that touch on the biological foundation of aging. With a focus on mortality, this article offers a perspective on recent developments in evolutionary biodemography. These include new theories, methods, and data that have resulted in striking new findings on the diversity of life courses (including the option of escape from aging for some species) that is licensed by nature across the tree of life. As the human life course is rapidly changing due to unimpeded population aging, advances in development of biodemographic theories, methods and databases may prove useful and inspire advances in sociology.     

Caloric restriction in trans

Caloric (or dietary) restriction (CR) is the most potent, robust, and reproducible known means of extending longevity and decreasing morbidity in laboratory mammals. Two of the major questions faced by researchers in this field are the applicability to humans and the biochemical mechanism(s) involved in the actions of CR. Studies in nonhuman primates are beginning to address the former; studies in phylogenetically lower organisms such as yeast and Drosophila are beginning to address the latter. de Cabo and colleagues now provide evidence that some aspects of CR can be reproduced in mammalian tissue culture cells exposed to sera from rats and monkeys subjected to CR. This work presents the initial development of a new model with which to approach mechanistic studies of CR and provides a new form of direct evidence that CR exerts at least some of its effects in trans.     

Subfield history: use of model organisms in the search for human aging genes

The National Institute on Aging (NIA) started a program in 1993 to identify genes involved in the regulation of longevity in a variety of species, including yeast, nematodes, fruit flies, and mice. The initial success of this program has attracted the interest of many investigators working with these organisms. Of primary interest are single-gene mutants that have identified genes and processes involved in longevity regulation across species. These processes include the insulin-like signaling pathway, stress resistance, and most recently, chromosome and nuclear architecture. Mutations in genes that regulate these processes indirectly are also being identified in this program. The ultimate goal of this program is to extend these results to humans to identify the major biological risk factors for age-related decline of function in human physiological systems.     

Does sex age you?

The evolution of aging and longevity has typically been considered to be a resolution of the conflicting demands on an organism to grow, reproduce, and survive. When social or environmental factors change the opportunities for reproduction in a way that affects differently aged individuals, there will be an evolutionary response in the schedule of senescence. This means that social dynamics can have an important effect on aging. A recent study by Berec and Boukal has shown that the dynamics of mating and divorce can also affect observed life spans through their effect on population dynamics. If females cannot find and maintain mating pairs for long enough to replace themselves, the population will become extinct. This puts a lower limit on the levels of longevity that will be observed in nature.     

Aging-related research in the "-omics" age

The application of high-throughput technologies to aging-related research has the potential to dramatically enhance our understanding of how longevity is determined at a molecular level. Genome-scale studies are being carried out in every major model system used for aging-related research, and new technologies are being developed to rapidly identify mutations or small-molecules that increase life span. A meta-analysis of data derived from genome-wide studies of aging in simple eukaryotes will allow the identification of conserved determinants of longevity that can be tested in mammals.     

Why females live longer than males: control of longevity by sex hormones

Females live longer than males in many species, including humans. We have traced a possible explanation for this phenomenon to the beneficial action of estrogens, which bind to estrogen receptors and increase the expression of longevity-associated genes, including those encoding the antioxidant enzymes superoxide dismutase and glutathione peroxidase. As a result, mitochondria from females produce fewer reactive oxygen species than those from males. Administering estrogens has serious drawbacks, however--they are feminizing (and thus cannot be administered to males) and may increase the incidence of serious diseases such as uterine cancer in postmenopausal women. Phytoestrogens, which are present in soy or wine, may have some of the favorable effects of estrogens without their undesirable effects. Study of gender differences in longevity may help us to understand the basic processes of aging and to devise practical strategies to increase the longevity of both females and males.     

Building a Humane Society for Older People: Compassionate Policy Making for Integration,Participation, and Positive Ageing Within a Framework of Intergenerational Solidarity

This article explores the global challenge of population aging with a specific focus on the concepts of integration and participation of older people in society within the context of “realizing a society for all ages” as promoted by the United Nations. It is proposed that governments worldwide need to embrace new ways of thinking about population aging that include strategic initiatives for strengthening the social contract that fosters generational interdependence. The meaning of “positive aging” is explored at both the individual and social levels, with implications for quality-of-life issues involving intergenerational relationships. The point is made that while the promotion of positive aging is commendable on both philosophical and health grounds it can be problematic for those older people who for a range of legitimate reasons are unable to fulfill the notion of positive or active aging. The longevity revolution will require the emergence of a more humane society that undertakes to reconceptualize what older age means, together with exploring new ways of enhancing the citizenship status of older people through the development and promotion of innovative intergenerational relationships. A call is made for a wider engagement of the citizenry in the processes involved in the formulation and implementation of policy making.