SIRT7 links H3K36ac epigenetic regulation with genome maintenance in the mouse testis

Reproductive aging is an increasing health concern that affects family planning and overall well-being. While extensively studied in females, the mechanisms driving male reproductive aging remain largely unexamined. Here, we found that mammalian Sirtuin 7 sustains spermatogenesis in an age-dependent manner. Sirtuin 7 deficiency in mice increases histone H3 lysine 36 acetylation in spermatogonia and spermatocytes, a pattern also observed during natural aging, and leads to altered chromatin accessibility and increased vulnerability to genotoxic stress. Importantly, undifferentiated spermatogonia, required for continuous sperm production, become prematurely lost in Sirtuin 7 deficient mice and show increased genome damage accumulation during aging or environmental stress. These changes are concurrent with age-dependent defects in double-strand break repair and a meiotic delay. Taken together, our results indicate that Sirtuin 7 connects histone H3 lysine 36 acetylation epigenetic regulation to long-term genome stability in male germ cells, ensuring steady-state spermatogenesis during the lengthy male reproductive lifespan.