SIRT1-MEDIATED CENTRAL ADAPTATION TO DIET RESTRICTION

描述（申请人提供）：饮食摄入改变的生理反应如何影响衰老和长寿的过程，是理解代谢与衰老之间复杂联系的系统调控的基础问题。饮食限制（DR），一种已知的最可靠的延缓衰老和延长多种生物寿命的方案，为解决这一重要问题提供了一个独特的模型。本研究计划旨在了解哺乳动物对DR生理适应反应的分子机制，特别是中枢适应反应。我们一直对进化上保守的nad依赖性去乙酰化酶/ adp -核糖基转移酶（也称为sirtuins） SIR2（沉默信息调节因子2）家族感兴趣。我们的新研究最近证明了哺乳动物SIR2同属体SIRT1在下丘脑中的新功能，特别是在下丘脑背内侧核和外侧核（分别为DMH和LH）中，作为控制食欲素2型受体（OX2R）介导的信号传导的关键介质，以响应由dr诱导的外周信号，包括胃促生长素（胃分泌的一种促食激素）。在本研究中，我们假设SIRT1通过上调Ox2r表达和DHM和LH的神经激活来控制DR的中枢适应性反应，包括增强身体活动和维持体温。为了解决这一假设，我们将研究1)SIRT1如何通过新发现的靶同源结构域转录因子上调Ox2r基因的转录以响应DR， 2)将表达针对SIRT1或SIRT1靶转录因子的shRNA的慢病毒立体定向注射到DMH和/或LH中是否会消除对DR的中心适应性反应，3)DR如何增强DMH和LH中的SIRT1活性。4) sirt1介导的中枢适应性反应是否对小鼠寿命的控制也很重要。由于对DR的核心适应机制知之甚少，因此拟议的研究将为协调DR反应的生理机制提供关键见解，并可能确保哺乳动物的长寿。

DESCRIPTION (provided by applicant): How physiological responses to alterations in dietary intake affect the process of aging and longevity is a fundamental question to understand the systemic regulation of the complex connection between metabolism and aging. Diet restriction (DR), the single, most reliable regimen known to retard aging and extend lifespan in a variety of organisms, has provided a unique model to address this important question. This research proposal aims to understand molecular mechanisms underlying physiological adaptive responses to DR, particularly the central adaptive response, in mammals. We have been interested in the evolutionarily conserved SIR2 (silent information regulator 2) family of NAD-dependent deacetylases/ADP-ribosyltransferases, also called "sirtuins," as a critical regulator that coordinates physiological responses to DR. Our new study has recently demonstrated a novel function of the mammalian SIR2 ortholog SIRT1 in the hypothalamus, particularly in the dorsomedial and lateral hypothalamic nuclei (DMH and LH, respectively), as a key mediator that controls the orexin type 2 receptor (OX2R)-mediated signaling in response to peripheral signals including ghrelin, an orexigenic hormone secreted from stomach, induced by DR. Therefore, in this proposal, we hypothesize that SIRT1 controls central adaptive responses to DR, including the augmentation of physical activity and the maintenance of body temperature, through the up-regulation of the Ox2r expression and the neural activation in the DHM and LH. To address this hypothesis, we will examine 1) how SIRT1 up-regulates the transcription of the Ox2r gene through a newly identified target homeodomain transcription factor in response to DR, 2) whether stereotactic injection of lentiviruses expressing shRNA against Sirt1 or the SIRT1 target transcription factor into the DMH and/or LH abrogates the central adaptive response to DR, 3) how SIRT1 activity is augmented by DR in the DMH and LH, and 4) whether SIRT1-mediated central adaptive response is also important for the control of longevity in mice. Because very little has been known about the central adaptive mechanism for DR, the proposed study will provide critical insights into the physiological mechanism that orchestrates responses to DR and may assure longevity in mammals. PUBLIC HEALTH RELEVANCE: The proposed study will ultimately enhance our understanding of the regulation of metabolism and aging in mammals and provide critical insights into possible anti-aging interventions in humans for the following reasons: First, this study will elucidate the importance of a novel central regulatory circuit involving SIRT1 and orexin signaling in the hypothalamus. Second, the proposed study will shed a new light on the importance of a specific subset of neurons, namely, OX2R-positive neurons in the DMH and LH, in the regulation of central adaptive responses to DR. Lastly, this study will provide important support for the concept of the NAD World that we have recently proposed and also open a new possibility to develop nutriceutical interventions for age- associated neurological complications, including complications of ingestive behavior in the elderly, called "the anorexia of aging."