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

项目摘要。百岁老人(100岁)和更多的半百岁老人(105-109岁) 超百岁老人(110岁以上)是异类，不仅是因为他们超长的寿命，而且也是因为他们 更长的女性生育力和对衰老相关残疾和疾病(如阿尔茨海默病)的抵抗力， 心脏病、中风、糖尿病和癌症。他们的后代也表现出延迟的发病率和较低的死亡率 与他们出生的同龄人相比。在非人类物种中，包括裸鼠在内的啮齿动物也 与其他体重相似的哺乳动物相比，它们在寿命上的差异引起了人们的注意。蛋白质组学 百岁老人中与极长寿(EL)相关的特征以及转录和蛋白质组学的整合 NMRS中的数据表明，对这些人和动物产生的多个组学数据进行综合分析 延缓衰老和抵抗衰老相关疾病的模型可以告诉我们 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 例如阿尔茨海默氏症。这项提议的UH2和UH3阶段有两个具体的目标。目标1：在UH2中 阶段，新英格兰百岁老人研究和爱因斯坦百岁老人和后代研究将建立一个 来自中国的700名受试者的标准化表型数据和生物样本采集协议 每项研究(n=1400)。详细的认知功能测试将确定是否存在可能的 阿尔茨海默氏症。表型鉴定方案将与长寿联盟的百岁老人使用的相同 项目(n=350)，以便将他们的数据添加到这项工作中，以获得总计1,750个样本。世界级的 多学科团队将规划要执行的多组学数据生成以及分析和翻译工作 在目标2中。这些努力将与转录学、蛋白质组学和微生物组学的比较研究相平行 寿命差异很大的非人类哺乳动物物种以及通过创建EL特异性IPSCs文库 这将被分化成无限数量的肝细胞和神经元。目标2：在UH3阶段，我们将 生成百岁老人的转录组、甲基组学、代谢组学、蛋白质组和微生物组数据 百岁后代(在大约三分之一的样本中从两个时间点产生)。多组学的研究方法 在AIM 1中编译的数据集成将用于发现与EL和Healthy相关的分子图谱 衰老表型，包括延缓或逃脱阿尔茨海默病。与来自的分子轮廓集成 IPSC来源的神经元和肝细胞的弹性功能及分子图谱研究 多个物种的寿命延长将指向机制，并产生候选的小 分子和化合物治疗学。所有生成的数据和独特的生物资源，包括EL- IPSC来源的肝细胞和神经元，将与财团和个人研究人员共享 阿尔茨海默氏症，其他与衰老有关的疾病，以及更一般的衰老的基本机制。

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.