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

A set of 31,744 CpG loci exhibit highly consistent methylation profiles in the blood of young, healthy individuals.

• These loci were identified as epigenetically stable reference points for detecting disease-associated methylation changes.
• The identification relied on blood samples from young, healthy individuals as the baseline.
• These stable loci were then used to assess alterations across 8,886 individuals in 29 diverse cohorts.

Methylation pattern disruption at epigenetically stable loci was observed in both myeloid and lymphoid malignancies.

• The study included hematological cancer cohorts with n=3,159 individuals.
• Disruption at stable loci correlated with clonal burden dynamics throughout leukemia treatment.
• Methylation disruption also correlated with mutation frequency during leukemia treatment.
• Both myeloid and lymphoid malignancy subtypes showed this pattern of disruption.

Methylation levels at epigenetically stable loci become increasingly variable with age in non-cancer cohorts.

• This age-associated increase in methylation variability was observed in non-cancer individuals.
• Non-cancer cohorts included cardiovascular complication patients (n=2,788) and healthy controls (n=2,939).
• The shift in methylation variability with age was identified as a distinct phenomenon from mean methylation level changes.
• This increasing variability represents epigenetic instability as a function of aging.

Age-associated methylation variability at epigenetically stable loci is linked to higher cardiovascular disease risk.

• The increase in methylation variability with age was associated with elevated cardiovascular disease risk.
• This association was observed across cohorts including those with cardiovascular complications (n=2,788).
• The study assessed 29 diverse cohorts in total, spanning hematological cancers, cardiovascular complications, and healthy controls.

Age-associated methylation variability at epigenetically stable loci is linked to lower survival rates.

• Higher methylation instability was associated with lower survival rates in non-cancer cohorts.
• This finding was observed in the context of cardiovascular disease cohorts.
• The total study population assessed was 8,886 individuals across 29 cohorts.

A mechanistic link was uncovered between methylation dynamics and the expansion of maladaptive hematopoietic clones.

• The study identified a connection between methylation instability and clonal hematopoiesis.
• Clonal burden dynamics throughout leukemia treatment correlated with methylation disruption at the identified stable loci.
• This mechanistic link connects epigenetic instability to the biology of aberrant clonal expansion in blood.

The study assessed methylation alterations at epigenetically stable loci across 29 diverse cohorts totaling 8,886 individuals.

• Cohorts included hematological cancer patients (n=3,159), cardiovascular complication patients (n=2,788), and healthy controls (n=2,939).
• The 29 cohorts represented diverse disease and demographic contexts.
• This large multi-cohort design enabled cross-disease comparison of methylation instability signatures.

DNA methylation instability at blood-based epigenetically stable loci is highlighted as a biomarker for both hematological cancer and cardiovascular disease.

• The same set of 31,744 stable CpG loci showed utility across cancer and non-cancer disease contexts.
• Disruption was detectable in blood, making this a blood-based biomarker approach.
• The complexity of context-dependent methylation heterogeneity was addressed by focusing on loci that are stable in young healthy blood.
• This approach aims to enable early detection of and intervention in disease processes.