Age-related downregulation of dihydrotestosterone-inactivating enzymes in human scalp sebaceous glands

Abstract Background Aging alters the systemic steroid environment, including reductions in circulating androgens. In peripheral tissues, androgen exposure is regulated mainly by local steroid metabolism, which can activate or inactivate androgens independently of systemic concentrations. In the scalp, 5α-reductase–mediated generation of dihydrotestosterone (DHT) has been studied extensively in relation to conditions such as androgenetic alopecia. In contrast, age-related regulation of DHT-inactivating pathways, including the aldo–keto reductase family 1 member C (AKR1C) family, remains insufficiently defined. Methods We examined AKR1C1–4 expression in scalp tissues from individuals of different ages, sexes, and hair loss conditions using immunohistochemistry (IHC), quantitative PCR (qPCR), and reanalysis of publicly available RNA-sequencing (RNA-seq) datasets. Androgen receptor (AR) localization was assessed in multiple scalp compartments. AKR1C expression was also analyzed in immortalized human sebaceous gland cells (SEB-1) and dermal papilla cells (DPCs). In addition, the effect of sulforaphane on AKR1C expression was evaluated. Results AKR1Cs were strongly expressed in male sebaceous glands (SGs) but declined with age. AKR1C4, previously considered liver specific, was detected in SGs and hair follicles (HFs) by IHC and further confirmed by qPCR in SEB-1 cells and DPCs. AR expression was predominant in SGs, with lower levels in sweat glands, the epidermal granular layer, and the HF infundibulum, but not detected in dermal papillae and bulge regions. AR localization was cytoplasmic in the epidermis but nuclear in SGs and sweat glands, and was unaffected by age, sex, or hair loss condition. Sulforaphane treatment upregulated AKR1C expression in both SEB-1 cells and DPCs. Conclusions We identify scalp SGs as a principal site of AR expression and AKR1C-mediated androgen inactivation, including AKR1C4, and demonstrate that AKR1C expression in SGs is sex dependent and declines with age. These findings suggest that age-associated changes in SG steroid metabolism may influence local androgen metabolism within the scalp microenvironment, with implications for HF homeostasis during aging.