Somatic mutation rates in healthy aging

健康老龄化中的体细胞突变率

• 批准号: 10800911
• 负责人: Gilad David Evrony
• 金额: $ 75.91万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10800911
• 关键词: Age; Aging; Biological Aging; Biological Markers; Blood; Blood specimen; Cancer Prevention Study II; Cells; Clinical; Cytosine; DNA Damage; DNA Sequence Alteration; DNA sequencing; Data; Deamination; Disease; Environmental Risk Factor; Epidemiology; Epigenetic Process; Foundations; Future; Genetic; Genome; Genomics; Germ-Line Mutation; Health; Height; Hematopoiesis; Human; Human body; Individual; Infrastructure; Intervention; Joints; Life Style; Link; Longevity; Longitudinal cohort; Longitudinal cohort study; Masks; Measurement; Measures; Methods; Methylation; Mutagens; Mutation; Outcome; Pattern; Persons; Phenotype; Population; Prevalence; Preventive; Process; Property; Research Design; Resources; Risk; Running; Sampling; Series; Sex Differences; Somatic Mutation; Techniques; Technology; Testing; Time; Tissues; United States; Weight; Woman; Women' s Health; clinical biomarkers; cohort; disability; disorder risk; epidemiology study; epigenetic marker; epigenome; health data; healthy aging; improved; lifestyle factors; men; methylation biomarker; molecular marker; mortality; mortality risk; novel; novel marker; nutrition; predictive marker; sex; tool

PROJECT SUMMARY/ABSTRACT Somatic mutations accumulate over time in every healthy cell, and these mutations have long been hypothesized to be an important contributor to aging. However, many unknowns remain about this fundamental process of aging because only recently have ultra-high fidelity sequencing technologies become available that can detect somatic mutations in bulk poly-clonal samples of healthy cells, such as blood. For example, it is entirely unknown how widely aging-related somatic mutation rates (SMRs) vary among individuals in the population, whether SMRs predict mortality and aging-related disease, whether genetic or environmental modifiers may cause outlier SMRs, and whether SMRs are associated with epigenetic aging of the genome. Notably, no study to date has measured SMRs in large numbers of individuals, and no study has measured SMRs with associated individual health, lifestyle, and exposure data. The Women’s Health Initiative and the Cancer Prevention Study-II Nutrition Cohort are longitudinal studies that present a unique opportunity to study the variability, modifiers, and mechanisms of SMRs in the human population. These cohorts’ > 20 years of longitudinal data and blood samples from > 20 years ago enable this proposal’s first large-scale measurements of SMRs in the human population and the first measurements of SMRs in combination with detailed human health data. Here, we will perform ultra-high fidelity profiling of SMRs and mutational patterns in the blood of 3,000 individuals from these cohorts, which is almost an order of magnitude more individuals than all prior SMR studies combined. This study will directly test several fundamental open questions and hypotheses about SMRs, including how widely SMRs and mutational patterns vary among individuals, whether SMRs vary between sexes, whether there are outlier individuals in the population with identifiable causes for their higher or lower SMR, and whether SMR predicts mortality and aging-related disease. Since prior studies suggest that deamination of methylated cytosines is a significant contributor to SMRs, we will also perform the first joint SMR and methylation profiling of the same individuals to assess the mechanistic relationship between genetic and epigenetic aging of the genome. Apart from achieving the first population-level characterization of SMRs and an improved mechanistic understanding of SMRs, this study may establish SMRs as a novel, clinically useful biomarker for healthy aging. As the population ages and the prevalence of aging-related diseases increases, our study may motivate the use of SMRs as a biomarker for predicting aging-related disease risk, potentially enabling early preventive clinical interventions. This study will further establish a scalable approach for studying SMRs—which reflect the cumulative effect of endogenous and exogenous mutagens over the lifespan—in large cohorts, with potential for significant impact on our understanding of human health and aging.

项目总结/摘要 随着时间的推移，体细胞突变在每个健康细胞中积累，这些突变长期以来一直存在。 被认为是导致衰老的重要因素。然而，关于这一基本面仍有许多未知数， 因为直到最近才有超高保真测序技术可用， 可以检测健康细胞（如血液）的大量多克隆样品中的体细胞突变。例如，它是 完全不知道与衰老相关的体细胞突变率（SMR）在个体之间的差异有多大， 人口，SMR是否预测死亡率和与衰老有关的疾病，无论是遗传的还是 环境修饰剂可能导致离群SMR，以及SMR是否与表观遗传有关 基因组的老化值得注意的是，迄今为止还没有研究测量了大量个体的SMR， 研究测量了SMR与相关的个人健康，生活方式和暴露数据。妇女 健康倡议和癌症预防研究-II营养队列是纵向研究， 研究人群中SMR的变异性、修饰剂和机制的独特机会。 这些队列> 20年的纵向数据和> 20年前的血液样本使这一点成为可能。 该提案首次大规模测量了人群中的SMR， 结合详细的人类健康数据进行SMR测量。在这里，我们将执行超高 来自这些队列的3,000名个体的血液中SMR和突变模式的保真度分析， 几乎比之前所有SMR研究的总和还要多一个数量级。这项研究将直接测试 关于SMR的几个基本的开放问题和假设，包括SMR和突变在多大程度上 模式因个体而异，SMR是否因性别而异， 具有可识别的SMR较高或较低原因的人群，以及SMR是否可预测死亡率， 与衰老有关的疾病。由于先前的研究表明甲基化胞嘧啶的脱氨基是一个重要的生物学过程， 作为SMR的贡献者，我们还将对同一个体进行第一次联合SMR和甲基化分析， 评估基因组的遗传和表观遗传老化之间的机械关系。除了 实现了首次在人口一级对工管关系的定性， SMRs，这项研究可能建立SMRs作为一种新的，临床上有用的生物标志物，健康老龄化。为 随着人口老龄化和与老龄化有关的疾病的患病率增加，我们的研究可能会促使人们使用 SMR作为预测衰老相关疾病风险的生物标志物，可能使早期预防性临床 干预措施。这项研究将进一步建立一个可扩展的方法来研究SMR-这反映了 内源性和外源性诱变剂对寿命的累积效应-在大的队列中， 对我们理解人类健康和衰老有重大影响。