GLUTATHIONE, OXIDATIVE STRESS, AND AGING

说明(改编自《调查员摘要》)： 拟议的研究是为了测试氧化应激假说的有效性 衰老，它假设与年龄相关的功能能力丧失是 很大程度上是由于分子氧化损伤的增加。的关注点 这项研究是为了调查这一假说的主要预测之一， 也就是说，氧化应激水平的变化，由 抗氧化防御的实验改变，应该相应地 影响衰老速度。具体地说，这项研究将确定 指细胞合成和再生能力的增强或降低 还原型谷胱甘肽对果蝇衰老过程的影响谷胱甘肽 可以与各种自由基物种反应，并与 超氧化物歧化酶，提供的主要机制或减弱 氧化应激。果蝇具有更强的合成和合成能力 转基因过表达GSH将产生再生的GSH 谷氨酰半胱氨酸合成酶(谷胱甘肽合成的限速酶) 和葡萄糖-6-磷酸脱氢酶(它产生NADPH，是 氧化谷胱甘肽还原为GSH)。相比之下，苍蝇 合成和再生GSH的能力下降将通过以下方式获得 分离这些基因的突变等位基因。过度和过度的影响 这些基因的低表达对寿命和各种 与衰老过程有关的生化/生理变化将是 下定决心。随后，这些基因的共同过度表达与 其他抗氧化基因(如铜、锌超氧化物歧化酶和过氧化氢酶) 苍蝇的老化过程将被确定。结果应(I)提供 直接测试与维持谷胱甘肽有关的基因在 老化过程，(Ii)允许进一步评估以下各项的有效性 衰老的氧化应激假说，以及(Iii)有助于设计类似的 在哺乳动物身上的研究。

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.