SIRT1 as a regulator of health and lifespan of mammals

描述（由申请人提供）：Sirtuins是NAD+依赖性脱乙酰酶家族，其被认为已经进化以增加生物体在逆境中存活的机会。它们存在于细菌、真菌、植物和动物中。在哺乳动物中，sirtuins参与介导卡路里限制（CR）的许多健康益处。哺乳动物有7种sirtuins，SIRT 1 -7。SIRT 1是研究得最好的。SIRT 1控制的主要过程包括DNA修复、蛋白质折叠、脂肪酸和葡萄糖代谢、缺氧反应、自噬和抗凋亡机制。SIRT 1的过表达在各种常见的年龄相关疾病模型中保护小鼠。我们的细胞包含两个基因组，核和线粒体。这些必须严格共同调节，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，人们知之甚少。我们未发表的研究表明，当SIRT 1在年轻的成年小鼠中被删除时，两个基因组之间的正常转录同步被破坏，导致电子传递链（ETC）化学计量的损失，呼吸和ATP减少，活性氧（ROS）和乳酸增加，以及肌肉线粒体无法适应禁食的代谢。引人注目的是， 随着年龄的增长，野生型小鼠也会出现同样的缺陷。因此，基因组同步性的丧失可能是正常衰老的潜在且可逆的原因。我们已经追踪到缺陷的可能原因是一种新的SIRT 1介导的途径，不涉及经典因子PGC- 1或NRF 1/2。本提案的目的1将研究SIRT 1在骨骼肌中维持基因组同步和ETC化学计量的机制，而不依赖于经典的PGC- 1 <$/<$途径。这将提供新的和基本的机制见解（i）线粒体如何响应饮食调节和（ii）基因组同步如何随着时间的推移而丢失。目的2：使用新的遗传和药理学方法恢复老年小鼠的基因组同步，以测试是否可以通过评估代谢，运动功能和认知来逆转高能量器官和组织中衰老的任何有害影响。最近C. elegans和Drosophila的研究表明，一种细胞类型中线粒体功能的改变（例如破坏ETC）可以通过诱导推定的“丝裂因子”的分泌来延长寿命。由于对线粒体如何在细胞内或与其他组织进行通信及其在哺乳动物衰老中的潜在作用知之甚少，Aim 3将部分利用我们对人类基因组的筛选来研究这些基本过程，该筛选已确定了98个新的线粒体调节因子。由于我们的进化起源，我们的细胞包含两个基因组。我们发现它们之间的交流在衰老过程中会中断。通过了解这两个基因组如何相互交流，以及如何与体内其他细胞交流，这项研究可能会为对抗罕见的线粒体疾病和常见的衰老疾病带来新的实用策略。

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 Our unpublished studies indicate that when SIRT1 is deleted in young adult mice, the normal transcriptional synchrony between the two genomes is disrupted, leading to loss of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.