Project Summary Advanced age is a major risk factor for age-related diseases such as type 2 diabetes (T2D), Alzheimer’s disease (AD) and many others. It remains elusive what aging mechanisms, or more generally what biological mechanisms are responsible for promoting the development of multiple age-related diseases. To address this question, we believe it is essential to investigate the heterogeneity of human aging. We posit that human aging can be generally divided into two major subtypes, i.e., the healthy and pathological aging, and the pathological aging contains critical information on the link between aging and age-related diseases. Using tissues’ transcriptomes, we can divide a cohort into two major subgroups which roughly correspond to healthy and pathological conditions. Molecular mechanisms associated with pathological tissue aging can be learned by comparing the differential gene regulations between the two major subgroups. Using this general approach, we will focus on studying the common pathological aging mechanisms between brain (e.g., hippocampus, and frontal cortex) and adipose tissues (e.g., visceral adipose tissue VAT and subcutaneous adipose tissue SAT). We will also examine the potential molecular mechanisms underlying the adipose-brain cross-tissue talk. We will perform experimental validation for the findings using mouse models. This proposal is innovative as to our best knowledge, the systematic study of the heterogeneity of human tissue aging, the classification of healthy and pathological aging, and identification of the molecular mechanisms shared between adipose-brain tissues and their crosstalk have not been well-examined. The project will help to elucidate the common molecular mechanisms related to pathological aging in metabolic and neurological disorders using an unbiased data-driven approach. We will work on the following two Specific Aim. In Aim 1, we will Identify common gene regulations between brain and adipose tissues in pathological subgroups and the gene regulations putatively mediating adipose-brain cross-tissue talk using GTEx data and other existing human tissue transcriptomic data. In Aim 2, we will experimentally validate the transcriptomic changes involved the adipose- brain axis that may mediate the inter-organ communication and promote pathological brain conditions. In summary, our proposed work represents a novel comprehensive unbiased framework to study the human tissue aging heterogeneity and to identify the key molecular mechanisms shared by brain and adipose tissue. It will generate important pilot results and new insights into the pathological aging mechanism across human body and how the pathological aging in peripheral tissues could contribute to the disease development in the brain.