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

Rula Sa, Xiang Zhang, Kesong Shi, Baoluri Wang, Haiquan Yu

State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock (RRBGL), Inner Mongolia University, Hohhot, 010070, China.State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock (RRBGL), Inner Mongolia University, Hohhot, 010070, China. · pubmed

Paper

Abstract

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.

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Research summary

Decreased expression of Rrm2 in theca-interstitial cells accelerates ovarian aging by impairing cell proliferation and increasing DNA damage. This study addresses a potential root cause of ovarian aging, suggesting that targeting cellular senescence in somatic cells could be a strategy for mitigating age-related decline in ovarian function.

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