Promises and limitations of current ancient human epigenetic clocks

SUMMARY Age-at-death estimation of archaeological human remains is central to palaeodemographic research yet remains particularly challenging for adults where osteological methods often produce imprecise age ranges. Epigenetic clocks can accurately predict chronological age in modern humans, but their applicability to ancient human DNA is unclear due to data limitation and indirect methylation inference. Here, we evaluate the performance of existing epigenetic clocks on reconstructed ancient human methylomes combining high-coverage genomic data and a correction framework adapted to mitigate damage-derived sequence bias. Across multiple CpG window sizes, neither direct clock application nor regression-based retraining produced reliable continuous age-at-death estimates. Reframing age inference as adult-subadult classification did not return statistically supported age classes either. In contrast, sex estimation based on X-chromosome methylation achieved perfect accuracy, before and after correction. Together, these results indicate that current palaeo-epigenetic approaches reliably recover global biological signals but are not sufficiently sensitive to capture gradual, age-related variation in humans. Estimating age-at-death from ancient methylomes will therefore require methodological advances beyond correction alone, including reference data and improved models for inferring damage-derived epigenetic signals. Competing Interest Statement The authors have declared no competing interest.