Single-Cell Atlas of Aging Human Skin Reveals FOSB-Related Transcriptional Programs and Druggable Targets.

BACKGROUNDWhile human skin aging involves complex transcriptional alterations, the cell-type-specific regulatory mechanisms and therapeutic targets remain incompletely defined. The study aims to investigate aging-associated transcriptional programs and drug-responsive signatures at single-cell resolution.

METHODHere we performed a single-cell RNA sequencing of young and elder human skin cells and provided a comprehensive analysis of aging-related genes, a gene regulatory network with immunohistochemistry (IHC) validation, cell-cell interference as well as potential chemical reactions.

RESULTTotal 10 distinct cell populations were analyzed based on the scRNA sequencing data. Gene regulatory network analysis showed decreased lactotransferrin gene expression and increased FOSB(+) and DDIT3(+) regulons' regulatory activity. IHC identified the FOSB as an aging-related transcription factor. Despite uniform MT1 protein distribution across epidermal layers, single-cell data revealed subcluster-specific MT1 mRNA dynamics linked to metal ion homeostasis. Drug response prediction experiments revealed possible drug targets and potential antiaging drugs for the skin.

CONCLUSIONOur data showed the skin cell clusters presented distinct transcriptional signatures during skin aging. We highlighted the versatile expression profiles of metallothionein family genes and identified the aging-related signature FOSB in the aged skin. We also provided potential target resources for antiaging therapies.