Small Nonhuman Primates as Potential Models of Human Aging

Steven N. Austad, Ph.D., is Professor of Zoology in the Department of Biological Science, University of Idaho, Moscow, Idaho. Both theoretical and practical reasons exist for developing a small nonhuman primate model for aging research (a fuller treatment of the logic of selection of animal models for aging research may be found in Sprott and Austad 1996 ). Conceptually, the issue is evolutionary propinquity to humans. Any animal species will bear some traits that are relatively general, that is, shared by large groups of animals, and other traits that are more idiosyncratic, or particular to more narrowly defined groups. It is an axiom of comparative biology that species with a close evolutionary relationship share, on average, more traits than more distantly related species, whether those traits are anatomical features like skull shape or functional characteristics such as mechanisms of aging ( Harvey and Pagel 1991 ). For instance, humans share with the great apes and Old World monkeys, but with few other mammals, the age-related phenomenon of menopause ( Hayssen and others 1993 ; NRC 1981 ) as well as a tendency to develop atherosclerotic vascular disease ( NRC 1981 ). in principle, then, the most relevant animal model of any human trait would be chimpanzees (Pan troglodytes) or bonobos (Pan paniscus), equally close biological relatives of humans. However, there are insupportable drawbacks to the use of large apes as models for aging research, including their prohibitive acquisition and maintenance costs and their longevity, which can be more than 5 decades in captivity. By contrast, laboratory rodents, the best defined and most practical mammalian models of aging, are relatively distantly related to humans, our lineages having diverged some 80 to 100 million years ago ( Benton 1990 ; Novacek 1992 ); and there is likely to be a range of idiosyncratic human aging traits that such models will not address. For instance, because laboratory rodents have estrous, not menstrual, cycles and exhibit persistent vaginal cornification accompanied by continuous behavioral estrus at the age-related cessation of cycling, they have limited use as models of human reproductive aging. Additionally, typical laboratory rodent strains synthesize their own ascorbate, like most mammals except humans and other primates. Ascorbate is a potent scavenger of reactive oxygen species, and because reactive oxygen species are currently thought to be a major contributor to aging (reviewed in Sohal 1993 ; Martin and others 1996 ), rodents may manage oxidative stress in a manner having little relevance for humans. Even beyond consideration of their evolutionary distance, humans and laboratory rodents also differ in where they fall along a continuum of fast-to-slow mammalian life history. Such life history differences are likely to reflect underlying functional differences. It is well-known that small mammals have telescoped lives compared with large mammals. Yet even controlling for body size, laboratory rodents develop, reproduce, and senesce rapidly compared with humans and other primates ( Read and Harvey 1989 ; Promislow and Harvey 1990 ). As a compromise between practicality and evolutionary relatedness to humans, Old World monkeys, particularly rhesus (Macaca mulatta) and pigtail (Macaca nemestrina) macaques, have been used as models of some aspects of the aging process (for example, Bowden 1979 ; Davis and Leathers 1985 ; Kemnitz and others 1993 ; Lane and others 1996 ). It is estimated that Old World monkeys diverged from the human lineage sometime between 20 and 35 million years ago ( Sarich and Cronin 1976 ; Martin 1993 ) and therefore are substantially more closely related to humans than rodents. With adult body masses of approximately 5 to 15 kg, these monkeys are smaller, less expensive to acquire and maintain, and somewhat shorter-lived (maximum captivity longevity of 30 to 40 years) than chimpanzees or bonobos. They are also still relatively similar to humans in some important respects having to do with aging--they develop atherosclerotic vascular disease and Alzheimer's-type brain lesions, and females undergo a true menopause ( Bowden 1979 ; Davis and Leathers 1985 ; vom Saal and others 1994 ). However, they are still extremely long-lived and expensive to maintain compared with smaller, more common laboratory animals. A different but potentially more satisfactory compromise between practicality and human propinquity may be small primate models of aging. Small primates, specifically the species that are rat-size or smaller, are far less costly to house and maintain than larger primates. These species also reach sexual maturity more quickly and reproduce more copiously than larger primates, so that large numbers of individuals can be generated relatively quickly. In addition, they typically live only 1 to 2 decades in captivity ( Table 1 ), and at least some species have been reported to develop age-related diseases with specific relevance to human late-life diseases (for example, Bons and others 1992 ; Cheverud and others 1993 ). Life history parameters for some primate species with mass of 500 g or less Life history parameters for some primate species with mass of 500 g or less As with all animal models, small primates also exhibit some drawbacks as models of humans. They do not experience menstrual cycles like humans and the Old World monkeys, for instance, which limits their utility as models of human reproductive aging. Additionally, some species are seasonal breeders, and at least 1 species may be unique among mammals in exhibiting continuous primary oogenesis throughout adulthood (Butler and Juma 1970). Moreover, not having been genetically domesticated like laboratory rodents, they may experience high levels of stress in captivity (Stonerook and others 1994). Stress, of course, affects immune and reproductive function and may lead to a number of diseases (Sapolsky 1992). One issue that must be con