# CH in Aging and Exceptional Longevity

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2024 · $1,085,789

## Abstract

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.

## Key facts

- **NIH application ID:** 10973774
- **Project number:** 1R01AG088659-01
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Sofiya Milman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,085,789
- **Award type:** 1
- **Project period:** 2024-08-15 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10973774

## Citation

> US National Institutes of Health, RePORTER application 10973774, CH in Aging and Exceptional Longevity (1R01AG088659-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10973774. Licensed CC0.

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