Genome maintenance and human longevity

摘要（项目4） 来自该计划项目（PPG）的证据表明，基因组维护缺陷导致 小鼠的过早衰老。然而，基因组维持对人类寿命的贡献仍有待进一步研究。 确立了习项目4（前项目5）的主要目标是将PPG的突破转化为 通过检验假设，在涉及人类的基因座多态性变异， 基因组维持与人类的长寿和健康衰老表型有关。研究项目4 导致发现与人类寿命相关的遗传和表观遗传特征：（1）富集 预测会改变参与信号传导和修复的蛋白质的功能和/或表达的罕见变体 与对照组相比，百岁老人的DNA双链断裂（DSB）;（2）微RNA上调 与对照组相比，在百岁老人的永生化B细胞和血浆中检测到了miRNAs。有趣的是， 项目1发现这些miRNAs中的一些可诱导细胞保存反应和细胞死亡 在未修复的DNA损伤的存在下抑制。我们假设一群保护性的 （epi）基因组中的基因型维持基因调控网络是实现异常 人类的长寿为了证实和扩展我们的观察，支持这一假设，我们提出了一个 系统的多学科方法来验证长寿相关（epi）基因型签名， 研究潜在的分子机制，以确定所观察到的阳性反应的功能相关性。 通过在短期细胞培养研究中合作测试细胞适应性的各种参数， 所有其他项目。功能相关的基因变异和miRNAs将被进一步研究， 通过与Core B合作在小鼠中对其进行建模，研究衰老过程中的体内效应。的信息 在项目4中产生的将提供对基因型之间因果关系的机械理解， miRNA表达和相关表型，可能导致促进生存的干预措施 和健康的人没有遗传倾向，以特别长寿。

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 longevity, however, remains to be established. The main objective of Project 4 (Previous Project 5) 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 relates to longevity and healthy aging phenotypes in humans. Research in Project 4 has led to the discovery of genetic and epigenetic signatures associated with human longevity: (1) enrichment of rare variants predicted to change the function and/or expression of proteins involved in signaling and repair of DNA double strand breaks (DSBs) in centenarians as compared to controls; and (2) upregulated microRNAs (miRNAs) in both immortalized B-cells and plasma of centenarians as compared to controls. Interestingly, some of these miRNAs were found, by Project 1, to induce cell preservation responses and cell death repression in the presence of unrepaired DNA damage. We hypothesize that a cluster of protective (epi)genotypes in the genome maintenance gene regulatory network is necessary to achieve exceptional longevity in humans. To confirm and extend our observations that support this hypothesis, we propose a systematic multidisciplinary approach to validate the longevity-associated (epi)genotype signatures and investigate the underlying molecular mechanisms to ascertain the functional relevance of observed positive associations by testing various parameters of cellular fitness in short-term cell culture studies in collaboration with all other Projects. Functionally relevant gene variants and miRNAs will then be further studied for their in vivo effect during aging by modeling them in the mouse in collaboration with Core B. The information generated in Project 4 will provide a mechanistic understanding of the causal relationships between genotypes, miRNA expression, and the associated phenotypes, potentially leading to interventions that promote survival and health in people without genetic predisposition to exceptional longevity.