Caloric restriction (CR) may retard aging processes and extend lifespan in organisms by altering energy-metabolic pathways. In CR rodents, glucose influx into tissues is not reduced, as compared with control animals fed ad libitum (AL), although plasma concentrations of glucose and insulin are lower. Gene expression profiles in rodents have suggested that CR promotes gluconeogenesis and fatty acid biosynthesis in skeletal muscle. In the liver, CR promotes gluconeogenesis but decreases fatty acid synthesis and glycolysis. In lower organisms such as yeasts and nematodes, incomplete blocks in steps of insulin/insulin-like growth factor-1 (IGF-1) signal pathway extend lifespan. The life-prolonging effect of CR in yeasts requires NPT1 and SIR2 genes, both of which relate to sensing energy status and silencing genes. These findings stress the substantial role of energy metabolism on CR. Future studies on metabolic adaptation and gene silencing with regard to lower caloric intake will be warranted to understand the mechanisms of the anti-aging and life-prolonging effects of CR.