PerspectiveCell Biology

Rapamycin Paradox Resolved

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Science  30 Mar 2012:
Vol. 335, Issue 6076, pp. 1578-1579
DOI: 10.1126/science.1221365

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The goal of aging research is to extend healthspan, the period of life free of chronic disease. It has been known for decades that calorie restriction—a regime of reduced calorie consumption without malnutrition—extends the life span of mammals (1) and other model organisms. A primary effect of calorie restriction is to improve glucose homeostasis, which may underlie increased longevity. In the last few years, the focus has turned from characterizing genes and molecular mechanisms that drive aging (2) to small-molecule interventions, and in 2009, rapamycin was the first drug reported to extend the life span of mice—roughly 15% in females and 10% in males (3). Rapamycin has been proposed as a calorie restriction mimetic and, at least in mouse models, it is proving beneficial in preventing the onset of many age-related diseases (4). However, there is a fly in the ointment regarding its use (or that of rapalog derivatives) to extend healthspan. Rapamycin causes glucose intolerance and insulin resistance in mice and humans (5), effects that could outweigh longevity benefits. On page 1638 of this issue, Lamming et al. (6) identify a mechanism by which the drug confers insulin resistance, and show that rapamycin's effect on glucose homeostasis and longevity can be uncoupled.