Role of UVA-driven cellular senescence via mTOR activation in dihydrotestosterone-induced hair loss in androgenetic alopecia mouse model

Abstract

Background

Androgenetic alopecia (AGA) is one of the most common forms of hair loss, and recent studies suggest that dihydrotestosterone (DHT)-induced senescence of dermal papilla cells (DPCs) plays a crucial role in its pathogenesis. Clinically, we previously observed an overlap between areas exposed to ultraviolet (UV) radiation and regions affected by androgenetic hair loss. However, the relationship between UVA radiation and AGA onset remains unclear. Therefore, we aimed to investigate the role of UVA in intensifying DHT-induced hair loss, with focus on potential activation of cellular senescence pathways.

Methods

We used an AGA mouse model combined with UVA irradiation to examine the role of UVA in delaying DHT-induced hair growth. To further investigate the mechanisms of the interaction between DHT and UVA, we isolated human dermal papilla cells and performed transcriptome sequencing analysis. Senescence-associated β-galactosidase (SA-β-Gal) staining, quantitative PCR, and western blotting were used to assess senescence and autophagy. Rapamycin was tested in vivo for its ability to mitigate hair loss.

Results

UVA accelerated DHT-Induced hair growth delay in AGA mouse model. UVA exposure intensified DHT-induced cellular senescence in hDPCs. This process was associated with the activation of mTOR pathway. However, rapamycin alleviated UVA- and DHT-induced cellular senescence by modulating autophagy dysfunction. Furthermore, rapamycin effectively reversed UVA-exacerbated DHT-induced hair loss in AGA mouse model.

Conclusion

UVA exposure can affect autophagy via the mTOR pathway, enhancing DHT-induced cellular senescence in DPCs. Rapamycin shows potential as a therapeutic agent to counteract these effects, offering a novel strategy for treating AGA.