Recent studies demonstrate that the hypothalamus functions as a high-order “control center of aging”, counteracting age-associated pathophysiological changes and thereby promoting longevity in mammals. Our group demonstrated that the mammalian NAD+-dependent protein deacetylase SIRT1 in the hypothalamus, particularly the dorsomedial and lateral hypothalamic nuclei (DMH and LH, respectively), is critical to counteract age-associated physiological decline and promote longevity in mice. In the DMH, SIRT1 and its binding partner Nkx2-1 highly colocalize, allowing us to identify a specific subset of DMH neurons, namely, SIRT1/Nkx2-1-double positive neurons. Recently, we have identified a set of genes specifically expressed in these SIRT1/Nkx2-1-double positive DMH neurons. One of these genes is Prdm13, which encodes a member of the PR domain family of transcriptional regulators. Prdm13 is one of the downstream target genes regulated by SIRT1 and Nkx2-1 in the DMH. DMH-specific Prdm13-knockdown mice exhibit decreased sleep quality, increased adiposity, and reduction in adipose Nampt, a key systemic NAD+ biosynthetic enzyme secreted from adipose tissue to remotely regulate hypothalamic function. On the other hand, we found that the DMH- specific knockdown of the thyrotoropin-releasing hormone (Trh) gene, another gene highly and selectively expressed in the SIRT1/Nkx2-1-double positive DMH neurons, caused defects in skeletal muscle mitochondrial gene expression, specific myokine expression, and physical activity. These results suggest that SIRT1/Nkx2-1-double positive DMH neurons contain at least two functionally distinct neuronal subpopulations, namely, Prdm13- and Trh-positive neurons, and that each subpopulation regulates distinct inter-tissue feedback loops between the hypothalamus and adipose tissue or skeletal muscle. In this research proposal, we will extensively investigate the physiological importance of these two inter-tissue feedback loops. We will also examine whether maintaining the activity of these feedback loops can counteract age-associated pathophysiological changes and possibly extend lifespan in mice. The anticipated outcome from the proposed research will make a significant impact to our understanding of the systemic regulation of aging and longevity in mammals.