3 CALORIE RESTRICTION (CR), the selective reduction of energy intake without compromising other essential nutrients, is the most powerful intervention known to retard biological aging in mammals, as assessed by extension of mean and maximum lifespan, reduced incidence or progression of age-associated diseases, and preserved physiological function and molecular fidelity with age.1 Yet although CR research dates back nearly 70 years, it was regarded largely as a laboratory curiosity for most of that time, because of the belief that CR worked through retarding growth early in the life history. This notion was reinforced by numerous failed attempts to replicate CR’s antiaging effects when the regimen was instituted in adult organisms (reviewed in Ref. 2). Twenty years ago, this belief was overturned by a classic report by Weindruch and Walford,2 who were the first to unambiguously demonstrate that, if imposed gradually and with a generous provision of essential nutrients (so as to allow for the lesser metabolic adaptability of older organisms), adult-onset CR could exert the same robust anti-aging effects observed when the regimen is implemented in weanlings. The result initiated a new era of interest in CR as a method of experimental manipulation of the aging process—both as tool for investigating the mechanisms of aging, and in hopes of designing alternative interventions which might exploit the mechanisms of CR to extend healthy lifespan in humans (“CR mimetics”3). There have remained, however, reasons for caution regarding the efficacy of CR in older organisms. Reasonable grounds for scepticism included limits on older animals’ ability to metabolically adapt to the CR regime, given young adult animals’ evidently reduced capacity in this regard relative to weanlings; the ability of late-life CR to meaningfully improve functionality, given the previous accumulation of a lifetime of molecular disarray; the time required, relative to the remaining life expectancy of animals in late middle age, for CR’s anti-aging mechanisms to translate into clinically significant functional improvements relative to an ad libitum (AL) cohort; and the established fact of CR’s age-retarding benefits being proportional to the time an organism spends on a CR regimen (Fig. 1). Studies on surrogate outcomes also suggested limits on late-life CR’s effectiveness. Thus CR was found to rapidly reduce levels of carbonyl and loss of sulfhydryl groups in the brain, but was unable to preserve cardiac sulfhydryl groups;4 CR lowered the level of altered heat-labile hepatic, renal, and cerebral proteins, and hepatic mitochondrial (but not cytosolic) carbonylated proteins;5 and while one year of late-onset CR reduced “ragged red” muscle fiber segments and mitochondrial DNA deletions, this effect manifested at 50%, but not