The role of Procyanidins in delaying the Premature Ovarian Insufficiency through regulatory Sirt1-p53-p21 signaling Pathway in Female Germline Stem Cells

Abstract As women age, their ovarian follicle pool naturally declines. However, female germline stem cells (FGSCs) possess a unique ability to differentiate into oocytes and continuously self-renew, providing an effective means of delaying ovarian aging by replenishing the primordial follicle pool. Therefore, activating FGSCs is critical in reshaping and safeguarding ovarian function. In this study, we investigated the biological activity of proanthocyanidins (PACs), natural antioxidants that exhibit anti-aging and anti-inflammatory properties beneficial for both male and female reproduction. Our in vivo and in vitro experiments demonstrate that PACs promote FGSCs proliferation while delaying ovarian aging. Specifically, PACs increase the number of primordial follicles, primary follicles, corpus luteum while reducing cystic follicles, and elevate estradiol(E 2 ) levels along with anti-mullerian hormone(AMH) concentration levels in mice. Additionally, PACs significantly boost FGSC proliferation time- and dose-dependently by upregulating mRNA & protein expressions for FGSC-specific markers such as Mvh and Oct-4 while downregulating p53/p21 via activation of Sirt1 signaling pathway. The effects of PACS on FGCS were found to be impeded by the Sirt1 inhibitor EX527.Overall, this research provides strong evidence suggesting that PACS delay premature ovarian failure through regulating the Sirt1-p53-p21 signaling pathway involving female germline stem cells.