Genome maintenance and human longevity

基因组维护和人类长寿

• 批准号: 8742955
• 负责人: YOUSIN SUH
• 金额: $ 51.86万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8742955
• 关键词: Age; Aging; Apoptosis; Ashkenazim; B-Lymphocytes; Biological Preservation; Cell Aging; Cell Culture System; Cell Culture Techniques; Cell Death; Cells; Centenarian; Collaborations; Computer Simulation; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Resequencing; Defect; Development; Disease; Epigenetic Process; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genome; Genome engineering; Genomic Instability; Genotype; Health; Human; IGF1 gene; Intervention; Longevity; Maintenance; MicroRNAs; Modeling; Molecular; Mus; Mutagens; Mutation; Outcome; Pathway interactions; Phenotype; Plasma; Premature aging syndrome; Prevention therapy; Regulator Genes; Repression; Research; Signal Transduction; Testing; Translating; Validation; Variant; age related; base; cohort; fitness; follower of religion Jewish; genetic variant; healthy aging; human FRAP1 protein; in vivo; interdisciplinary approach; interest; mouse model; novel strategies; prevent; programs; protein expression; rare variant; repaired; response; tool; validation studies

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.

摘要（项目4） 该计划项目（PPG）的证据表明，基因组维持原因的缺陷 小鼠过早衰老。然而，基因组维持对人寿命的贡献仍然是 已确立的。项目4的主要目标（以前的项目5）是翻译PPG的突破 通过检验以下假设，即与基因座的多态性变化有关 基因组维持与人类的寿命和健康的衰老表型有关。项目4中的研究 导致发现与人类长寿相关的遗传和表观遗传学特征：（1）富集 预计将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）上调的microRNA （miRNA）与对照组相比，百岁老人的永生B细胞和等离子体。有趣的是， 通过项目1发现了其中一些miRNA，以诱导细胞保存反应和细胞死亡 在没有修复的DNA损伤的情况下进行抑制。我们假设一群保护性 （EPI）基因组维持基因调节网络中的基因型对于实现特殊 人类长寿。为了确认并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寿命相关（EPI）基因型特征和 研究潜在的分子机制，以确定观察到的阳性的功能相关性 通过在合作中的短期细胞培养研究中测试细胞适应性的各种参数来进行关联 与所有其他项目。然后将进一步研究与功能相关的基因变异和miRNA 通过与CoreB合作将衰老过程中的体内效应在鼠标中进行建模。 项目4中产生的将提供对基因型之间的因果关系的机械理解， miRNA表达和相关的表型，可能导致促进生存的干预措施 和没有遗传倾向的人的健康。