Somatic mutation rates in healthy aging - 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.
