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

确定百岁老人的保护性组学特征并将其转化为预防和治疗策略

• 批准号: 10678171
• 负责人: THOMAS T PERLS
• 金额: $ 499.8万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678171
• 关键词: Address; Age; Age of Onset; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Animal Model; Attention; Biocompatible Materials; Biological; Biological Assay; Biological Process; Birth; Cardiovascular system; Case Study; Cell Line; Cells; Centenarian; Cognitive; Collection; Complex; Data; Development; Diabetes Mellitus; Disease; Enrollment; Exhibits; Generations; Genetic; Health; Heart Diseases; Hepatocyte; Human; Individual; Induced pluripotent stem cell derived neurons; Knowledge; Lead; Libraries; Longevity; Malignant Neoplasms; Mammals; Medicine; Methods; Modeling; Mole Rats; Molecular; Molecular Profiling; Morbidity - disease rate; Multiomic Data; Neurons; New England; Onset of illness; Pathway interactions; Persons; Phase; Phenotype; Preventive; Proteomics; Protocols documentation; Research; Research Personnel; Resistance; Resources; Rodent; Sample Size; Sampling; Standardization; Stroke; Survivors; Testing; Therapeutic; Time; Tissues; Translating; Translations; Variant; Visit; bioinformatics tool; cell type; cognitive function; cohort; college; comparative; data integration; disability; female fertility; flexibility; healthy aging; human model; induced pluripotent stem cell; metabolomics; methylomics; microbiome research; molecular phenotype; mortality; multidisciplinary; novel therapeutics; offspring; phenotypic data; prevent; proteomic signature; resilience; resistance mechanism; sample collection; small molecule; tool; transcriptomics

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.

项目摘要。百岁老人（年龄 >100 岁），甚至半超级百岁老人（年龄 105-109 岁） 岁）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，还因为他们 女性生育能力更长，并且能够抵抗与衰老相关的残疾和疾病，例如阿尔茨海默氏病， 他们的后代也表现出延迟的发病率和较低的死亡率。 与非人类物种相比，包括裸鼹鼠在内的啮齿类动物也出现了这种情况。 与其他具有相似蛋白质组的哺乳动物相比，它们的寿命差异引起了人们的关注。 与百岁老人的极端长寿（EL）相关的特征以及整合的转录组和蛋白质组 核磁共振数据表明，对这些人类和动物产生的多个组学数据进行综合分析 缓慢衰老和抵抗衰老相关疾病的模型可以告诉我们以下生物机制： 这些生存和健康优势的基础，以及最终预防疾病的潜在疗法 例如阿尔茨海默病，与该提案的 UH2 和 UH3 阶段并行：在 UH2 中。 阶段，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本采集方案，用于对来自 700 名受试者的亲自访问 每项研究（n=1400）将确定是否存在可能的认知功能。 阿尔茨海默氏症的表型分析方案将与长寿联盟的百岁老人使用的相同。 项目 (n=350)，这样他们的数据就可以添加到这项工作中，样本总数达到 1,750 A 世界级。 多学科团队将规划要执行的多组学数据生成、分析和翻译工作 目标 2。这些努力将同时进行比较转录组学、蛋白质组学和微生物组学研究 寿命差异很大的非人类哺乳动物物种，并通过创建 EL 特异性 IPSC 库 目标 2：在 UH3 阶段，我们将分化为无限数量的肝细胞和神经元。 生成来自百岁老人的转录组学、甲基组学、代谢组学、蛋白质组学和微生物组数据 百岁后代（从大约三分之一的样本中的两个时间点生成）。 目标 1 中编译的数据集成将用于发现与 EL 和健康相关的分子谱 衰老表型，包括延迟或逃避阿尔茨海默病与分子谱的整合。 使用 iPSC 衍生的神经元和肝细胞以及分子谱进行弹性功能研究 与多个物种寿命延长相关的机制将指向机制并产生候选小分子 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联盟和个人研究人员共享 阿尔茨海默氏症、其他与衰老相关的疾病以及更普遍的衰老的基本机制。