Scientists have taken an important step toward understanding why human eggs become more prone to chromosomal errors as we age, and whether the decline could one day be avoided.
The study, published in November in the journal Nature Aging, introduces a new tool that allows scientists to reproduce the changes seen in eggs during the aging process. Using mouse egg cells, this technique allows researchers to focus on the different forces that can contribute to egg attrition, without having to wait for mice to age or collect aging human eggs for study.
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Although this research is still in its early stages, the study authors hope that ultimately it will help expand the fertile window for women who plan to have children in the future.
“Ageing in female fertility is a major source of inequality,” said study lead author Binyam Moghese, assistant professor of medicine at Yale University. When considering when to start a family, “women have to make choices that men have to make.” Notably, in the United States, the birth rate for those over 30 years of age is increasing, while the birth rate for those under 30 years of age is currently on the decline. That means more women are having children at an older age, when the rate of chromosomal abnormalities begins to rise.
“Even if we could extend this reproductive period by three years, it would have a huge impact on the lives of so many people,” Moghesi told Live Science.
aged egg model
Women are born with all their egg cells, and over time, those eggs are released through the menstrual cycle. Eggs that have not yet been released hang out in the ovary, and many will remain there for decades.
Around the age of 30, the risk of aneuploidy in this waiting period for egg supply increases rapidly. This means that the egg is more likely to have an abnormal number of chromosomes (more or less than 46). Research shows that the risk of egg aneuploidy increases almost exponentially after age 35, and then spikes again at age 40 and 45. These chromosomal abnormalities can contribute to infertility and miscarriage in women, as well as genetic disorders in children. This may cause severe disability or death.
Scientists still don’t know why the risk of aneuploidy increases so much with age. “A leading theory is that the force that holds these chromosomes together before they separate at fertilization gradually declines with age,” Moghesi said.
At different points in the egg’s cell cycle, each of its chromosomes contains two “sister chromatids” held together by molecular glue, and the sisters are later pulled apart. This glue weakens with age and is known to cause chromatid segregation problems that contribute to aneuploidy. But that doesn’t tell the whole story. Moghese said there is no explanation why chromosomal abnormalities increase rapidly around the age of 30.
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To investigate this mystery, researchers developed an experimental setup that uses high-resolution time-lapse microscopy to induce “aging-like” changes in eggs and then observe how they change. A key part of the model was using the gene editing system CRISPR to fine-tune a protein called REC8, a key component of the molecular glue that holds chromosomes together.
This tweak added a switch to REC8 that, when turned “on,” degraded the protein. Using this system, scientists were able to tightly control the extent of REC8 degradation in eggs and simulate what occurs naturally during aging.
“In animals, these processes can take years to occur, but in humans they can take decades,” Moghesi said. But with new technology, “we can do this within 60 to 90 minutes.”
Previously, Mogessie and his collaborators had tinkered with REC8 using antibodies in a similar way, but Mihalas noted that this required injecting the antibodies into delicate egg cells, a finicky and labor-intensive process that made it difficult to control the extent of degradation. Advantages of the new system include eliminating the need for egg injection and allowing for more precise adjustment of REC8 levels. “It’s very elegant,” she said.
Paving the way for future treatments
The researchers demonstrated that varying degrees of degradation of REC8 led to chromosome segmentation errors and aneuploidy, as would be expected to be seen in naturally aged eggs. This also allowed us to pinpoint the specific threshold of REC8 loss at which the error rate suddenly spikes.
Loss of REC8 can cause these problems, but scientists know that eggs decrease even more with age. To model this, the researchers tinkered with other proteins involved in holding chromosomes together, as well as the filaments that pull them apart at the right time. These perturbations increased the rate of chromosomal errors beyond that seen with REC8 deletion alone.
Taken together, these results suggest that disruption of the molecular glue of chromosomes is likely to prime the stage for aneuploidy. But the sudden spike seen in people in their 30s and 40s is likely due to a “synergistic failure” of multiple parts of this chromosome segregation machinery, the researchers said.
Further research is needed to fully understand the effects of aging on eggs, but new models should enable such studies. “Mouse models provide consistency,” Mihalas said. Given the ethical challenges and limitations of working with human eggs, “this is the best model we have,” Mihalas added.
In the long term, this model could be used to screen and test the effectiveness of potential treatments. There may be a way to turn back the clock and reduce chromosomal errors to ensure eggs divide as they did at a younger age.
“At least in IVF, this is the stage for preventive measures aimed at improving egg quality.” [in vitro fertilization] “I think the setting of the clinic has a huge impact,” Moghese said.
This article is for informational purposes only and does not provide medical advice.
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