CH in Aging and Exceptional Longevity

Project Summary Clonal Hematopoiesis (CH) is characterized by somatic mutations originating from a few hematopoietic stem cell clones. CH is well known to be an age associated phenomenon and is associated with an increased risk of developing hematologic neoplasms, cardiovascular disease and all-cause mortality , but paradoxically is associated with a lower risk of Alzheimer’s disease. The complex relationship between CH, aging and age- related diseases requires a thorough investigation. Cohorts enriched for exceptional longevity and in particular centenarians (age > 95 years), have been extensively studied to gain deep insights into human lifespan as well as healthspan. They exhibit significant delays in mortality and in the incidence of age-related diseases, such as cancer, cardiovascular disease (CVD), and Alzheimers Disease (AD). Our research proposal will investigate CH in a unique population that is enriched for exceptional longevity, focusing on the trajectory of CH during healthy aging, its association with clinical outcomes and protection from age-related diseases. The study will be conducted in two unique Ashkenazi Jewish longevity cohorts at the Albert Einstein College of Medicine. They are well-characterized clinically and have comprehensive genetic, proteomic, and methylomic data available for analysis. Aim 1: Determine the prevalence and mutational spectrum of CH and its relationship with age-related diseases in populations with exceptional longevity. In this aim, the prevalence and mutational spectrum of CH in centenarians, their offspring, and in sex- and age-matched controls will be compared at baseline. We will examine the associations between CH and clinical outcomes. We hypothesize that exceptional longevity is associated with a lower age adjusted CH prevalence, distinct CH mutational patterns and reduced risk of age- related diseases in the presence of CH. Aim 2: Establish the evolution of CH in aging and longevity. We will analyze longitudinal DNA samples to identify incident CH and study changes prospectively in clonal populations over a 5-year period. We hypothesize that the incidence of CH and clonal profiles will differ between offspring and controls. Aim 3: Identify the biological pathways that modify the risk of CH and CH-related diseases. We will conduct targeted and untargeted multi-omic analyses to identify longevity-related genetic variants, proteins and DNA methylation profiles related to CH and its clinical associations. We hypothesize that longevity-related genotypes can afford protection against the emergence of harmful CH variants.