Genetics of extreme human longevity

项目总结/摘要 世界人口正在老龄化。由于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急剧增加， on our healthcare健康systems系统.本U19提出了一项综合研究，以测试一种新的方法， 治疗与年龄有关的疾病。我们不是关注个别疾病，而是探索遗传差异 在成功老年的健康百岁老人和没有极端肥胖家族史的对照个体之间， 中心blog我们的长期目标是利用在百岁老人基因组中发现的丰富基因变体作为潜力 开发药物的目标，预防，延迟发病和进展，甚至可能逆转许多 多种与年龄有关的疾病。项目1的总体目标是阐明基因组中富集的遗传变异， 百岁老人基因组，基于我们的中心假设，即罕见的变异构成了一个重要组成部分， 人类衰老的遗传结构，并在多基因风险背景下影响人类寿命， 常见变体这一假设是基于我们最近的全外显子组测序而提出的 这项研究使用爱因斯坦百岁老人队列，并将通过追求三个具体目标进行测试： 识别和复制基于罕见变异长寿关联;（II）开发一个整合的常见变异- 基于多基因评分的长寿;（III）研究与极端人类相关的基因调控途径 使用百岁老人血细胞的单细胞和单分子分析。研究的基本原理 项目1是这样的变体可以通过项目2和3功能化，并用作药物筛选的靶标 由项目4开发的试验。我们提出的研究将产生重要的积极影响：更好地 我们对百岁老人群体的研究提供了对人类极端长寿遗传学的理解， 使我们能够确定新的治疗方法，减缓或减轻衰老和所有相关疾病。

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.