Targeting dysregulated phago-/auto-lysosomes in Sertoli cells to ameliorate late-onset hypogonadism

Age-related changes in testicular function can impact health and well-being. The mechanisms underlying age-related testicular dysfunction, such as late-onset hypogonadism (LOH), remain incompletely understood. Using single-cell RNA sequencing on human testes with LOH, we delineated Sertoli cells (SCs) as pivotal metabolic coordinators within the testicular microenvironment. In particular, lysosomal acidity probing revealed compromised degradative capacity in aged SCs, hindering autophagy and phagocytic flux. Consequently, SCs accumulated metabolites, including cholesterol, and have increased inflammatory gene expression; thus, we termed these cells as phago-/auto-lysosomal deregulated SCs. Exposure to a high-fat diet-induced phago-/auto-lysosomal dysregulated-like SCs, recapitulating LOH features in mice. Notably, efferent ductular injection and systemic TRPML1 agonist administration restored lysosomal function, normalizing testosterone deficiency and associated abnormalities in high-fat diet-induced LOH mice. Our findings underscore the central role of SCs in testis aging, presenting a promising therapeutic avenue for LOH. Late-onset hypogonadism (LOH) can occur with male reproductive aging and is characterized by declining testosterone levels as well as other clinical symptoms. Here the authors show that dysregulated phago-/auto-lysosomes in Sertoli cells are a key feature of LOH, linking metabolism and aging, and that pharmaceutical targeting of lysosome dysfunction can alleviate LOH in mice.