Another focus of research activity stems from the observation that caloric restriction extends lifespan. The phenomenon appears to have a mitochondrial connection. Scientists have noted that animals fed diets in which calories have been cut by as much as 40% live longer, so long as vital nutrients are supplied in adequate amounts. The goal in these experiments is to achieve "undernutrition without malnutrition." Caloric restriction clearly affects many bodily processes, but its effect on the oxidative activity of mitochondria may be the key to its effect on lifespan. Animals fed a calorie-restricted diet exhibit much less age-related oxidative damage to their mitochondria than do control animals fed a normal diet. A study in rats and mice found that caloric restriction begun in late middle age can slow age-associated fiber loss and other age-related changes in skeletal muscle fibers that have enzyme abnormalities in their mitochondria.

Why does caloric restriction prevent mitochondrial damage? Scientists are still debating the issue. Dr. Richard Weindruch, an expert on caloric restriction at the University of Wisconsin, has hypothesized that mitochondrial oxygen use is minimized by a very-low-calorie diet. This means fewer damaging oxidants are produced. In a recent article published in the American Journal of Physiology, Weindruch and his colleagues found even deeper effects of dietary control. Caloric restriction, it appears, changes the activity of genes. The mitochondria of liver cells taken from aging mice, they found, showed a marked stress response, and most age-related, stress-induced genetic alterations were either completely or partially prevented by caloric restriction.