Oxidation and Damage to DNA, Protein, and Lipids

Oxidative damage to DNA, proteins and other macromolecules accumulates with age and has been postulated to be a major, but not the only, type of endogenous damage leading to aging. Superoxide(O2.-), hydrogen peroxide (H2O2), and hydroxyl radical (.OH), which are mutagens produced by radiation, are also by-products of normal metabolism. Lipid peroxidation gives rise to mutagenic lipid epoxides, lipid hydroperoxides, lipid alkoxyl and peroxyl radicals, and enals ([[alpha]], ß-unsaturated aldehydes). Singlet oxygen, a high energy and mutagenic form of oxygen, can be produced by transfer of energy from light, the respiratory burst from neutrophils, or lipid peroxidation.

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Animals have numerous antioxidants defenses, but since these defenses are not perfect, some DNA is oxidized. Oxidatively damaged DNA is repaired by enzymes that excise the lesions, which are then excreted in the urine. We have developed methods to assay several of these excised damaged bases in the urine of rodents and humans almost all of which appear as the free base from repair by glycosylases. We estimate that the number of oxidative hits to DNA per cell per day is about l00,000 in the rat and about l0,000 in the human. DNA repair enzymes efficiently remove most, but not all, of the lesions formed. Oxidative lesions in DNA accumulate with age, so that by the time a rat is old (2 years) it has about two million DNA lesions per cell, which is about twice that in a young rat. Mutations also accumulate with age . For example, the somatic mutation frequency in human lymphocytes, of which the contribution of oxidative DNA lesions is unknown, is about nine times greater in elderly people than in neonates. The importance of oxidative DNA lesions in cancer and aging is underscored by the existence of specific repair glycosylases that excise these lesions from DNA. In the case of 8-hydroxy-2'-deoxyguanosine, a lesion formed from oxidative damage to guanine residues in DNA, loss of a specific glycosylase activity leads to an appreciable increase in the spontaneous mutation rate, indicating the intrinsic mutagenic potential of this DNA lesion. Many other oxidative DNA lesions are likely to be important as well.

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Mitochondrial DNA (mtDNA) from rat liver has more than ten times the level of oxidative DNA damage than does nuclear DNA from the same tissue. This increase may be due to a lack of mtDNA repair enzymes, lack of histones protecting mtDNA, and the proximity of mtDNA to oxidants generated during oxidative phosphorylation. The cell defends itself against this high rate of damage by a constant turnover of mitochondria, thus presumably removing those damaged mitochondria that produce increased oxidants. Despite this turnover, oxidative lesions appear to accumulate with age in mtDNA at a higher rate than in nuclear DNA.

Oxidative damage could also account for the mutations in mtDNA that accumulate with age

Endogenous oxidants also damage proteins. Stadtman and his colleagues have shown that the proteolytic enzymes that hydrolyze oxidized proteins are not sufficient to prevent an age-associated accumulation of oxidized proteins. In two human diseases associated with premature aging, Werner's syndrome and progeria, oxidized proteins accumulate at a much higher rate than is normal. Fluorescent age pigments, which are thought to be due in part to cross-links between protein and lipid peroxidation products, also accumulate with aging.