Could aging eggs be 'rejuvenated'? New tool may help pave the way to fertility-extending treatments
Scientists have taken a significant step toward understanding why human eggs become more susceptible to chromosomal errors as they age and whether this decline could be reversed in the future.
The research, published in November in the journal Nature Aging, introduces a novel tool that enables scientists to replicate the changes observed in eggs during the aging process. This technique, utilizing mouse egg cells, eliminates the need for researchers to wait for the mice to age or collect aged human eggs for study. It allows them to focus on the various factors contributing to an egg's decline.
While this research is still in its early stages, the study authors envision its potential to extend the reproductive windows of women who plan to have children later in life.
"Female reproductive aging is a significant source of inequity," said senior study author Binyam Mogessie, an assistant professor at the Yale University School of Medicine. "Women have to make choices men don't have to consider when deciding when to start a family." The trend in the U.S. shows a decrease in births among women under 30 and an increase in births among women over 30. This shift means more women are having babies at older ages, when the risk of chromosomal abnormalities begins to rise.
"Even if we can extend this reproductive window by just three years, it would have a profound impact on the lives of countless individuals," Mogessie told Live Science.
A Model of Aging Eggs
Women are born with all the egg cells they will ever have, and over time, these eggs are released through the menstrual cycle. Eggs that have not yet been released remain in the ovaries, where many can stay for decades.
Around age 30, the waiting egg supply shows a sharp increase in aneuploidy risk, indicating a higher likelihood of carrying an abnormal number of chromosomes (either more or less than 46). Studies reveal that the risk of egg aneuploidy grows almost exponentially after age 35, and then rises again at 40 and 45. These chromosomal abnormalities can lead to infertility, pregnancy loss, and genetic disorders in children, some of which can cause severe disability or death.
Scientists are still uncertain about the reasons behind the significant increase in aneuploidy risk with age. "The leading theory is that the forces holding these chromosomes together, before they are separated during fertilization, are progressively failing with age," Mogessie explained.
At various stages of an egg's cell cycle, its chromosomes contain two "sister chromatids" held together by molecular glue, which later separates. This glue is known to weaken with age, leading to chromatid separation issues that contribute to aneuploidy. However, Mogessie noted that this explanation doesn't fully account for the sharp rise in chromosomal errors starting around age 30.
To investigate this mystery, the researchers developed an experimental setup to trigger "aging-like" changes in eggs and observe subsequent changes using high-resolution time-lapse microscopy. A crucial component of the model was the use of the gene-editing system CRISPR to modify a critical component of the molecular glue holding chromosomes together: a protein called REC8.
This modification added a switch to REC8, which, once toggled "on," would cause the protein to degrade. By using this system, scientists could precisely control the degree of REC8 breakdown in an egg, simulating the natural aging process.
"In animals, it can take years; in humans, it can take decades for these processes to arise," Mogessie said. "But the new technique allows us to do this within 60 to 90 minutes."
Paving the Way to Future Treatments
The team demonstrated that degrading REC8 to varying degrees led to errors in chromosome splitting and aneuploidy, similar to what is observed in naturally aged eggs. This also enabled them to identify a specific threshold of REC8 loss where the rate of errors suddenly spiked.
While the loss of REC8 could trigger these issues, scientists are aware that eggs decline in multiple ways with age. To model this, the team manipulated other proteins involved in holding chromosomes together and filaments that pull them apart when the time is right. These perturbations accelerated the rate of chromosomal errors beyond what was seen with REC8 loss alone.
Taken together, these findings suggest that the breakdown of chromosomes' molecular glue likely sets the stage for aneuploidy. However, the sudden spike observed in people in their 30s and 40s is attributed to the "synergistic failure" of multiple parts of this chromosome-separating machinery, according to the team.
Further research is necessary to fully understand the impact of aging on eggs, but the new model should facilitate such work. "The mouse model provides consistency," noted researcher Mihalas. Given the ethical challenges and limitations of working with human eggs, "it's the best model we have," she added.
In the long run, the model could be used to screen for and test the effects of potential treatments. There may be a way to reverse the aging process and help eggs divide reliably with fewer chromosomal errors, similar to how they would at younger ages.
"It really sets the scene for preventive measures aimed at improving the quality of eggs, at least in an IVF clinic setting," Mogessie said. "I think that would have a huge impact."
Disclaimer
This article is for informational purposes only and is not meant to offer medical advice.
