In mammals the male reproductive system outlasts the female reproductive system over the course of aging, but mechanisms of damage and dysfunction still eventually lead to a loss of fertility. The epididymis, where sperm cells mature, is a critical portion of the testes. As researchers here note, while observations of degeneration are readily available, there is relatively little understanding of the aging of the epididymis at the detailed level of cellular biochemistry. After better characterizing epididymal cells in young and aged non-human primates, the researchers found a proximate cause of problems: loss of FOXO1 expression drives cellular senescence, and senescent cells then disrupt structure and function in the surrounding tissue via their inflammatory secretions.
Aging of the male reproductive system is characterized by declining fertility, with epididymal dysfunction being a critical yet poorly understood contributor. Through a multimodal analysis in non-human primates that integrated histology and transcriptomics, we delineated a coherent epididymal aging phenotype encompassing epithelial senescence, chronic inflammation, fibrosis, and functional decline. Single-nucleus transcriptomics revealed principal cells (PCs) as the predominant and most transcriptionally perturbed epithelial cell type. Within PCs, the longevity-associated transcription factor FOXO1 was markedly downregulated with age.
Functional studies in human epididymal epithelial cells demonstrated that FOXO1 deficiency drives cellular senescence. Mechanistically, FOXO1 transcriptionally activates LHX1, and this axis is essential for counteracting senescence. Furthermore, intervention with senescence-resistant mesenchymal progenitor cells or their exosomes mitigated epididymal aging phenotypes and restored FOXO1 expression in vivo and in vitro. Our study establishes the FOXO1-LHX1 axis as a key protective pathway against primate epididymal aging, providing mechanistic insights and potential therapeutic targets for preserving male reproductive health.
