In a recent study, researchers identified that an increase in the expression of ribosome-related genes and a loss of protein homeostasis contribute to the age-related decline in female fertility. Rapamycin restored this balance and increased fertility rates in a human trial [1].
The first system to age
The loss of fertility is one of the first signs of aging in women, with the first signs of fertility decline occurring around the mid-thirties. This fertility decline is primarily attributed to decreased oocyte quality and quantity. However, many more molecular changes occur in the oocyte and the surrounding cells, such as cumulus and granulosa cells.
In this study, the researchers investigated molecular changes in aging oocytes and cumulus cells and tested a possible intervention for improving clinical fertility outcomes.
Loss of balance
Analyzing the gene expression of the oocytes and cumulus cell samples donated for this study, along with an independent cohort dataset of oocytes from women of different ages, showed age-related changes with a “distinct shift in oocyte gene expression profiles” that “emerged around the age of 34.” Among the various pathways that were impacted by age, the researchers specifically noted that increased age was correlated with an enrichment in ribosome signaling and increased expression of ribosome-related genes, suggesting a link between ribosome dysregulation and oocyte aging.
Cumulus cells showed even more age-related changes in gene expression. Among many affected processes, those related to ribosomes were also increased in aging cumulus cells.
Ribosomes are cell structures where the translation of RNA into protein occurs; therefore, disruptions in ribosome-related processes might suggest disrupted protein homeostasis, which is exactly what researchers have observed in the cumulus cells. Specifically, those cells showed the presence of protein aggregates. The authors suggest that such aggregates can be there for two reasons: an increase in synthesis or a decrease in degradation.
The researchers observed both problems. There was decreased gene expression relating to lysosomes and proteasomes, both of which play a role in protein degradation, and a decrease in the activity of lysosomes with age. 18S and 28S rRNAs, key structures in ribosomes, were increased with age in cumulus cells, which suggests a related increase in translation and protein synthesis. This was further confirmed by additional tests.
However, the researchers also noted that rapamycin, a well-known drug in the aging field, reduced the increase in age-related protein synthesis in cumulus cells, helping restore the disrupted protein homeostasis.
Regulating gene accessibility
Changes in gene expression can result from changes in DNA methylation. The researchers observed that DNA methylation levels were modestly increased in aging oocytes, and the pattern of changes suggests that methylation might be responsible for the age-related changes in gene expression in oocytes, at least for some genes.
Cumulus cells showed minimal changes in DNA methylation; however, the changes that were present suggested that they might impact the expression of ribosome-related genes.
Along the same lines, the researchers observed changes in chromatin composition. Chromatin is a DNA and protein complex. Changes in its composition can make genes more accessible (euchromatin) or less accessible (heterochromatin) for transcription.
The heterochromatin levels in cumulus cells differed in young and old cells, showing an overall decrease in the level of heterochromatin with age. In young cells, heterochromatin-rich areas were associated with genes related to ribosome biogenesis, while in the old cells, heterochromatin-rich regions were associated with negative regulation of translation. Additionally, heterochromatin levels related to ribosome-related genes were decreased in old cumulus cells. All this suggests that the transcription of ribosomal biogenesis- and translation-related genes might be inhibited at the chromatin level in young cells, but aging reduces this inhibition, resulting in increased transcription of ribosomal genes.
Such regulation on the chromatin composition level was also observed for the lysosome-related genes, and it was correlated with a decrease in the expression of lysosome-related genes.
Delaying fertility loss in mice
Since the researchers observed an increase in ribosome-related gene expression, which suggests an increase in translation in aged oocytes and cumulus cells, they hypothesized that decreasing these processes might help delay the reduction in fertility. They first tested this assumption in mice, which showed similarities in gene expression changes with humans.
Comparison of rapamycin-treated ovaries from young (2-month-old) and old (10-month-old) mice showed that rapamycin reduced translation and ribosome biogenesis. In old cells, rapamycin inhibited the activity of senescence-related markers and decreased reactive oxygen species (ROS) levels. Rapamycin also reduced chromosomal abnormalities that are increased in aged oocytes, which suggests that rapamycin helps to delay oocyte aging.
More babies
Most importantly, the researchers continued by conducting a controlled clinical trial with 100 women undergoing in vitro fertilization (IVF). Half of the participants received only the standardized GnRH agonist long protocol, a standard IVF treatment; the other half received the same treatment, combined with 1mg rapamycin treatment for 21-28 days.
The authors note that “significantly more zygotes, embryos, and good-quality embryos were obtained in the rapamycin group than in the control group.” Comparing oocyte retrieval and embryo development between the groups, the researchers concluded that rapamycin treatment “can effectively improve oocyte quality and subsequent embryo development following the fertilization of retrieved oocytes.”
They also observed higher rates of pregnancy in females who took rapamycin compared to controls (50.0% vs. 28.2%) without a negative impact on live birth. However, they note that when they compared data regarding different stages of embryo transfer, they observed that it might be more beneficial for patients who take rapamycin to transfer their embryos at the 5- to 6-day stage instead of the 3-day stage.
Real-life benefits
All in all, in this study, the researchers identified that increased levels of ribosome-related genes and disruptions in proteostasis have a negative impact on oocytes and surrounding cells, contributing to age-related fertility problems.
Using rapamycin to remedy those issues resulted in improved ovarian functioning and increased fertility not only in mouse models but in human females undergoing IVF. While the trial results are encouraging, the researchers suggest optimization of dosage and duration of treatment might yield even better effects; however, for this, a trial with a higher number of participants might be required.
Literature
[1] Li, J., Wang, H., Zhu, P., Chen, H., Zuo, H., Liu, C., Liu, L., Ye, X., Feng, G., Wu, Y., Liu, Q., Yang, T., Keefe, D. L., Bai, X., Shang, W., Wu, X., & Liu, L. (2025). Ribosome dysregulation and intervention in age-related infertility. Cell reports. Medicine, 102424. Advance online publication.
