# Clonal hematopoiesis in human aging and disease

> **NIH NIH DP2** · STANFORD UNIVERSITY · 2020 · $2,365,500

## Abstract

Diseases of aging such as heart disease and stroke are usually thought to occur due to a
combination of hereditary and environmental influences. Recently, we discovered that somatic
mutations (DNA alterations acquired after birth) in blood cells may be another factor that
contributes to these diseases. Approximately 15-20% of people age 70 or older carry a cancer-
associated somatic mutation in a substantial proportion of their blood cells, even though the vast
majority do not have cancer. This condition has been termed “clonal hematopoiesis of
indeterminate potential”, or CHIP. It most commonly arises due to loss-of-function mutations in
regulators of DNA methylation. CHIP carriers develop blood cancers at a higher rate than the
general population, which is expected because it represents the “first-hit” on the path to cancer.
Surprisingly, CHIP is also associated with increased all-cause mortality and higher risk of
developing non-neoplastic diseases, like atherosclerotic cardiovascular disease. Mechanistically,
ablation of these genes in hematopoietic cells increases atherosclerosis in mouse models due to
heightened transcription of inflammatory genes in the mutated innate immune cells. CHIP is the
first example of somatic variation acting as a causal factor for common diseases of aging apart
from cancer, but a detailed understanding of its consequences for human health is lacking.
Because of its link to immune function, inflammation, and aging, we hypothesize that CHIP will
also influence many other diseases of aging. Here, we will use human cohorts with genetic
sequencing data from 100,000s of people to identify novel disease associations of CHIP. We will
use innovative approaches to interrogate sequence data from these datasets to identify factors
that correlate with the rate of growth of mutant clones. We will also leverage the information
collected in these biobanks to improve our ability to predict who will suffer adverse consequences,
which is a major barrier to developing clinical interventions for CHIP. Finally, we will use tissue
samples from humans with CHIP to understand the effect of these mutations on immune cell
function and to address questions about tissue macrophage ontogeny in humans for the first time.
These studies will broadly advance our knowledge about the causes and consequences of this
common, newly described condition of aging.

## Key facts

- **NIH application ID:** 10001998
- **Project number:** 1DP2HL157540-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Siddhartha Kumar Jaiswal
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,365,500
- **Award type:** 1
- **Project period:** 2020-08-26 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001998

## Citation

> US National Institutes of Health, RePORTER application 10001998, Clonal hematopoiesis in human aging and disease (1DP2HL157540-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10001998. Licensed CC0.

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