The relationship between ageing and changes in the human blood and brain methylomes

Changes in DNA methylation have been found to be strongly correlated with age, enabling the creation of “epigenetic clocks”. Previously, studies on the relationship between ageing and DNA methylation have assumed a linear relationship, but no study has shown this always to be the case. We show that the relationships between significant methylation changes and ageing are different in different tissues, and that these changes show variable rates across life. Further, we observe a tendency for saturation as ageing proceeds. We provide a straightforward method of assessing all methylation-age relationships and cluster them according to their relative change rates based on fold change. Less than 13% of the significant markers selected here are used in the most common epigenetic clocks. When the significant markers display largely non-linear relationships, our fold change selection outperforms the most common epigenetic clocks in predicting age. We also show that the saturation observed at older ages explains the earlier observations that the epigenetic clock consistently underestimates the age in older samples. The findings imply that markers selected from linear adjustments or correlations do not represent the most meaningful biological changes.