# Blood-based epigenetic instability linked to human aging and disease

## TL;DR

This study identifies stable DNA methylation sites in blood that become disrupted with aging and disease, offering a potential biomarker for early detection of blood cancers and cardiovascular issues.

## Contribution

The study introduces a novel approach to identify epigenetically stable CpG loci in blood and links their disruption to aging and disease progression.

## Key findings

- Methylation instability at stable CpG loci correlates with hematological cancers and treatment dynamics.
- Methylation variability at these loci increases with age and is associated with higher cardiovascular disease risk.
- The study reveals a mechanistic link between methylation dynamics and maladaptive hematopoietic clone expansion.

## Abstract

The abundance, dynamics, and context-dependent heterogeneity of DNA methylation, where a pattern considered abnormal in one cell type may be normal in another, complicate the identification of early methylation changes that drive or signal disease development. This complexity can obscure early markers of increased disease risk, making it challenging to detect and intervene in disease processes at their inception. Here, we report 31,744 CpG loci exhibiting highly consistent methylation profiles in the blood of young, healthy individuals. We assess alterations at these epigenetically stable loci in 8,886 individuals across 29 diverse cohorts, including those with hematological cancers (n = 3159), cardiovascular complications (n = 2788), and healthy controls (n = 2939). Our findings reveal methylation pattern disruption in myeloid and lymphoid malignancies, correlating with clonal burden dynamics and mutation frequency throughout leukemia treatment. In non-cancer cohorts, we observe that methylation levels at epigenetically stable loci become increasingly variable with age, a shift linked to higher cardiovascular disease risk and lower survival rates. This study highlights DNA methylation instability as a blood-based biomarker for both hematological cancer and cardiovascular disease and uncovers a mechanistic link between methylation dynamics and the expansion of maladaptive hematopoietic clones.

DNA methylation heterogeneity and dynamics hinder distinguishing early pathological changes from normal variation. Here, the authors identify stable sites whose disruption is linked to blood cancers, aging, and cardiovascular risk.