DNA methylation clocks for clawed frogs reveal evolutionary conservation of epigenetic ageing

ABSTRACT DNA methylation-based biomarkers of ageing (epigenetic clocks) have been developed for many mammals, but not yet for amphibian species. We generated DNA methylation data from African clawed frogs ( Xenopus laevis ) and Western clawed frogs ( Xenopus tropicalis ), from adult tissues, whole embryos, and tadpoles. We used an array platform designed for CpGs that are highly conserved in mammals to build multiple DNA methylation-based estimators of age for Xenopus . We found that dual species clock could be developed that apply to both humans and frogs (human-clawed frog clocks), and whose high accuracy supports that epigenetic ageing processes are evolutionary conserved outside mammals. Crossing vast evolutionary distances, we characterize age-related CpGs in Xenopus and mammalian species. Highly conserved positively age-related CpGs are located in neural-developmental genes such as uncx, tfap2d as well as nr4a2 implicated in age-associated disease. As in human clocks, positively age-related CpGs are associated with Polycomb repressive complex 2 (PRC2) target sites. Negative age-related CpGs are associated with genes involved in synaptic transmission. We conclude that signatures of epigenetic ageing are evolutionary conserved between frogs and mammals and that the associated genes relate to neural-developmental processes, altogether opening opportunities to employ Xenopus as a model organism to study development and ageing.