# THE ROLE OF DORSOMEDIAL HYPOTHALAMIC NEURONS IN MAMMALIAN AGING AND LONGEVITY

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $312,625

## Abstract

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.

## Key facts

- **NIH application ID:** 9927545
- **Project number:** 5R01AG037457-10
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** SHIN-ICHIRO IMAI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $312,625
- **Award type:** 5
- **Project period:** 2011-05-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9927545

## Citation

> US National Institutes of Health, RePORTER application 9927545, THE ROLE OF DORSOMEDIAL HYPOTHALAMIC NEURONS IN MAMMALIAN AGING AND LONGEVITY (5R01AG037457-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9927545. Licensed CC0.

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