SIRT1-MEDIATED CENTRAL ADAPTATION TO DIET RESTRICTION

描述（由申请人提供）：对饮食摄入量变化的生理反应如何影响衰老和寿命的过程是理解代谢和衰老之间复杂联系的系统调节的基本问题。饮食限制（DR）是已知的延缓衰老和延长多种生物体寿命的唯一、最可靠的方案，为解决这一重要问题提供了独特的模型。本研究旨在了解哺乳动物对DR的生理适应性反应，特别是中枢适应性反应的分子机制。我们一直对进化上保守的SIR 2我们的新研究最近证实了哺乳动物SIR 2直系同源物SIRT 1在下丘脑，特别是在下丘脑背内侧核和外侧核中的新功能（分别为DMH和LH），作为控制食欲素2型受体（OX 2 R）介导的信号传导的关键介质，其响应于外周信号，包括由DR诱导的胃分泌的促食欲激素ghrelin。因此，在该提议中，我们假设SIRT 1控制对DR的中枢适应性反应，包括通过上调DHM和LH中Ox 2 r表达和神经激活来增强体力活动和维持体温。为了解决这一假设，我们将研究1）SIRT 1如何通过新鉴定的靶同源结构域转录因子上调Ox 2 r基因的转录以响应DR，2）将表达针对Sirt 1或SIRT 1靶转录因子的shRNA的慢病毒立体定向注射到DMH和/或LH中是否消除了对DR的中枢适应性反应，3）SIRT 1活性如何被DMH和LH中的DR增强，以及4）SIRT 1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的中枢适应机制知之甚少，因此拟议的研究将为协调DR反应的生理机制提供重要见解，并可能确保哺乳动物的长寿。 公共卫生相关性：这项拟议的研究将最终增强我们对哺乳动物代谢和衰老调节的理解，并为人类可能的抗衰老干预提供重要见解，原因如下：首先，这项研究将阐明涉及SIRT 1和食欲素信号传导的新型中枢调节回路的重要性。其次，这项研究将揭示一个特定的神经元子集的重要性，即DMH和LH中的OX 2 R阳性神经元，在调节对DR的中枢适应性反应中的重要性。最后，这项研究将为我们最近提出的NAD世界的概念提供重要支持，并为开发与年龄相关的神经系统并发症的营养干预提供新的可能性，包括老年人进食行为的并发症，称为“老年厌食症”。"

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."