According to Nankai University, a groundbreaking study conducted by the School of Life Sciences and the National Key Laboratory of Medicinal Chemistry Biology's Developmental Biology and Stem Cell Team has brought new hope to women who suffer from infertility due to age or unknown reasons. The study has revealed in depth the age molecular clock - ribosome dysregulation - behind the decline in fertility in women after the age of 34, and preliminarily validated that the drug rapamycin can be a potential, safe, and effective treatment method to help patients with repeated in vitro fertilization (IVF) failures achieve successful pregnancy and live birth. This indicates that rapamycin may bring new breakthroughs in infertility treatment. This important research was jointly conducted by the Nankai team, Shanxi Children's Hospital (Shanxi Maternal and Child Health Hospital), the Sixth Medical Center of the People's Liberation Army General Hospital, Tianjin Medical University General Hospital, and other units. The results were published in the internationally renowned journal Cell Reports Medicine. As is well known, female fertility decreases with age, especially after the age of 35. But the specific reasons behind it, especially many cases of unexplained infertility, have been troubling scientists and doctors. The research team's work shows that when women reach the age of 34, significant transcriptome changes occur in their oocytes and surrounding cumulus cells. One of the most prominent features is the abnormally elevated transcription level of ribosomal genes. At the same time, consistent with previous reports, the expression of genes related to meiosis, actin, and mucin is downregulated in oocytes, and lysosome activity is reduced and protein homeostasis is disrupted in cumulus cells. Our work suggests that abnormal ribosome function is a previously overlooked driving force behind the decline in egg quality. This is not only a problem with the oocyte itself, but also with the surrounding helper cells, cumulus cells, which undergo similar changes and collectively affect the developmental ability of the egg and embryo. ”Li Jie, the first author of the article and a 2020 doctoral graduate in Cell Biology from Nankai University, said. Further mechanistic research reveals that the "overactivity" of ribosomal genes is closely related to epigenetic loss of control - specific genomic loci exhibit DNA hypomethylation and local reduction of H3K9me3 heterochromatin, similar to the disorder of the instruction system controlling gene "switches" in the nucleus, leading to abnormally high expression of ribosomal genes and increased synthesis of abnormal proteins. Based on these results, the research team attempted to conduct mouse intervention experiments using the drug rapamycin, which inhibits MTOR and ribosome translation, intervenes in aging, and is widely used to suppress immune rejection. The results indicate that rapamycin can effectively 'brake', reduce overall intracellular translation activity, and reshape protein homeostasis, thereby improving the ovarian microenvironment and egg quality. It is exciting that this study has been validated in clinical applications. Based on the aforementioned mechanism, the research team conducted a randomized controlled trial and confirmed that short-term treatment with rapamycin can enable patients with repeated IVF failures and embryonic development arrest to obtain high-quality blastocysts, and successfully achieve pregnancy and live birth. The preliminary results are encouraging and open up a new path for understanding and treating age-related infertility, "said Wu Xueqing, director of Shanxi Children's Hospital." However, larger scale, multi center clinical trials are still needed in the future to further validate its efficacy and optimize treatment plans