Gene Expression, Compensation Mechanisms, and Successful Cognitive Aging

描述(由申请者提供)：成功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基石，所以基因表达模式必须是成功认知衰老的基石。在衰老过程中保持或维持认知功能的一种机制可能涉及参与补偿，这是一个从人脑成像数据中出现的概念。我们建议基于一种多学科的方法来确定衰老中可能的补偿机制，该方法使用微阵列分析来描述临床特征良好的人脑组织中的基因表达模式，并辅之以动物模型来测试体力活动防止认知下降的机制，然后将动物数据转换到人类。在目标1中，将使用一组临床和病理上定义良好的人体组织。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，以帮助保护认知功能。为了解决这个问题，案例将被分为认知五分位数，我们将从其中选择前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基因动员，我们将评估成功老龄化队列中的基因表达谱，比较低病理水平和中等病理水平的基因。此外，为了保持病理在中等水平不变，我们将评估前四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选定的基因类别和基因的下调上，特别是与突触完整性、可塑性和能量新陈代谢相关的基因。各种生活方式因素正在成为成功认知衰老的关键，特别是增加体力活动。因此，在目标2中，使用人类和动物组织，我们将评估这一假设，即体育活动通过参与补偿基因机制来帮助维持成功的认知衰老，特别是在脆弱人群中。在出现认知障碍的老年动物中，我们假设运动将逆转这种障碍，并动员支持认知/可塑性的基因图谱。在携带载脂蛋白E4基因的转基因小鼠模型中，我们测试了一种假设，即运动在改善认知功能和动员可塑性相关基因表达方面，在E4动物中可能比E3动物更有效，这一假设自相矛盾。载脂蛋白E4基因是人类认知能力下降的主要风险因素。最后，我们试图将动物研究转化为一组人类病例，在这些病例中，身体活动和认知得到了监测，使用死后脑组织来分析高活动人群和相对不活动人群的大脑基因表达模式。综上所述，我们的项目将为人类成功认知衰老的基因表达谱提供新的见解，这些基因表达谱目前尚不清楚。 公共卫生相关性：人类人口正在老龄化，因此非常需要促进成功的认知老龄化。我们的研究将确定那些成功实现认知衰老的人的大脑中的基因表达谱，并确定运动是否会通过对基因表达的作用来建立和加强老化的大脑。因此，这些研究将有助于为将锻炼作为促进衰老过程中成功认知健康的公式提供合理性。

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.