GLUTATHIONE, OXIDATIVE STRESS, AND AGING

描述(改编自申请人的摘要)：主要目的 建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丧失 功能能力在很大程度上是由于分子的积累 氧化损伤。本研究的重点是调查其中一个主要的 对这一假说的预测，即水平的变化 由抗氧化剂的实验变化引起的氧化应激 防御，应该相应地影响衰老过程的速度。 具体地说，这项研究将确定增加或增加 细胞合成和再生还原型谷胱甘肽的能力降低， 黑腹果蝇衰老过程的研究苍蝇有一种 将提高合成和再生谷胱甘肽的能力 转基因过表达γ-谷氨酰半胱氨酸合成酶( 谷胱甘肽合成限速酶)和谷胱甘肽还原酶 (将氧化的谷胱甘肽转化为还原型谷胱甘肽)。 相比之下，果蝇的合成和再生能力降低 通过分离这些基因的突变等位基因，将获得谷胱甘肽。 这些基因的过度和低表达对寿命和寿命的影响 与衰老有关的各种生化/生理变化 过程，将被确定。随后，共过度表达的影响 这两个基因与其他抗氧化基因(铜/锌-超氧化物歧化酶，锰-超氧化物歧化酶， 和过氧化氢酶)，对苍蝇的衰老过程进行测定。它是 建议结果应提供对(I)有效性的直接测试 衰老的氧化应激假说，以及(Ii)基因的作用， 参与谷胱甘肽的维持，在衰老过程中。

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.