Pathway-level insights into the epigenetic ageing of human skin.

Skin ageing emerges from the interplay of intrinsic biological decline, environmental exposures and disease-related remodelling, yet the pathway-level epigenetic programs that integrate these processes remain largely unresolved. Here, we develop a skin-specific PathwayAge clock that aggregates DNA methylation into biologically interpretable gene ontology pathways, enabling both precise quantification of epigenetic age and mechanistic dissection of cutaneous ageing. The model demonstrates high accuracy and strong generalisability across multiple independent cohorts, providing a robust foundation for mapping pathway-level ageing biology in human skin. Comprehensive analyses reveal four core functional modules underlying skin epigenetic ageing, encompassing cellular process, stress and immune responses, developmental process, and signal and regulation. These programs show substantial concordance with systemic ageing pathways in blood, indicating shared epigenetic architecture across tissues. Sun-exposed skin exhibits pronounced age acceleration driven by oxidative stress, inflammatory activation and metabolic perturbation, defining the molecular signature of photoageing. In disease settings, actinic keratosis and squamous cell carcinoma display marked ageing acceleration with proliferative and extracellular matrix dysregulation; melanoma progression involves coordinated remodelling of stress, immune, structural and metabolic ageing programs; and psoriasis demonstrates inflammation- and differentiation-driven premature ageing. Together, these findings position the skin-specific PathwayAge clock as a mechanistic and quantitative framework for decoding intrinsic ageing, photoageing and disease-associated remodelling. This work advances a unified understanding of cutaneous ageing biology and provides a foundation for precision assessment and targeted intervention in skin ageing.