P42 Differential ATF4 expression in intrinsically and extrinsically aged human Black skin

Abstract Introduction and aims Skin ageing is the biological attrition of skin that occurs as a result of genetically determined intrinsic factors, and extrinsic factors including exposure to chronic ultraviolet radiation (UVR). The transcription factor ATF4 has been implicated in ageing and ageing-associated diseases and is an effector of the integrated stress response (ISR). The ISR is a tightly regulated gene expression programme enabling cells to adapt to stress and may be hyperactivated in ageing. Therefore, we investigated possible changes in ATF4 expression and related targets in both intrinsically and extrinsically aged Black skin. Methods The expression of ATF4 and the ATF4 target gene ADM2 was assessed in young (three female participants; 19–27 years) and aged (three female participants; 67–73 years) photoprotected buttock and photoexposed forearm skin of Black volunteers using RNAScope. ATF4+ and ADM2+ cell counts were normalized to epidermal thickness. The expression of the mitochondrial marker TOMM20 was also analysed by immunofluorescence. Results The proportion of ATF4+ keratinocytes was elevated (P = 0.0037) in photoexposed skin of both young and older donors, suggesting that ATF4 plays a role in the epidermal response to UVR. Interestingly, there were no age-­dependent differences in photoexposed skin. In contrast, the proportion of ATF4+ cells was markedly increased in old photoprotected skin as compared with young photoprotected skin (P = 0.0378), indicating a role in intrinsic skin ageing. The acute stress marker and ATF4 target gene, ADM2, was minimally expressed in skin samples, and TOMM20 expression was unchanged, indicating stable mitochondrial function despite changes observed with ATF4 expression. Conclusions Our data demonstrate that ATF4 is elevated in response to chronic UVR and in intrinsic skin ageing. Further investigation of additional ATF4 target genes and cell stress markers is required to determine the activation of the ISR in these contexts.