Deciphering the Contribution of Circular <scp>RNAs</scp> to Age‐Related Decline in Sertoli Cell Survivor

Male fertility declines during aging. This process mainly affects spermatogonia and Sertoli cells, leading to impaired spermatogenesis and poor-quality sperm production. Circular RNAs (circRNAs) are covalently closed RNA molecules produced by backsplicing. In the field of male reproduction, circRNAs boast great potential in the regulation of spermatogenesis and sperm morpho-functional skills. However, their potential role in age-related male reproductive anomalies remains largely elusive. Here, we analyzed the reproductive phenotype of the aged male mouse experimental model, pointing our attention to a putative functional link between circRNAs and Sertoli cell survival. Our results confirm several testicular age-related defects including: (i) altered morphology of the seminiferous epithelium; (ii) affected spermatogenesis; and (iii) decreased sperm production. In particular, aged spermatozoa (SPZ) were decreased in number in association with low motility and abnormal morphology (sperm head anomalies and tail bents). The expression analysis of selective spermatic circRNAs demonstrated a de-regulated expression profile in Aged versus Young SPZ. Among them, we turned the lens on circAbcb9 as a spermatic circRNA potentially involved in the Sertoli cell senescence pathway via the circRNA/miRNA/mRNA network (ceRNET). Indeed, a significant shutdown of circAbcb9-dependent network associated with a prominent increase in Sertoli cell senescence occurred in Aged testis. Interestingly, circAbcb9 was also expressed in human SPZ at decreased levels in Aged men, suggesting a conserved role. Collectively, our study stimulates greater interest in circRNAs as involved in the molecular mechanisms behind the age-related effect on Sertoli cell survival, also providing new implications for fused protein in sarcoma (FUS) protein in sertolian circRNA biogenesis.