GLUTATHIONE, OXIDATIVE STRESS, AND AGING

谷胱甘肽、氧化应激和衰老

• 批准号: 6693034
• 负责人: WILLIAM C. ORR
• 金额: $ 25.72万
• 依托单位: SOUTHERN METHODIST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-01 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6693034
• 关键词: Drosophilidae; aging; catalase; enzyme activity; enzyme induction /repression; genetically modified animals; glucose 6 phosphate dehydrogenase; glutathione; glutathione reductase; oxidative stress; superoxide dismutase

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.

描述（改编自研究者的摘要）：主要目的 拟议的研究是为了测试氧化应激假说的有效性 衰老，假设与年龄相关的功能能力丧失是 主要是由于分子氧化损伤的累积。重点是 这项研究是为了调查这个假设的主要预测之一， 即氧化应激水平的变化，由 抗氧化防御的实验性改变，应该相应地 影响衰老速度。具体来说，这项研究将确定影响 细胞合成和再生能力的增强或减弱 还原型谷胱甘肽（GSH）对果蝇衰老过程的影响。还原型谷胱甘肽 可以与多种自由基发生反应，并与 超氧化物歧化酶，提供主要机制或减弱 氧化应激。具有增强合成能力的苍蝇 再生 GSH 将通过转基因过度表达产生 γ-谷氨酰半胱氨酸合成酶（GSH 合成中的限速酶） 和葡萄糖-6-磷酸脱氢酶（产生 NADPH，这是 氧化型谷胱甘肽还原为 GSH）。相比之下，苍蝇 合成和再生 GSH 能力下降的 分离这些基因的突变等位基因。过度和的影响 这些基因的表达不足对寿命和各种 与衰老过程相关的生化/生理变化将 决定。随后，这些基因与 其他抗氧化基因（例如铜、锌超氧化物歧化酶和过氧化氢酶） 将确定苍蝇的老化过程。结果应 (i) 提供 直接测试参与维持 GSH 的基因的作用， 老化过程，（ii）允许进一步评估 衰老的氧化应激假说，以及（iii）有助于设计类似的 哺乳动物研究。