Glutathione, Oxidative Stress, and Aging

这项研究的首要目标是直接测试氧化应激的有效性。 通过确定抗氧化防御的遗传操作的影响而提出衰老假说 黑腹果蝇。本研究中要检验的具体假设是实验性的 谷胱甘肽(GSH)-NADPH系统的增强将降低氧化应激水平 减缓老化过程的速度，而这一系统效率的下降将提高 氧化应激水平和加速衰老过程。GSH和NADPH提供了大部分 降低电池中的功率，并协同行动，消除各种活性氧物种(ROS)。 通过转基因提高细胞合成GSH和NADPH的能力 谷氨酸半胱氨酸连接酶亚基(GCL)和葡萄糖-6-磷酸脱氢酶的过表达 (G6PH)。四个具体目标是：(一)确定超额和 GCL在人体不同部位和不同生命周期中的表达对衰老的影响 进程。(Ii)测定葡萄糖-6-磷酸脱氢酶高表达和低表达的影响 (G6PD)在身体的不同部位和生命周期的不同时期对衰老过程的影响。 (ILL)确定GCL和G6PD共同过表达对小鼠寿命和型式的影响 生理性衰老。(Iv)确定GCL和G6PD的过度和过低表达对氧化还原的影响 组织状态用GSH、GSSG、混合蛋白二硫化物、NADPH、NADP+、NADH和NAD+表示。这个 这些研究最令人信服的理由是，我们最近的发现表明，GCL的过度表达 (催化亚单位)和G6PD使相对长寿的果蝇品系的寿命增加高达50%。结果 这些前瞻性研究的结果将直接检验氧化应激假说对衰老和 提示细胞还原能力的增强是否可以显著延长苍蝇的寿命。

The overarching goal of the proposed research is to directly test the validity of the oxidative stress hypothesis of aging by determining the effects of genetic manipulations of the antioxidative defenses in Drosophila melanogaster. The specific hypothesis to be tested in the present study is that experimental augmentation of the glutathione (GSH) - NADPH system would lower the level of oxidative stress thereby slowing the rate of the aging process, while a decrease in the efficiency of this system would elevate the level of oxidative stress and accelerate the aging process. GSH and NADPH provide the bulk of the reducing power in cells and act in concert to eliminate various reactive oxygen species (ROS). Enhancement of cellular ability to synthesize GSH and NADPH will be achieved by transgenic overexpression of y-glutamate-cysteine ligase subunits (GCL) and glucose-6-phosphate dehydrogenase (G6PH), respectively, in D. melanogaster. The four specific aims are: (I) Determine the effects of over and under expression of GCL in different regions of the body and at different periods of life cycle on the aging process. (II) Determine the effects of over and under expression of glucose-6-phosphate dehydrogenase (G6PD) in different regions of the body and at different periods of the life cycle on the aging process. (Ill) Determine the effects of co-overexpression of GCL and G6PD on the life span and patterns of physiological aging. (IV) Determine the effects of over and under expression of GCL and G6PD on the redox state of tissues indicated by GSH, GSSG, mixed protein disulfides, NADPH, NADP+, NADH and NAD+. The most compelling rationale for these studies is that our recent findings indicate that overexpression of GCL (catalytic subunit) and G6PD increases life span of relatively long-lived strains of flies by up to 50%. Results of the prospective studies would directly test the predictions of the oxidative stress hypothesis of aging and indicate whether augmentation of cellular reductive capacity can significantly extend the life span of flies.