Organisms have evolved neuroendocrine and metabolic response systems to enhance survival during periods of food shortage, which occur frequently in nature. The anti-aging effect of caloric restriction (CR) might derive from these adaptive responses to maximize organism survival. The present article discusses the potential role for leptin, a hormone secreted from adipocytes, as a key signal that induces the adaptive responses relevant to CR. Evidence indicates that a CR-induced reduction of the plasma leptin concentration suppresses the gonadal, somatotropic, and thyroidal axes, and activates the adrenal axis. Metabolic adaptation, a shift in fuel utilization mainly conducted in the liver, seems to require leptin signaling. Although alternative signaling pathways might also mediate the anti-aging effects of CR, leptin signaling could be a substantial pathway involved in these effects. Molecular dissection of the mechanisms underlying the effects of CR will contribute to a better understanding of the aging process, leading to the extension of a healthy lifespan in humans.