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An unbiased comparison of 14 epigenetic clocks in relation to 10-year onset of 174 disease outcomes in 18,859 individuals.

Mavrommatis, C.; Belsky, D.; Ying, K.; Moqri, M.; Campbell, A.; Richmond, A.; Gladyshev, V.; Chandra, T.; McCartney, D.; Marioni, R.

2025-07-15 epidemiology
10.1101/2025.07.14.25331494 medRxiv
Show abstract

Epigenetic Clocks have been trained to predict chronological age, healthspan and lifespan. Such clocks are often analysed in relation to disease outcomes - typically using small datasets and a limited number of clocks. Here, we present the first large-scale (n=18,849), unbiased comparison of 14 widely used clocks as predictors of 174 incident disease outcomes and all-cause mortality. Second-generation clocks significantly outperformed first-generation clocks, which have limited applications in disease settings. Of the 176 Bonferroni significant (P<0.05/174) associations, there were 27 diseases (including primary lung cancer and diabetes) where the hazard ratio for the clock exceeded the clocks association with all-cause mortality. Furthermore, there were 35 instances where adding a clock to a null classification model with traditional risk factors increased the classification accuracy by >1% with an AUCfull > 0.80. Second-generation epigenetic clocks show promise for disease risk prediction, particularly in relation to respiratory and liver-based conditions.

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