Mechanisms Involved in Human Scalp Aging Revealed in New Study

Hair loss and graying arise as hair follicle stem cells (HFSCs) and their surrounding niche gradually lose function with age. In a study published recently in hLife, researchers from Tongji University used single-cell RNA sequencing on 11 human scalp samples and spatial transcriptomic sequencing on 1 sample to generate a detailed blueprint of human scalp aging and to identify molecular processes that deteriorate over time. This work focuses on early aging and examines how different scalp cell types and their interactions change as people reach middle age.

Keratinocytes, which form the skin epidermis and hair follicle structure, synthesize keratin, create a protective barrier, limit water loss, and participate in wound healing and skin immune responses. The team identified a group of mitotic cells spread across the interfollicular epidermis (IFE), the hair follicle bulge/outer root sheath (ORS), and the hair matrix on the spatial transcriptomic chip. Further subdivision showed three mitotic subpopulations—IFE Mitotic, ORS Mitotic, and Matrix Mitotic cells—and pseudo-time analysis indicated that these cells occupy a transitional stage of differentiation.

Fibroblasts, the main dermal cells, regulate the hair cycle, support hair follicle regeneration, and mediate damage repair. Subpopulation analysis of human scalp fibroblasts identified Dermal Papilla (DP) cells and Dermal Sheath (DS) cells, with gene expression patterns that differ substantially from those seen in mice. Using an integrated bioinformatics pipeline, the researchers mapped cell-type-specific changes and complex intercellular communication networks associated with early aging.

Differential cell-type abundance analysis showed that key progenitor populations, including ORS and bulge (Bu) cells, are reduced in middle-aged scalps. Gene Set Enrichment Analysis revealed increased gene signatures linked to senescence, SASP, and apoptosis across multiple cell types. Communication between cells weakened markedly, especially in signaling pathways essential for hair cycling and stem cell maintenance. Signals such as BMP and non-canonical WNT (ncWNT) were significantly decreased in the crosstalk between DP cells, described as master regulators of hair growth, and neighboring keratinocytes in the middle-aged group.

At the same time, the Activator Protein 1 (AP-1) transcription factor complex was significantly activated in keratinocytes from middle-aged individuals, forming a regulatory network that affects inflammation and stem cell homeostasis. The DCT gene, linked to melanin synthesis, was up-regulated in melanocytes, and the study suggests that "inflammaging" may drive hyperactive or dysregulated melanin synthesis and age-related pigment changes.

Overall, this work provides a high-resolution, cell-resolved map of the human scalp in early aging and highlights over-activation of AP-1 and collapse of BMP/ncWNT signaling as molecular targets that may guide future drug development, while emphasizing that further research is needed to test their causal roles.