SIRT1 as a regulator of health and lifespan of mammals

研究计划摘要 尽管进行了大量的研究来了解衰老过程，但我们仍然不能自信地回答 基本问题：为什么我们会变老，我们能在人类身上延缓衰老吗？最近的研究表明，不同的 与年龄相关的病理生理状况可能有共同的基础，即所谓的衰老特征 这包括线粒体缺陷、细胞衰老和炎症。我们的研究小组已经为 对依赖NAD+的赖氨酸脱乙酰酶，称为sirtuins(SIRT1-7)的研究已有十多年。 多亏了这笔资金，我们发现了一个新的衰老原因，可以解释线粒体功能下降的原因 随着年龄的增长，这一过程我们称之为“基因组异步化”。基因组不同步在心脏和肌肉组织中的表现 (可能还有其他组织)作为核-线粒体通讯中断，由于 NAD+水平和SIRT1活性丧失。结果是缺氧因子HIF-1α在 无低氧(我们称之为“假低氧”现象)和对核的有效抑制作用-- 线粒体通讯。重要的是，通过给老年小鼠喂食NAD+前体烟酰胺 单核苷酸(NMN)，为期一周，从而将NAD+恢复到年轻时的水平，使老年人的线粒体缺陷 肌肉可以迅速逆转，表明NAD+是小鼠衰老和 衰老的各个方面是可逆的。在研究中，我们发现NMN治疗能够 迅速逆转肌肉衰老的关键标志，表明NAD+水平下降可能是基础 衰老过程中的炎症。我们发现，NAD+水平和HIF-1α特异性地控制IL-18和 IL-1β通过调节炎症小体的活动，这是哺乳动物健康寿命的关键调节因素。 在下一阶段的拨款中，我们将确定调节炎症的NAD+依赖机制 以及它在衰老细胞分泌表型(SASP)中的作用和试验干预以抵消 这些小路。目标1是使用来自转基因小鼠的原代巨噬细胞(GEMM)，以及 新的表观遗传操作技术和临床准备就绪的小分子来验证我们的假设。在目标2中， 我们将在体内使用来自这两个群体的幼鼠和老年鼠对这一途径进行全面的研究 野生型和转基因动物体内或特定组织中NAD+和HIF-1水平发生变化 肌肉和大脑。在目标3中，我们将评估最好的NAD+调节化合物的疗效(来自目标1) 延长小鼠的健康寿命和寿命。我们还将测试最好的化合物在黄金中的功效- 急性痛风的标准模型(一种常见的与年龄相关的炎症性疾病，目前尚无有效治疗方法 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，创造新的疗法来延长人类 健康长寿。

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.