The oxidative damage theory of aging

Abstract

The oxidative stress theory of aging postulates that age-associated reductions in physiologic functions are caused by a slow steady accumulation of oxidative damage to macromolecules, which increases with age and which is associated with life expectancy of organisms. A corollary is that the rate of aging should be retarded by attenuation of oxidative damage. A large body of evidence has accumulated in support of this hypothesis. Increases in oxidative damage to DNA, proteins, and lipids have all been found with normal aging. Genetic manipulation of oxidative damage can increase life expectancy in animals. Overexpression of Cu/Zn superoxide dismutase or manganese superoxide dismutase appears to extend life span. Overexpression of methionine sulfoxide reductase in Drosophila resulted in a 70% increase in survival, and a 50% reduction in methionine sulfoxide reductase in mice resulted in a 30% reduction in life span. Caloric restriction, which extends life span, also reduces oxidative stress. Manipulation of gene expression in Drosophila with phenylbutyrate significantly increases lifespan, and is associated with a 50-fold increase in expression of manganese superoxide dismutase. We recently further examined the mitochondrial DNA theory of aging, which proposes that mitochondrial DNA accumulates mutations with age and that these contribute to the physiological decline in aging. Using a PCR-cloning-sequencing strategy, we found a significant increase in aggregate burden of mitochondrial DNA point mutations in brain in elderly subjects compared to younger subjects. The average aggregate mutational burden in elderly subjects was 2 × 10-4 mutations per base. The bulk of these mutations were individually rare point mutations, and 60% changed an amino acid. Cytochrome oxidase activity correlated negatively with increased mutational burden. These findings bolster the possibility that oxidative damage to mitochondrial DNA may play a significant role in normal aging. © 2003 Elsevier Science B.V. All rights reserved.