Genetic control of genome maintenance in human aging and longevity

摘要（项目4） 来自该计划项目（PPG）的证据表明，基因组维护的缺陷会导致早产儿 衰老的老鼠然而，基因组维持对人类衰老和长寿的贡献仍有待进一步研究。 确立了习项目4的主要目标是将PPG的突破性发现转化为 人类的情况，通过测试的假设，多态性变异的基因座参与基因组的维护 (GM)通过改变转基因基因功能网络，有助于人类衰老和长寿。研究 项目4发现了与长寿相关的基因组维持的人类遗传特征 和衰老：1）预测改变参与信号传导的蛋白质功能的稀有编码变体的富集 与对照组相比，百岁老人的DNA损伤和修复; 2）常见非编码区的富集 预测改变参与信号传导和修复以及细胞反应的基因表达的变体 许多与年龄有关的疾病，包括心血管疾病、神经退行性疾病、 疾病和广泛的其他慢性疾病和病症。我们的研究结果提供了强有力的证据， 基因组维持的遗传调节可以对寿命产生有益或有害的影响， 人类的健康状况。我们必须更清楚地了解功能性遗传控制 基因组的维护，塑造人类衰老和长寿的更好的策略，以促进健康寿命。 本提案中概述的实验正是通过研究机械联系来实现这一目标的 通过创新的研究策略， 结合人类基因发现、数据挖掘和整合、高通量技术和细胞模型 系统.这个项目的最终影响在于它有可能揭示转基因作为一种基本机制， 人类衰老，并作为多种年龄相关疾病的治疗靶点， 1、2和3以及核心B。

ABSTRACT (PROJECT 4) Evidence from this program project (PPG) demonstrated that defects in genome maintenance cause premature aging in mice. The contribution of genome maintenance to human aging and longevity, however, remains to be established. The main objective of Project 4 has been to translate the PPG’s breakthrough discoveries into the human situation by testing the hypothesis that polymorphic variation at loci involved in genome maintenance (GM) contributes to aging and longevity in humans by altering the GM gene functional networks. Research in Project 4 has led to the discovery of human genetic signatures of genome maintenance associated with longevity and aging: 1) enrichment of rare coding variants predicted to change the function of proteins involved in signaling and repair of DNA damage in centenarians as compared to controls; and 2) enrichment of common non-coding variants predicted to change the expression of genes involved in signaling and repair of, and cellular response to, DNA damage in numerous age-related diseases, including cardiovascular disease, neurodegenerative diseases and a wide range of other chronic diseases and conditions. Our results provide strong evidence that genetic modulation of genome maintenance can exert either beneficial or deleterious effects on lifespan and healthspan in humans. It is imperative that we develop a clearer understanding of the functional genetic control of genome maintenance that shapes human aging and longevity for better strategies to promote healthspan. The experiments outlined in this proposal are aimed at exactly this goal by investigating the mechanistic link between genetic variation in GM genes, longevity, and healthspan through an innovative research strategy combining human genetic discovery, data mining and integration, high-throughput technologies, and cell model systems. The ultimate impact of this project lies in its potential to reveal GM as fundamental mechanisms of aging in humans and as therapeutic targets for multiple age-related diseases in close collaboration with Projects 1, 2, and 3, and Core B.