Insufficiency of melatonin in follicular fluid is a reversible cause for advanced maternal age-related aneuploidy in oocytes

Age-related decline in female fertility is a common feature that occurs in the fourth decade of women as a result of a reduction in both oocyte quality and quantity [1]. However, strategies to prevent the deterioration of maternal aged oocytes and relevant mechanisms are still underexplored. Here, we find that the reduced abundance of melatonin in the follicular fluid highly correlates with the advanced maternal age-related aneuploidy. Of note, we show that exposure of oocytes from aged mice both in vitro and in vivo to exogenous melatonin not only eliminates the accumulated reactive oxygen species-induced DNA damage and apoptosis, but also suppresses the occurrence of aneuploidy caused by spindle/chromosome defect that is frequently observed in aged oocytes. Importantly, we reveal that melatonin supplementation reverses the defective phenotypes in aged oocytes through a Sirt1/Sod2-dependent mechanism. Inhibition of Sirt1 activity abolishes the melatonin-mediated improvement of aged oocyte quality. Together our findings provide evidence that supplementation of melatonin is a feasible way to protect oocytes from advanced maternal age-related meiotic defects and aneuploidy, demonstrating the potential for improving the quality of oocytes from aged women and the efficiency of assisted reproductive technology.