ILAR Journal Online, Volume 38(3) 1997: Animal Models of Aging Research

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ILAR Journal V38(3) 1997
Animal Models of Aging Research

Small Nonhuman Primates as Potential Models of Human Aging
Steven N. Austad

Steven N. Austad, Ph.D., is Professor of Zoology in the Department of Biological Science, University of Idaho, Moscow, Idaho.

INTRODUCTION

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).

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 considered when seeking to develop new primate species as biomedical models is availability. Some species currently deemed to be currently threatened with extinction in the wild are listed in Appendix I of the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES l). Appendix I species cannot be traded internationally except under exceptional circumstances and only for noncommercial purposes. In practice, listing in Appendix I limits legal trade to a few hundred individuals each year (Lyster 1985); and in the United States, considerable restrictions apply to the use of animals, blood, or tissues for research. All primates not listed in Appendix I are listed in Appendix II, which also places some restrictions on international trade.

SMALL PRIMATES

A total of approximately 20 species of small (less than 500 g) primates have been described (Nowak 1991 ). Some of these species are commonly kept in captivity, in zoos or in specialized primate facilities; others are virtually unknown and have only recently been described in nature. Consequently, information about appropriate husbandry, common pathologies, and typical (and maximum) longevity will be reliable for some species but highly provisional or nonexistent for others.

The importance of appropriate husbandry and accurate longevity information is that it allows planning for longitudinal population studies and facilitates a reasonable subdivision of individuals into different age categories (for example, young, middle-aged, old) for cross-sectional studies. Typically, aging research requires animals to be as disease-free as possible, and great care is typically taken to keep animals healthy. Health standards for zoos or other captive facilities

may not be as stringent as is required for aging research. For instance, the maximum longevity of squirrel monkeys (Saimiri sciureus) has been widely reported to be less than 20 years, based on a reasonable sample of several hundred animals from zoo records (Anonymous 1960; Jones 1982) and a general consideration that their captive survival was "good" (NRC 1981). Yet a sizable cohort of squirrel monkeys acquired for a caloric restriction study and attentively cared for by the Gerontology Research Center of the National Institute on Aging is now approaching 20 years of age while still appearing very healthy. A smaller, even older, cohort is now in its mid-20s (G.S. Roth and M.A. Lane personal communication 1996). Thus, previously published reports of captive squirrel monkey life span were misleading with respect to their potential longevity when maintained under conditions placing exceptional emphasis on their disease status. This caveat about the accuracy of longevity information may be very relevant to small primates, which generally have not been maintained as frequently in captivity as larger primates.

Information about how common species are kept in captivity and whether they breed well (a reasonable index of adequately developed husbandry) may be found in the annual volumes of the International Zoo Yearbook, which includes records of mammals currently bred in captivity. In addition, facilities such as the Duke University Primate Center, which specialize in the breeding and conservation of specific primate groups, can be contacted directly. The Duke facility specializes in prosimian primates (lemurs, lorises, galagos, tarsiers), which include many small species. Considerable information about primates in captivity and in the field is also available through the Internet. The "Electronic Zoo" primate page (http://netvet.wustl.edu/primates.htm) is a particularly useful entry point for this information.

Small primates occur in 3 distinct taxonomic groups--the Old World strepsirrhini (lemurs, lorises, galagos), the tarsiers, and the New World callitrichidae (marmosets or tamarins). The strepsirrhini are the primate group generally considered to be most distantly related to humans. Now considered to be a unified taxonomic group (Yoder and others 1996), the strepsirrhini diverged from the rest of the primates 60 to 70 million years ago (Martin 1993; Yoder and others 1996) compared with 20 to 35 million years for Old World monkeys such as rhesus macaques (Sarich and Cronin 1976; Martin 1993).

The advantages for aging research represented by some of the strepsirrhines can be summarized as follows: (1) A number of species are small--60 to 500 g; (2) they are relatively short-lived for a primate--12 to 18 years typically; (3) they mature rapidly--generally less than 1 year; and (4) they frequently produce twins (Table 1). These traits in sum suggest they would be vastly more productive in captivity than the larger, Old World primates; colony sizes could be rapidly expanded, and aging studies would not take 4 or 5 decades. Small strepsirrhine species are typically nocturnal, solitary (as opposed to group-living), and able to subsist primarily on small arthropods, fruit, and plant exudates. Their naturally solitary existence may make them more resistant than more social species to the psychopathology associated with individual housing, something that may be necessary for some experimental studies.

The tarsiers, as currently described, consist of 5 species in a single genus and are of uncertain affinity among primates (Nowak 1991). Most current opinion places them as a sister group of the monkeys and apes and estimates their time of divergence from the human lineage as 45 to 65 million years ago (Szalay 1975; Martin 1993), somewhat more recent than the strepsirrhini. However, some authors still consider the tarsiers to be a sister group to the lemurs and lorises (Schwartz 1986), which would place their divergence from humans with the strepsirrhini.

Far less is known about the tarsiers than the other small primate groups. All species are less than 200 g in body mass and are nocturnal or crepuscular and arboreal. They are exclusively carnivorous, eating mostly insects but in captivity readily accepting other prey such as small lizards and shrimp. Male-female pairs are often seen together in nature, and small family groups share a sleeping nest in some species. Their typical litter size is 1, and gestation may last 6 months. Tarsier neonates are approximately 3 times the size of the strepsirrhini. Breeding is thought to occur year-round, and adult body weight is attained by 15 to 18 months (accounts synthesized from Van Horn and Eaton 1979; Izard and others 1985; Bearder 1986; Wright and others 1987). Currently, only 1 zoo reporting to the International Zoo Yearbook is having even limited success breeding tarsiers (Anonymous 1994). Availability is thus severely limited (Wright and others 1989), and tarsiers will not be considered further as practical models of aging.

The callitrichid primates consist of 5 New World genera and about 20 species found in Central and South America. They are considered to have diverged from the human lineage 30 to 50 million years ago (Szalay 1975; Sarich and Cronin 1976; Martin 1993), even more recently than the tarsiers. All species weigh less than 1 kg.

Adapted to run along horizontal branches and leap between trees in the forest canopy, the callitrichids eat insects, soft fruits, nectar, and plant exudates (Nowak 1991). Unlike most strepsirrhini and tarsiers, they are diurnal, living in small groups with male group members contributing to infant care. They are typically mature by 12 to 18 months of age and have I to 3 young per litter. Approximately 80% of litters consist of twins, and total litter mass ranges from 14 to 24% of maternal weight. In captivity, all callitrichids appear capable of producing 2 litters per year, and they thrive best when kept in breeding pairs or larger social groups. Like humans but unlike many other primates including chimpanzees, female callitrichids apparently are continually sexually receptive, that is, copulation is not confined to the periovulation period. Even in nature, copulations have been observed during pregnancy, during lactation, and after the weaning of young (Goldizen 1986). Life spans of the smaller callitrichids are reported to be generally 15 to 20 years (Table 1). They often grow quite docile in captivity, and the husbandry of several species is well-developed (Segal 1989).

SOME SPECIFIC CANDIDATE SPECIES

Among the strepsirrhini, 2 species seem particularly worth developing for aging research. One of these is the mouse lemur, Microcebus murinus, which weighs 50 to 100 g and is omnivorous, nocturnal, and typically solitary (Table 1). Females become sexually mature in less than 1 year and commonly have 2 or 3 offspring per year thereafter. A current field study finds that their longevity in nature is I to 3 years (J. Schmid personal communication 1994), and in captivity individuals typically live 8 to 12 years with a reported maximum of 13 to 15 years (Harvey and others 1986; M. Perret personal communication 1994). At advanced ages, mouse lemurs show signs of senescence such as fur whitening, blindness due to lens opacity, the development of tumors, and even brain lesions similar to Alzheimer's lesions in humans accompanied by a range of behavioral changes (Bons and others 1992).

Under shortened day length, mouse lemurs enter a semi-torpid state in which activity and metabolic rate are reduced and sexual activity ceases. However, maintenance of animals under long day-length (14 hours light/day) photoperiods prevents this physiological response (Perret and Schilling, 1993).

More than 20 primate facilities and zoos throughout the world keep mouse lemurs without apparent difficulty. The Parc Zoologique de Paris has a colony of more than 100 individuals and produced more than 40 offspring in 1992 (Anonymous 1994). A research colony of about 200 individuals currently maintained in Brunoy, France, has been in existence since 1970 (M. Perret personal communication 1994). In the United States, the largest collection of Microcebus is probably the Duke University Primate Center, which currently has 16 individuals. This species is listed in Appendix I of CITES, signifying by international agreement that it cannot be taken from the wild and that commercial trade of captive individuals is highly regulated.

A second strepsirrhine species worthy of development as an aging model is the lesser bushbaby or galago (Galago senegalensis) (Table 1), which is slightly larger than Microcebus at about 125 to 300 g. Galagos eat insects and tree gum in nature and are nocturnal and often solitary. Females have reached sexual maturity in as little as 7 months. Under captive conditions, females cycle year-round, with an average cycle length of 29 to 39 days (Darney and Franklin 1982). Twins are born in about half of all births, and up to 2 litters per year can be produced. The maximum recorded lifespan is 16.5 years (Nowak 1991). This species does not enter torpor (W. Hess personal communication 1994) regardless of photoperiod.

Lesser galagos have been successfully bred in a number of zoos and primate centers around the world (Anonymous 1994). Their generalized suitability for laboratory life is discussed in Doyle (1978). Descriptions of caging, diet, reproductive management, and medical problems in a successful colony may be found in Wright and others (1989). There have been no published reports describing age-related changes in bushbaby appearance or physiology; however, some evidence exists that galagos may be particularly prone to renal disease in captivity (Boraski 1981), possibly due to an inadequate captive diet.

Among the callitrichidae, 2 additional species appear to be well-suited for development as aging models. Large captive colonies of both these species currently exist, as does considerable information on their reproduction, husbandry, health, and pathology.

The first of these is the common marmoset (Callithrix jacchus). Unlike the 2 species described above, marmosets are diurnally active and gregarious in nature, with group sizes ranging as high as 15 individuals (Nowak 1991). Females are sexually mature by about I year of age, and in captivity litters of 3 are most common, although twins are also very common (Rothe and others 1992). Estrous cyclicity is not affected by photoperiod (Harter and Erkert 1993). This species has been used to examine follicular dynamics of a polyovular primate as well as nutritional impacts upon reproduction (Tardif and others 1993; Tardif and Jaquish 1994). When housed in multifemale groups, ovulation will be suppressed in all except 1 adult female (Saltzman and others 1994).

A number of spontaneous lesions have been described in marmosets (Okazaki and others 1996). In addition, age-related alterations in T-lymphocyte subsets have been observed using monoclonal antisera to human T-lymphocyte antigens (O'Neill and Levy 1986), as have neurodegenerative changes in the frontal cortex and hippocampus. Histological signs of Alzheimer's-type pathology, such as neurofibrillary tangles, neuritic plaques, or amyloid deposits, have not been observed to occur spontaneously (Honavar and Lantos 1987); however, amyloid plaques have been induced by intracerebral inoculation with brain tissue from a human patient with early-onset Alzheimer's disease (Baker and others 1993).

Common marmosets should be widely available, as they are kept in many captive primate facilities. For instance, in the United States, the New England Regional Primate Research Center in Southborough, Massachusetts, maintains an active breeding colony of about 150 individuals and produces about 60 infants per year (Lee-Parritz and Hunt personal communication 1996).

The second callitrichid of potential value as an aging model is the cotton-top tamarin, Saguinus oedipus. This species, like the common marmoset, is diurnally active and social, with groups consisting of up to 19 individuals, including only I breeding pair. Typically captive litters consist of twins, and reproductive maturity is reached in 18 to 24 months. Captive individuals have been reported to survive up to nearly 20 years of age but are apparently reproductively senescent from at least age 14 (Tardif and Ziegler 1992). Husbandry information may be found in Snowdon and others (1985). Age-related trends in mortality and pathology have not been compiled for this species, but such information likely exists at one of the facilities, such as the New England Regional Primate Research Center or the Oak Ridge Associated Universities Marmoset Research Center, which have large captive colonies. A high incidence of colonic adenocarcinoma (15 to 39%), possibly due to chronic colitis, has been reported in both wild-caught and captive-born individuals of this species (Chalifoux and Bronson 1981; Cheverud and others 1993).

CONCLUSION

Considerable advantages attend the development of small primate models for aging research. These advantages include much lower maintenance cost per animal, a greater potential for the quick development of a large colony dedicated to aging research, and the considerably shorter life span than that of larger primates. I have suggested 4 species that seem to hold special promise for development; however, these candidate species are by no means the only ones that could be developed for aging research. They are, however, the species about which most is currently known, and captive-born individuals are easily available.

¹Abbreviation used in this article: CITES, Convention on International Trade in Endangered Species of Wild Fauna and Flora.

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TABLE 1 Life history parameters for some primate species with mass of 500 g or less

Species	Mass (g)	Age at maturity (months)	Litter size	Captive maximum longevity (years)	Source
Strepsirrhini
Arctocebus calabarensis
Golden potto	266-465	8-10	1	13	Jones 1982; Nowak 1991
Loris tardigradus
Slender lori	85-348	10-18	1-2	12.4	Nowak 1991; Rasmussen and Izard 1988
Galago senegalensis
Lesser galago or bushbaby	125-300	10	1-2	16.5+	Jones 1982
Galagoides demidoff
Demidoff's galago	46-120	8-10	1	14.0	Harvey and others 1986; Bearder 1986
Microcebus murinus (I)
Lesser mouse lemur	50-100	7-29	2	12-15	Bons and others 1992; Nowak 1991
Mirza coquereli (I)
Coquerel's dwarf lemur	280-335	9	1-2	15+	Jones 1982; Nowak 1991; Richard 1986
Cheirogaleus major
Greater dwarf lemur	400	12?	2	8.8	Harvey and others 1986
Cheirogaleus medius
Fat-tailed dwarf lemur	180	12	1	9.0	Harvey and others 1986; Richard 1986
Tarsiers
Tarsier spectrum
Spectral tarsier	140-200	14	1	12.0	Harvey and others 1986
Tarsier syrichta
Philippine tarsier	120-130	?	1	13.4	Nowak 1991
Callitrichidae
Callithrix jacchus
Common marmoset	300	12	2-3	16+	Lee-Parritz personal communication
Saguinus oedipus (I)	480	18	2	18+	Lee-Parritz personal communication
Cebuela pygmaea
Pygmy marmoset	150	24	2	10	Harvey and others 1986