The two faces of oxygen

Scientists have suspected for half a century that reactive oxygen species (ROS) are major instigators of aging. These byproducts of metabolism batter a wide variety of molecules within cells, and an organism's ability to repair the damage declines with age. Now, some researchers say they're wrapping up the case against ROS, at least for lower organisms. By counteracting this destruction with protective enzymes, researchers have extended the average lifetime of some invertebrates. But the verdict isn't in yet, because recent studies have revealed that ROS also make key contributions to normal cell signaling.     

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.     

Nitric oxide and oxidative stress in cardiovascular aging

The long-standing free radical theory of aging, which attributes cellular pathology to the relentless accumulation of reactive oxygen species (ROS), remains attractive but controversial. Emerging insights into the molecular interactions between ROS and reactive nitrogen species (RNS) such as nitric oxide suggest that, in biological systems, one effect of increased ROS is the disruption of protein S-nitrosylation, a ubiquitous posttranslational modification system. In this way, ROS may not only damage cells but also disrupt widespread signaling pathways. Here, we discuss this phenomenon in the context of the cardiovascular system and propose that ideas regarding oxidative stress and aging need to be reevaluated to take account of the balance between oxidative and nitrosative stress.     

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.     

Making young tumors old: a new weapon against cancer?

As the population of industrial nations ages, the incidence of cancer and cancer mortality is increasing. Intuitively, older organisms may be less able to cope with accumulated damage and thus be more prone to develop cancer. However, so far, the links between aging and cancer have been only partially explored. Strikingly, four recent studies now indicate that premature senescence accompanied by cell cycle arrest occurs in tumors initiated by an oncogenic mutation. Thus, senescence may act as a key tumor suppressor mechanism in young tumors in vivo.     

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.     

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.     

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.     

Meeting report: 4th European Congress of Biogerontology

The 4th European Congress of Biogerontology took place in Newcastle upon Tyne in November 2004. Leading figures in the biology of aging presented their recent work, providing new insights into fundamental mechanisms of aging as it occurs in organisms ranging from yeast to the human species. Highlights of these presentations are presented here.     

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.     

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.     

More than a sum of our cells

Cells in the body grow and die, cells in lab dishes grow and die, and individual organisms grow and die. The parallels seem maddeningly obvious, but scores of scientists still labor to draw the correct connections, to uncover the mechanisms that underlie aging in cell culture flasks and in whole animals. Do our cells stop growing, quit working, cease dividing, or start dying as we age? Do we die when our cells do, or are we somehow more than the sum of our cells? For decades, scientists have searched for evidence that links changes in cell growth, cell function, cell division, and cell death to the phenomenon we call aging. Although definitive proof eludes them, researchers continue to conduct experiments in tissue culture and in animal models, amassing information that points us toward a greater understanding of what aging is--and is not.     

Is whole-body vibration beneficial for seniors?

Normal aging processes result in losses of functional flexibility and muscular strength, which increase seniors’ fall risk and dependence on others. A relatively new intervention to reduce and/or reverse the adverse effects of aging is whole-body vibration (WBV) exercise. The purpose of this article is to review the established effects of WBV exercise exclusively with the aging population. A systematic search utilizing PubMed and Sport Discus databases uncovered journal articles specific to seniors and whole-body vibration. An extensive hand search supplemented the database results to find other relevant articles. Twenty-seven articles were obtained; all articles have been published in the past 8 years, reflecting the recent and growing interest in this area. Researchers have determined that WBV training can reduce fall risk and improve postural control in seniors. It has also been determined that WBV training can be as effective as conventional resistance training to improve seniors’ lower body strength. However, little is known about the effect of WBV exercise on flexibility and upper body strength in the aging population. More research is required to establish how effective WBV training is on these specific components and how it may affect seniors’ quality of life.     

Lipid peroxidation and the aging process

Consistent evidence supports the hypothesis that a progressive accumulation of oxidative damage to important cellular molecules is a fundamental mechanism involved in most senescence-associated alterations. Oxidative damage occurs when free radicals produced within an organism are not completely destroyed by the appropriate endogenous defense systems. Because lipids are a major component of living organisms and probably the first easy target of free radicals once they are produced, lipid peroxidation might play an important role in initiating and/or mediating some aspects of the aging process. It has been widely demonstrated that there is an age-associated increase in the steady-state concentrations of lipid peroxidation products. However, establishing the involvement of this phenomenon in the pathogenesis of the aging process has not been an easy task. The recent development of more reliable techniques to measure lipid peroxidation, together with more well-defined animal models of aging, should be of great help in future studies in this field. The current evidence for the presence and importance of lipid peroxidation in the aging process is discussed in this review.     

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.     

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.     

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.     

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.     

Gonadal decline-related manifestations in aging hospital doctors

Andropenic manifestations related to declining gonadal function were assessed in a group of aging hospital doctors (50–66 years) and were compared with those of a group of administrative personnel of similar age (50–64 years) and two groups of younger doctors (30–40 years) or other hospital employees (30–40 years). Evaluation included measurements of follicle stimulating hormone (FSH) luteinizing hormone (LH), sex hormone binding globulin (SHBG), thyroid stimulating hormone (TSH) and prolactin (PRL) concentrations and responses to a special questionnaire. Mean testosterone concentration in aging doctors (374 ± 86 ng/ml) was no different from that of hospital employees of the same age (361 ± 77). However, concentrations of LH, SHBG and PRL in the former group were significantly lower (p < 0.04, 0.01 and 0.004, respectively). Furthermore, the testosterone : LH ratio was higher in the aging doctors group (p < 0.001). Mean testosterone concentration in the combined groups of aging men was lower than that of the younger men (p < 0.00001). Andropenic manifestations related to sexual, physical and mental activity were markedly better in the group of aging doctors in comparison to aging hospital employees. By and large, it appeared that aging hospital doctors had a better physical and mental activity than aging employees and this may have been related to their better lifestyle conditions.