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. 2025 Jan;24(1):e14358.
doi: 10.1111/acel.14358. Epub 2024 Oct 6.

Mapping epidermal and dermal cellular senescence in human skin aging

Grace T Yu  1 , Clarisse Ganier  2 , David B Allison  3 , Tamara Tchkonia  4 , Sundeep Khosla  5   6 , James L Kirkland  4 , Magnus D Lynch  2   7 , Saranya P Wyles  6   8
Affiliations

Mapping epidermal and dermal cellular senescence in human skin aging

Grace T Yu et al. Aging Cell. 2025 Jan.

Abstract

Single-cell RNA sequencing and spatial transcriptomics enable unprecedented insight into cellular and molecular pathways implicated in human skin aging and regeneration. Senescent cells are individual cells that are irreversibly cell cycle arrested and can accumulate across the human lifespan due to cell-intrinsic and -extrinsic stressors. With an atlas of single-cell RNA-sequencing and spatial transcriptomics, epidermal and dermal senescence and its effects were investigated, with a focus on melanocytes and fibroblasts. Photoaging due to ultraviolet light exposure was associated with higher burdens of senescent cells, a sign of biological aging, compared to chronological aging. A skin-specific cellular senescence gene set, termed SenSkin™, was curated and confirmed to be elevated in the context of photoaging, chronological aging, and non-replicating CDKN1A+ (p21) cells. In the epidermis, senescent melanocytes were associated with elevated melanin synthesis, suggesting haphazard pigmentation, while in the dermis, senescent reticular dermal fibroblasts were associated with decreased collagen and elastic fiber synthesis. Spatial analysis revealed the tendency for senescent cells to cluster, particularly in photoaged skin. This work proposes a strategy for characterizing age-related skin dysfunction through the lens of cellular senescence and suggests a role for senescent epidermal cells (i.e., melanocytes) and senescent dermal cells (i.e., reticular dermal fibroblasts) in age-related skin sequelae.

Keywords: cellular senescence; dermis; epidermis; single‐cell gene expression analysis; skin aging; skin pathology; spatial analysis.

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Conflict of interest statement

J.L.K. and T.T. have financial interest related to this research, including patents, and pending patents covering senolytic drugs and their uses that are held by Mayo Clinic. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and was conducted in compliance with Mayo Clinic and Cedars‐Sinai conflict of interest policies. M.D.L. is a co‐founder of Fibrodyne and has two patents related to skin fibroblasts. In the last twenty‐four months, D.B.A. has received personal payments or promises for same from: Novo Nordisk Foundation; and Zero Longevity Science (as stock options). D.B.A.'s institution, Indiana University, and the Indiana University Foundation have received funds or donations to support his research or educational activities from: Eli Lilly and Company; Pfizer, Inc.; and numerous other for‐profit and non‐profit organizations to support the work of the School of Public Health and the university more broadly.

Figures

FIGURE 1
FIGURE 1
CDKN1A (p21) versus CDKN2A (p16) as cellular senescence markers. (a, b) CDKN1A+ cells in G0/G1 of cell cycle. (c, d) CDKN2A+ cells in G0/G1 of cell cycle. (e) CDKN1A and CDKN2A expression versus anatomic location and sun exposure in fibroblasts and melanocytes. (f) CDKN1A and CDKN2A expression versus age in fibroblasts and melanocytes in sun‐exposed skin. ns: p > 0.05; *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.001; ****p ≤ 0.0001.
FIGURE 2
FIGURE 2
A novel panel of skin senescence markers, SenSkin™. SenSkin™, were grouped approximately by gene function based on review of GeneCards (Stelzer et al., 2016), in (a) CDKN1A+ cells in G0/G1 (139/165 genes congruent) and (b) CDKN2A+ cells in G0/G1 (44/165 genes congruent) versus all other cells. SenSkin™ was more congruent with CDKN1A+ cells in G0/G1 than CDKN2A+ cells in G0/G1 (p < 2.2 × 10−16). Red dots represent gene upregulation, and blue dots represent gene downregulation. Dot size represents percent of cells expressing the gene. (c) SenSkin™ composite score versus sun exposure. (d) SenSkin™ composite score in sun‐exposed skin versus age.
FIGURE 3
FIGURE 3
Epidermal senescence is driven by CDKN1A+ non‐replicating melanocytes in human adult skin. SenSkin™ composite score in (a) non‐sun‐exposed versus sun‐exposed melanocytes, (b) sun‐exposed melanocytes with age, and (c), non‐replicating CDKN1A+ versus all other melanocytes. (d) Melanin synthesis gene expression in non‐replicating CDKN1A+ melanocytes versus all other melanocytes in sun‐exposed skin; specifically, the Reactome melanin biosynthesis gene set and genes for c‐kit (KIT), eumelanin (MC1R), pheomelanin (SLC7A11), and carotenoid metabolism (BCO2). Red dots represent gene upregulation, and blue dots represent gene downregulation. Dot size represents percent of cells expressing the gene. (e) CDKN1A expression across non‐replicating melanocyte clusters from sun‐exposed skin, labelled clusters E (early), L1 (late 1), and L2 (late 2). (f) Pseudotime across clusters. Higher pseudotimes represents later timepoints in cell trajectories. (g) Immune‐related genes across non‐replicating melanocyte clusters. (h) Melanin synthesis genes across non‐replicating melanocyte clusters. ns: p > 0.05; *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.001; ****p ≤ 0.0001.
FIGURE 4
FIGURE 4
Dermal senescence is driven by CDKN1A+ non‐replicating reticular fibroblasts in human adult skin. (a) Localization of fibroblast subpopulations. Created with BioRender.com. (b) SenSkin™ composite score across fibroblast subpopulations in non‐replicating CDKN1A+ fibroblasts versus other fibroblasts in the same subpopulation. (c) Collagen‐related genes and (d) elastic fiber‐related genes given by Reactome Elastic Fibre Formation gene set (except BMP10, which did not meet scRNA‐seq quality control) in CDKN1A+ non‐replicating reticular dermal (F2) fibroblasts versus other reticular dermal fibroblasts. Red dots represent gene upregulation, and blue dots represent gene downregulation. Dot size represents percent of cells expressing the gene. (e) CDKN1A expression across clusters of non‐replicating F2 fibroblasts from sun‐exposed skin, labelled clusters E (early) and L (late). (f) Pseudotime across clusters. Higher pseudotimes represent later timepoints in cell trajectories. (g) Proinflammatory gene expression across clusters. (h) Heat shock protein genes across clusters. ns: p > 0.05; *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.001; ****p ≤ 0.0001.
FIGURE 5
FIGURE 5
Spatial transcriptomics localization of cellular senescence markers in human adult skin. CDKN1A (p21) and CDKN2A (p16) spatial localization compared to SDHA housekeeping gene in (a) body skin (less sun‐exposed) and (b) facial (more sun‐exposed) skin. The color at each grid location corresponds to the magnitude of expression for each marker in the tissue section (blue representing none or low expression, yellow, medium expression, and red, high expression). (c) Example of clustering, with colored spots signifying high CDKN1A expression. Yellow spots represent spots that are in a cluster, that is, spots that have positive adjacent dots, and blue dots represent dots that are not in clusters, that is, have no positive adjacent dots. (d) Proportion of spots in clusters of highly‐CDKN1A‐expressing spots. (e) Tendency for clustering of highly‐CDKN1A‐expressing spots, where percentile >0.5 indicates a tendency for spots to cluster, and percentile <0.5 indicate a tendency for spots to disperse. *Samples removed if not express gene at threshold (SCT‐transformed gene expression values of 1 for CDKN1A‐highly‐expressing).
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