Abstract Transposable elements (TEs) are DNA sequences that expand selfishly in the genome, possibly causing severe cellular damage. While normally silenced, TEs have been shown to activate during aging. DNA methylation is one of the main mechanisms by which TEs are silenced and has been used to train highly accurate age predictors. Yet, one common criticism of such predictors is that they lack interpretability. In this study, we investigate the changes in TE methylation that occur during human aging. We find that evolutionarily young LINE1s (L1s), the only known TEs capable of autonomous transposition in humans, undergo the fastest loss of methylation, suggesting an active mechanism of de-repression. We then show that accurate age predictors can be trained on both methylation of individual TE copies and average methylation of TE families genome wide. Lastly, we show that while old L1s gradually lose methylation during the entire lifespan, demethylation of young L1s only happens late in life and is associated with cancer.

Transposable element methylation state predicts age and disease