Brain aging and antioxidant supplementation

描述（由申请人提供）：内源性抗氧化剂维生素E、维生素C和辅酶Q （CoQ）被认为在维持细胞氧化还原状态和保护细胞免受氧化损伤方面具有重要的相互作用。拟议的项目将确定这些化合物在多大程度上可以相互作用，以改善或防止小鼠的功能性脑老化，当以两种或三种方式补充时。在一项实验（ai1）中，补充抗氧化剂组合将在晚年开始，在大脑功能障碍已经出现的年龄。一系列行为测试将用于评估抗氧化剂补充方案逆转与年龄相关的认知功能丧失（联想学习、工作记忆和空间学习）以及感觉和精神运动功能丧失（听觉和体感反应、反应时间、协调、平衡、肌肉力量）的能力。同样的一系列行为测试将用于确定如果在与年龄相关的脑功能障碍发展之前开始补充抗氧化剂，是否可以预防功能丧失（Aim2）。为了确定抗氧化方案的有益效果是否取决于它们减少氧化应激/损伤的能力（目的3），在前两个目的中测试的小鼠的大脑将被解剖到不同的区域以确定：(i)对蛋白质或脂质（蛋白质羰基、硫代巴比妥反应性物质）的氧化损伤量，（ii）谷胱甘肽氧化还原状态的变化以及氨基硫醇、蛋白质巯基和混合二硫化物的量，以及（iii） CoQ水平，在治疗期间的不同时间测定血浆中的氨基硫醇状态和白蛋白相关羰基含量（目的4），以确定氧化应激/损伤的血浆标志物是否是抗氧化剂补充对认知/精神运动表现影响的有用预测因子。这些研究将提供关于抗氧化方案的性质的具体信息，这些抗氧化方案最有可能对大脑衰老有益，并将确定预期的益处年龄。此外，它们将提高对抗氧化剂补充的神经学后果的理解，这是最关键的有益效果，并可能确定临床有用的生物标志物，预测成功的治疗。

DESCRIPTION (provided by applicant): The endogenous antioxidants vitamin E, vitamin C, and coenzyme Q (CoQ) are thought to have significant interactions in the maintenance of cellular redox state and in cellular protection form oxidative insult. The proposed project will determine the extent to which these compounds can interact to ameliorate or prevent functional brain aging in mice, when supplemented in two- and three-way combinations. In one experiment (Aim1), supplementation with the antioxidant combinations will be initiated in late life, at age when brain dysfunction is already present. A battery of behavioral tests will be used to estimate the ability of the antioxidant supplementation regimens to reverse age-related losses of cognitive functions (associative learning, working memory, and spatial learning) as well as losses of sensory and psychomotor functions (auditory and somatosensory responsiveness, reaction time, coordination, balance, muscle strength). The same battery of behavioral tests will be used to determine whether or not the antioxidant supplementation regimens can prevent functional losses if supplementation is initiated prior to development of age-related brain dysfunction (Aim2). To determine whether or not beneficial effects of the antioxidative regimens depend on their ability to reduce oxidative stress/damage (Aim 3), brains from the mice tested in the first two aims will be dissected into different regions for determining: (i) amounts of oxidative damage to proteins or lipids (protein carbonyls, thiobarbituric reactive substances), (ii) shifts in glutathione redox state and amounts of aminothiols, protein sulfhydryl and mixed disulfides and (iii) levels of CoQ, vitamin E and vitamin C. The aminothiols status and albumin-associated carbonyl content of plasma will be determined at different times during treatments (Aim 4) to determine whether or not plasma markers of oxidative stress/damage are useful predictors of the effects of antioxidant supplementation on cognitive/psychomotor performance. These studies will provide specific information about the nature of antioxidant regimens most likely to be beneficial against brain aging and will identify the ages at which benefits should be expected. Moreover, they will improve understanding of the neurological consequences of antioxidant supplementation that are most critical to the beneficial effects and may identify clinically useful biological markers predictive of successful treatment.