Unraveling the complexity of skin’s biological aging utilizing epigenetic clocks

BACKGROUND: DNA methylation (DNAm) plays a pivotal role in regulating gene expression and tissue function in the skin, which exhibits a high degree of responsiveness to environmental and lifestyle factors. These factors are believed to contribute to epigenetic drift, a hallmark of aging marked by increased methylation variability and changes in regulatory regions. While epigenetic clocks have advanced our understanding of skin aging, the effects of many modifiable factors on the skin methylome remain largely unknown. METHODS: We analyzed DNAm data from 851 participants in a population-based cohort and comprehensive phenotyping of 326 lifestyle, physiological, and pharmacological factors. The DNAm age was estimated using a published skin-specific epigenetic clock, and associations with individual factors were tested using regression models. Epigenome-wide association studies have identified differentially methylated positions linked to significant factors, with further analyses examining their genomic context. The broader relevance of these findings was assessed using other established non-skin-specific epigenetic clocks and phenotypic skin aging measures. RESULTS: Our analysis identified 20 factors associated with decelerated and 17 with accelerated DNAm age in human skin, reflecting both positive and negative associations with epigenetic aging. We observed that factors associated with DNAm age acceleration tended to coincide with reduced methylome variance, a feature of epigenetic drift, while factors associated with DNAm age deceleration were mapped to methylation differences in transcription elongation regions, supporting transcriptional integrity. Intervention analyses showed that compounds, such as dihydromyricetin and aspirin, are associated with methylation patterns consistent with decelerated epigenetic aging. Several associations were validated in an independent cohort and were consistent across both skin-specific and general epigenetic clocks, suggesting broader relevance of these findings. CONCLUSIONS: These findings suggest that both environmental exposures and certain interventions are associated with variations in the epigenetic trajectory of skin aging. The identified modifiable factors associated with DNAm age and skin phenotypes generate testable hypotheses regarding potential determinants of skin longevity. Longitudinal studies and interventional study designs will be needed to evaluate causality.