Genetics of extreme human longevity

人类极端长寿的遗传学

• 批准号: 10714391
• 负责人: Zhengdong Zhang
• 金额: $ 59.22万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714391
• 关键词: ATAC-seq; Affect; Age; Aging; American; Biological Assay; Biological Process; Blood; Blood Cells; Cells; Centenarian; Chronic Disease; Clinical Trials; Complex; Country; DNA Sequence Alteration; Data Set; Disease; Drug Screening; Drug Targeting; Economics; Elasticity; Elderly; Environmental Risk Factor; Family history of; Frequencies; Funding; Gene Frequency; Genes; Genetic; Genetic Epistasis; Genetic Risk; Genome; Goals; Health; Healthcare Systems; Heritability; Human; Individual; Intervention; Knowledge; Longevity; Maintenance; Measures; Methods; Mission; Modeling; Morbidity - disease rate; Mutagens; Mutation; Organism; Pathology; Pathway interactions; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Population; Population Study; Public Health; Regulator Genes; Regulatory Pathway; Research; Risk; Risk Factors; Signal Pathway; Stress; Testing; Tissues; United States; Untranslated RNA; Variant; age related; aged; aging population; burden of illness; causal variant; cell type; cohort; comparison control; disability; drug discovery; exome; exome sequencing; follower of religion Jewish; functional gain; gene regulatory network; genetic architecture; genetic variant; genome wide association study; global health; healthy aging; human old age (65+); insight; machine learning framework; model organism; mouse model; multi-ethnic; novel strategies; novel therapeutics; prevent; rare variant; single molecule; single-cell RNA sequencing; statistics; success; therapeutic target; therapy development; trait; transcription factor; virtual

PROJECT SUMMARY/ABSTRACT The world's population is aging. Since most of older people have at least one but more commonly multiple debilitating chronic diseases, this demographic shift will result in a dramatic increase in morbidity and a burden on our healthcare systems. This U19 proposes an integrated study to test a new approach for developing therapies for age-related diseases. Rather than focusing on individual diseases, we explore genetic differences between successfully aged, healthy centenarians and control individuals with no family history of extreme longevity. Our long-term goal is to use gene variants found enriched in the centenarian genome as potential targets for developing drugs that prevent, delay onset and progression, and possibly even revert many of the multiple age-related diseases. The overall objective of Project 1 is to elucidate genetic variants enriched in the centenarian genome, based on our central hypothesis that rare variants constitute an important part of the genetic architecture of human aging and influence human lifespan on the polygenic risk background defined by common variants. This hypothesis has been formulated on the basis of our recent whole exome sequencing study of longevity using the Einstein centenarian cohort and will be tested by pursuing three specific aims: (I) To identify and replicate rare variant-based longevity association; (II) To develop an integrated common variant- based polygenic score of longevity; and (III) To study gene regulatory pathways associated with extreme human longevity using single-cell and single-molecule analyses of centenarian blood cells. The research rationale for Project 1 is that such variants can be functionalized by Projects 2 and 3 and used as targets for drug screening assays to be developed by Project 4. Our proposed research will have an important positive impact: better understanding of the genetics of extreme human longevity provided by our study of centenarian cohorts will enable us to identify novel therapeutics that slow or mitigate aging and all associated diseases.

项目摘要/摘要 世界人口正在老龄化。因为大多数老年人至少有一个，但更常见的是多个 这种人口结构的转变将导致发病率和负担的急剧增加，使人衰弱的慢性疾病 在我们的医疗系统上。该U19提出了一项综合研究，以测试一种新的开发方法 与年龄有关的疾病的治疗。我们探讨的不是个别疾病，而是遗传差异。 在成功老龄化、健康的百岁老人和没有极端家族史的对照组之间 长寿。我们的长期目标是利用在百岁老人基因组中发现的基因变异作为潜在的 开发预防、延缓发病和进展的药物的目标，甚至可能逆转许多 多种与年龄相关的疾病。项目1的总体目标是阐明富含在 百岁老人基因组，基于我们的中心假设，即稀有变异构成 人类衰老的遗传结构和影响人类寿命的多基因风险背景 常见的变种。这一假说是基于我们最近的整个外显子组测序提出的 使用爱因斯坦百岁老人队列研究长寿，并将通过追求三个具体目标进行测试：(I) 确定和复制罕见的基于变异的长寿关联；(Ii)开发一个综合的共同变异-- 基于长寿的多基因评分；以及(Iii)研究与极端人类相关的基因调控途径 使用百岁血细胞的单细胞和单分子分析来延长寿命。研究的基本原理是 项目1是这样的变体可由项目2和项目3功能化，并用作药物筛选的目标 测试将由项目4开发。我们提议的研究将产生重要的积极影响： 我们对百岁老人遗嘱的研究提供了对人类极端长寿的遗传学的理解 使我们能够确定延缓或减轻衰老和所有相关疾病的新疗法。