Genome maintenance and human longevity

摘要(项目4) 来自该计划项目(PPG)的证据表明，基因组维护中的缺陷导致 小鼠的早衰。然而，基因组维护对人类长寿的贡献仍有待于 已经成立了。项目4(之前的项目5)的主要目标是将PPG的突破 通过测试以下假设来发现人类状况：基因座上的多态变异与 基因组维持与人类的长寿和健康衰老表型有关。项目4中的研究具有 导致了与人类长寿相关的遗传和表观遗传特征的发现：(1)丰富的 预测会改变参与信号传递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)；以及(2)上调的microRNAs 与对照组相比，百岁老人永生化B细胞和血浆中的miRNAs。有趣的是， 项目1发现，其中一些miRNAs可以诱导细胞保存反应和细胞死亡 在存在未修复的DNA损伤的情况下进行抑制。我们假设一群保护性的 (EPI)基因型在基因组维持基因调控网络中是必要的，以实现异常 人类的长寿。为了证实和扩展我们支持这一假设的观察结果，我们提出了一个 系统的多学科方法来验证长寿相关(Epi)基因签名和 研究潜在的分子机制以确定观察到的阳性的功能相关性 通过在合作的短期细胞培养研究中测试细胞适合性的各种参数来关联 所有其他项目。功能相关的基因变体和miRNAs将被进一步研究，以便在 与Core B合作，在小鼠中对衰老过程中的活体效应进行建模。 在项目4中生成的数据将提供对基因类型之间因果关系的机械理解， MiRNA的表达和相关的表型，可能导致促进生存的干预 以及没有超长寿命遗传倾向的人的健康状况。

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.