Dietary caloric restriction (CR) is the only intervention conclusively and reproducibly shown to slow aging and maintain health and vitality in mammals. Although this paradigm has been known for over 60 years, its precise biological mechanisms and applicability to humans remain unknown. We began addressing the latter question in 1987 with the first controlled study of CR in primates (rhesus and squirrel monkeys, which are evolutionarily much closer to humans than the rodents most frequently employed in CR studies). To date, our results strongly suggest that the same beneficial "antiaging" and/or "antidisease" effects observed in CR rodents also occur in primates. These include lower plasma insulin levels and greater sensitivity; lower body temperatures; reduced cholesterol, triglycerides, blood pressure, and arterial stiffness; elevated HDL; and slower age-related decline in circulating levels of DHEAS. Collectively, these biomarkers suggest that CR primates will be less likely to incur diabetes, cardiovascular problems, and other age-related diseases and may in fact be aging more slowly than fully fed counterparts. Despite these very encouraging results, it is unlikely that most humans would be willing to maintain a 30% reduced diet for the bulk of their adult life span, even if it meant more healthy years. For this reason, we have begun to explore CR mimetics, agents that might elicit the same beneficial effects as CR, without the necessity of dieting. Our initial studies have focused on 2-deoxyglucose (2DG), a sugar analogue with a limited metabolism that actually reduces glucose/energy flux without decreasing food intake in rats. In a six-month pilot study, 2DG lowered plasma insulin and body temperature in a manner analagous to that of CR. Thus, metabolic effects that mediate the CR mechanism can be attained pharmacologically. Doses were titrated to eliminate toxicity; a long-term longevity study is now under way. In addition, data from other laboratories suggest that at least some of the same physiological/metabolic end points that are associated with the beneficial effects of underfeeding may be obtained from other potential CR mimetic agents, some naturally occurring in food products. Much work remains to be done, but taken together, our successful results with CR in primates and 2DG administration to rats suggest that it may indeed be possible to obtain the health- and longevity-promoting effects of the former intervention without actually decreasing food intake.