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Glutathione, Oxidative Stress, and Aging

谷胱甘肽、氧化应激和衰老

基本信息

批准号：
7216825
负责人：
WILLIAM C. ORR
金额：
$ 30.36万
依托单位：
SOUTHERN METHODIST UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-12-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7216825
关键词：
Adult Age Aging Aging-Related Process Anabolism Antioxidants Body Regions Brain Caenorhabditis elegans Catalytic Domain Cells Disulfides Drosophila genus Drosophila melanogaster Electron Transport Electrons Enzymes Equilibrium Exhibits Fat Body Gene Activation Generations Glucosephosphate Dehydrogenase Glutamate-Cysteine Ligase Glutathione Glutathione Disulfide Goals Holoenzymes Hydrogen Peroxide Hyperoxia Life Life Cycle Stages Longevity Measures Mediating Metabolic Mitochondria Monitor Muscle Cells NADH NADP Natural regeneration Neurons Numbers Nutrient Oxidation-Reduction Oxidative Stress Oxygen Paraquat Pathway interactions Pattern Pentosephosphate Pathway Peroxides Physiological Predisposition Process Progress Reports Prospective Studies Protein Overexpression Proteins Purpose RNA Interference Rate Reactive Oxygen Species Research Research Personnel Role Site Speed System Testing Time Tissues Transgenic Organisms Walking age related base design fitness fly genetic manipulation indexing mutant novel novel strategies programs research study

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：拟议研究的总体目标是通过确定基因操作对果蝇抗氧化防御的影响，直接测试衰老的氧化应激假说的有效性。在本研究中要测试的具体假设是，谷胱甘肽（GSH）- NADPH系统的实验性增强将降低氧化应激水平，从而减缓衰老过程的速率，而该系统效率的降低将提高氧化应激水平并加速衰老过程。GSH和NADPH在细胞中提供大部分还原能力，并协同作用以消除各种活性氧（ROS）。通过转基因过量表达γ-谷氨酸-半胱氨酸连接酶亚基（GCL）和葡萄糖-6-磷酸脱氢酶（G6 PH），将分别提高D.黑腹菌这四个具体目标是：（I）确定GCL在身体的不同区域和生命周期的不同时期的过度和不足表达对衰老过程的影响。(II)确定葡萄糖-6-磷酸脱氢酶（G6 PD）在身体不同部位和生命周期不同时期的过度和表达不足对衰老过程的影响。(Ill)确定GCL和G6 PD的共过表达对寿命和生理老化模式的影响。(IV)测定GCL和G6 PD过度表达和表达不足对组织氧化还原状态的影响，所述氧化还原状态由GSH、GSSG、混合蛋白二硫化物、NADPH、NADP+、NADH和NAD+指示。这些研究最令人信服的理由是，我们最近的研究结果表明，GCL（催化亚基）和G6 PD的过表达增加了相对长寿的果蝇品系的寿命高达50%。前瞻性研究的结果将直接检验衰老的氧化应激假说的预测，并表明细胞还原能力的增强是否可以显着延长苍蝇的寿命。