Ultraviolet radiation reshapes the transcriptomic landscape of human skin aging: Insights from a multi-age comparative study

BACKGROUND: Skin aging arises from both intrinsic processes and extrinsic factors, with ultraviolet (UV) radiation being the primary extrinsic cause of photoaging. However, the molecular mechanisms that differentiate these processes across the human lifespan remain incompletely characterized. OBJECTIVE: This study aimed to comprehensively compare the dynamic transcriptomic profiles of photoaged (neck, high UV exposure) and intrinsically aged (chest, low UV exposure) skin across three age groups (young, middle-aged, elderly), and to integrate these findings with biophysical skin measurements. METHODS: We performed transcriptomic analysis on skin biopsies from the neck and chest of 30 healthy female volunteers (n = 10 per age group). This was followed by differential gene expression, Gene Ontology (GO), and KEGG pathway enrichment analyses. The molecular findings were then correlated with an extensive panel of biophysical skin parameters assessing barrier function, elasticity, pigmentation, and microstructure. RESULTS: Photoaged neck skin exhibited accelerated age-dependent transcriptomic dysregulation, marked by enrichment in pathways related to DNA damage response (e.g., CHEK1), stress signaling (e.g., MAPK/STK3), metabolic reprogramming (e.g., AMPK/PPARG), and oncogenic transformation (e.g., WNT10B). A persistent pseudo-inflammatory state, mirrored by herpes simplex virus 1 infection pathway enrichment, was also observed. Notably, sirtuin expression (SIRT1, SIRT5) was severely depleted in photoaged skin, with SIRT1 specifically linked to attenuated AMPK signaling in middle age. In contrast, intrinsic aging in chest skin involved a more gradual decline in homeostatic processes like metabolism and immune vigilance. Comparative analysis further revealed UV-specific disruption in gap junction assembly and cytoskeletal organization, and in elderly skin, activation of pathways associated with neurodegenerative diseases. Finally, canonical correlation analysis (CCA) confirmed strong links between key gene expression patterns (e.g., FGFBP1 with erythema, CHEK1 with age) and clinical skin aging phenotypes. CONCLUSION: Our study provides a high-resolution molecular map of human skin aging, demonstrating that UV radiation does not merely accelerate but fundamentally rewires the aging network, driving pathways distinct from intrinsic aging. Key identified drivers include sirtuin depletion, aberrant stress signaling, and a chronic pseudo-inflammatory response, offering novel targets for anti-photoaging interventions.