OXIDATIVE STRESS AND BRAIN AGING

氧化应激和大脑老化

• 批准号: 8431379
• 负责人: MICHAEL J. FORSTER
• 金额: $ 23.77万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8431379
• 关键词: Acetylcysteine; Aconitate Hydratase; Address; Adenine Nucleotide Translocase; Age; Age-associated memory impairment; Aging; Antioxidants; Attenuated; Behavioral; Bioenergetics; Brain; Brain region; Caloric Restriction; Cell physiology; Cognition; Cognitive; Complex; Frequencies; Functional disorder; Funding; Glutathione; Impaired cognition; Impairment; Insecta; Intervention; Long-Term Potentiation; Measures; Mediating; Memory; Memory impairment; Mitochondria; Mitochondrial Proteins; Mus; Neurodegenerative Disorders; Oxidation-Reduction; Oxidative Stress; Performance; Play; Process; Progesterone; Progress Reports; Proteins; Psychomotor Impairments; Psychomotor Performance; Reactive Oxygen Species; Recovery; Regimen; Research; Research Personnel; Rodent; Role; Signal Transduction; Signaling Molecule; Site; Synaptic plasticity; Testing; age difference; age effect; age related; aged; aging brain; anti aging; behavioral impairment; cognitive function; computerized data processing; enzyme activity; improved; loss of function; macromolecule; middle age; motor impairment; oxidation; oxidative damage; programs; protein function; research study; senescence

The ability of reactive oxygen species (ROS) to produce dysfunctional macromolecules is thought to play a significant role in brain aging and in neurodegenerative diseases. However, it is also well established that ROS serve as important signaling molecules involved in cellular processes that underlie different cognitive functions. In the current application, it is hypothesized that age-dependent increases in ROS may cause age- associated cognitive or motor impairment by (i) promoting deleterious accumulation of oxidative damage to specific mitochondrial proteins, (ii)causing a decrease in efficiency of ROS-mediated signaling and/or(iii) initiating compensatory shifts in signaling mechanisms underlying brain processes. Under Aim 1 of this application, we will identify proteins in mitochondria from different brain regions that are associated with age- related increases in carbonyls, in aged mice with and without cognitive or motor impairments. The functional significance of these impairment-associated oxidized proteins will be addressed further under Aim 2, in which it is proposed to determine the correlation between impaired bioenergetic activity of oxidized proteins and age-related behavioral dysfunction. Aim 3 of this application will assess whether or not the age-related increase in "unregulated ROS" contributes to impairment of synaptic plasticity and memory function, and assess whether or not this contribution is age-dependent. Aim 4 of the application is to determine if behavioral impairments associatedwith ROS can be reversed by experimental interventions that produce reductive shifts in the redox state of glutathione, or promote recovery of bioenergetic functions of specific oxidized proteins. The Aim 4 studies will also address whether or not the ability of interventions to reverse age-related impairments is age-dependent. The results of these studies should refute or validate the idea that oxidative damage to specific mitochondrial proteins is a factor in age-related decrements in cognitive or psychomotor performance, and may identify specific molecules that should be targeted by anti-aging interventions. These studies will also address the hypothesis that increases in unregulated ROS directly impair cognition during aging and promote relatively non-reversible derangement of underlying signaling processes. Finally, these studies will identify periods of senescence for which antioxidative treatment of cognitive decline is most likely to be successful.

活性氧（ROS）产生功能失调的大分子的能力被认为可以发挥 在大脑衰老和神经退行性疾病中的重要作用。但是，也已经确定了 ROS充当参与细胞过程的重要信号分子，这些分子是不同认知基础的细胞过程 功能。在当前的应用中，假设ROS的年龄依赖性增加可能会导致年龄 通过（i）促进有害氧化损伤的有害积累到相关的认知或运动障碍 特定的线粒体蛋白，（ii）导致ROS介导的信号传导和/或（iii）的效率降低 启动大脑过程基础信号传导机制的补偿性转移。在目标1下 应用，我们将鉴定出与年龄相关的不同大脑区域的线粒体中的蛋白质 在患有和没有认知或运动障碍的老年小鼠中，羰基的相关增加。功能 这些受损相关的氧化蛋白的意义将在AIM 2下进一步解决 提议确定氧化蛋白的生物能活性受损之间的相关性 和与年龄有关的行为功能障碍。本申请的目标3将评估是否与年龄有关 增加“不受管制的ROS”有助于突触可塑性和记忆功能的损害，并且 评估该贡献是否取决于年龄。申请的目标4是确定是否 与ROS相关的行为障碍可以通过产生的实验干预措施逆转 谷胱甘肽的氧化还原状态的还原性转移，或促进特定的生物能功能的恢复 氧化蛋白。目标4研究还将解决干预措施逆转的能力 与年龄相关的障碍与年龄有关。这些研究的结果应驳斥或验证这个想法 对特定线粒体蛋白的氧化损害是认知或年龄相关的因素 心理运动表现，并可能识别应通过抗衰老靶向的特定分子 干预措施。这些研究还将解决以下假设，即直接增加了不受管制的ROS 在衰老期间损害认知并促进基础信号的相对不可逆的危险 过程。最后，这些研究将确定衰老期的抗氧化治疗期 认知能力下降最有可能成功。