GLUTATHIONE, OXIDATIVE STRESS, AND AGING

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DESCRIPTION (Adapted from the investigator'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 aging. Specifically, this study will determine the effects of an increased or a decreased ability of cells to synthesize and regenerate reduced glutathione (GSH) on the aging process of Drosophila melanogaster. GSH can react with a variety of free radical species and, in conjunction with superoxide dismutase, provide the main mechanism or the attenuation of oxidative stress. Flies that have an increased ability to synthesize and regenerate GSH will be created by the transgenic overexpression of gamma-glutamylcysteine synthetase (the rate-limiting enzyme in GSH synthesis) and glucose-6-phosphate dehydrogenase (which generates NADPH, required for reduction of oxidized glutathione to GSH), respectively. In contrast, flies with a decreased ability to synthesize and regenerate GSH 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 genes with other antioxidative genes (e. Cu,Zn-superoxide dismutase and catalase) on the aging process of the flies will be determined. Results should (i) provide a direct test of the role of the genes, involved in the maintenance of GSH, in the aging process, (ii) permit further assessment of the validity of the oxidative stress hypothesis of aging, and (iii) aid in the design of similar studies in mammals.