Axolotl epigenetic clocks offer insights into the nature of negligible senescence

Renowned for their regenerative abilities, axolotls also exhibit exceptional longevity, resistance to age-related diseases and apparent lack of physiological declines through lifespan, and have thus been considered organisms of negligible senescence. Whether axolotls display epigenetic hallmarks of ageing remains unknown. Here, we probe the axolotl DNA methylome throughout lifespan and present its first epigenetic clocks. Both at tissue-specific or pan-tissue levels, the clocks are biphasic, capable of predicting age during early life but not for the rest of its lifespan. We show that axolotls exhibit evolutionarily conserved features of epigenetic ageing during early life, yet their methylome is remarkably stable across lifespan, including at Polycomb Repressive Complex 2 (PRC2) target sites, suggesting that this species deviates from known patterns of epigenetic ageing. Lastly, we uncover structure-specific rejuvenation events upon regeneration. This study provides molecular insights into negligible senescence and furthers our understanding of the interplay between regeneration and ageing.