Skin epigenetic clocks can differentiate exogenous from endogenous skin ageing, with an exogenous skin clock showing significant associations with sun-exposure parameters and skin gene expression while endogenous clocks did not.
Key Findings
Methods
Exogenous and endogenous skin epigenetic clocks were successfully trained on a large skin sample dataset.
Clocks were trained in more than 400 skin samples.
Three clocks were compared: the newly developed Exogenous Skin clock, the Endogenous Skin clock, and the previously published Horvath 'Skin and Blood' epigenetic clock.
The clocks 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 older in sun-exposed arm samples compared to donor-matched sun-protected samples.
Difference was significant at p < 0.001.
Effect was observed in both epidermal samples (n=24) and cultured fibroblast samples (n=8).
Samples were donor-matched, meaning sun-exposed and sun-protected comparisons were made within the same individuals.
Sun-exposed samples were from the arm, while sun-protected samples served as the comparison.
Results
Exogenous Skin clock age acceleration was significantly correlated with sun-seeking behaviour.
Correlation coefficient Rho = 0.18, p = 0.004.
Analysis was conducted in whole skin abdomen samples (n=364).
Age acceleration refers to clock-estimated age after controlling for chronological age.
Results
Exogenous Skin clock age acceleration was associated with differential mRNA expression in skin samples.
202 genes had q < 0.05 in whole skin abdomen samples (n=364).
These mRNA level differences were consistent with sun-exposed versus sun-protected older arm mRNA differences (n=12 donors).
This consistency suggests the gene expression signal captured by the Exogenous clock reflects biologically relevant sun-exposure effects.
Results
Exogenous Skin clock age acceleration was significantly correlated with facial photodamage grading.
Analysis was conducted in 44 facial skin swabs.
Correlation coefficient rho = 0.33, p = 0.028.
Facial photodamage was assessed by grading, providing a clinically relevant measure of cumulative sun damage.
Results
The Endogenous Skin clock and the Horvath 'Skin and Blood' clock were more strongly correlated with chronological age than the Exogenous clock, but their age acceleration was not associated with sun-exposure parameters.
Age acceleration estimates of both the Endogenous and 'Skin and Blood' clocks were not significantly associated with sun-exposure parameters.
Neither clock's age acceleration was significantly associated with mRNA levels in skin.
This distinguishes them functionally from the Exogenous Skin clock, which captures UV-related biological variation.
What This Means
This research suggests that the skin ages through two distinct processes: endogenous ageing, driven by internal factors like hormones and nutrients, and exogenous ageing, driven by external factors like ultraviolet (UV) radiation from the sun that penetrate the skin's outer layer. Scientists developed two new epigenetic clocks — molecular tools that estimate biological age by reading chemical modifications on DNA — specifically designed to capture each of these ageing pathways in skin. They then tested whether the exogenous clock was better at detecting sun-related damage compared to the endogenous clock and an existing general-purpose skin clock.
The study found that the exogenous skin clock consistently measured older biological ages in sun-exposed skin compared to sun-protected skin from the same donors, and this effect was seen in both surface skin cells and deeper fibroblast cells. The exogenous clock's age acceleration — how much older the skin appeared beyond what would be expected for a person's actual age — was significantly linked to sun-seeking behaviour, facial photodamage scores, and patterns of gene activity that matched known sun-damage signatures. In contrast, the endogenous and general-purpose clocks, while better at tracking chronological age overall, showed no significant relationship with any of these sun-exposure measures.
This research suggests that different epigenetic clocks capture different biological realities about skin ageing, and that a clock specifically trained on exogenous ageing can serve as a molecular readout of cumulative sun damage. This could have future applications in studying how lifestyle and environmental factors accelerate skin ageing at a molecular level, and potentially in evaluating skin protection or anti-ageing interventions.