Calorie restriction in rhesus monkeys Julie A. Mattison * , Mark A. Lane, George S. Roth, Donald K. Ingram Intramural Research Program, Gerontology Research Center, National Institute on Aging, NIH, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA Received 1 May 2002; accepted 9 May 2002 Abstract Calorie restriction (CR) extends lifespan and reduces the incidence and age of onset of age-related disease in several animal models. To determine if this nutritional intervention has similar actions in a long-lived primate species, the National Institute on Aging (NIA) initiated a study in 1987 to investigate the effects of a 30% CR in male and female rhesus macaques (Macaca mulatta ) of a broad age range. We have observed physiological effects of CR that parallel rodent studies and may be predictive of an increased lifespan. Specifically, results from the NIA study have demonstrated that CR decreases body weight and fat mass, improves glucoregulatory function, decreases blood pressure and blood lipids, and decreases body temperature. Juvenile males exhibited delayed skeletal and sexual maturation. Adult bone mass was not affected by CR in females nor were several reproductive hormones or menstrual cycling. CR attenuated the age-associated decline in both dehydroepiandrosterone (DHEA) and melatonin in males. Although 81% of the monkeys in the study are still alive, preliminary evidence suggests that CR will have beneficial effects on morbidity and mortality. We are now preparing a battery of measures to provide a thorough and relevant analysis of the effectiveness of CR at delaying the onset of age-related disease and maintaining function later into life. q 2002 Elsevier Science Inc. All rights reserved. Keywords: Aging; Nutritional modulation; Glucoregulation; Biomarkers; Lifespan 1. Introduction Virtually all information known about the effect of calorie restriction (CR) on aging processes and longevity comes from research conducted with rodents and other short-lived species. In the last decade, results have emerged suggesting that long-lived nonhuman primates (NHP) will benefit similarly from CR. This suggestion comes not directly from mortality results, as the average lifespan for rhesus monkeys, the most widely used NHP model, is around 25 years; thus, it will be several years before current monkey studies can yield significant survival results. Rather, the hypothesis that this intervention will increase lifespan in NHPs receives support from striking parallels between findings from studies in rhesus monkeys on CR with those from rodent studies. These similarities include changes in body composition, maturation and reproduction, metabolism, and the reduction of risk factors for diabetes and cardiovascular disease (reviewed in Lane et al., 1997a). This hypothesis is further supported by findings that CR effectively attenuated the age-related decline in hormones such as dehydroepiandrosterone (DHEA) and melatonin in monkeys. In 1987 the National Institute on Aging (NIA) initiated a study to determine the effectiveness of the CR paradigm in an animal model closely related to humans. This study began with a group of 30 male rhesus monkeys and was doubled to 60 in 1988. Sixty females were added in 1992. Monkeys ranged in age from 1 to 17 years at the initiation of the study and have been fed either a diet approximating ad libitum (CON) intake or a CR diet that targeted 30% less calories than age- and weight-matched controls for 13–15 years (males) or 10 years (females). This large age range provided a unique opportunity to study CR initiated in juvenile, adult, and old animals. Animal diet and husbandry have been described previously (Ingram et al., 1990; Lane et al., 1992). While data on morbidity and mortality would provide the most compelling evidence that CR could retard aging and enhance longevity, the maintenance of function—cellular, organ, physiologic, and behavioral—is an equally important component of any aging study. Therefore, the NIA is currently developing a battery of assays to conduct over the next several years that will assess these functions. These data, in combination with morbidity and mortality, will 0531-5565/03/$ - see front matter q 2002 Elsevier Science Inc. All rights reserved. PII: S0531-5565(02)00146-8 Experimental Gerontology 38 (2003) 35–46 www.elsevier.com/locate/expgero * Corresponding author. Tel.: þ 1-301-435-7637; fax: þ1-301-480-0504. E-mail address: mattisonj@mail.nih.gov (J.A. Mattison).