Aging, Oxidative Stress and Cell Death

衰老、氧化应激和细胞死亡

• 批准号: 6795831
• 负责人: BRIAN A. HERMAN
• 金额: $ 124.36万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6795831
• 关键词: aging; cell death; oxidative stress

DESCRIPTION (adapted from the application): Harman originally proposed that cellular damage by oxygen-free radicals may be the principle driving force for aging and substantial evidence has accumulated that suggests a major contribution of reactive oxygen species (ROS) to the age-dependent deteriorization of physiological functions. Because mitochondria constitute the main site of free radical generation (and other reactive oxygen forms) in the cell, they represent a significant and highly vulnerable target of oxidative stress. Oxidant stress is also a well-known inducer of apoptosis, causing programmed cell death by compromising mitochondrial structure and function. The findings that mitochondria: a) generate reactive oxygen species; b) are targets of oxidative stress; c) initiate oxidant-induced apoptosis; and d) exhibit increased oxidant-induced damage with age, suggest that oxidant-induced alterations in mitochondrial function may underlie in part the aging phenotype. Unfortunately, the mechanisms by which oxidant stress damages mitochondria and leads to dysfunction remain unknown. Using a variety of transgenic mouse models coupled with new and novel optical imaging approaches, the investigators in this proposal will test the hypothesis that oxidative stress contributes to aging by alterations in mitochondrial structure and function. One theory advanced to explain aging is failure of normal apoptotic regulation, leading to accumulation of damaged cells and/or loss of differentiated ceils. In Project 1, the hypothesis that that oxidative stress over the lifespan of an organism, leads to failure of normal apoptotic regulation, resulting in accelerated apoptosis contributing to aging will be examined. Age associated increases in mtDNA deletions and other mutations, increased oxidative damage to mtDNA and increased levels of aberrant forms of mtDNA have all been observed. Project 2 will examine the hypothesis that increased oxidative base damage in mtDNA leads to increased mitochondrial dysfunction and aging. If free radical reactions are the major cause of aging, over expression of cellular/mitochondrial antioxidants should in principle retard aging with a concomitant increase in maximum lifespan. Project 3 will test the hypothesis that altered steady state accumulation of oxidative damage in mitochondria (through transgenic manipulation of mitochondrial antioxidant levels), results in altered mitochondrial function and aging. Oxidant-induced mitochondrial damage has been implicated in a number of age-dependent neuronal diseases, and may involve oxidant-induced alterations in mitochondrial Ca2+ metabolism. Studies in Project 4 will examine the hypothesis that age-dependent oxidant stress alters astrocyte mitochondrial Ca2+ signaling leading to increased neuronal excitotoxicity and apoptosis. Lastly, two of the most important lipid peroxides formed during oxidant stress are 4-hydroxynonenol and malondialdehyde. Project 5 will test the hypothesis that age-related oxidative stress damages key components of the mitochondrial respiratory chain by oxidation of cardiolipin and by direct inhibition by 4-hydroxynonenal, a toxic product of fatty acid oxidation.

描述（改编自申请）：哈曼最初提出 氧自由基造成的细胞损伤可能是细胞损伤的主要驱动力 老化和积累的大量证据表明， 活性氧（ROS）对年龄依赖性的贡献 生理功能退化。因为线粒体构成 自由基（和其他活性氧形式）产生的主要场所 细胞，它们代表了一个重要且高度脆弱的目标 氧化应激。氧化应激也是众所周知的细胞凋亡诱导剂， 通过损害线粒体结构引起程序性细胞死亡 功能。研究结果表明线粒体：a) 产生活性氧； b) 是氧化应激的目标； c) 启动氧化剂诱导的细胞凋亡；和 d) 随着年龄的增长，氧化剂引起的损伤增加，表明氧化剂引起的损伤 线粒体功能的改变可能是衰老的部分原因 表型。不幸的是，氧化应激损害的机制 线粒体并导致功能障碍仍然未知。使用各种 转基因小鼠模型与新颖的光学成像方法相结合， 该提案中的研究人员将测试氧化的假设 压力通过改变线粒体结构而导致衰老 功能。一种解释衰老的理论是正常细胞凋亡的失败 调节，导致受损细胞的积累和/或损失 分化的细胞。在项目 1 中，假设氧化应激 在生物体的整个生命周期中，导致正常细胞凋亡失败 调节，导致加速细胞凋亡，从而导致衰老 检查了。与年龄相关的 mtDNA 缺失和其他突变的增加， mtDNA 氧化损伤增加，异常形式水平增加 mtDNA均已被观察到。项目 2 将检验以下假设： 线粒体DNA氧化碱基损伤增加导致线粒体增加 功能障碍和衰老。如果自由基反应是衰老的主要原因， 细胞/线粒体抗氧化剂的过度表达原则上应该 延缓衰老，同时延长最大寿命。项目3将 检验改变氧化损伤稳态积累的假设 在线粒体中（通过线粒体抗氧化剂的转基因操作 水平），导致线粒体功能改变和衰老。氧化剂诱导 线粒体损伤与许多年龄依赖性神经元损伤有关 疾病，并可能涉及氧化剂诱导的线粒体 Ca2+ 改变 代谢。项目 4 的研究将检验以下假设：年龄依赖性 氧化应激改变星形胶质细胞线粒体 Ca2+ 信号传导 增加神经元兴奋毒性和细胞凋亡。最后说两个最 氧化应激期间形成的重要脂质过氧化物是 4-羟基壬烯醇 和丙二醛。项目 5 将检验年龄相关的假设 氧化应激损害线粒体呼吸链的关键组成部分 通过心磷脂的氧化和 4-羟基壬烯醛的直接抑制，a 脂肪酸氧化的有毒产物。