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.

项目摘要/摘要 在每个健康细胞中，体细胞突变会随着时间的流逝而积累，这些突变长期以来一直是 假设是衰老的重要因素。但是，关于这个基本的许多未知数仍然存在 衰老过程，因为直到最近才有超高的忠诚测序技术可用 可以检测健康细胞（例如血液）的散装多链样品中的体细胞突变。例如，是 完全未知与衰老相关的体细胞突变率（SMR）在个体中有多不同 人口，SMR是否预测死亡率和与衰老有关的疾病，无论是遗传还是 环境修饰符可能会导致离群值SMR，以及SMR是否与表观遗传相关 基因组的衰老。值得注意的是，迄今为止还没有研究大量个人的SMR，没有 研究已经测量了与相关的个人健康，生活方式和暴露数据的SMR。女人的 健康计划和预防癌症研究-II营养队列是纵向研究， 研究人口中SMR的可变性，修饰符和机制的独特机会。 这些队列> 20年前的20年纵向数据和血液样本启用 提案对人口中SMR的首次大规模测量和第一个 SMR的测量与详细的人类健康数据结合使用。在这里，我们将执行超高 SMR的忠诚分析和来自这些队列中3,000名个人的血液中的突变模式，这是 几乎一个数量级的个体比所有先前的SMR研究都多。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和突变程度如何 个体之间的模式各不相同，SMR在性别之间是否有所不同，是否有异常值 具有可识别原因较高或更低SMR的人口，SMR预测死亡率和 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都很重要 SMR的贡献者，我们还将执行同一个人的第一个关节SMR和甲基化分析 评估基因组的遗传和表观遗传衰老之间的机械关系。除了 实现SMR的第一个人口级特征，并提高了对机械的理解 SMRS，这项研究可能会将SMRs建立为一种新型的，临床上有用的生物标志物，用于健康衰老。作为 人口年龄和与衰老有关的疾病的患病率增加，我们的研究可能会激发使用 SMR是预测与衰老相关疾病风险的生物标志物，有可能实现早期预防性临床 干预措施。这项研究将进一步建立一种可扩展的研究SMR的方法，这反映了 内源性和外源性诱变剂在整个寿命中的累积作用 - 在大型同类中，潜力 为了对我们对人类健康和衰老的理解产生重大影响。