Blood cell composition reveals distinct biological interpretation of DNA methylation age and age acceleration.

Blood cell composition accounts for up to 53% of variation in DNA methylation age, with distinct influences on epigenetic clock measures and biological processes.

• Why it matters: Understanding the biological basis of epigenetic clocks is crucial for their use as accurate biomarkers of aging and health risk prediction, yet their underlying mechanisms remain unclear.
• What they did: A principal component analysis method was developed to address collinearity in blood cell counts, and the contribution of cell composition to DNA methylation age and age acceleration was quantified in over 4,000 samples, with further testing in nearly 19,000 individuals.
• The result: Cell counts, especially the balance of naive and memory T cells, explain a significant portion of age variation and influence associations with health outcomes, but their impact on mortality and disease links is modest, indicating different biological processes are reflected by different epigenetic clocks.