Facial skin aging: an integrative analysis of genetics, epigenetics, and lifestyle factors

Facial wrinkling is a prominent sign of aging, yet individuals exhibit unique trajectories of biological aging, contributing to the variability in facial appearance. Here, we present a pioneering study exploring the association between lifestyle choices, DNA methylation, and SNP genotypes with a range of facial skin aging phenotypes. The study demonstrated that age-related facial skin phenotypes are influenced by multiple environmental stressors. Epigenome-wide association analyses identified differentially methylated cytosines mapped to 151 loci, including novel genes associated with facial wrinkles, such as EDAR (cg02925966, p = 4.96 × 10^-8) and NRG1 (cg26267340, p = 4.64 × 10^-8), both involved in wound healing. Sensitivity analysis, conditioning on the top meQTLs, showed minor attenuation, suggesting an association independent of genetic variants. Accelerated epigenetic aging, measured in the blood of over 700 Polish individuals, was found to correlate with facial wrinkle area, photoaging, telangiectasias, and perceived facial age, with the GrimAge and FitAge clocks showing the most robust associations. Genome-wide SNP analysis identified rs73943403 (RP11-78F17.1, p = 3.72 × 10^-8) associated with wrinkle area and rs113125564 (ZC3H4, p = 1.23 × 10^-8) associated with perceived facial age, potentially implicating stress response and adiposity in skin aging. Finally, the study revealed the additive value of methylation and SNP data for predicting two continuous skin phenotypes, with 59.0% of the variation explained in facial wrinkle area and 26.2% in perceived facial age. The findings underscore the relevance of genetic and epigenetic factors, revealing novel candidate genes and molecular pathways involved in skin aging. These insights hold substantial translational value for dermatology, the cosmetics industry, and anti-aging strategies.