The Canine as an Animal Model of Human Aging

犬作为人类衰老的动物模型

基本信息

批准号：
8326043
负责人：
Carl Wayne Cotman
金额：
$ 79.51万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-09-30 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8326043
关键词：
Accounting Acetylation Aerobic Exercise Age Age-associated memory impairment Aging Alzheimer&apos s Disease Amyloid Animal Model Animals Antioxidants Area Attenuated Automobile Driving Award Behavioral Biological Markers Blood Volume Brain Brain Diseases Brain Pathology Brain region Brain-Derived Neurotrophic Factor Canis familiaris Caspase Cells Cerebrum Cognition Cognitive Complex Cytosol Data Diet Elderly Environment Epigenetic Process Episodic memory Event Exercise Functional disorder Funding Gene Expression Genes Goals Grant Gray unit of radiation dose Growth Factor Health Hippocampus (Brain)Histone Acetylation Histones Human Impaired cognition Individual Instruction Insulin-Like Growth Factor I Intervention Intervention Studies Learning Life Life Style Link Long-Term Effects Magnetic Resonance Imaging Memory Memory impairment Metabotropic Glutamate Receptors Methylation Mitochondria Mitochondrial DNA Modeling Molecular Monitor N-Methyl-D-Aspartate Receptors Nerve Degeneration Neurons Oxidative Stress Pathology Pathway interactions Pattern Peptide Hydrolases Performance Peripheral Physical activity Physiological Plasma Prefrontal Cortex Principal Investigator Process Production Progress Reports Proteins Protocols documentation Relative (related person)Reporting Reversal Learning Rodent Series Signal Transduction Surrogate Markers Synapses Synaptic plasticity Testing Time Translations Treatment Efficacy Validation activation product age related aged aging brain brain tissue calmodulin-dependent protein kinase II caspase-3 caspase-8 caspase-9 cofactor cognitive change cognitive function combat dentate gyrus design effective intervention environmental enrichment for laboratory animals executive function follow-up frontal lobe human data improved improved functioning in vivo indexing innovation insertion/deletion mutation lifestyle intervention mitochondrial DNA mutation mitochondrial dysfunction mouse model neurogenesis neuron loss neuronal survival normal aging oxidative damage prevent pro-apoptotic protein programs social success white matter

项目摘要

Our overall objective is to use the aged canine to identify effective intervention strategies to reduce age-related cognitive decline and to prevent or reverse cellular and molecular events linked to cognitive dysfunction. We have shown that a diet enriched with antioxidants (AOX), both alone and in combination with behavioral enrichment (ENR), can improve and maintain cognitive function in aged dogs. The current proposal aims to refine our understanding ofthe mechanisms responsible for improved cognition and reduced brain pathology, building on our progress from the current grant period. We have demonstrated that the treatments reduce oxidative damage, improve mitochondrial function, reduce hippocampal neuron loss, and support neurogenesis. Interestingly, our recent data suggest that p-amyloid accumulation was not a primary target of the interventions, consistent with recent studies in humans. Rather, the interventions may be targeting cell health directly by curtailing pro-degenerative pathways driven by protease cascades. In Aim 1, we will follow up on our recent discovery that the interventions attenuate mechanisms of neuronal degeneration, in particular activation of caspase cascades. In Aim 2, we build on the success ofthe AOX and ENR inten/entions by teasing apart and optimizing the original ENR program. We test the hypothesis that long-term exercise intervention is the predominant ENR factor driving improved cognition and reduced age-related brain dysfunction. As in vivo indices of exercise-induced changes in brain function, we will use MRI to assess changes in cerebral blood volume and grey/white matter volume, and evaluate plasma and CSF biomarkers associated with aging and cognitive decline. In Aim 3, we will characterize the cellular and molecular changes induced in the brain by exercise to delineate mechanisms underlying cognitive improvements. A strength of the proposed design will be validation of physiological and cognitive changes assessed in vivo with post mortem histological findings so that the protocol may be applied to humans to monitor the acquired benefit of exercise for each individual. These results will be compared to our previous findings, and will allow the parcelling out of key factors contributing to successful aging.

我们的总体目标是利用老年犬来确定有效的干预策略，以减少与年龄相关的认知能力下降，并预防或逆转与认知相关的细胞和分子事件功能障碍。我们已经证明，富含抗氧化剂（AOX）的饮食，无论是单独还是组合通过行为丰富（ENR），可以改善和维持老年犬的认知功能。目前的该提案旨在加深我们对负责改善认知和认知的机制的理解减少大脑病理，建立在我们当前资助期间取得的进展的基础上。我们已经证明了这些治疗减少氧化损伤，改善线粒体功能，减少海马神经元损失，并支持神经发生。有趣的是，我们最近的数据表明 p-淀粉样蛋白的积累并不是干预措施的主要目标，与最近的人类研究一致。相反，干预措施可能通过减少蛋白酶级联驱动的促退行性途径来直接针对细胞健康。瞄准 1，我们将跟进我们最近的发现，即干预措施会削弱神经元的机制变性，特别是半胱天冬酶级联的激活。在目标 2 中，我们以 AOX 的成功为基础通过梳理和优化原始 ENR 程序来确定 ENR 意图/意图。我们检验假设长期运动干预是推动认知改善和减少 ENR 的主要因素与年龄相关的脑功能障碍。作为运动引起的脑功能变化的体内指标，我们将使用 MRI 可评估脑血容量和灰质/白质体积的变化，并评估血浆和脑脊液生物标志物与衰老和认知能力下降相关。在目标 3 中，我们将描述细胞和运动引起大脑的分子变化，以描绘认知机制改进。所提出的设计的优势在于验证生理和认知变化通过尸检组织学结果进行体内评估，以便该方案可应用于人类监控每个人从运动中获得的益处。这些结果将与我们之前的结果进行比较调查结果，并将有助于分析出有助于成功老龄化的关键因素。