SIRT1 as a regulator of health and lifespan of mammals

研究计划摘要 尽管有大量的研究努力来了解衰老过程，我们仍然不能自信地回答 基本问题：我们为什么会衰老，我们能延缓人类的衰老吗？最近的研究表明， 与年龄相关的病理生理条件可能有共同的基础，即所谓的衰老标志 包括线粒体缺陷细胞衰老和炎症我们的研究小组已经为 十多年来，依赖NAD+的赖氨酸脱乙酰酶被称为Sirtuins（SIRT 1 -7）。 多亏了这项资助，我们发现了一种新的衰老原因，可以解释线粒体功能下降的原因 我们称之为“基因组不同步”基因组多态性在心脏和肌肉组织中表现出来 (and可能是其他组织）作为一个崩溃，在核线粒体通讯由于下降， NAD+水平和SIRT 1活性的丧失。结果是缺氧因子HIF-1α在细胞中的稳定性， 缺乏缺氧（我们称之为“假性缺氧”的现象）和对核- 线粒体通讯重要的是，通过给老年小鼠喂食NAD+前体， Monopolytide（NMN），持续一周，从而将NAD+恢复到年轻水平， 肌肉可以迅速逆转，这表明NAD+是小鼠衰老方面的关键调节因子， 衰老是可逆的在研究过程中，我们发现NMN治疗能够 快速逆转肌肉衰老的关键标志物，表明NAD+水平下降可能是 老化过程中的炎症。我们发现，NAD+水平和HIF-1α特异性地控制IL-18的分泌， IL-1β通过调节炎性小体的活性，炎性小体是哺乳动物健康寿命的关键调节因子。 在下一阶段的资助中，我们将确定调节炎症的NAD+依赖机制。 沿着其在衰老细胞分泌表型（SASP）中的作用，以及测试干预以抵消 这些途径。目的1是使用来自遗传修饰小鼠（GEMM）的原代巨噬细胞，沿着 新的表观遗传操作技术和临床可用的小分子来测试我们的假设。在目标2中， 我们将使用来自两种种群的年轻和年老的小鼠，在体内对这一通路进行全面的研究。 在整个身体或特定组织中具有改变的NAD+和HIF-1 α水平的野生型和GEMM， 肌肉和大脑在目标3中，我们将评估最佳NAD+调节化合物的功效（来自目标1） 来延长老鼠的健康和寿命。我们还将测试最好的化合物在黄金中的功效- 急性痛风标准模型（一种常见的与年龄相关的炎性疾病， 治疗），从而为快速人体临床试验铺平了道路。这项工作将产生深远的影响 通过改变我们对衰老发生原因的理解，并创造新的疗法来延长人类寿命， 健康和长寿。

Abstract of the Research Plan Despite significant research effort to understand the aging process, we are still not able to confidently answer fundamental questions: Why do we age and can we delay it in humans? Recent studies suggest that various age-related pathophysiological conditions may have common underpinnings, the so-called hallmarks of aging that include mitochondrial defects, cellular senescence and inflammation. Our research group has worked for more than a decade on NAD+-dependent lysine deacetylases known as the Sirtuins (SIRT1-7). Thanks to this grant, we discovered a new cause of aging that explains why mitochondrial function declines with age, a process we call “Genome Asynchrony”. Genome asynchrony manifests in heart and muscle tissue (and possibly other tissues) as a breakdown in nuclear-mitochondrial communication due to a decline the NAD+ levels and loss of SIRT1 activity. The result is the stabilization of the hypoxia factor HIF-1α in the absence of hypoxia (a phenomenon we call “pseudohypoxia”) and a potent inhibitory effect on nuclear- mitochondrial communication. Importantly, by feeding old mice the NAD+ precursor, nicotinamide mononucleotide (NMN), for one week, thus restoring NAD+ to youthful levels, the mitochondrial defects of old muscle can be rapidly reversed, demonstrating that NAD+ is a key regulator of aspects of aging in mice and that aspects of aging are reversible. During the study we discovered that the NMN treatment was able to rapidly reverse key markers of aging in the muscle, suggesting declining NAD+ levels may underlie inflammation during aging. We find that NAD+ levels and HIF-1α specifically control the secretion of IL-18 and IL-1β by regulating the activity of the inflammasome, a key regulator of healthspan in mammals. In the next phase of the grant, we will determine the NAD+-dependent mechanisms that regulate inflammation along with its role in the secretory phenotype of senescent cells (SASP) and test interventions to counteract these pathways. Aim 1 is to use primary macrophages from genetically modified mice (GEMMs), along with novel epigenetic manipulation technologies and clinic-ready small molecules to test our hypotheses. In Aim 2, we will perform a comprehensive study of this pathway in vivo using young and old mice from colonies of both wildtype and GEMMs with altered levels of NAD+ and HIF-1 throughout the body or in specific tissues such as muscle and brain. In Aim 3, we will evaluate the efficacy of the best NAD+ modulating compounds (from Aim 1) to prolong healthspan and lifespan in mice. We will also test the best compounds for their efficacy in a gold- standard model of acute gout (a common age-associated inflammatory disease for which there are no effective treatments) thereby paving the way for rapid human clinical trials. The work will have far-reaching implications by changing our understanding of why aging occurs and creating novel therapeutics to prolong human healthspan and longevity.