Unraveling hair aging: a molecular atlas of human hair follicle senescence drawn by single-cell and spatiotemporal sequencing

Hair loss and graying, the earliest visible signs of skin aging, are fundamentally driven by the functional decline of the hair follicle stem cells (HFSCs) and their surrounding niche. The research, led by Dr. Zhao and colleagues, leveraging single-cell RNA sequencing of 11 human scalp samples and spatial transcriptomic sequencing of 1 sample, has created a detailed blueprint of human scalp aging and pinpointing the molecular mechanisms that break down as we age for the first time.

Keratinocytes, the main cells composing the skin epidermis and hair follicle structure, are responsible for synthesizing keratin, creating a protective barrier, resisting external damage and water loss, and playing important roles in wound healing and skin immune responses. The research team found that a group of mitotic cells were spatially distributed across the interfollicular epidermis (IFE), the hair follicle bulge/outer root sheath (ORS), and the hair matrix on the spatial transcriptomic chip. Further subdivision of these cells revealed three distinct subpopulations: IFE Mitotic cells, ORS Mitotic cells, and Matrix Mitotic cells. Pseudo-time analysis further confirmed that these cells were in a transitional stage of cell differentiation.

Fibroblasts are the main cells composing the dermis and play crucial roles in hair cycle regulation, hair follicle regeneration, and damage repair. Subpopulation analysis of human scalp fibroblasts identified Dermal Papilla (DP) cells and Dermal Sheath (DS) cells, noting significant differences in their gene expression compared to their mouse counterparts.

Their integrated bioinformatics pipeline allowed for the mapping of cell-type-specific changes and complex intercellular communication networks associated with early aging process. Differential cell-type abundance analysis revealed a reduction in key progenitor populations, including ORS and bulge (Bu) cells, in the middle-aged group, and Gene Set Enrichment Analysis (GSEA) showed a significant increase in gene signatures related to senescence, SASP, and apoptosis across multiple cell types. The research revealed a dramatic weakening of communication, particularly in the critical signaling pathways that govern hair cycling and stem cell maintenance. Essential signals like BMP and non-canonical WNT (ncWNT) signaling were found to be significantly decreased in the vital crosstalk between DP cells (the master regulators of hair growth) and the surrounding keratinocytes in the middle-aged group. Concurrently, the Activator Protein 1 (AP-1) transcription factor complex—known for its role in cellular stress, senescence, and transcriptional reprogramming—was found to be significantly activated in the keratinocytes of middle-aged individuals. Downstream targets of AP-1 form an intricate regulatory network that influences inflammation and stem cell homeostasis. Furthermore, the DCT gene, associated with melanin synthesis, was found to be up-regulated in melanocytes, suggesting that "inflammaging" (chronic low-grade inflammation) may lead to hyperactive or dysregulated melanin synthesis contributing to age-related pigment changes.

This study fills a critical gap by providing the first high-resolution, cell-resolved map of human scalp during the early aging process. The identified molecular targets—specifically the over-activation of AP-1 and the collapse of BMP/ncWNT signaling—offer potential pathways for future drug development. Further research is necessary to confirm the causal role of AP-1-centered network and ncWNT pathway in scalp aging.

About Author

Dr Qian Zhao holds a B.S. in Biomedical Engineering from Huazhong University of Science and Technology and a Ph.D. in Biochemistry and Molecular Biology from Shanghai Jiao Tong University, followed by a two-year postdoctoral fellowship at Duke University. She is an expert in leveraging genomic and multi-omics technologies for the   identification of biomarkers and the elucidation of disease mechanisms, with substantial professional experience spanning product development and quality management in the biotech industry. Dr. Zhao's current professional interest is dynamically shifting towards the molecular mechanisms underlying skin conditions (including aging) and the translational potential of gene therapies in rejuvenation strategies. She is proactively seeking strategic collaborations and partnerships in the areas of dermatological research, regenerative medicine, and gene therapy development.