Epigenetic clocks are increasingly recognized as important biomarkers of biological age, yet their biological underpinnings remain somewhat elusive. In this study, the authors investigate the role of blood cell composition in influencing DNA methylation age and age acceleration, which are critical components of epigenetic clocks.
What this study does not show
This study does not establish a direct causal relationship between blood cell composition and health outcomes, nor does it provide evidence for clinical utility in predicting health outcomes based on DNA methylation age.
Evidence scorecard
- Analytic validity: Established
- Clinical validity: Partial
- Clinical utility: Not established
The evidence for analytic validity is based on the robust principal component analysis (PCA) method developed to account for collinearity in blood cell counts. Clinical validity is rated as partial due to the study’s exploration of associations between age acceleration and health outcomes, but it does not measure health outcomes after acting on the test result. Clinical utility remains unestablished as the study does not demonstrate how these findings could be applied in a clinical setting.
The authors utilized a comprehensive dataset comprising 4,058 samples to quantify the contribution of cell composition to DNA methylation age and age acceleration, estimated by various epigenetic clocks. Their findings suggest that up to 53% of the variation in DNA methylation age can be attributed to cell counts, particularly the balance between naïve and memory T cells. In contrast, the association between age acceleration and cell counts is weaker, explaining up to 21% of the variance, with neutrophils playing a significant role in 2nd-generation clocks.
Moreover, the study highlights that blood cell composition significantly attenuates the association between age acceleration and 176 incident health outcomes, although the effect is described as modest. This indicates that while cell composition does influence the biological interpretation of age acceleration, it only minimally contributes to its association with mortality and disease outcomes.
In conclusion, the distinct differences in how DNA methylation age and age acceleration relate to blood cell composition suggest that they may reflect different biological processes. This study underscores the complexity of interpreting epigenetic clocks and the need for further research to elucidate their implications for health and longevity.