Caloric restriction and genomic stability.

Caloric restriction (CR) without malnutrition is the only experimental manipulation that has consistently been shown to increase the mean and maximum lifespan of laboratory rodents. It has been suggested that CR extends the longevity of rodents and reduces the incidence of age-related pathological lesions by reducing the levels of DNA damage and mutations that accumulate with age within a cells genome. This hypothesis is attractive because the integrity of the genome is essential to a cell/organism and because it is supported by the observations that both cancer and immunological defects, which increase significantly with age and are delayed by CR, are associated with changes in DNA damage. However, all the evidence supporting the premise that the accumulation of DNA damage/mutations plays a role in aging and CR is correlative, i.e., the anti-aging action of CR-fed rodents is correlated with decreased DNA damage and mutation and increased DNA repair capacity. Therefore, additional experiments are required which employ more accurate assays of the DNA repair pathways as well as genetically engineered animal models to establish the role of specific DNA repair pathways and/or enzymes in the anti-aging action of CR. In this paper, we review the proposed mechanisms of DNA damage/repair while providing insight into current research that may assist in "unlocking" the mechanisms behind the life-prolonging effect of CR.