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: 10017131
• 负责人: THOMAS T PERLS
• 金额: $ 430.23万
• 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017131
• 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; 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），甚至更高的半居民（105-109岁） YRS）和超级中心人（110岁以上）不仅是异常长的寿命，而且是他们的寿命 女性生育能力较长和对与衰老有关的残疾和病毒的抵抗力，例如阿尔茨海默氏病， 心脏病，中风，糖尿病和癌症。他们的后代还暴露了延迟的发病率和较低的死亡率 与他们的出生队列相比。在非人类物种中，包括裸mole大鼠在内的啮齿动物也有 与其他体重相似的哺乳动物相比，它们的寿命变化引起了人们的注意。蛋白质组学 与百岁老人和综合转录组和蛋白质组学相关的签名 NMR中的数据表明，对这些人和动物产生的多种OMIC数据的综合分析 缓慢衰老和对衰老相关疾病的抗性模型可以告知我们有关生物学机制 这些生存和健康优势是预防疾病的潜在疗法的基础 例如阿尔茨海默氏症。该提案的UH2和UH3阶段的两个具体目的是平行的。目标1：在UH2中 阶段，新英格兰一百派研究和爱因斯坦一百派和后代研究将建立 标准化的表型数据和生物样品收集方案，用于亲自访问700名受试者 每项研究（n = 1400）。详细的认知功能测试将确定有问题的存在或不存在 阿尔茨海默氏症。表型协议将与长寿财团一百居住 项目（n = 350），以便可以将其数据添加到这项工作中，以使总样本为1,750。世界一流的 多学科团队将计划多摩斯数据生成以及分析和翻译工作 在AIM 2中。这些努力将通过比较转录组，蛋白质组学和微生物研究的相似 非人类的哺乳动物种类范围很大，并通过创建EL特异性IPSC的库 这将分化为无限数量的肝细胞和神经元。目标2：在UH3阶段，我们将 产生转录组，甲基甲基学，代谢组学，蛋白质组学和微生物组数据，来自百岁老人和 百年纪念的后代（大约三分之一的样本中的两个时间点产生）。多运动的方法 AIM 1中编译的数据集成将用于发现与EL和健康相关的分子曲线 衰老表型，包括延迟或逃避阿尔茨海默氏病。与来自分子曲线的集成 使用IPSC衍生的神经元和肝细胞以及分子谱进行弹性的功能研究 与多种物种的寿命增加有关，将指向机制并产生候选者小 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财团和研究人员共享 阿尔茨海默氏症，其他与衰老有关的疾病，更普遍地是衰老的基本机制。