Historical Development of Animal Models of Aging

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Richard L. Sprott and Steven N. Austad

The use of animal models for research parallels the rise of modern science, beginning in the late 19th century with relatively primitive experiments and increasing in sophistication as relevant science progressed. The science of aging (gerontology) was relatively late in development, and its rise both parallels and is the result of the development of new, effective animal models. Many models, including inbred strains of mice and diet-restricted mice and rats, were first developed for cancer research. As investigators began to explore the underpinnings of cancer reductions and cancer biology in these models, their utility for aging was soon apparent. The creation of the NIA in 1975 provided a powerful boost to the development of models. The NIA developed a deliberate, rational strategy for animal model development, then funded the endeavor. NIA continues to be central to model development through its contract colonies and grant programs. Rodent models now number in the hundreds ranging from strains to "designer" individual genotypes. At the same time, models from a wide variety of other species have been developed and are becoming more generally available. Particular interest is being paid to the development of new, suitable nonhuman primate models.

Introduction

The history of animal model development in the United States is inextricably tied to the history of the National Institute on Aging (NIA). The rapid rise of biological, biomedical and behavioral research on aging beginning in the 1970s was a response to the growing realization of both the scientific and political establishments that the American population was aging and that the Baby Boomers would reach retirement in less than 50 years, an eternity for politicians and a moment for scientists. Even before NIA was created, scientists interested in aging began searching for animal models for their study. From the time of Clive McKay's calorie restriction (CR) studies in the 1930s through Morris Ross's CR studies in the late 1960s and early 1970s, most aging models resulted from studies actually developed to study cancer. With the advent of the NIA, the field began to develop rational strategies for selection and provision of animal models. Over the ensuing 3% decades the variety of animal models developed and available for aging research has grown enormously in quality and sophistication. At the same time, most investigators still make too many choices based on convenience rather than on the basis of a real knowledge of the available models and their suitability for any specific research question.

This chapter treats the historical development of vertebrate models only. We have made no attempt to present the history of invertebrate models or the thousands of "designer" mouse mutants and special stocks which are well covered in subsequent chapters.

Caloric Restriction (CR)

For a complete history of this topic, see Edward Masoro's summary in his SAGE KE article ''Subfield History: Caloric restriction, slowing aging, and extending life'' (Masoro, 2003).

The modern history of the use of animal (at least rodent) models for research on aging begins with the research of Clive McKay, a noted nutritionist in the 1930s. In the course of research on cancer, McKay and his colleagues (McKay et al., 1935) discovered that severe calorie restriction (to 60% of ad libitum levels) resulted in significant increases in the lifespan of rats. Interestingly, since McKay was primarily interested in cancer, the increased longevity effects were not followed up until the work of Morris Ross in the 1960s using Sprague-Dawley rats (Ross, 1961). Ross, too, was primarily interested in the impact of CR on tumor incidence and age of occurrence in his rat models. Ross's very careful studies through the 1960s and early 1970s brought caloric restriction's effects on longevity to the attention of geron-tologists just at the time that gerontological research was receiving an influx of interest and funding in anticipation of the creation of the NIA.

Following the interest created by Ross and others, two major research programs exploring CR's effects on lifespan using rodent models arose in the 1970s.

Handbook of Models for Human Aging

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One group based in the laboratory of Roy Walford at UCLA began studies of immune function in C57BL/6J mice under CR conditions (M. Gerbasse-Delima et al., 1975). Over a period of years, Walford and his colleagues, most notably Richard Weindruch, studied the effects of CR on models ranging from mouse to rhesus monkeys and humans. These studies are ongoing and provide a lively subtext to the lifespan extension literature, as CR is to date the only intervention that reliably increases lifespan in mammals (Weindruch et al., 1982; Yu et al., 1985; Walford et al., 1992).

At the same time the Walford group was engaged in its program with the objective of developing a human CR research agenda, another rigorous program of rodent CR research was developed by Edward Masoro and B.P. Yu at the University of Texas, Health Science Center, San Antonio using specific pathogen-free (SPF) F344 rats (Masoro et al., 1982). The Masoro group concentrated on F344 rats. The evolution of that group's research has favored the development of more sophisticated rodent models, rather than progressing toward human research. Roger McCarter, now at Penn State, has worked to understand the physiological basis of the CR effect using F344 rats and the involvement of energy metabolism in the mechanism of action of CR using transgenic and nontransgenic C57BL/6 mice (McCarter et al., 1997; McCarter et al., 2002). As will be seen in the rest of this chapter, CR has a central place in the development of animal models for all of basic gerontology, not just in connection with lifespan extension.

The National Institute on Aging (NIA)

Even before it was formally created, the NIA played a pivotal role in the development of animal models for aging. For a more complete discussion of this topic, see (Sprott, 1991; Sprott and Austad, 1996). In 1970, aging research was the province of a small branch of the National Institute of Child Health and Human Development (NICHHD). But it was obvious that a new institute focused on aging was likely to be authorized as the political system was beginning to consider the consequences of the aging of the baby boom cohort. In the very earliest meetings to consider what an institute focused on research on aging might need, it was quickly apparent that the development of readily available, affordable models for basic research would be crucial to development of a robust research enterprise. A small task force was convened and asked to recommend ''the best animal model for aging.'' The task force had no trouble quickly agreeing that no single model would suffice, as different research questions would demand different models, and providing a very detailed set of recommendations for ''Development of the Rodent as a model system of aging'' (Gibson, 1972). That recommendation was accepted by the research administrators responsible for planning the resources of a new institute. Not only was the recommendation accepted; to everyone's great surprise, it was actually acted upon. Those recommendations are presented in: Development of the Rodent as a Model System of Aging Book II (Gibson, et al., 1979).

In response to the recommendations of the task force, the Aging Branch created the first central colony of aging rodents for use by gerontologists under contract to Charles River Breeding Laboratories in 1974. The NIA was formally established in 1974 and began to function in 1975. The initial rodent colony contained two rat genotypes (F344 and Sprague-Dawley) and three mouse genotypes (C57BL/6J, DBA/2J, and the Fi hybrid B6D2F1). The first aged animals were available for use by investigators by 1977. A key observation quickly became apparent as these animals were incorporated into aging research programs. By selecting these genotypes and making them broadly and easily available, the NIA had, in effect, seriously channeled the directions in which aging research could go, since the colony soon became the sole source of aged animals in the United States. In addition, it soon became apparent that Sprague-Dawley rats were susceptible to multiple pathologies that shortened lifespan, and that the F44 rats fed normal diets had a high incidence of renal pathology in the environments that were then prevalent. The solutions were twofold. First, there was agreement that the number of mouse and rat genotypes needed to be expanded and that more F1 hybrids, with hybrid vigor, needed to be made available. In 1978, the number of mouse genotypes was increased to nine (and later reduced to seven). Second, intercurrent diseases in NIA-supported contract facilities and to an even greater extent in the colony spaces utilized by grantees were clearly resulting in much research being conducted on sick and dying animals or on unrepresentative survivors. These environments ranged from what could be charitably called ''maintenance'' to ''clean conventional.'' In 1980, the institute began to address this disease problem. SPF facilities were just beginning to come into use. In a very controversial move at the time, the institute decided that providing ''clean conventional'' animals allowed the existing disease problems to persist. NIA decided to provide only SPF animals even though this meant that animals coming from an NIA facility would likely get sick upon arrival in a grantee facility that had an intercurrent disease problem. Nevertheless, this policy was implemented in 1982 in the hope that the result would be a broad improvement in the facilities receiving animals. That decision was in our opinion one of the major factors in the rapid improvement in the quality of animal research being supported by the NIA. Today, SPF barrier facilities are the norm. In subsequent years, the NIA has refined the array of mice and rats available. Current information on available animal resources from NIA is available at

http://www.nia.nih.gov/ResearchInformation/Scientific Resources/AgedRodentColoniesHandbook.

The National Academy of Sciences (NAS)

In December 1976, NIA held a workshop to address the question of whether an array of species might be needed to serve as models for various human conditions and processes. The outcome of that conference was a recommendation to commission a National Academy of Sciences study of the issues and the state of knowledge about all known mammalian models. The study was carried out by the Institute of Laboratory Animal Resources (ILAR) of the NAS, which created a ''Committee on Animal Models for Research on Aging'' for that purpose. The report of that committee was issued in book form (Mammalian Models for Research on Aging, NAS, 1981).

Subcommittees on carnivores, lagomorphs and rodents other than rats and mice, mice, rats, and nonhuman primates, reviewed the world's literature in the areas of nervous system and behavior, visual system, auditory system, skeletal system, respiratory system, cardiovascular system, endocrine system, reproductive system and obesity. That review, done nearly 25 years ago, remains the only major assessment of model systems for the broad range of questions of importance to investigators of aging. Given the tremendous advances in model development that have occurred since then, it is surely time for a new assessment. While such an assessment is expensive, it would be expected to more than pay for itself in increased efficiency of agency planning for provision of model animals and investigator choice of suitable models.

The Search for Biomarkers of Aging (NIA)

As soon as gerontologists began to be interested in interventions that might lengthen life, the question of how to test such interventions arose. The problem is trivial in very short-lived animals such as yeast, nematodes, fruit flies, and mice, since many generations of animals can be tested in the course of a single three-year experiment (NIH grant). However, the problem is far from trivial in longer lived species like dogs, monkeys, and humans. The best solution would be to develop a set of measures that could be used to assess the life-lengthening effects of an intervention in significantly less than the full lifespan of the organism. Such measures are called biomarkers of aging. For a full discussion of the issues see the special issue of Experimental Gerontology; Biomarkers of Aging (Sprott and Baker, 1988).

The need for biomarkers of aging also arises from the observation that chronological age and ''biological'' age are not synonymous. Obviously species age at different rates, but the question of whether individuals within a species do so as well has generated much controversy in the aging literature. If one assumes that aging is the net result of environmental damage (oxidative damage to DNA for example), then the question is moot. If, on the other hand, one assumes that there are basic aging processes that determine the rate at which organisms age (as there clearly are in annual plants), then assessing the rate of aging becomes a necessary part of the assessment of interventions designed to change that rate. Only in the case of a pure wear and tear or DNA damage theory would biomarkers of aging be an irrelevant concept. Since different species have different, but very predictable, lifespans (fruit flies 2 months; mice 2 to 3 years; chimpanzees as long as 60 years; and humans as long as 120 years), the question of how to compare the biological age status of individuals across species in order to make animal models useful became a primary rational for the development of biomarkers of aging.

In 1987 the NIA together with the National Center for Toxicological Research (NCTR) established colonies of mice and rats to be used in a ten-year, 18-laboratory effort to develop biomarkers of aging that could eventually be used to test interventions in humans. Since CR was then the only intervention that had ever been reliably been shown to increase longevity (slow the rate of aging?) in any organism, the NIA/NCTR colonies provided both ad libitum and calorie-restricted mice and rats on the assumption that any useful biomarker would have to be sensitive to CR as a longevity promoting intervention. These colonies were the first to make CR mice and rats available for widespread use. NIA continues to make CR rats of three genotypes available; see http://www.nia. nih.gov/ResearchInformation/ScientificResources/Aged RodentColoniesHandbook for details and current availability.

Twenty percent of all of the animals produced in the biomarker colonies were set aside for pathological assessment (10% cross-sectional and 10% longitudinal). These studies provided the most complete characterization of the pathology of three rat genotypes (Brown Norway, F344, Brown Norway, Brown Norway x F344 F1) hybrid and four mouse genotypes (C57BL/6N, DBA/ 2J, C57BL/6N x DBA2/J F1 hybrid, and C57BL/ 6N x C3H hybrid) ever accomplished (Bronson, 1990; Lipman et al., 1999 A and B; Turturo et al., 1999). One of the questions to arise from these studies was whether the ad libitum feeding regimen is the optimum regimen or an abnormal one for rodents. While the issue is not yet resolved, interest in some level of CR as the ''normal'' diet is growing. Differences in diet content and amount between laboratories contribute a great deal of variability to studies of everything from biomarkers to pathology. The NIA Biomarkers Program controlled for this variability by rearing all test animals and shipping them to investigators in the program. In the absence of such control, it is often difficult to make cross-laboratory comparisons. See Hart et al. (1995) for a very thorough treatment of this issue.

The Senescence Accelerated Mouse

The Senescence Accelerated Mouse (SAM) strains of mice were developed by Toshio Takeda at the Chest Disease Research Institute, Kyoto University, as the result of an accidental outcrossing of AKR/J mice and another unknown albino mouse strain in 1968. After receiving several pairs of AKR/J mice Takeda began brother-sister mating to provide animals for his research. He soon began to notice that in some litters of the offspring most of the mice ''showed a moderate to severe degree of loss of activity, hair loss and lack of glossiness, periopthalmic lesions, increased lordosis, and early death'' (Takeda, 2004). Beginning in 1975 five litters of mice showing the accelerated senescence phenotype were selected to become the progenitors of lines of senescence-prone (P series) mice, while three litters of mice that were resistant to accelerated aging were selected as progenitors of the senescence resistant (R series). Lines from these progenitor litters were then maintained as inbred lines to create three lines of resistant and five prone lines. These lines can be considered a set of recombinant inbred mice resulting from a cross between AKR and at least one (possibly two) unknown albino strains. Geno-typing studies are ongoing to determine the genotype of the outcross animals.

Over the ensuing three decades Takeda and his colleagues have characterized these mice for an extraordinary range of characteristics including behavior, pathology, reproductive capacity, lifespan, response to husbandry, and physiology. For the most current exploration of this set of mouse strains, see Nomura et al. (2004). This approach to development of models for aging research is very different from that used in the United States. American investigators are very resistant to the use of models of ''accelerated'' aging, as they believe that it is impossible to distinguish between accelerated aging and the life-shortening effects of disease or environmental insult. Only recently have any investigators in the United States and Europe begun to use these mice. One of the factors in the slight shift in attitude has been the fact that the differences in lifespan among SAM lines have persisted after the mice were moved to SPF facilities (Suzuki et al., 2004). SAM mice are widely used in Asia for pharmacologic and neurodegenerative research, and are obtained in Asia from the SAM Research Council. SAM mice are available in the United States and Western Europe from the International Biogerontology Resource Institute (IBRI) through an arrangement with Harlan Sprague Dawley.

The International Biogerontology Resources Institute (IBRI)

An international resource development institute (IBRI) was begun at San Pietro al Natisone, Friuli, Italy in 1998.

The mission of IBRI is to foster international collaboration on the biological resources needed to conduct aging research including cells, tissues, organs, and whole organisms, from C. elegans to nonhuman primates. Early emphasis has been placed on rats (Rattus norvegicus) and mice (Mus domesticus) to provide for the shared development of biological resources and for the development of research methods to utilize these resources; provide space, core shared research resources, and a core staff of research scientists with maximum opportunities for international collaboration with visiting scientists and fellows; provide an international education effort regarding the use of animal models in gerontological research; provide maximum barrier facilities to house defined pedigreed stocks and strains of rats, mice, and other animals in one location accessible to the worldwide scientific community; provide guidance, worldwide, for the efficient, cost-effective, and reliable production and distribution of animal models for aging research; and provide a facility for holding international conferences and symposia on biogerontologic resources. This fledgling organization is made up of a consortium of universities from the United States and Europe and its corporate partner, Harlan Sprague Dawley. The SAM Council maintains an active role in the provision and certification of SAM lines maintained by IBRI.

The major objective of IBRI is to collect and maintain all of the major animal models for aging research in one place and make them available to investigators at that facility for pilot experiments, and by shipment to an investigator's laboratory for more extensive experiments. IBRI hopes to soon develop new rodent and nonhuman primate models as well. Further information about IBRI can be obtained by contacting the first author of this chapter.

Other Rodents

Laboratory rodents are among the shortest-lived mammals known, which defines in a certain sense their value for life-span studies. Their already short lives may have been further shortened by hundreds of generations of inadvertent selection for rapid growth and high reproductive rate that mass breeding entails. In the 1960s, George Sacher began searching for a longer lived rodent species, similar in size and basic biology to the laboratory mouse, to investigate what it exactly is that longer lived species do better in the ''protection-stabilization, and repair of its essential molecules'' when compared with a mouse (Sacher and Hart, 1978). In 1962, Sacher began laboratory breeding of wild-caught house mice (Mus musculus) and white-footed mice (Peromyscus leucopus) trapped near the Argonne Laboratory site in northeast Illinois. The white-footed mouse was abundant near Argonne and had already been used in a variety of biomedical research contexts (King, 1968). Although he noticed that wild-caught house mice lived somewhat longer than laboratory mice, he did not pursue this line of inquiry. The white-footed mouse turned out to live more than twice as long as either wild-caught or laboratory house mice—more than 3.75 years on average with the longest-lived individuals surpassing 8 years. Sacher's laboratory published about a dozen papers comparing house and white-footed mice, as did Ron Hart's laboratory at the National Center for Toxicological Research. In the 1980s and early 1990s George Smith of UCLA began to inbreed Peromyscus leucopus. Although Dr. Smith is now retired, the strains he produced have now been inbred for more than 30 generations. They, along with various subspecies of seven species of Peromyscus and a variety of mutants, are currently available from the Peromyscus Genetics Stock Center (http://stkctr.biol.sc.edu) at the University of South Carolina in Columbus, South Carolina.

Although George Sacher did not follow up his observation that wild-caught house mice lived longer than domesticated laboratory mice, he alerted researchers to the possibility that wild populations of house mice might contain longevity-associated genes that had been lost in laboratory mice. Austad (1996) observed that the wide range of mouse body sizes in geographically diverse populations suggested that many wild mouse populations might bear local adaptations that would make them of considerable gerontological interest. Miller and colleagues (1999) pointed out that the history of laboratory mice from their initial derivation from ''fancy mice'' to their inadvertent selection for rapid growth, high fecundity and cancer-prone genotypes to the extensive inbreeding that had made them so valuable in one sense may have led to shortening of life as well. Mice captured from three field locales (Idaho; Majuro in the Marshall Islands; and Pohnpei in Micronesia) were compared for body size, developmental rate, various hormone parameters, and longevity with a synthetic laboratory stock bred from crossing four inbred strains (Miller et al., 2000, 2002). Mice derived from the wild remained smaller than the laboratory stock even given unlimited food. They also grew more slowly, matured later, and had smaller litters compared with the laboratory mice. Mice from Idaho and Majuro lived somewhat longer than the laboratory stock whereas the Pohnpei mice did not. Associated with their longer life, Idaho mice exhibited reduced serum levels of IGF-1, leptin, and glycosylated hemoglobin compared with laboratory mice. Surprisingly, Majuro mice were hyperglycemic compared to laboratory mice despite their longer lives (Harper et al., 2005). Genes present in these long-lived mice may be valuable tools for the analysis of the physiology and biochemistry of aging mice. Moreover, wild-derived mice have exceptional levels of physical performance, e.g., running speed, endurance, agility, compared with laboratory mice (Dohm et al., 1994) and may be useful in dissecting the genetics of muscle physiology and coordination.

In recent years, a novel rodent species of exceptional gerontological interest has been discovered, the naked mole-rat (Heterocephalus glaber). This mouse-sized African species had been studied since the 1970s, mainly for its unique social system that resembles the eusocial colony organization of bees and ants (Sherman et al., 1991). However, as captive colonies were maintained for longer and longer, it became clear that naked mole-rats were equally interesting for their very long lives. The current captive longevity record is more than 28 years, and many individuals live into their teens and twenties (O'Connor et al., 2002; Buffenstein and Jarvis, 2002) and continue to function at a high level. The longevity record-holding male successfully inseminated a female shortly before his death. Rochelle Buffenstein's laboratory along with her many collaborators are now seriously pursuing mechanistic studies to elucidate how this species can live nearly 10 times longer than the similar-sized laboratory mouse.

Nonhuman Primates

Nonhuman primates have been employed in medical research since the second millennium BC in ancient Egypt; however, their modern medical use began in the late 19th century when they were used mainly to investigate infectious diseases such as syphilis (Fridman, 2002). Elie Metchnikov, the Nobel Prize-winning bacteriologist, was probably the first investigator to consider the study of nonhuman primates for the insights they might offer into human aging. On the occasion of his 70th birthday in 1915, he suggested that primate nurseries be constructed for the captive rearing of monkeys and apes, thus laying the conceptual groundwork for the primate research centers that exist today (Fridman, 2002). In a somewhat embarrassing first direct use of primates to address human aging, S.A. Voronoff developed a colony of baboons and chimpanzees in southern France to provide testicular tissue for transplantation into humans to achieve their ''rejuvenation.'' This facility also provided primates to other researchers, such as I.P. Pavlov. The first major primate center specifically dedicated to research in the United States was established in Florida by Robert Yerkes in 1930.

The advantage of primates for aging research is their close evolutionary affinity with humans and consequent similarity (compared with rodents) in such traits as complex cognitive abilities, and similarity of response to drugs and vaccines.

Maintaining primates in good physical and mental health in captivity has always presented complex problems. Because of these complex husbandry issues, even defining what is an ''aged'' individual of a given species has not been easy. For instance, the maximum lifespan of rhesus macaques, capuchin monkeys, and marmosets reported in a 1979 review was 33, 43, and 9 years, respectively (Bowden and Jones, 1979). With improved husbandry, we now know that these three primates can live at least 40-44 years, 55 years, and 16 years, respectively, some 25-75% longer than previously thought (Roth et al., 2004; Nowak, 1999; Smucny et al.,

2004). Their long lives and complex social needs make primate aging research difficult and expensive. However, the human relevance of health problems associated with aging in nonhuman primates is unparalleled. They must be studied.

The NIA has sought to help make aged rhesus macaques available to the research community by supporting their maintenance at several primate research facilities around the United States. Currently, about 150 macaques between 18 and 35 years of age are available for noninvasive research (http://www.nia.nih.gov/ ResearchInformation/ScientificResources/). The Institute keeps a repository of stored primate tissue as well, also mostly from rhesus macaques.

The most serious and systematic studies of nonhuman primate aging have developed as a consequence of an attempt to determine whether caloric restriction extends life and prevents disease in primates as it does in laboratory rodents. Two such ongoing studies exist. In 1987, the intramural program of the NIA initiated an investigation of long-term caloric restriction in male rhesus macaques and squirrel monkeys. In both species, restriction was imposed at several ages by reducing food intake by 30% relative to age- and size-matched controls. Five years later, female rhesus were added to the study. In the intervening years, various short-term restriction experiments were also added, so that about 200 monkeys in sum are being investigated (Lane et al., 2002; Mattison et al., 2003). Similarly, at the Wisconsin Regional Primate Research Center, a caloric restriction study of 30 rhesus males (15 restricted, 15 controls) was initiated in 1989. Five years later, 30 females and an additional 16 males were added to the study. As in the NIA studies, the experimental animals are restricted to 70% of the control diet (Ramsey et al., 2000). Due to the long life of monkeys (mean thought to be 25-26 years for rhesus, and maximum at least 40 years), definitive results are not yet available for either study. However, a side benefit of these studies is to characterize more thoroughly than ever before, the life- and health-span of very well cared for primates. For instance, squirrel monkeys were chosen as one species for the NIA study, because it was thought that their maximum longevity was less than 20 years. However the oldest animals in that study are now in their mid-to late 20s (J. Mattison, personal communication,

2005). Thus with excellent care, longevity increased fairly dramatically. It will be interesting to see whether there is also such an increase in longevity in the rhesus population.

One approach to making primate aging research less costly and time consuming would be the development of a small primate model (Austad, 1997). Advantages of a small model (rat-sized or smaller) are (1) lower per capita housing and maintenance costs; (2) the potential to maintain the animals in SPF conditions in standard laboratory animal facilities as is now standard for aging mouse and rat research; and (3) their accelerated life history, being that they reach sexual maturity earlier and are shorter-lived than larger primates. The most promising candidate species for a small primate model for aging research is the common marmoset (Callithrix jacchus). This species is native to eastern Brazil and has been used in biomedical research since the early 1960s (Ludlage and Mansfield, 2003). One major advantage of common marmosets compared with other small primates is that they are not listed in Appendix I of the Convention on International Trade in Endangered Species (CITES). Listing in CITES Appendix I severely limits availability of animals for research and prohibits commercial trade in a species. Marmosets are rat-sized, 300-400 g, reach sexual maturity at 12-18 months of age, typically produce twin births, have a mean longevity of 6-7 years (are considered ''old'' by 8-10 years) (Tardif, personal communication, 2004), and have a record maximum longevity of 16 years (Smucny et al., 2004). Their captive husbandry and clinical care are well-developed (Ludlage and Mansfield, 2003), and they are currently maintained at five major research facilities (Smucny et al., 2004). It is quite possible that the mean and maximum longevity reported for marmosets would creep upward as they begin to be maintained in SPF conditions, but even a 50% increase would still make them an exceptionally attractive primate aging model. Because of their high reproductive rate relative to larger primates, colonies can be expanded comparatively rapidly. Their habit of twinning would also allow littermates to be randomly assigned to treatment and control groups, giving some measure of genetic control in experimental protocols. A further advantage is that as of March 1, 2005 common marmosets have joined the official species queue for complete genome sequencing by the NIH/National Human Genome Research Institute.

Summary and Conclusions

Modern animal model use for aging research began with the calorie restriction studies of Clive McKay and Morris Ross. This research, initially for cancer, led to studies to understand the CR effect and eventually to the development of special colonies of mice and rats for that purpose. Beginning in the mid-1970s the NIA created central colonies of aged rodents, centrally raised by contract, fed uniform diets, and maintained in barrier facilities. These animals became the models of choice for almost all biological research on aging for a decade. Subsequently, many more rodent models were created and supplied by NIA. Nonhuman primate resources began to be developed and are now just beginning to become available. Currently primate research is conducted in a small number of laboratories at DRR supported primate centers and at the NIA intramural facilities.

Other animal models such as nematodes and fruit flies are being used for basic studies of many aging phenomena. These models are discussed in later chapters.

The history of animal model development for aging research is in many ways the history of biological research on aging. Without widely available and suitable animal models for research, the astonishing developments that have occurred in the last 4 or 5 decades in our understanding of aging could not have occurred. It should be obvious that support for models development is absolutely required for the continued development of this field of knowledge.

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