Blood cell composition explains substantial variation in DNA methylation age
Cell counts explain less variation in age acceleration and only modestly affect its links to mortality and 176 incident health outcomes.
Genome medicine · 2 Oct · Jonkman TH, Richmond A, BIOS Consortium et al.
In a human study analyzing 4,058 samples, researchers evaluated how blood cell composition influences DNA methylation age and age acceleration across six first- and second-generation epigenetic clocks. Using a collinearity-robust principal component analysis method, the team found that cell counts accounted for up to 53% of the variation in DNA methylation age, driven strongly by the ratio between naive and memory T cells. In contrast, cell composition explained up to 21% of the variation in age acceleration, with second-generation clocks primarily tied to neutrophil levels. The team validated these patterns using artificial cell mixtures. Across a separate dataset of 18,859 individuals, cell composition caused only modest attenuation in the associations between age acceleration and 176 incident health outcomes, indicating that cell shifts contribute minimally to these disease associations.
Why it matters
The findings show that DNA methylation age and age acceleration reflect distinct biological processes. They clarify that immune cell shifts primarily influence raw epigenetic age estimates rather than disease-predictive age acceleration.
Caveats
The findings rely on observational human data, and the attenuation of disease risk associations by cell composition remained modest.
The paper
Blood cell composition reveals distinct biological interpretation of DNA methylation age and age acceleration
Jonkman TH, Richmond A, BIOS Consortium et al.
Genome medicine
doi.org/10.1186/s13073-026-01751-6