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，而衰老是年龄相关性衰老的关键驱动因素。 病理学我们的计划是领导努力了解细胞衰老和老化的表观遗传学。我们 总的假设是表观基因组是固有的动态/可塑性，以提供灵活的调节， 在衰老过程中，这种动态表观基因组经历整体完整性的丧失。这种表观基因组完整性的丧失， 反过来，有助于细胞和组织信号传导事件的二级级联反应，也加剧了衰老， 实施例衰老细胞中的衰老相关分泌表型（SASP），是“炎性老化”的原因。 我们创造了“染色体停滞”一词，用于细胞和组织试图管理其染色体的过程。 动态/可塑性表观基因组，以维持表观基因组的完整性、转录保真度，并因此促进健康 老化和长寿。根据我们的出版物（56），当前的P01资助期非常成功 总数），合作努力（20个合作出版物），以及我们对老龄化和 表观遗传学（自2008年首次资助以来发表了104篇论文）。 我们在本资助期的具体主要成就是：（1）我们发现了戏剧性的 衰老的人类细胞内表观基因组景观的变化，其中一些也发生在老年人和 病变组织我们发现了这种改变的表观基因组景观背后的机制，包括 异染色质的破坏和自噬的核底物的第一个例子。(2)我们发现了新的 在衰老细胞中激活SASP的机制，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 在小鼠中发现了一个DNA甲基化时钟，并通过不同的长寿干预显示其减缓。 (4)本研究对HUCA（HIRA/UBN 1/CABIN 1/ASF 1a）组蛋白伴侣的结构和功能进行了详细的分析， 复合物，衰老细胞中组蛋白动力学的关键介质，并定义了HUCA的分子基础， 组蛋白H3.3变体选择性。(5)我们发现了与年龄相关的保守染色质因子的改变， 导致基因体不适当的隐蔽转录，并表明这是衰老的一个新原因。 在更新此PO 1时，我们将（1）利用多学科发现平台， （2）确定染色体稳态改变与染色体稳态缺陷的相关性， 小鼠/人衰老，和（3）剖析次级促衰老信号传导事件的潜在机制， 确定药理学方法来阻止这些过程，以促进健康的衰老。

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.