Skin DNA Methylation Encodes Multidimensional Facial Aging Phenotypes with Distinct Biological Architectures
Dwaraka, V. B.; Hassouneh, S. A.-D.; Seale, K.; Sheikh, D.; Weiter, J.; Gretzula, J. C.; Sivamani, R.; Georgievskaya, A.; Kiselev, K.; Fisher, G. M.; Cui, Y.; Popescu, L.; Smith, R. M.
Show abstract
Whether distinct visible aging traits, e.g., wrinkling, pigmentation, and inflammation, reflect shared or independent epigenetic programs remains unknown; existing clocks compress aging into a single chronological axis, leaving the phenotype-specific architecture of cutaneous aging uncharacterized. Here, we integrate AI-derived facial phenotypes with skin DNA methylation profiles from 706 individuals to develop EpiVision, a panel of 21 epigenetic predictors spanning structural, pigmentary, inflammatory, and textural aging traits. Predictors reveal shared and trait-specific pathways, including developmental patterning, epithelial remodeling, hormonal signaling, and UV damage responses, and capture environmentally induced acceleration in sun-exposed skin alongside lifestyle and topical treatment-associated variation. These findings establish that visible skin aging comprises molecularly distinct axes with shared regulatory substrates and trait-specific drivers, providing a scalable epigenetic framework for intervention evaluation and aging biology research.
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