Single-cell transcriptome analysis reveals the molecular mechanisms underlying age-related changes in human testis

The decline in reproductive health observed in aging males is a well-documented phenomenon. However, the molecular and cellular mechanisms underlying testis aging remain poorly understood. In an effort to gain deeper insights into this process, we conducted a comprehensive analysis of 99,130 single-cell transcriptomes derived from testicular cells spanning an age range of 21 to 69 years. Our machine learning analysis revealed a more pronounced response to aging in somatic cells compared to germ cells. Our analysis identified two distinct waves of aging-related changes within testicular cell clusters. Notably, age-related alterations in somatic cells exhibited consistent and specific responses to the aging process. These age-related changes were found to involve immune response pathways, while cell-specific pathways, such as the response to insulin in Sertoli cells at 50s, and extracellular matrix and NOTCH signaling in TPC cells at 30s, were also observed. Of particular significance was the substantial decrease in the frequency of haploid germ cells in individuals with higher BMI across different age groups, suggesting a synergistic interplay between BMI and age.