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。拟议的项目将确定当以双向和三向组合补充时，这些化合物在多大程度上可以相互作用来改善或防止小鼠的功能性大脑衰老。在一项实验(Aim1)中，抗氧化剂组合的补充将在晚年开始，也就是在大脑功能障碍已经存在的年龄。一系列行为测试将被用来评估抗氧化剂补充方案扭转与年龄相关的认知功能(联想学习、工作记忆和空间学习)以及感觉和精神运动功能(听觉和躯体感觉反应性、反应时间、协调性、平衡性、肌肉力量)丧失的能力。同样的一组行为测试将用于确定如果在老年性脑功能障碍(AIM2)发生之前开始补充抗氧化剂是否可以防止功能损失。为了确定抗氧化疗法的有益效果是否取决于它们减少氧化应激/损伤的能力(目标3)，将在前两个目标中测试的小鼠的大脑被解剖成不同的区域，以确定：(I)对蛋白质或脂类(蛋白质羰基、硫代巴比妥酸反应物质)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，维生素E和维生素C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的羰基含量(目标4)，以确定血浆氧化应激/损伤标志物是否有助于预测补充抗氧化剂对认知/精神运动能力的影响。这些研究将提供关于最有可能对大脑老化有益的抗氧化剂养生法的性质的具体信息，并将确定预期受益的年龄。此外，他们将提高对补充抗氧化剂的神经后果的理解，这些后果对有益的效果最关键，并可能识别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.