Epigenetics of Aging and Age-Associated Diseases

总体摘要 表观遗传学是衰老和长寿的关键决定因素，而衰老是与年龄相关的关键驱动因素 病理学。我们的计划正在领导理解细胞衰老和衰老的表观遗传学的努力。我们的 总的假设是表观基因组是固有的动态/可塑性的，以提供灵活的调节，以及 在衰老过程中，这个动态的表观基因组经历了整体完整性的丧失。表观基因组完整性的丧失，在 反过来，促进了细胞和组织信号事件的次级级联，这也加剧了衰老， 例：衰老细胞中的衰老相关分泌表型(SASP)，这是“炎症老化”的原因。 我们创造了“染色质稳定”这个术语，用来描述细胞和组织试图控制它们的 动态/塑料表观基因组以保持表观基因组的完整性、转录的保真度，从而促进健康 衰老和长寿。目前的P01赠款期间非常成功，从我们的出版物来看(56 )、合作努力(20份合作出版物)，以及我们对老龄和卫生领域的贡献 表观遗传学(自2008年最初资助以来发表了104篇论文)。 我们在本赠款期间的具体主要成就是：(1)我们发现了戏剧性的 衰老的人类细胞内表观基因组图谱的变化，其中一些也发生在老年人和 有病的组织。我们发现了这种改变表观基因组图景的机制，包括 破坏异染色质和核底物自噬的第一个例子。(2)我们发现新的 衰老细胞中SASP的激活机制，并开创了新的小分子/药物基础 抑制SASP和促进健康衰老的方法，包括MLL和HDAC抑制剂。(3)我们 在小鼠体内发现了DNA甲基化时钟，并通过不同的长寿干预显示其放缓。 (4)分析了HUCA(Hira/UBN1/CABIN1/ASF1a)组蛋白伴侣蛋白的结构和功能 复合体，衰老细胞组蛋白动力学的关键介体，并定义了HUCA的分子基础 组蛋白H3.3变异体选择性。(5)我们发现了与年龄相关的保守染色质因子的变化 导致来自基因体的不适当的隐蔽转录，并表明这是一种新的衰老原因。 在此PO1的续订中，我们将(1)利用多学科发现平台来发现 染色质抑制不足的机制，(2)确定变色反应在 小鼠/人类衰老，以及(3)剖析次级促衰老信号事件的潜在机制和 找出阻止这些过程的药理学方法，以促进健康衰老。

OVERALL ABSTRACT Epigenetics is a critical determinant of aging and longevity, and senescence is a key driver of age-associated pathologies. Our program is leading efforts to understand the epigenetics of cell senescence and aging. Our overall hypothesis is that the epigenome is inherently dynamic/plastic to provide for flexible regulation, and during aging, this dynamic epigenome undergoes a loss of overall integrity. This loss of epigenome integrity, in turn, contributes to a secondary cascade of cell and tissue signaling events that also exacerbate aging, for example Senescence-Associated Secretory Phenotype (SASP) in senescent cells, a cause of “inflamm-aging”. We have coined the term “chromostasis” for the process whereby cells and tissues attempt to manage their dynamic/plastic epigenome to maintain epigenome integrity, transcriptional fidelity and, hence, promote healthy aging and longevity. The current P01 grant period was highly successful, as measured by our publications (56 total), collaborative efforts (20 collaborative publications), and our contributions to the fields of aging and epigenetics (104 publications since initial funding in 2008). Our specific major accomplishments in the current grant period are: (1) We uncovered dramatic changes to the epigenomic landscape within senescent human cells, some of which also occur in aged and diseased tissues. We discovered mechanisms underlying this altered epigenomic landscape, including disruption heterochromatin and the first example of a nuclear substrate of autophagy. (2) We discovered new mechanisms for activation of the SASP in senescent cells, and pioneered new small molecule/drug-based approaches to inhibit the SASP and promote healthy aging, including MLL and HDAC inhibitors. (3) We discovered a DNA methylation clock in mouse, and showed its slowing by diverse prolongevity interventions. (4) We dissected the structure and function of the HUCA (HIRA/UBN1/CABIN1/ASF1a) histone chaperone complex, a key mediator of histone dynamics in senescent cells, and defined the molecular basis of HUCA’s histone H3.3 variant selectivity. (5) We found age-correlated alterations in conserved chromatin factors that lead to inappropriate cryptic transcription from gene bodies, and showed this to be a novel cause of aging. In the renewal of this PO1, we will (1) leverage multi-disciplinary discovery platforms to uncover mechanisms underlying deficient chromostasis, (2) determine relevance of altered chromostasis in mouse/human aging, and (3) dissect mechanisms underlying the secondary pro-aging signaling events and identify pharmacological approaches to block these processes to promote healthy aging.