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显著的相互作用。拟议的项目将确定这些化合物在双向和三向组合补充时可以相互作用以改善或预防小鼠功能性脑老化的程度。在一个实验中（Aim 1），抗氧化剂组合的补充将在晚年开始，在大脑功能障碍已经存在的年龄。将使用一系列行为测试来评估抗氧化剂补充方案逆转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。如果在发生年龄相关脑功能障碍之前开始补充抗氧化剂，则将使用相同的行为测试电池来确定抗氧化剂补充方案是否可以预防功能丧失（Aim 2）。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），将来自在前两个目的中测试的小鼠的脑解剖成不同的区域以确定：（i）对蛋白质或脂质的氧化损伤的量（蛋白质羰基，硫代巴比妥反应物质），（ii）谷胱甘肽氧化还原状态的变化和氨基硫醇的量，蛋白质巯基和混合二硫化物和（iii）辅酶Q、维生素E和维生素C的水平。将在治疗期间的不同时间测定血浆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/精神表现影响的有用预测因子。这些研究将提供关于抗氧化剂方案的性质的具体信息，这些抗氧化剂方案最有可能对大脑衰老有益，并将确定预期受益的年龄。此外，它们将提高对抗氧化剂补充的神经学后果的理解，这对有益效果至关重要，并可能确定预测成功治疗的临床有用的生物标志物。

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.