OXIDATIVE DAMAGE, MITOCHONDRIAL OXIDANT GENERATION AND ANTIOXIDANT DEFENSES DURING AGING AND IN RESPONSE TO FOOD RESTRICTION IN THE MOUSE

This study was conducted in order to test the concept that oxidative d amage is associated with aging and may be a factor in the modulation o f life span in response to variations in caloric intake. Mice fed a di et that was 40% lower in calories (DR) than the ad libitum fed (AL) an imals exhibited a 43% extension in average life span and a 61% prolong ation in mortality rate doubling time. A comparison of AL and DR mice at 9, 17 and 23 months of age indicated that the protein carbonyl cont ent in the brain, heart and kidney increased with age and was signific antly greater in the AL than DR group in each organ at each of the thr ee ages. Mitochondrial state 4 or resting respiratory rate increased w ith age in the AL, but not the DR group, and was also relatively highe r in the former. The rates of mitochondrial superoxide and hydrogen pe roxide generation increased with age and were higher in the AL than DR mice in all the three organs at each age. In contrast, there was no c lear-cut overall pattern of age-related or dietary-related changes in antioxidant defenses provided by superoxide dismutase, catalase and gl utathione peroxidase. Results suggest that mechanisms of aging and lif e span shortening by enhanced caloric intake are associated with oxida tive damage arising from corresponding changes in mitochondrial oxidan t production. Protein carbonyl content, and mitochondrial O-2(.-) and H2O2 generation may act as indices of aging.