Does oxidative damage to DNA increase with age?

Abstract

The levels of 8-oxo-2-deoxyguanosine (oxo8dG) in DNA isolated from tissues of rodents (male F344 rats, male B6D2F1 mice, male C57BL͞6 mice, and female C57BL͞6 mice) of various ages were measured using sodium iodide to prevent oxidative damage to DNA during DNA isolation. Oxo8dG was measured in nuclear DNA (nDNA) isolated from liver, heart, brain, kidney, skeletal muscle, and spleen and in mitochondrial DNA (mtDNA) isolated from liver. We observed a significant increase in oxo8dG levels in nDNA with age in all tissues and strains of rodents studied. The age-related increase in oxo8dG in nDNA from old mice was shown not to the result of the tissue's reduced ability to remove the oxo8dG lesion. Rather, the increase in oxo8dG levels appears to arise from an age-related increase in the sensitivity of these tissues to oxidative stress. We also observed an age-related increase in oxo8dG in mtDNA isolated from the livers of the rats and mice. Dietary restriction, which is known to retard aging and increase the lifespan of rodents, was shown to significantly reduce the agerelated accumulation of oxo8dG levels in nDNA in all tissues of male B6D23F1 mice and in most tissues of male F344 rats. Our study also showed that dietary restriction prevented the age-related increase in oxo8dG levels in mtDNA isolated from the livers of both rats and mice. T he oxidative stress hypothesis of aging (or the free radical hypothesis as it was first proposed) is currently one of the most popular explanations for how aging occurs at the biochemical level. The basic tenet of the oxidative stress hypothesis is that the age-related loss of physiological function and aging are because of the progressive and irreversible accumulation of oxidative damage (1). Over the past decade, the oxidative stress hypothesis of aging has gained wide acceptance because numerous studies have shown a strong correlation between increasing age and the accumulation of oxidative damage to cellular macromolecules (2, 3) and because the increased survival observed with dietary restriction has been correlated to reduced oxidative damage (3,4). It also appears that certain types of pathological lesions that arise with age are associated with increased levels of oxidative damage to cellular macromolecules (5, 6).In 1990, Ames' laboratory reported the first data on the effect of aging on DNA oxidation (7). They observed a significant (Ϸ2-fold) increase in 8-oxo-2-deoxyguanosine (oxo8dG) levels in nuclear DNA (nDNA) isolated from liver, kidney, and intestine of male rats between 2 and 24 months of age. Later, Ames et al. (5) reported that the levels of oxo8dG in mitochondrial DNA (mtDNA) isolated from male rat liver increased 2-to 3-fold with age. Since 1990, a number of research groups have observed an age-related increase in the level of oxo8dG in both nDNA and mtDNA in a variety of tissues of rats and mice (8).On the other hand, many investigators have been unable to detect a significant increase in DNA oxidation in rodent tissues with increasing age (9). The most lik...

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