Gene Expression, Compensation Mechanisms, and Successful Cognitive Aging

描述（由申请人提供）：成功的认知老化的神经和行为特征是什么？因为基因活动为细胞功能和功能障碍提供了基本的构建块，基因表达模式必须是成功的认知衰老的基石。衰老过程中认知功能保存或维持的一个潜在机制可能涉及代偿机制，这是一个从人脑成像数据中出现的概念。我们建议基于多学科方法，利用微阵列分析来描述临床特征良好的人类脑组织中的基因表达模式，并辅以动物模型来测试身体活动防止认知能力下降的机制，然后将动物数据翻译到人类，以确定衰老中可能的代偿机制。在Aim 1中，将使用一组临床和病理上定义明确的人体组织。我们假设在病理存在的情况下，代偿性基因表达将被动员起来帮助保持认知功能。为了解决这个问题，我们将案例分为认知五分位数，从中选择前20个认知百分位数，代表成功的认知老化。为了确定可能的代偿性基因动员，我们将评估成功衰老队列中的基因表达谱，比较低和中等病理水平的基因。此外，为了将病理保持在中等水平，我们将评估前4个认知五分位数的基因表达谱，以确定基因表达模式如何随着认知能力的下降而变化。我们假设认知能力的下降将反映在特定基因类别和基因的下调上，特别是与突触完整性、可塑性和能量代谢相关的基因。各种生活方式因素正在成为成功实现认知衰老的关键，尤其是增加体育锻炼。因此，在Aim 2中，我们将使用人类和动物组织来评估体育活动通过参与代偿性基因机制来帮助维持成功的认知衰老的假设，特别是在弱势群体中。在表现出认知障碍的老年动物中，我们假设运动将逆转这种损伤，并调动支持认知/可塑性的基因谱。在携带ApoE4基因（人类认知能力下降的主要危险因素）的转基因小鼠模型中，我们验证了运动在改善认知功能和调动可塑性相关基因表达方面可能比E4动物更有效的假设。最后，我们试图将动物研究转化为一组人类病例，其中身体活动和认知已经被监测，使用死后脑组织分析大脑基因表达模式在高活动和相对不活动的人。综上所述，我们的项目将为人类基因表达谱提供新的见解，这些基因表达谱是目前未知的成功认知衰老的基础。

DESCRIPTION (provided by applicant): What are the neural and behavioral profiles that serve successful cognitive aging? Because gene activity provides the fundamental building blocks for cellular function and dysfunction, gene expression patterns must be the cornerstone of successful cognitive aging. One mechanism underlying preservation or maintenance of cognitive function in aging may involve engagement of compensation, a concept that is emerging from human brain imaging data. We propose to identify possible compensatory mechanisms in aging, based on a multidisciplinary approach using microarray analyses to profile gene expression patterns in clinically well-characterized human brain tissues, complemented by animal models to test mechanisms by which physical activity prevents cognitive decline, followed by a translation of the animal data to humans. In Aim 1, a set of clinically and pathologically well-defined human tissues will be used. We hypothesize that in the presence of pathology, compensatory gene expression will be mobilized to help preserve cognitive function. To address this, cases will be divided into cognitive quintiles, from which we will select the top 20th cognitive percentile, representing successful cognitive aging. To identify possible compensatory gene mobilization, we will assess gene expression profiles in the successful aging cohort, comparing gene those with low vs moderate levels of pathology. In addition, maintaining pathology constant at a moderate level, we will assess gene expression profiles across the top 4 cognitive quintiles to identify how gene expression patterns change with declining cognition. We hypothesize that declines in cognition will be reflected in a downregulation of select gene classes and genes, particularly genes linked to synaptic integrity, plasticity and energy metabolism. Various lifestyle factors are emerging as key for successful cognitive aging, in particular, increased physical activity. Thus, in Aim 2, using both human and animal tissue, we will evaluate the hypothesis that physical activity helps maintain successful cognitive aging by engaging compensatory gene mechanisms, particularly in vulnerable populations. In aged animals showing cognitive impairment, we hypothesize that exercise will reverse the impairment and mobilize a gene profile supportive of cognition/plasticity. In transgenic mouse models carrying the ApoE4 gene, a major risk factor for cognitive decline in humans, we test the hypothesis that exercise may be paradoxically more effective in E4 than E3 animals, in improving cognitive function and mobilizing plasticity-related gene expression. Finally, we seek to translate the animal research to a set of human cases where physical activity and cognition have been monitored, using post-mortem brain tissue to analyze brain gene expression patterns in high- active vs. relatively inactive people. Taken together, our project will provide new insight into gene expression profiles in the human that underlie successful cognitive aging, which are currently unknown. PUBLIC HEALTH RELEVANCE: The human population is aging and thus there is a great need to promote successful cognitive aging. Our studies will define the gene expression profiles in the human brain of those who have achieved successful cognitive aging, and determine if exercise will build and strengthen the aging brain through action on gene expression. Accordingly, these studies will help provide a rational for including exercise as a formula to promote successful cognitive health during aging.