Elamipretide reverses female fertility decline during reproductive aging via regulating VEGF in oocytes

Aging is one of the primary drivers for the decline of female fertility, and oocyte quality is the main cause for ovary aging, which is related with infertility. Although some effective anti-aging natural components have been reported, highly efficient strategies for reversing ovary aging remain lacking. In this study, we reported that peptide elamipretide reserved ovary function for female fertility during maternal aging. Our findings demonstrated that elamipretide improved aged human oocyte maturation and fertilization. Elamipretide injection increased the litter size of aged mice, and improved oocyte quality with the reverse of follicle and embryo development defect. Metabolomic and transcriptomic analyses demonstrated that multiple biological processes in oocytes were significantly reserved. Both nuclear maturation and cytoplasmic maturation of aged oocytes were improved, showing with enhancing cytoskeletal dynamics, mitochondrial metabolism and organelle rearrangement. In vitro supplementation during culture also restored oocyte developmental competence in both mouse and porcine oocytes. Mechanistic analysis suggested that elamipretide reversed age-related ovarian damage via synergistic activation of the Vitamin B6-VEGF axis. Therefore, our study proposed a new peptide therapy for aging-induced infertility, showing that elamipretide reverses aged oocyte quality for fertility by promoting both nuclear and cytoplasmic maturation through the coordination with VEGF signaling pathway.