SIRT1 as a regulator of health and lifespan of mammals

描述(由申请人提供)：sirtuins是一个依赖NAD+的脱乙酰酶家族，被认为已经进化成增加有机体在逆境中生存的机会。它们存在于细菌、真菌、植物和动物体内。在哺乳动物中，sirtuins参与调节卡路里限制(CR)的许多健康益处。有七种哺乳动物sirtuin，SIRT1-7。SIRT1是研究最深入的。SIRT1调控的主要过程包括DNA修复、蛋白质折叠、脂肪酸和葡萄糖代谢、低氧反应、自噬和抗凋亡机制。在各种常见的年龄相关疾病模型中，SIRT1的过表达对小鼠具有保护作用。我们的细胞包含两个基因组，核和线粒体。这些必须紧密地共同调节，以确保正常的组织功能。这是如何实现的，以及这是否与衰老有关，目前还知之甚少。我们未发表的研究表明，当SIRT1在年轻成年小鼠中缺失时，两个基因组之间的正常转录同步性被破坏，导致电子传输链(ETC)化学计量比的丧失，呼吸和ATP减少，活性氧(ROS)和乳酸增加，肌肉线粒体无法适应禁食。令人惊讶的是， 随着野生型小鼠年龄的增长，同样的缺陷也会发生在它们身上。因此，基因组同步性的丧失可能是正常衰老的一个潜在的、可能是可逆的原因。我们已经追踪到缺陷的可能原因是一种新的SIRT1介导的途径，该途径不涉及规范因子PGC-1？/？或NRF1/2。本提案的目的1将研究SIRT1维持骨骼肌基因组同步性等化学计量学的机制，而不是典型的PGC-1？/？途径。这将为(I)线粒体如何对饮食做出反应以及(Ii)基因组同步性如何随着时间的推移而丧失提供新的和基本的机械性见解。目的2利用新的遗传学和药理学方法恢复老龄小鼠的基因组同步性，以测试是否可以通过评估新陈代谢、运动功能和认知来逆转高能器官和组织中衰老的任何有害影响。线虫和果蝇的最新证据表明，一种细胞中线粒体功能的改变(例如破坏ETC)可以通过诱导假定的“有丝分裂素”的分泌来延长寿命。由于人们对线粒体如何在细胞内或与其他组织沟通以及它在哺乳动物衰老中的潜在作用知之甚少，因此Aim 3将利用我们对人类基因组的筛选来研究这些基本过程，该基因组已经确定了98个新的线粒体调节因子。相关性由于我们的进化起源，我们的细胞包含两个基因组。我们发现，随着年龄的增长，它们之间的交流会中断。通过了解这两个基因组是如何相互通信的，以及如何潜在地与身体中的其他细胞进行通信，这项研究可能会导致对抗罕见的线粒体疾病和常见的衰老疾病的新的实用策略。

DESCRIPTION (provided by applicant): Sirtuins are a family of NAD+-dependent deacetylases that are thought to have evolved to increase an organism's chances of surviving adversity. They are found in bacteria, fungi, plants and animals. In mammals, sirtuins are implicated in mediating many of the health benefits of calorie restriction (CR). There are seven mammalian sirtuins, SIRT1-7. SIRT1 is the best studied. Major processes controlled by SIRT1 include DNA repair, protein folding, fatty acid and glucose metabolism, hypoxic responses, autophagy, and anti-apoptotic mechanisms. Over expression of SIRT1 protects mice in a variety of common age-related disease models. Our cells contain two genomes, the nuclear and the mitochondrial. These must be tightly co-regulated to ensure normal tissue function. How this is achieved, and whether this has relevance to aging, is poorly understood. Our unpublished studies indicate that when SIRT1 is deleted in young adult mice, the normal transcriptional synchrony between the two genomes is disrupted, leading to loss of electron transport chain (ETC) stoichiometry, reduced respiration and ATP, increased reactive oxygen species (ROS) and lactate, and a failure of muscle mitochondria to adapt their metabolism to fasting. Strikingly, this same defect occurs in wild type mice as they age. Thus, loss of genome synchrony may be an underlying, and potentially reversible, cause of normal aging. We have traced the likely cause of the defect to a novel SIRT1-mediated pathway that does not involve the canonical factors PGC- 1¿/¿ or NRF1/2. Aim 1 of this proposal will investigate the mechanisms by which SIRT1 maintains genome synchrony and ETC stoichiometry in skeletal muscle, independent of the canonical PGC- 1¿/¿ pathway. This will provide new and fundamental mechanistic insights into (i) how mitochondria are regulated in response to diet and (ii) how genome synchrony is lost over time. Aim 2 uses novel genetic and pharmacological approaches to restore genome synchrony in aged mice to test whether any of the deleterious effects of aging in highly energetic organs and tissues can be reversed by assessing metabolism, motor function, and cognition. Recent evidence from C. elegans and Drosophila indicates that alterations in mitochondrial function in one cell type (e.g. disrupting the ETC) can extend lifespan by inducing the secretion of putative "mitokines". Because so little is known about how mitochondria communicate within the cell or with other tissues, and its potential role in mammalian aging, Aim 3 will investigate these fundamental processes, in part, by taking advantage of our screen of the human genome that has identified 98 new mitochondrial regulators. Relevance Because of our evolutionary origins, our cells contains two genomes. We find that communication between them breaks down during aging. By understanding how the two genomes communicate -- between each other and potentially to other cells in the body -- the study could lead to new practical strategies for combating rare mitochondrial diseases and common diseases of aging.