Genome Maintenance and Human Longevity -- AECM

这个项目的主要目标是检验这样一种假设，即基因座上的多态变异涉及到 基因组维持与人类衰老表型的开始和严重程度有关，并且可能与 总体而言，老龄化速度。为了解决这一假设，我们提出了一种发现遗传变异的方法。 参与富含(有益等位基因)或耗尽的基因组维持途径 (有害等位基因)在异常长寿的家庭中。为此，我们计划确定功能 -100基因在5个基因组维护中的SNP单倍型(综合候选基因方法) 与衰老相关表型的关联分析路径，包括异常健康的衰老 正在进行的德系犹太人百岁老人研究队列的个人。候选基因包括所有 已发现可遗传突变与小鼠衰老加速相关的基因以及 与这些“关键基因”相互作用的基因和作用于同一途径的其他基因。以确定 观察到的正关联、候选基因-SNP单倍型的功能相关性将在 在短期细胞培养研究中筛选细胞适合性的各种参数，以提供 洞察它们的生物学意义。然后可以进一步研究功能相关的基因变体 通过在小鼠身上建模，它们在衰老过程中的体内效应。预计结果将提供第一个 有证据表明，导致小鼠过早衰老表型的相同基因的变异是 实际上，在与衰老相关的表型和寿命的人群中进行隔离。这将有助于 将在方案项目中获得的结果转化为有针对性和个性化的干预策略， 最终提高老年人口的生活质量。

The main objective of this project is to test the hypothesis that polymorphic variation at loci involved in genome maintenance relates to the onset and severity of aging phenotypes in humans and, possibly, to aging rate in general. To address this hypothesis, we propose an approach to discover genetic variants involved in genome maintenance pathways that are either enriched (beneficial alleles) or depleted (deleterious alleles) in families with exceptional longevity. For this purpose, we plan to identify functional SNP haplotypes (comprehensive candidate gene approach) of -100 genes in 5 genome maintenance pathways for association analysis with aging-related phenotypes, including exceptionally healthy aging, in individuals of an ongoing Ashkenazi Jewish Centenarian Study Cohort. The candidate genes include all genes in which heritable mutations have been found associated with accelerated aging in mice as well as genes interacting with these "key genes" and other genes acting in the same pathway. To ascertain the functional relevance of observed positive associations, candidate gene-SNP haplotypes will be modeled in cells and screened for various parameters of cellular fitness in short term cell culture studies to provide insight into their biological significance. Functionally relevant gene variants can then be further studied for their in vivo effect during aging by modeling them in the mouse. The results are expected to provide the first evidence that variants of the same genes found to give rise to premature aging phenotypes in the mouse are actually segregating in human populations with aging-related phenotypes and life span. This will help to translate the results obtained in the program project into targeted and personalized intervention strategies, ultimately leading to improved quality of life of the elderly population.