Decreased expression of ribonucleotide reductase M2 accelerates ovarian aging by suppressing cell proliferation and inducing DNA damage in mouse theca-interstitial cells

Natural aging affects the ovary, leading to declining function and age-related female infertility. This study investigated the role of theca-interstitial cells (TICs) in ovarian aging, a previously understudied area. Transcriptomic analysis of young and aged mouse ovaries revealed ribonucleotide reductase M2 (Rrm2)-a gene involved in DNA replication and repair-to be significantly downregulated in aged ovaries. Functional experiments revealed that Rrm2 knockdown in TICs reduced DNA synthesis, induced G1-phase arrest, inhibited proliferation, and promoted early apoptosis. Additionally, it triggered DNA damage and cellular senescence by inactivating the PI3K/AKT/mTOR pathway and upregulating p21. In vivo, RRM2 inhibition reduced primordial follicle counts, induced ovarian DNA damage, and suppressed DNA repair gene expression. Overall, these findings highlight that Rrm2 downregulation drives TIC senescence, suggesting that targeting somatic cell senescence may offer a therapeutic strategy to decelerate ovarian aging.