O23 Spatially resolved transcriptional divergence in photoageing at pigmentary extremes
Michael Peake, Bezaleel Mambwe, Clare O’Connor, Mike Bell, Mark Farrar, Abigail LangtonAbstract
Introduction and aims
Photoageing exhibits distinct clinical and histological patterns in light and dark skin, with delayed onset and slower progression in darker skin. Despite these differences, the transcriptional mechanisms underlying photoageing remain poorly defined. This study applied spatial transcriptomics to characterize gene expression changes in photoexposed and photoprotected skin and aimed to elucidate molecular pathways underlying photoageing.
Methods
Skin biopsies from photoexposed forearm and photoprotected buttock skin in young (22–29 years) and old (> 69 years) adults with light (White Northern European; n = 3) and dark (Black African American; n = 3) individual typology angle skin types were cryosectioned and profiled using a custom 475-gene panel on the Xenium In Situ platform (10x Genomics). Differentially expressed genes (DEGs) were identified using a log2 fold-change threshold > 1 or < –1 and adjusted Q-value < 0.05.
Results
Compared with photoprotected skin, photoexposed skin exhibited 78 DEGs in older White individuals – the highest across all groups. In young White individuals, 33 DEGs were identified, 18 overlapping with older White skin, including MMP9, involved in extracellular matrix degradation. Most were enriched for immune and lymphoid signalling pathways (CD3D, CD3E, CD3G, CD1B, JAK3, CCL22), indicating increased T-cell presence and activation even in younger skin. Notably, LEPR, an adipokine expressed by papillary fibroblasts, was downregulated in photoexposed skin of young and old White individuals and old Black individuals, but not young black individuals. Uniform manifold approximation and projection-based fibroblast analysis revealed a higher proportion of reticular fibroblasts in older White individuals; young White photoexposed skin also showed increased reticular fibroblasts, whereas this shift was absent in Black individuals.
Conclusions
These findings reveal divergent transcriptional ageing phenotypes at pigmentary extremes, with pronounced immune activation and fibroblast remodelling in light skin and attenuated responses in dark skin. Pigmentation shapes both immune and stromal contributions to photoageing, supporting its photoprotective role and highlighting the importance of pigmentation-informed strategies in dermatological research.