In the realm of epigenetics, DNA methylation age has emerged as a significant biomarker for biological aging. However, the underlying biological mechanisms that drive this biomarker remain inadequately understood. The study titled ‘Blood cell composition reveals distinct biological interpretation of DNA methylation age and age acceleration’ aims to shed light on these mechanisms by examining the role of blood cell composition.
Background
Previous research indicated that epigenetic clocks, which estimate biological age based on DNA methylation patterns, are influenced by the proportions of different T cell types in the blood, particularly naïve and memory T cells. This suggests that variations in blood cell composition could significantly impact the readings of epigenetic clocks. However, analyzing these cell compositions is challenging due to the collinearity between different cell fractions.
Methods
The researchers developed a principal component analysis (PCA) method that effectively addresses the issue of collinearity in blood cell counts. This innovative approach allowed for a more nuanced understanding of how blood cell composition contributes to DNA methylation age and age acceleration. The study analyzed a substantial dataset comprising 4,058 samples to quantify this contribution.
Furthermore, the team explored the influence of blood cell composition on the relationship between age acceleration and 176 different health outcomes by examining a larger cohort of 18,859 individuals.
Results
The findings revealed that up to 53% of the variation in DNA methylation age could be attributed to blood cell counts, with a notable influence from the balance between naïve and memory T cells. In contrast, the associations between age acceleration and blood cell counts were weaker, accounting for up to 21% of the variance explained. Notably, for second-generation epigenetic clocks, neutrophils played a significant role.
Additionally, the study validated the contribution of cell counts to epigenetic clocks through experiments involving artificial cell mixtures. Importantly, the analysis showed that blood cell composition significantly attenuates the association of age acceleration with health outcomes, although this effect was described as modest.
Conclusions
The results indicate that DNA methylation age (DNAmAge) and age acceleration (AgeAccel) reflect different biological processes, as evidenced by their distinct associations with blood cell composition. Surprisingly, the contribution of blood cell composition to age acceleration only has a minor impact on its association with mortality and incident disease outcomes.
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 insights into the specific mechanisms by which these associations occur.
Evidence scorecard
- Analytic validity: Established
- Clinical validity: Not established
- Clinical utility: Not established
The evidence is derived from primary research involving human subjects.