GLUTATHIONE, OXIDATIVE STRESS, AND AGING

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DESCRIPTION (Adapted from the Applicant's Abstract): The main purpose of the proposed studies is to test the validity of the oxidative stress hypothesis of aging, which postulates that the age-associated loss of functional capacity is substantially due to the accrual of molecular oxidative damage. The focus of this study is to investigate one of the main predictions of this hypothesis, namely, that variations in the level of oxidative stress, induced by experimental alterations in antioxidative defenses, should correspondingly affect the rate of the aging process. Specifically, this study will determine the effects of an increased, or a decreased ability of cells to synthesize and regenerate reduced glutathione, on the aging process of Drosophila melanogaster. Flies that have an increased ability to synthesize and regenerate glutathione will be created by the transgenic overexpression of gamma-glutamylcysteine synthetase (the rate-limiting enzyme in glutathione synthesis) and glutathione reductase (which converts oxidized glutathione to reduced glutathione), respectively. In contrast, flies with a decreased ability to synthesize and regenerate glutathione will be obtained by isolating mutant alleles of these genes. The effects of over- and under-expression of these genes on life span and a variety of biochemical/physiological alterations, related to the aging process, will be determined. Subsequently, the effects of co-overexpression of these two genes, along with other antioxidative genes (Cu/Zn-SOD, Mn-SOD, and catalase), on the aging process of the flies will be determined. It is suggested that the results should provide a direct test of (i) the validity of the oxidative stress hypothesis of aging, and (ii) the role of the genes, involved in the maintenance of glutathione, in the aging process.