The objective of this study was to explore the role of molecular oxidative damage and caloric intake in the aging process. The concentration of 8-hydroxydeoxyguanosine (8-OHdG), a product of DNA oxidation, was compared in five different tissues of mice (skeletal muscle, brain, heart, liver and kidney) as a function of age and in response to dietary restriction. A comparison of 8- and 27-month-old mice indicated that the age-related increase in 8-OHdG concentration was greater in skeletal muscle, brain and heart, which are primarily composed of long-lived, post-mitotic cells, than in liver and kidney, which consist of slow-dividing cells. Dietary restricted (DR) mice kept on 60% caloric intake as compared to the ad libitum-fed (AL) mice showed a lower concentration in 8-OHdG content in all the tissues compared to AL mice. The DR-related amelioration of DNA oxidative damage was greater in the post-mitotic tissues compared to those undergoing slow mitoses. Results support the hypothesis that oxidative damage to long-lived post-mitotic cells may be a key factor in the aging process.