Molecular profiling of AMA oocytes: from basic biology to improving fertility in aged women

In a world where more and more women are delaying motherhood, age-related fertility decline poses a significant challenge. Age-related infertility is primarily attributed to oocytes, as they diminish in both quantity and quality as women age. The deteriorating quality of ageing oocytes is closely associated with aneuploidy and alterations in cytoplasmic content. Nevertheless, the precise mechanisms driving this decline in oocyte quality remain unclear. The objective of the thesis studies was employed cutting-edge omic technologies to unravel the molecular intricacies of the oocyte maturation process and to determine the extent to which they are impacted by age and reflected in oocyte quality. Comprehensive molecular profiling was conducted on a substantial number of human oocytes sourced from women spanning nearly two decades of reproductive life and two oocyte maturation stages. This effort resulted in the creation of an innovative dataset. This research uncovered crucial insights into the transcriptomic, DNA methylation, and proteomic landscape of human oocytes, establishing a significant connection with maternal age. The findings highlight distinctive changes in both transcript and protein abundance during oocyte meiotic maturation, while CpG methylation levels exhibit remarkable consistency. Notably, most of these changes are evident in both young and advanced maternal age oocytes. Additionally, age-related modifications in oocytes are predominantly observed at the protein level. Specifically, several proteins crucial for meiosis control and proteostasis exhibited a decline with age, particularly within immature oocytes. This includes noteworthy changes in the proteasome complex which has also been validated to have a pivotal role in human oocyte maturation. The observed alterations in proteasome quantity, combined with other identified changes, likely contribute to the reduction in oocyte quality. The resulting dataset holds immense potential for informing the scientific community about oocyte ageing, offering valuable insights that can aid ongoing and future age-related studies in humans and other species. In conclusion, proteasome complex is proposed as a promising target for future interventions and treatments aimed at enhancing oocyte quality in reproductively aged women.