It is well established that female fertility decreases with age, and that this is largely due to diminishing oocyte quality that can impair embryo development and cause failure of assisted reproductive technology such as in vitro fertilization (IVF). Aneuploidy is one of the leading causes of reproductive aging, and factors contributing to it include precocious separation of sister chromatids, chromosome misalignment, spindle disruption, and deficient spindle checkpoints. Other contributors to ovarian aging include DNA damage responses, oxidative stress, mitochondrial dysfunction, telomere attrition, autophagy, inflammation, and fibrosis. Previous studies focusing on single-cell sequencing methods have typically grouped individuals as “young” or “old.” This study, however, used transcriptome analysis through correlation analysis with age and other factors to characterize molecular changes in aging oocytes and the cumulus cells (CCs) surrounding them. This study was conducted using a mouse model and subsequent human models, with the human models including 100 patients undergoing IVF after previous failure of more than one IVF cycle as a clinical trial of rapamycin. Exclusion criteria for these patients were a history of endometriosis, cancer, chronic infections, and autoimmune or genetic disease, or a diagnosis of male factor infertility. Standard long GnRH agonist protocols, oocyte retrieval, fertilization, and planned embryo transfer were used. Patients were randomized to either the control or rapamycin group. The primary outcomes were oocyte number and embryo number, and the secondary outcome was the rate of clinical pregnancy. A total of 71 oocytes and 114 CC samples were obtained from human donors, and showed that the antral follicle count, number of follicles greater than 12 mm, number of oocytes retrieved during IVF, and estrogen levels all decreased with age, and the levels of follicle-stimulating and luteinizing hormones increased, consistent with expectations based on previous evidence. Sequencing of RNA showed cutoffs of correlation coefficients at 0.4 for oocytes and 0.5 for CCs, which produced significant differences between age and gene expression. A significant shift was identified around age 34, showing 517 downregulated and 253 upregulated genes in older oocytes. Age-related changes were more prominent in CCs than in oocytes, with 2181 downregulated and 396 upregulated genes. Aging showed significant differences in several mechanisms, including ribosome dysregulation and DNA methylation in both oocytes and CCs. In light of these observed mechanisms, a clinical trial was performed to test whether rapamycin could improve oocyte quality, embryo development, and clinical pregnancy rates in IVF for patients with more than one previous IVF cycle failure. A significantly increased number of zygotes, embryos, and embryos of good quality were identified in the rapamycin group ( P = 0.012 for zygotes, P = 0.001 for embryos, and P < 0.001 for good-quality embryos). A total of 40 patients in the rapamycin group and 39 patients in the control group had undergone embryo transfer at the time of this paper, with a significantly increased clinical pregnancy rate in the rapamycin group ( P = 0.047). When separated based on embryo stage (day 5 to 6 blastocyst vs day 3 embryo), this difference was driven by the blastocyst transfers ( P = 0.021). Live birth rate to date was not significantly different between groups. These results indicate that increasing transcription of ribosome genes as individuals age can at least partially explain poor embryo development and fertility associated with age. This confirms previous findings as well as more fully characterizes some mechanisms, and also shows that this increase in transcription is in conjunction with increased protein aggregation and disrupted proteostasis in CCs. This is further validated by the preliminary success of rapamycin in the clinical portion of this study, which should be explored more fully in larger and more diverse cohorts. Future research should also assess other methods of targeting ribosome dysregulation to improve fertility in multiple contexts. (Summarized from Li J, Wang H, Zhu P, Chen, et al. Ribosome dysregulation and intervention in age-related infertility. Cell Rep Med. 2025; 6(11):102424. doi: https://doi.org/10.1016/j.xcrm.2025.102424)
David L. Keefe (Sun,) studied this question.