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.
The proposed study will ultimately enhance our understanding of the systemic regulation of aging and longevity in mammals and provide critical insights into possible anti-aging interventions in humans for the following reasons: First, this study will elucidate the role of a novel subset of hypothalamic neurons, namely SIRT1/Nkx2-1-double positive neurons, in mammalian aging and longevity control. Second, we will manipulate genes specifically expressed in two functionally distinct neuronal subpopulations and examine whether age-associated pathophysiologies and longevity are affected. Lastly, this study will open a new possibility to develop therapeutic and/or preventive interventions for age-associated complications and achieve ?productive aging? in humans.
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