The interaction effects of genetic variants, age, diet, sex and mitochondrial copy number on Alzheimer's disease, aging-phenotypes and longevity

随着人口平均年龄的增长，了解长寿的生物学和衰老的疾病 越来越重要。线粒体在阿尔茨海默病（AD）和致病性衰老中的关键作用， 在跨物种的研究中建立，并使用基因工程进行机械验证 模型线粒体DNA拷贝数（mtDNAn）随着年龄和饮食的变化，在各种组织中， 跨越物种。较高的mtDNA Acn与老年人更好的健康结果相关， 减少的mtDNA Acn与包括AD在内的衰老疾病有关。但我们不 了解遗传变异、mtDNA、饮食、性别、衰老和AD之间的相互作用机制。这里 我们建议确定基因与环境的相互作用（GxE），将mtDNA与AD和衰老相关的 已在重组近交系BXD和转基因AD-BXD小鼠品系中收集的表型，包括 寿命、记忆、学习、运动和神经解剖表型。在目标1和2中，我们将测试GxE， 确定在三个“外周”（皮肤、血液、肌肉）和三个“中枢”（肝脏， 肾、海马）组织。我们将使用先前从45个BXD菌株收集的组织， 24-个月大，喂食标准食物或高脂肪饮食，并定量mtDNAc n。在目标3中， 将使用组织，确定mtDNA、年龄、性别和家族性AD转基因（5XFAD）之间的关系， 已从AD-BXD收集。作为目标2和3的一部分，我们将重新生产上述菌株的一个子集 并对线粒体功能和活性氧的产生进行分析，以确定 mtDNA Acn和线粒体功能之间的联系。在目标4中，我们将整合生成的数据 与年龄相关的认知和其他行为和中枢神经系统变化的广泛行为数据产生 从BXD和AD-BXD。这将使我们能够确定AD的位点、候选基因和机制， 长寿，并系统地测试与年龄，性别，饮食和线粒体相关变化的关系， DNAcn或函数。最后，我们将整合以前生成的组学数据，我们为BXD和其他 基因组（例如，RNA-seq、meth-seq、代谢组和蛋白质组）， mtDNAc n GWAS和其他现有的组学数据。所有结果将通过强大的互联网公开分享 服务-小鼠表型组数据库，基因网络等数据和工作流程将符合公平。关键 可交付成果是关于基因、分子和生物学的更多定量、无偏见、全球性和可复制的数据， 环境过程与线粒体作用，介导认知丧失、AD和寿命。我们还将 提供因果分子和机制模型，结合现实的高水平的遗传多样性- 600万个DNA变异这项工作授权深入，公正的分析与年龄有关的功能下降 转化为人类群体。成功将提供一个平台，在其中测试新的干预措施， 这种在基因组上和环境上都可复制的种群--所谓的“实验性精确医学”。

As the average age of the population increases, understanding the biology of longevity and diseases of aging is increasingly important. The key role of mitochondria in Alzheimer’s disease (AD) and pathogenic aging has been established in studies across species and mechanistically validated using genetically engineered models. Mitochondrial DNA copy number (mtDNAcn) changes with age and diet, in various tissues, and across species. Higher mtDNAcn is associated with better health outcomes in aging and with increased longevity, while decreased mtDNAcn is linked to disorders of aging including AD. However, we do not understand the mechanistic interaction between genetic variants, mtDNAcn, diet, sex, aging and AD. Here we propose to identify gene-by-environment interactions (GxE) that link mtDNAcn to AD- and aging- relevant phenotypes already collected in the recombinant inbred BXD and transgenic AD-BXD mouse lines, including longevity, memory, learning, motor, and neuroanatomical phenotypes. In Aims 1 and 2, we will test GxE, and identify loci underlying these interactions in three “peripheral” (skin, blood, muscle) and three “central” (liver, kidney, hippocampus) tissues. We will use previously gathered tissue from 45 BXD strains between 6- and 24-months old that had been fed either standard chow or high-fat diet, and quantify mtDNAcn. In Aim 3, we will identify relationships between mtDNAcn, age, sex and the familial AD transgenes (5XFAD), using tissue already collected from the AD-BXD. As part of Aims 2 and 3, we will re-produce a subset of the above strains and carry out analysis of mitochondrial function and reactive oxygen species generation to determine the link between mtDNAcn and mitochondrial function across tissues. In Aim 4, we will integrate our generated data with extensive behavioral data on age-related cognitive and other behavioral and CNS changes generated from BXD and AD-BXD. This will allow us to define loci, candidate genes, and mechanisms of AD and longevity and to systematically test for associations with age, sex, diet, and linked changes in mitochondrial DNAcn or function. Finally, we will integrate previously generated -omics data that we have for BXD and other genomes (e.g., RNA-seq, meth-seq, metabolomes and proteomes) with data from large human AD and mtDNAcn GWASs, and other existing -omics data. All results will be shared openly using robust internet services—Mouse Phenome Database, GeneNetwork, etc. Data and workflows will be FAIR-compliant. Key deliverables are far more quantitative, unbiased, global, and replicable data on genetic, molecular, and environmental processes that act with mitochondria to mediate cognitive loss, AD and longevity. We will also deliver causal molecular and mechanistic models that incorporate realistically high levels of genetic diversity— 6 million DNA variants. This work empowers in-depth, unbiased analyses of age-related functional decline that translates to human populations. Success will provide a platform in which to test novel interventions in this genomically- and environmentally- replicable population — so called “experimental precision medicine”.