OXIDATIVE DNA DAMAGE, TRANSCRIPTION, REPAIR AND AGING

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Accumulated oxidative damage has been recognized for some time as a hallmark of aging cells. Also, the life span of a variety of organisms has been shown to be inversely proportional to their metabolic rates and directly related to accumulated oxidative DNA damage. The long-range goal of this research is to examine the role that oxidatively damaged DNA plays in the aging process. Since DNA is the central molecule controlling all cellular function, it is likely that sustained unrepaired damages will exert important effects. One important consequence of accumulated oxidative DNA damage is its potential deleterious effect on transcriptional transactions. It is well established that the production of reactive oxygen species increases during aging. These facts coupled with the possibility that aging cells exhibit a reduced capacity to remove oxidative DNA damage, are the basis for the hypothesis that the accumulation of unrepaired oxidative DNA damage exerts effects on deleterious effects on mRNA transcription that reduce cellular fitness and contribute to aging. To test this hypothesis, transcriptional capacity, repair capacity, and repair status for oxidative DNA damage will be examined using a well established replicative senescence model system, human fetal lung fibroblasts, and fibroblasts obtained from Werner and Cockayne syndrome patients. Similar studies will be done in differentiated human neuronal cells in culture. Using the experimental approaches designed, a direct relationship between unrepaired oxidative DNA damage, impaired transcription and loss of repair capacity could be directly linked to the aging process.