Calorie restriction and age-related oxidative stress.

Calorie restriction (CR) in mammals has been recognized as the best characterized and most reproducible strategy for extending maximum survival, retarding physiological aging, and delaying the onset of age-related pathologic conditions in mammals. The overwhelming majority of studies using CR have used short-lived rodent species, although current work using rhesus and squirrel monkeys will determine whether this paradigm is also relevant to manipulating the rate of primate aging. The mechanism by which restricted calorie intake modifies the rate of aging and pathology has been the subject of much controversy, although an attenuation in the lifetime accumulation of oxidative damage appears to be a central feature. Although the majority of studies have focused on the ability of cells from calorie-restricted animals to scavenge free radicals to explain the slower accrual of oxidative damage with age, it is not established that CR has a consistent effect to upregulate the activity of these enzymes in all tissues. A major effect of calorie-restricted feeding now appears to be on the rate of production or leak of free radicals from the mitochondria. The details of the adaptation and the signaling pathway that induces this effect are currently unknown.