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

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”.