Gene Expression, Compensation Mechanisms, and Successful Cognitive Aging

基因表达、补偿机制和成功的认知衰老

• 批准号: 8119609
• 负责人: Carl Wayne Cotman
• 金额: $ 33.67万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8119609
• 关键词: Academic Medical Centers; Address; Age; Aging; Alleles; Animal Experimentation; Animal Model; Animals; Apolipoprotein E; Behavior; Behavioral; Biological Preservation; Brain; Brain Pathology; Brain imaging; Brain region; Brain-Derived Neurotrophic Factor; Cell physiology; Cessation of life; Clinical Pathology; Cognition; Cognitive; Cognitive aging; Collaborations; Communication; Complement; Data; Down-Regulation; Energy Metabolism; Exercise; Financial compensation; Functional disorder; Gene Expression; Genes; Genotype; Growth Factor; Health; Hippocampus (Brain); Human; Impaired cognition; Impairment; Individual; Learning; Link; Maintenance; Memory; Modeling; Molecular; Molecular Profiling; Monitor; Mus; Neurofibrillary Tangles; Pathology; Pathway interactions; Pattern; Performance; Persons; Physical activity; Population; Prefrontal Cortex; Process; Protein Biosynthesis; Proteins; RNA; Risk; Risk Factors; Rodent; Rodent Model; Senile Plaques; Structure; Structure of superior frontal gyrus; Synapses; Testing; Tissue Microarray; Transgenic Mice; Translating; Translations; Up-Regulation; Variant; Vulnerable Populations; age related; aged; aging brain; animal data; animal tissue; apolipoprotein E-3; apolipoprotein E-4; base; brain tissue; case-based; cingulate gyrus; cognitive function; cognitive reserve; cohort; design; human tissue; improved; insight; interdisciplinary approach; juvenile animal; lifestyle factors; mild neurocognitive impairment; monitoring device; mouse model; normal aging; prevent; public health relevance; relating to nervous system; response

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.

描述（由申请人提供）：有助于成功认知老化的神经和行为特征是什么？由于基因活性为细胞功能和功能障碍提供了基本组成部分，因此基因表达模式必须是成功认知衰老的基石。衰老过程中认知功能的保存或维持的一种机制可能涉及补偿的参与，这是从人脑成像数据中出现的一个概念。我们建议基于多学科方法来确定衰老中可能的补偿机制，使用微阵列分析来分析临床上明确表征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能力下降的机制，然后进行将动物数据翻译给人类。在目标 1 中，将使用一组临床和病理学明确的人体组织。我们假设，在存在病理学的情况下，补偿性基因表达将被调动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。为了确定可能的补偿性基因动员，我们将评估成功老龄化队列中的基因表达谱，比较具有低病理水平和中度病理水平的基因。此外，在将病理学保持在中等水平的情况下，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中，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认知老化的关键，特别是增加体力活动。因此，在目标 2 中，我们将使用人类和动物组织来评估以下假设：体力活动通过参与补偿基因机制有助于维持成功的认知衰老，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障碍并调动支持认知/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，我们测试了这样的假设：在改善认知功能和调动可塑性相关基因表达方面，E4 动物的运动可能比 E3 动物更有效。最后，我们试图将动物研究转化为一系列人类案例，在这些案例中，身体活动和认知受到监测，使用死后脑组织来分析高活跃人群与相对不活跃人群的大脑基因表达模式。总而言之，我们的项目将为人类基因表达谱提供新的见解，这些基因表达谱是成功认知衰老的基础，而目前尚不清楚。 公共卫生相关性：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老化的人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构建和强化老化的大脑。因此，这些研究将有助于为将运动作为促进衰老过程中认知健康的公式提供合理性。