Single-Cell Analysis of Human Testis Aging, and Impact of Elevated Body Mass Index

SUMMARY Aging human males display reduced reproductive health, however testis aging is poorly understood at the molecular and genomic level. Here, we utilized single-cell RNA-seq to profile over 44,000 cells from both young and older men (>60 years old) – and examined age-related changes in germline development and in the somatic niche. Interestingly, age-related changes in spermatogonial stem cells appeared modest, whereas age-related dysregulation of spermatogenesis and the somatic niche ranged from moderate to severe. Altered pathways included signaling and inflammation in multiple cell types, metabolic signaling in Sertoli cells, hedgehog signaling and testosterone production in Leydig cells, cell death and growth in testicular peritubular cells, and possible developmental regression in both Leydig and peritubular cells. Remarkably, the extent of dysregulation correlated with body mass index in older, but not younger men. Taken together, we reveal candidate molecular mechanisms underlying the complex testicular changes conferred by aging, and their exacerbation by concurrent chronic conditions such as obesity.