# Clonal Hematopoiesis Aging Resiliency Mechanisms

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $1,349,483

## Abstract

Project Summary
With age, dividing cells acquire DNA mutations. A small number of these somatic mutations confer a selective
advantage leading to clonal outgrowth. In blood, this process is termed ‘clonal hematopoiesis’ (CH) which
includes both point mutations in cancer driver genes (eg. clonal hematopoiesis of indeterminate potential
‘CHIP’) and megabase-scale deletions, duplications and copy-neutral loss-of-heterozygosity (eg, mosaic
chromosomal alterations, ‘mCAs’). CH is associated with mortality, infection, cardiovascular disease, cancer
and other aging diseases with differential mutations conferring different risk. CH is commonly found in
extremely aged individuals implying that a set of individuals have resiliency to CH. Here we seek to identify
Clonal Hematopoiesis Aging Resilience Mechanisms (CHARMs). CH clones that expand to make up a larger
proportion of the blood confer worse health outcomes. However, we do not know what factors predict the rate
of clonal expansion, how rate expansion associates with disease outcomes and whether CH confers
differential disease risk across the lifespan. Overall, we hypothesize that CH with higher rates of clonal
expansion confer a greater impact on health and that the propensity to expand has genetic and environmental
underpinnings. A barrier to addressing this gap is a paucity of large-scale collections of longitudinally-sampled
blood. Our team has two recent accomplishments that enable us to address this gap: 1) a survey of CH in
>800,000 genomes and 2) development of a novel computational method to estimate the rate of CH expansion
from a single timepoint rather than requiring serial samples. The project comprises three key aims: In Aim 1,
we will apply a computational method called PACER, which estimates CH expansion rates from a single
genome sequenced blood sample to >1.6 Million individuals. This approach allows for the identification of
inherited genetic factors that confer resilience to CH expansion. In Aim 2, we will focus on the role of circulating
proteins, metabolites, and medications in modulating CH expansion. In vitro and in vivo models will be used to
elucidate the mechanisms underlying these CHARMs. In Aim 3, we seek to comprehensively assess the
impact of CH on health and disease across the entire human lifespan. By studying two large and diverse
cohorts, NIH All of Us (N~750,000) and Vanderbilt BioVU (N~250,000), encompassing individuals that span
the entire lifespan from birth to centenarians, the project will analyze the relationship between CH and aging
diseases. Our multidisciplinary team with deep expertise in CH, human genomics, experimental hematology,
and genetic epidemiology is uniquely poised to accomplish this scientific program. Successful execution of
these aims has the potential to improve risk models to stratify individuals with CH for personalized prevention
interventions. Additionally, each CHARM we identify would be a potential target for therapeutic development.

## Key facts

- **NIH application ID:** 10973752
- **Project number:** 1R01AG088657-01
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Alexander Bick
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,349,483
- **Award type:** 1
- **Project period:** 2024-08-15 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10973752

## Citation

> US National Institutes of Health, RePORTER application 10973752, Clonal Hematopoiesis Aging Resiliency Mechanisms (1R01AG088657-01). Retrieved via AI Analytics 2026-06-15 from https://api.ai-analytics.org/grant/nih/10973752. Licensed CC0.

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