Genome Maintenance and Human Longevity -- AECM

本项目的主要目的是检验以下假设： 基因组维持与人类衰老表型的发生和严重程度有关， 总的来说，老化率。为了解决这一假设，我们提出了一种发现遗传变异的方法 参与基因组维持途径的富集（有益等位基因）或耗尽 （有害等位基因）在家庭中具有特殊的长寿。为此，我们计划确定功能 5个基因组维护中约100个基因的SNP单倍型（综合候选基因方法） 与衰老相关表型的关联分析途径，包括异常健康的衰老， 一个正在进行的德系犹太百岁老人研究队列的个体。候选基因包括所有 在小鼠中发现与加速衰老相关的可遗传突变的基因，以及 与这些"关键基因"相互作用的基因以及在同一途径中起作用的其他基因。查明 观察到的正相关的功能相关性，候选基因-SNP单倍型将在 细胞，并在短期细胞培养研究中筛选细胞适合度的各种参数，以提供 了解它们的生物学意义。然后可以进一步研究功能相关的基因变异， 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，在小鼠中发现的引起过早衰老表型的相同基因的变体， 实际上在人群中与衰老相关的表型和寿命分离。这将有助于 将项目中获得的结果转化为有针对性的个性化干预策略， 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.