Effects of long-term diet restriction on aging and longevity in primates remain uncertain.

D IET restriction (DR) remains the only reproducible, nongenetic intervention for alteration of aging processes including extension of average and maximal life span, prevention and/or amelioration of many age-related diseases, and maintenance of more youthful physiological function later into life. A substantial literature has made it clear that these effects of DR are observed in nearly all species in which it has been tested (1,2). Despite this impressive body of experimental results, it remains unknown whether DR can impact positively upon human aging. Indeed, whether DR is relevant to human aging remains one of the most significant unanswered questions in contemporary biogerontology. Nonhuman primates have long been used as models for human disease including aging (3,4). To this end, the recent article by Bodkin and colleagues (5) reporting on agerelated morbidity and mortality in rhesus monkeys and the putative beneficial effects of DR provides an interesting, though preliminary, assessment of the possible relevance of reduced calorie intake to human aging. In general, Bodkin and colleagues concluded that DR increases average age at death associated with prevention of hyperinsulinemia and the mitigation of other age-related diseases and disease markers. Caution must be exercised to avoid over-interpretation of these findings. We contend that their results do not provide sufficient evidence to support the conclusion that DR exerts the same widespread beneficial effects in nonhuman primates (and by genetic similarity, human primates) as has been extensively reported in rodents over the last 75 years. The preliminary nature of these findings is dictated bymethodological issues, including study design, subject characteristics, and statistical methodology, any of which may limit the generalizability of these findings. Of significant concern is that several experimental controls typically used in rodent DR studies were not applied in the Bodkin and colleagues study. First, only 8 of the total 117 rhesus monkeys were in the DR group, and only 3 deaths occurred in this experimental group. This is an extremely small sample size for any mortality study. The typical rodent longevity study would include 30–40 animals per treatment group. Second, while the number of monkeys in the ad libitum (control) group is sufficiently large (n 1⁄4 109), control and DR monkeys did not enter the study at the same time, nor were they randomly assigned to either the control or DR groups. It is apparent that the study by Bodkin and colleagues was not designed at the outset to address the question to which the conclusions are directed, specifically the effects of DR on aging and age-related disease. The authors state that all subjects were part of a longitudinal study on aging, obesity, and spontaneous diabetes. Monkeys described in this paper were part of a series of individual experiments (6–15) rather than a single focused investigation of DR and aging. The 8 DRmonkeys were brought into the larger colony as a separate cohort of adult monkeys already on a weight stabilization protocol designed to maintain a normal adult body weight. For the most rigorous test of the hypothesis that DR retarded aging, environmental and procedural variables would also need to be controlled. Specifically, all monkeys would need to be housed in the same type cage, in the same or similar vivaria, and decisions regarding treatment of disease and euthanasia would have to be standardized. This type of environmental control was not described by Bodkin and colleagues. Thus, rather than a rigorous experimental design addressing the question of the effects of DR on mortality and morbidity, the current report would be more accurately described as a meta-analysis (though lacking appropriate statistical methodology) of many studies over several years from the same laboratory. Another methodological issue is that the paper does not make clear how many animals had a known date of birth and therefore a reliable age at death. The paper states explicitly that all animals had a recorded age (p. 213). The practice of recording an estimated age when the specific birth date is not known, particularly for wild-caught monkeys, is common in primate research. Therefore, monkeys frequently have a ‘‘recorded’’ age, but not a known date of birth. Over the 24-year span of this study, methodology for age estimation has no doubt improved, and it is likely that several individuals were responsible for these age estimations. Certainly these factors contribute to significant variability in estimated ages thereby negatively impacting any conclusions about differences in life span and age at onset of disease. Differences in the diet fed to monkeys in the study could have led to another methodological problem. Unlike most rodent DR studies in which diets for control and DR groups are highly controlled, it is apparent that monkeys in the Bodkin and colleagues study did not all consume the same diet. Standard monkey chow (17% protein, 70%