Epigenetic clocks can differentiate between exogenous and endogenous skin ageing

Abstract Context Whereas factors originating internally to the body, such as blood nutrients and hormones, influence endogenous skin ageing, exogenous skin ageing results from the penetration of harmful factors through the skin’s outer stratum corneum layer. Aim To test whether an exogenous skin ageing epigenetic clock is more strongly associated with aspects of sun-exposure than two endogenous epigenetic clocks. Methods Exogenous and endogenous skin clocks were trained in more than 400 skin samples. These two clocks and the Horvath ‘Skin and Blood’ epigenetic clock were tested for association with chronological age and, whilst controlling for chronological age (age acceleration), sun-exposure parameters and skin gene expression. Results Exogenous Skin clock ages were significantly ( p <0.001) older in both epidermal (n=24) and cultured fibroblast (n=8) sun-exposed arm samples than in donor matched sun-protected samples. Exogenous Skin clock age acceleration was significantly correlated (Rho = 0.18, p = 0.004) with sun-seeking behaviour and mRNA levels (202 genes had q < 0.05) in whole skin abdomen samples (n=364); the latter was consistent with sun-exposed versus sun-protected older arm mRNA differences (n=12 donors). In 44 facial skin swabs, exogenous age acceleration was also significantly correlated with facial photodamage grading (rho = 0.33, p = 0.028). Although the Endogenous and Skin and Blood clocks were more strongly correlated with chronological age, their age acceleration estimates were not significantly associated with sun-exposure parameters or mRNA levels in skin. Conclusion Skin epigenetic clocks can differentiate exogenous from endogenous skin ageing facilitating further study of the mechanisms underlying these two skin ageing phenomena.