Identifying protective omics profiles in centenarians and translating these into preventive and therapeutic strategies

项目摘要。百岁老人（年龄>100岁），甚至更多，半超级百岁老人（年龄105-109岁 年龄）和超级百岁老人（110岁以上）是异常值，不仅因为他们的寿命特别长，而且因为他们的年龄 女性生育力更长，对老年性残疾和阿尔茨海默病等疾病的抵抗力更强， 心脏病中风糖尿病和癌症它们的后代也表现出延迟发病和较低的死亡率 与他们的出生队列相比。在非人类物种中，包括裸鼹鼠在内的啮齿动物也 与其他体重相似的哺乳动物相比，它们的寿命差异引起了人们的注意。蛋白组 与百岁老人极端长寿（EL）相关的特征以及整合的转录组学和蛋白质组学 NMR数据表明，对这些人类和动物产生的多组学数据的综合分析 缓慢衰老和抵抗衰老相关疾病的模型可以告诉我们生物学机制， 是这些生存和健康优势的基础，最终是关于预防疾病的潜在疗法。 比如老年痴呆症本提案的UH 2和UH 3阶段有两个具体目标。目标1：在UH 2 新英格兰百岁老人研究和爱因斯坦百岁老人及其后代研究将建立一个 标准化表型数据和生物样品收集方案，用于700名受试者的亲自访问， 每项研究（n=1400）。详细的认知功能测试将确定可能的 老年痴呆表型分析方案将与长寿联盟的百岁老人使用的方案相同。 项目（n=350），以便他们的数据可以添加到这项工作中，总样本为1，750。世界一流 一个多学科小组将计划多组学数据的生成以及将要执行的分析和翻译工作 目标2这些努力将通过比较转录组学、蛋白质组学和微生物组学研究来证实， 具有广泛不同寿命的非人类哺乳动物物种，并通过创建EL特异性IPSC文库 分化成无限数量的肝细胞和神经元。目标2：在UH 3阶段，我们将 从百岁老人中生成转录组学、甲基组学、代谢组学、蛋白质组学和微生物组学数据， 百岁老人的后代（大约三分之一的样本在两个时间点产生）。多组学方法 目标1中汇编的数据集成将用于发现与EL和健康相关的分子谱 包括延迟或逃避阿尔茨海默病的老化表型。与分子图谱整合， 用iPSC衍生的神经元和肝细胞以及分子谱进行的弹性功能研究 与多个物种的寿命增加相关的机制将指向机制，并产生候选小 分子和化合物疗法。所有生成的数据和独特的生物资源，包括EL- iPSC衍生的肝细胞和神经元，将与研究的财团和个人研究者分享。 老年痴呆症，其他与衰老有关的疾病，更普遍的是，衰老的基本机制。

PROJECT ABSTRACT. Centenarians (ages >100 yrs) and even more-so, semi-supercentenarians (ages 105-109 yrs) and supercentenarians (110+ yrs) are outliers not only for their exceptionally long lifespans, but also for their longer female fertility and resistance to aging-related disability and morbidities such as Alzheimer’s disease, heart disease, stroke, diabetes and cancer. Their offspring also exhibit delayed morbidity and lower mortality compared to their birth cohort. Among non-human species, rodents including the naked mole rat have also gained attention for their variation in lifespan compared to other mammals with similar body mass. Proteomic signatures associated with extreme longevity (EL) in centenarians and integrated transcriptomic and proteomic data in NMRs suggest that integrated analyses of multiple omics data generated from these human and animal models of slow aging and resistance to aging related diseases can inform us about biological mechanisms that underlie these survival and health advantages and, ultimately, about potential therapeutics to prevent diseases such as Alzheimer’s. Two specific aims parallel the UH2 and UH3 phases of this proposal. Aim 1: In the UH2 phase, the New England Centenarian Study and the Einstein Centenarian and Offspring studies will establish a standardized phenotypic data and biological sample collection protocol for in-person visits of 700 subjects from each study (n=1400). Detailed cognitive function testing will determine presence or absence of probable Alzheimer’s. The phenotyping protocol will be the same as that used by the Longevity Consortium’s Centenarian Project (n=350), so that their data can be added to this effort for a total sample of 1,750. A world-class multidisciplinary team will plan the multi-omics data generation and analytic and translation efforts to be executed in Aim 2. These efforts will be paralleled by comparative transcriptomic, proteomic and microbiomic studies of non-human mammalian species of widely different life spans and by the creation of a library of EL-specific IPSCs that will be differentiated into unlimited numbers of hepatocytes and neurons. Aim 2: In the UH3 phase, we will generate transcriptomic, methylomics, metabolomics, proteomic and microbiomic data from centenarians and centenarian offspring (generated from two time points in about a third of the sample). Methods for multi-omic data integration compiled in Aim 1 will be used to discover molecular profiles that associate with EL and healthy aging phenotypes including delay of or escape from Alzheimer’s disease. Integration with molecular profiles from functional studies of resiliency performed with iPSC-derived neurons and hepatocytes and with molecular profiles associated with increased lifespan from multiple species will point to mechanisms and generate candidate small molecule and compound therapeutics. All generated data and unique biological resources, including the EL- iPSC derived hepatocytes and neurons, will be shared with consortia and individual investigators researching Alzheimer’s, other aging related diseases and more generally, basic mechanisms of aging.