GLUTATHIONE, OXIDATIVE STRESS, AND AGING

描述（改编自申请人的摘要）： 拟议的研究是为了测试氧化应激的有效性， 衰老假说，该假说假定与年龄相关的衰老 功能能力主要是由于分子的积累， 氧化损伤 本研究的重点是调查一个主要的 这一假设的预测，即，在水平的变化， 氧化应激，由抗氧化剂的实验性改变诱导 防御，应该相应地影响衰老过程的速度。 具体来说，这项研究将确定增加的影响，或 细胞合成和再生还原型谷胱甘肽的能力降低， 关于果蝇衰老过程的研究 苍蝇有一个 增加合成和再生谷胱甘肽的能力 通过γ-谷氨酰半胱氨酸合成酶的转基因过表达（ 谷胱甘肽合成中的限速酶）和谷胱甘肽还原酶 （其将氧化型谷胱甘肽转化为还原型谷胱甘肽）。 相反，合成和再生能力下降的果蝇 谷胱甘肽将通过分离这些基因的突变等位基因而获得。 这些基因的过度表达和表达不足对寿命的影响， 与衰老相关的各种生化/生理变化 过程，将被确定。 随后，共过表达的影响 在这两个基因中，沿着的还有其它抗氧化基因（Cu/Zn-SOD，Mn-SOD， 和过氧化氢酶）对果蝇衰老过程的影响。 是 建议，结果应提供一个直接的测试（i）的有效性 衰老的氧化应激假说，以及（ii）基因的作用， 在衰老过程中参与谷胱甘肽的维持。

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.