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.     

Sex-specific effects of interventions that extend fly life span

Genetic and environmental interventions that extend life span are a current focus in research on the biology of aging. Most of this work has focused on differences among genotypes and species. A recent study on fruit flies shows that life span extension because of dietary restriction can be highly sex-specific. Here we review the literature on sex-specific effects of 56 genetic and 41 environmental interventions that extend life span in Drosophila melanogaster. We found that only one-sixth of the experiments provided statistical tests of differences in response between males and females, suggesting that sex-specific effects have been largely ignored. When measured, the life span extension was female-biased in 8 of 16 cases, male-biased in 5 of 16 cases, and not significantly different in only 3 of 16 cases. We discuss possible explanations for the sex-specific differences and suggest various ways in which we might test these hypotheses. We argue that understanding sex differences in the response to life span-extending manipulations should lead to new insights about the basic mechanisms that underlie the biology of aging in both sexes.     

Not wisely but too well: aging as a cost of neuroendocrine activity

Progressive decline of some neuroendocrine signaling systems has long been assumed to cause age-related physiological impairments and limit life span. However, hypophysectomy--removal of the pituitary gland--can delay many aspects of the aging process, and recent genetic studies have confirmed that reducing the secretion of pituitary hormones can increase the life span of laboratory organisms. Most strikingly, reducing activity of the insulin/insulin-like growth factor-1 signaling system substantially increases life span. Conversely, activity of the reproductive system or activation of stress responses can curtail life span. Because caloric restriction also reduces the activity of several neuroendocrine systems while increasing life span, it now appears that the aging process is driven, at least in part, by neuroendocrine activity rather than by its decline with age.     

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.     

Death-bed prophecy

What's left to learn about aging? The burning question for many researchers is whether life-stretching pathways and genes from model organisms boost human life span. Researchers might be able to track down additional genes and pathways that adjust longevity by studying a broader range of organisms or by tracking the evolution of genes that promote aging. An alternative way to extend our lives might be to identify the genes behind late-life killers such as heart disease and diabetes. Lab animals last longer on a very low-cal diet, and scientists are probing whether humans can benefit from this austerity. Or better yet, perhaps researchers can design molecules that deliver the gain of calorie reduction without the pain. Scientists are also focusing on which parts of the cell incur damage as we age and how growth and reproduction tie in to longevity. The speed of the next round of advances will depend on whether movers and shakers in funding organizations recognize the importance of the research and are willing to pay for it.     

The quest for a general theory of aging and longevity

Extensive studies of phenomena related to aging have produced many diverse findings, which require a general theoretical framework to be organized into a comprehensive body of knowledge. As demonstrated by the success of evolutionary theories of aging, quite general theoretical considerations can be very useful when applied to research on aging. In this theoretical study, we attempt to gain insight into aging by applying a general theory of systems failure known as reliability theory. Considerations of this theory lead to the following conclusions: (i) Redundancy is a concept of crucial importance for understanding aging, particularly the systemic nature of aging. Systems that are redundant in numbers of irreplaceable elements deteriorate (that is, age) over time, even if they are built of elements that do not themselves age. (ii) An apparent aging rate or expression of aging is higher for systems that have higher levels of redundancy. (iii) Redundancy exhaustion over the life course explains a number of observations about mortality, including mortality convergence at later life (when death rates are becoming relatively similar at advanced ages for different populations of the same species) as well as late-life mortality deceleration, leveling off, and mortality plateaus. (iv) Living organisms apparently contain a high load of initial damage from the early stages of development, and therefore their life span and aging patterns may be sensitive to early-life conditions that determine this initial damage load. Thus, the reliability theory provides a parsimonious explanation for many important aging-related phenomena and suggests a number of interesting testable predictions. We therefore suggest adding the reliability theory to the arsenal of methodological approaches applied to research on aging.     

C. elegans gives the dirt on aging

The worm Caenorhabditis elegans has become a popular model organism for the study of mechanisms involved in aging. The C. elegans life span is controlled by several pathways that have been extensively characterized at the molecular level. These include pathways that regulate metabolism and development (namely, the insulin/IGF-1 pathway), nutrition, mitochondrial activity, and reproduction. Presentations at a recent C. elegans conference add to the growing body of knowledge about the genetic networks that control the complex process of aging and suggest new avenues for further investigations.     

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.     

Biologists finally horn in on senescence in the wild

In 1995, biologists discovered an unusual new species, the antler fly (Protophila litigata). Antler flies inhabit discarded moose and deer antlers for most of their life cycle, and male antler flies exhibit sexually selected behaviors on their home antlers. It now turns out that these curious flies might provide new insights into the evolution of aging. For years, biologists assumed that senescence did not occur in the wild. But over the past decade, several studies of natural populations of birds and mammals have found age-related declines in rates of reproduction or survival, indicating senescence. A new study of antler flies by Bonduriansky and Brassil provides the first evidence for senescence in a wild invertebrate. The researchers are able to mark individual flies and follow them throughout their entire, albeit short, life-spans. This small species offers huge opportunities to study senescence and age-related selection on fitness characters in the wild.     

Aging research grows up

Long viewed as an insoluble enigma, aging is shedding its cloak of mystery as scientists start to understand why and how we age. Many studies support the theoretical argument that aging occurs because natural selection weakens with age, leaving us vulnerable to harmful, late-acting genes. As for what causes aging, scientists have narrowed the pack of candidates to a handful, including free radicals and reactions between glucose and proteins. In recent decades, many mechanisms for lengthening life in animals have come to light. By extending this research, scientists may be closing in on ways to lengthen the human life-span.     

Murine models of life span extension

Mice are excellent experimental models for genetic research and are being used to investigate the genetic component of organismal aging. Several mutant mice are known to possess defects in the growth hormone/insulin-like growth factor 1 (GH/IGF-1) neurohormonal pathway and exhibit dwarfism together with extended life span. Their phenotypes resemble those of mice subjected to caloric restriction. Targeted mutations that affect components of this pathway, including the GH receptor, p66Shc, and the IGF-1 receptor (IGF-1R), also extend life span; mutations that affect IGF-1R or downstream components of the pathway decouple longevity effects from dwarfism. These effects on life span may result from an increased capacity to resist oxidative damage.     

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.     

Bear ye one another’s genetic burdens: the price of diversity and complexity

Genetic variability and diversity are the result of a mutation-selection balance that acts permanently within and between species. The presence of deleterious mutations is a necessary consequence of this process and thus “the price paid by a species for its capacity for further evolution” (Haldane 1937, Am Nat 71:337–349). Recent estimations of mutation rate in the human lineage has revived the debate as to whether the high number of deleterious mutations poses a severe problem for the future of mankind. Theoretical considerations allow a scenario in which the survival of the human race is maintained by truncation selection of deleterious mutations that removes as many mutations as appear anew in every generation. In this case our genetic burden is carried by those individuals that suffer a genetic death resulting from random distribution of deleterious alleles. Nevertheless, one has to ask whether the mutation rate may set absolute limits on the complexity of a species.     

To age or not to age--what is the question?

Over the past 50 years, a generally accepted theory about the evolution of aging has been developed. One common conclusion that has been deduced from this theory is that aging is inevitable in organisms in which there is a difference between offspring and parents. A recent paper by Sozou and Seymour questions this prediction using a mathematical model, but it remains to be seen whether their new results stand up to more general analysis.     

From genes to societies

Research on model organisms has substantially advanced our understanding of aging. However, these studies collectively lack any examination of the element of sociality, an important feature of human biology. Social insects present a number of unique possibilities for investigating social influences on aging and potentially detecting new mechanisms for extremely prolonged, healthy life spans that have evolved naturally. Social evolution has led to life spans in reproductive females that are much longer (up to over 100-fold) than those of males or of nonreproductive worker castes. These differences are particularly dramatic because they are due to environmental influences, as all individuals develop from the same genomes. Social insect colonies consist of semi-autonomous individuals, and the relationship between the colony and the individual creates many interesting predictions in the light of the common theories of aging. Furthermore, the variety of lifestyles of social insects creates the potential for crucial comparative analyses across distinct social systems.     

Natural neighborhood networks — Important social networks in the lives of older adults aging in place

Neighborhoods are important places of aging and meaningful contexts of life for many older people. The overall aim of this study was to explore the public life of older people aging in place in order to understand neighborhoods as the material places where public life occurs, networks as the social places of public life, and to examine how these neighborhoods and networks influence the experience of aging and wellbeing. Adopting a friendly visiting methodology, data was collected over an 8-month period using participant observation, visual methods and an innovative interview technique called the “go along method”. Data were analyzed using grounded theory and a coding strategy that integrated textual, visual, and auditory data. Results provide insights into the micro-territorial functioning of neighborhoods and highlight third places and transitory zones as significant sites for older residents. Embedded within these places is a natural neighborhood network — a web of informal relationships and interactions that enhance well being and shape the everyday social world of older adults aging in place.     

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.     

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.     

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.