THE ROLE OF DORSOMEDIAL HYPOTHALAMIC NEURONS IN MAMMALIAN AGING AND LONGEVITY

最近的研究表明，下丘脑起着高级“衰老控制中心”的作用， 对抗年龄相关的病理生理变化，从而促进长寿 哺乳动物。我们的研究小组证明了哺乳动物依赖NAD的蛋白去乙酰基酶 SIRT1在下丘脑，特别是下丘脑背内侧核和外侧核(DMH和 促黄体生成素(Lh)对抵消与年龄相关的生理衰退和延长寿命至关重要 在老鼠身上。在DMH中，SIRT1及其结合伙伴Nkx2-1高度共存，使我们能够识别出 DMH神经元的特定亚群，即SIRT1/Nkx2-1双阳性神经元。最近，我们有 鉴定了一组在这些SIRT1/Nkx2-1双阳性DMH神经元中特异表达的基因。 其中一个基因是Prdm13，它编码PR结构域转录家族的一个成员。 监管者。Prdm13是SIRT1和Nkx2-1调控的下游靶基因之一。 DMH。DMH特异性Prdm13基因敲除的小鼠表现出睡眠质量下降，肥胖增加， 脂肪NAMPT的还原，脂肪分泌的一种关键的NAD生物合成酶 组织来远程调节下丘脑功能。另一方面，我们发现DMH- 甲状腺激素释放激素(TRH)基因的特异性敲除，另一个基因高度和 选择性表达于SIRT1/Nkx2-1双阳性DMH神经元，导致骨骼缺陷 肌肉线粒体基因表达、特异性肌动因子表达和体力活动。这些 结果提示，SIRT1/Nkx2-1双阳性DMH神经元至少含有两种功能 不同的神经元亚群，即Prdm13和TRH阳性神经元，并且每个 亚群调节下丘脑和脂肪之间不同的组织间反馈环 组织或骨骼肌。在这项研究计划中，我们将广泛调查生理学 这两个组织间反馈环的重要性。我们亦会研究是否维持 这些反馈环的活动可以抵消与年龄相关的病理生理变化和 有可能延长小鼠的寿命。拟议研究的预期结果将使 对我们理解哺乳动物衰老和长寿的系统调控产生了重大影响。

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.