AS720 - Role of somatic mutation rate in healthy aging

Investigator Names and Contact Information

Gilad Evrony (Gilad.evrony@nyulangone.org)

Introduction/Intent

Discovery of new disease-predictive molecular biomarkers of aging is of critical importance for advancing clinical medicine towards a model of early intervention and pre-symptomatic prevention of aging-related diseases. A robust and easy-to-measure molecular marker that stratifies individuals into those with high versus low biological to chronological age ratios would enable prediction of aging-related disease risk. This stratification would in turn enable targeting of clinical interventions and could serve as an intermediate endpoint for the development of therapeutics. A novel molecular marker of aging would also enable new mechanistic studies of aging as well as identification of endogenous (i.e. genetic) and exogenous (i.e. environmental) factors that increase or decrease aging rates.

Ultra-high fidelity DNA sequencing technologies developed in the past 5 years by our groups and others have led to a remarkable discovery: somatic mutations accumulate in all healthy cells of the body at an approximately linear rate with age (~10-20 mutations per cell per year, depending on the cell lineage). The somatic mutation rate (SMR) of healthy cells is therefore a candidate novel molecular biomarker of aging. Furthermore, it is a direct measure of genome instability, which has long been hypothesized as a cause of aging.

However, SMRs of healthy cells have not yet been studied systematically at a scale that would establish the SMR as a molecular marker of aging and aging-related disease risk. To date, SMRs of healthy cells have only been measured in very small numbers of individuals (< 100 published total), due to the novelty of the ultra-high fidelity sequencing technologies required. The absence of large-scale SMR studies has precluded the evaluation of SMRs as a potential new biomarker of aging and aging-related disease risk. Specifically, two critical unknowns about SMR must be answered to establish it as a biomarker of aging with potential clinical utility:

Specific Aims

Aim 1) What are the extent and determinants of variability in SMRs among individuals in the population?

Aim 2) Do SMRs predict the risk of all-cause mortality, and aging-related disease? In this project, we will address these two key questions by ultra-high fidelity profiling of SMRs in blood samples from a very well profiled cohort (WHI) with detailed longitudinal aging and disease-related data.

Aim 3) In a third aim, we will study SMRs together with epigenetic biomarkers of aging in the same individuals to evaluate the relative robustness and predictive ability of SMRs for overall mortality and aging-disease risk, and because comparisons of these two biomarkers of aging in the same individuals may reveal mechanistic insight into molecular aging of the genome.

These three aims will directly test the interrelated hypotheses that SMRs: 1) are variable in the human population, 2) predict aging-related disease risk, and, 3) are correlated with aging-associated changes in the epigenome.

As the accumulation of mutations with time is the consequence of DNA damage from exogenous and endogenous mutagens and DNA repair, large-scale measurements of SMR will further establish its ability to serve as biomarker reflecting the impacts of these processes over a lifetime. This project’s critical assessment of SMRs as a potentially clinically meaningful biomarker for aging and aging-related disease risk, combined with our ability to interrogate detailed demographic, medical and exposure history over decades, has the potential to enable future studies of biological aging. Finally, defining how SMRs relate to epigenomic aging signatures will elucidate mechanisms by which the genome and epigenome change together over the lifetime.