Sci. Aging Knowl. Environ., 1 May 2002
Meeting Report--National Institute on Aging Workshop on the Comparative Biology of Aging
Huber Warner, Richard A. Miller, and Jill Carrington
H. Warner and J. Carrington are in the Biology of Aging Program at the National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. R. A. Miller is in the Department of Pathology, School of Medicine, University of Michigan, Ann Arbor, MI 48109, USA. E-mail: email@example.com://sageke.sciencemag.org/cgi/content/full/sageke;2002/17/pe5
Key Words: comparative biology aging rate life expectancy zooplots
Research on aging has yet to capitalize significantly on the obvious differences in life expectancy and aging patterns that exist among animal species whose maximum life-spans vary from as little as 1 day (mayfly) to 120 years (humans), or a range of more than 4 x 104. Thus, a workshop was held in February 2002 by the National Institute on Aging (NIA) in Bethesda, MD, to discuss ways to exploit similarities and differences in aging among diverse species to learn more about critical factors that affect aging and regulate life expectancy in animals. This Comparative Biology of Aging Workshop was organized by Jill Carrington of the NIA and a group of investigators that included Steven Austad, Caleb Finch, Michal Jazwinski, Richard Miller, George Taffet, and Richard Weindruch. The workshop was divided into four major sessions titled "Comparative Biology of Aging," "Comparative Biodemography," "Toward a Comparative Study of Biochemical Aging Mechanisms," and "Comparative Genomics." Our aim was to stimulate new approaches toward understanding the molecular bases for differences in aging rates and life expectancy among species. Such an understanding would make a major contribution toward clarifying the causes of the phenotypes associated with aging and what "times" aging in humans, with tremendous potential impact on the quality of life of the elderly.
Summary of Current Comparative Biology Findings in Biogerontology
Dr. Miller opened the workshop by summarizing what comparative biologists have done for gerontology. So far they have shown the following:
(i) Low-hazard niches often produce slow aging. For example, some bats, which spend much of their life in a safe environment because they can fly, live 30 years or more, a very long time compared to similar-sized nonflying mammals (mice, for example, which live for 2 to 3 years). However, work with guppies shows that simple hypotheses on the effects of high- versus low-predator environments might not always explain changes in life expectancy.
(ii) There are exceptions to the hypothesis that high metabolism associates with short life-span. Birds, for example, have very high metabolic rates compared to mammals, but are often much longer lived than mammals of comparable body size.
(iii) Within a species (dogs, for example), small breeds are typically longer lived.
(iv) One genome can produce organisms of quite different life expectancies. Worker honeybees live for 30 to 320 days, depending on season and environment, but queens live up to 8 years.
(v) A given order can include species of vastly different life expectancies (for example, mice versus naked mole rats (Fig. 1), which live 2 to 3 years and 25 to 30 years, respectively.)
(vi) Selective pressures can produce changes in life history traits quickly (as seen in studies with guppies and opossums).
(vii) Seasonal and photoperiod differences can affect life expectancy, notably in insects such as butterflies, grasshoppers, and fruit flies.
(viii) Single-gene mutations can dramatically increase life expectancy (for example, in nematodes, fruit flies, and mice). Snell dwarf mice, which contain a single-gene mutation, have a 40 to 50% increase in maximum life-span as compared to wild-type mice.
(ix) There are specific hypotheses about molecular mechanisms of aging that could be tested in mammals, including those related to stress resistance and insulin-signaling pathways (see Bartke Viewpoint).
Dr. Miller's introductory slides can be seen here.
Life in low-vulnerability niches
Drs. Miller and Austad both emphasized the research opportunities presented by species with exceptional longevity. In most cases, such species live in low-hazard environments, such as living underground, having the ability to fly, or living in predator-free surroundings. A promising opportunity lies in discovering the genetic changes that have occurred to increase life expectancy as a result of life in these low-vulnerability niches. These participants also pointed out that most research has focused on laboratory strains, which are usually inbred. Wild-caught strains might contain genes and alleles relevant to life expectancy that have been lost in laboratory strains through selective breeding for traits such as early fecundity. In fact, these researchers have found that some wild-derived mice do have longer life expectancies than those of laboratory strains.
Comparative approaches to deciphering mechanisms of aging
Several participants described their various approaches to understanding the mechanisms by which the changes associated with aging take place. These included biodemographic studies, examination of interspecies and subspecies differences in aging-related disease progression and susceptibility, studies of environmental influences on aging and life expectancy, and studies of organisms with properties that are particularly unusual in relation to prevalent aging theories (for example, many bird species). These approaches are likely to point us toward answers to questions related to current hypotheses on aging, as well as suggest new hypotheses about the mechanisms behind age-related changes. For example, experimental comparisons between closely related species or breeds with widely different life expectancies--such as chihuahua versus wolfhound, mouse versus naked mole rat, or lemur versus human--are likely to tell us something about biological properties that influence life expectancy. In addition, studies of organisms with different life expectancies that are very similar in one aging-relevant property (for example, the similar size of mice and naked mole rats) but differ in another aging-relevant property (such as metabolism) are likely to yield information on genetic, biochemical, and environmental influences on aging and life expectancy.
Studies on diverse species
The participants at the workshop shared data and information on a wide variety of species, including not only the traditional animal models used for studying aging [rats (Marco Pahor), mice (Richard Miller and Jan Vijg), fruit flies (Marc Tatar, James Carey, and Daniel Promislow), nematodes (Thomas Johnson), and yeast (Michal Jazwinski)], but also fish [including Xiphophorus (Ronald Walter and Steven Kazanis), guppies (David Reznick), zebrafish (Glenn Gerhard and John Postlethwait), and rockfish (Gregor Cailliet)], birds [Japanese quail (Mary Ann Ottinger) and budgiregars (Steven Austad)], nonhuman primates [lemurs, macaques, chimpanzees, and baboons (Mary Lou Voytko, Caleb Finch, and Marc Tatar)], other insects [honeybees (Kim Hughes) and butterflies and grasshoppers (Marc Tatar)], other mammals [naked mole rats (Timothy O'Connor), dogs (Elizabeth Head), bats (Jerry Wilkinson), and humans (George Martin, Marcelle Morrison-Bogorad, John Postlethwait, George Taffet, James Vaupel, and Woodring Wright)], and even plants (Deborah Roach).
Organisms such as fruit flies, nematodes, and yeast already receive much attention because of their highly malleable genetics; comparative biologists now need to decide to what extent information from these systems will guide us to insights into mammalian aging. Studies of lemurs, macaques, and baboons have, to different degrees, begun to identify the critical factors for maintenance and analysis of controlled colonies of these primates. Some fish species, such as zebrafish, are making key contributions to developmental genetics, and others, such as guppies, to experimental studies of evolution in natural environments, challenging biogerontologists to develop one or more of these species for studies of aging. Some of the species discussed at the meeting, such as the rockfish, naked mole rat, bats, and certain bird species, live far longer than other species of similar body size, providing potential opportunities to examine the molecular and hormonal bases for exceptional longevity. The challenge will be to decide how best to allocate limited resources toward developing new models to better answer gerontological questions.
Designing Rich Experiments
The structure of the workshop offered ample time for discussion among the meeting participants. Much of the dialogue, which is summarized below, was centered on how to use comparative biology approaches in future aging-related research.
Developing and validating mechanistic hypotheses
Studies must be developed that will not only define the biochemical, cellular, and hormonal pathways that account for aging rate differences among species, but also delineate the organs, cell types, and developmental periods most critical for these interspecies distinctions. Rather than focusing only on the production of new gene products, special attention should be given to quantitative differences in the amounts of specific mediators in key cell types. Subtle changes in the concentrations of key regulatory molecules might contribute substantially to changes in aging rate and longevity. Such studies are likely to help validate mechanistic hypotheses related to aging and will require the application of currently available technologies to new organisms.
Although plots comparing the specific properties of diverse species (zooplots) provide only broad insights into the mechanisms of aging, this knowledge of general associations and their exceptions should be useful in guiding the design of specific mechanistic experiments. This is particularly relevant in species that can be easily altered through genetic manipulations. Unfortunately, this is true of very few organisms.
Adapting new species for broader experimental use
Although there is abundant evidence for the existence of genes associated with longer and shorter longevity in simple organisms such as Caenorhabditis elegans, Drosophila melanogaster, and Saccharomyces cerevisiae, other organisms might be helpful in the translation of these data to mammals. Aging-related genes in lower eukaryotes might be multifunctional predecessors to a family of specialized genes in higher organisms, in which only selected members of the family affect the aging process. For example, Dr. Postlethwait pointed out that understanding gene duplication and specialization of functions in species such as zebrafish might help to clarify which genes are aging-relevant counterparts of genes that affect life expectancy in simple organisms.
Exploitation of comparative genomics will require collaborative interaction between scientists interested in both physiology (see Martin Viewpoint) and evolutionary biology: Physiologists are needed to provide guidance as to which integrative pathways and systems are most likely to modulate aging rate and late-life illnesses, and evolutionary biologists are needed to place the raw genomic data into the biologically meaningful context of selection for niches that vary widely in external hazard, population density, mating structures, and the pace of juvenile maturation.
The workshop highlighted the potential for study of a variety of species that are currently or potentially adaptable for broader laboratory use, but that are not being widely used for aging research. There are several difficulties to overcome in expanding research on nontraditional experimental models to its fullest potential. These include inadequate or nonexistent genome sequence information, supply of research animals, knowledge of optimal husbandry conditions, existing survival data, and transgenic technology. Furthermore, long life expectancy and animal welfare concerns limit the feasibility of studying some species. Because the cost of developing a suitable infrastructure for every potentially interesting animal model of aging is prohibitive, it is incumbent on the NIA, in partnership with the biogerontological research community, to identify the most promising species for study and the most useful comparative approaches to elucidate the genes and pathways that delay aging and promote healthy longevity.
For example, the selection of an animal model for the study of Alzheimer's disease (AD) is a current need. As putative biological risk factors for AD are discovered, investigators are generating a variety of transgenic mouse models of AD to use in understanding the molecular basis of the disease and as subjects for testing drugs and other interventions to prevent or ameliorate the disease. Gerontologists acknowledge that, compared to mice, nonhuman primates provide obvious advantages for such investigations. However, our knowledge base is currently too sparse to permit unequivocal selection of the optimal species to develop for research on various neurodegenerative diseases. More comparative information about aging and brain structure and function is needed before a particular nonhuman primate can be selected for development as a model for human neurodegenerative diseases. Similar arguments are valid with respect to the selection of models for studying aging-related pathology in other organs and tissues.
Evolution has many times produced long-lived species from short-lived ones, and gerontologists need to get busy exploiting these natural experiments to figure out how the trick has been managed. Does the evolution of long life require changes in DNA repair rates, stem cell turnover rates, antioxidant defenses, resistance to heavy metals and other toxins, and/or alterations in heat shock proteins and other guardians of protein integrity? Does the evolution of longevity typically involve alterations in the sequences of specific proteins, or, more plausibly but less often invoked, changes in the timing with which specific gene products are turned on and off in development and throughout life? Do physiological pathways that modulate longevity differences within a species also play a role in the much more dramatic differences in longevity between species? (Dr. Miller's workshop summary slides can be seen here.)
We are still far from envisioning, let alone providing, satisfactory answers to the two most basic questions in biogerontology: How does the aging process lead to the manifestations of aging, and what sets the rate of the aging process? The National Institutes of Health (NIH) and the scientific community in general have settled into a "disease at a time" strategy, in which resources, both financial and intellectual, are directed to the study of the many individual diseases of aging, from cancer to immunodeficiency to frailty to AD to renal and vascular diseases. Yet patterns and exceptions displayed by species available for comparative research show that there may be a variety of methods for delaying all of these diseases, along with so many other late-life tribulations, by factors of at least 30 within the mammals alone. Single-gene mutations and caloric restriction protocols have proven that it is a simple matter to delay aging in mice and rats, with effects on life expectancy that are substantially greater than those achievable by the abolition of most of the major killers (cancer, heart disease, kidney disease, and diabetes) put together. The delay or decrease in the signs of aging and the resultant extension of healthy life, rather than increased life expectancy alone, might be the major contribution of research on aging. The keys to this advance in health may well lie with some unusual organisms. Time will tell whether biogerontology researchers, with their friends and colleagues in research administration, will be able to take up the banner of comparative biology and move it over to the lamppost where the master keys are hidden.
May 1, 2002
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