Human egg cells are often prone to chromosomal errors. As women age, the error rate increases sharply - and can contribute to infertility, pregnancy loss, and genetic disorders. Yet why this sudden rise happens remains unknown.
In a new study, Yale researchers take one step closer to finding an answer.
Writing in the journal Nature Aging, they describe a rapid and controllable method they've developed to simulate "aging-like" chromosome errors in mouse eggs without waiting for the animals to age. Using this method, they found that a combination of failures - from the partial loss of an essential protein to weakened connections between chromosomes - can cause errors that increase with maternal age.
The method, researchers say, can be used to study and eventually prevent chromosome abnormalities in the eggs of older women.
"In the long run, understanding and ultimately extending reproductive longevity in females could have far-reaching implications, not only for fertility and healthy aging, but also for enabling women to make life and career choices without being limited by a narrow reproductive window, thereby promoting equality of opportunity between women and men in at least one fundamental way," said Binyam Mogessie, assistant professor of Molecular, Cellular, and Developmental Biology, and of Obstetrics, Gynecology, and Reproductive Sciences at Yale University and corresponding author of the new study.
In women, reproductive aging is accompanied by a sharp increase in rates of egg aneuploidy, or an abnormal number of chromosomes in egg cells, also called oocytes. Egg aneuploidy is a leading cause of infertility, pregnancy loss, and genetic conditions. Yet there still isn't a lot known about why egg aneuploidy increases as women age. The underlying chromosomal errors develop over years in mice and decades in humans, making them nearly impossible to study directly.
Prior studies have found that a multiprotein complex known as cohesion - the molecular glue that holds sister chromatids together - gradually weakens with age and contributes to chromosome errors. But it hasn't been clear whether cohesion weakening is the sole cause of egg aneuploidy or if other age-related changes also play a role.
For the new study, the researchers investigated that by creating a so-called "synthetic oocyte aging" system in mouse eggs to rapidly and precisely decrease the levels of a key cohesion protein, known as REC8.
Specifically, they used CRISPR genome editing to modify REC8, which holds chromosomes together and is one of the most reliable molecular markers of age-related decline in cohesion. And for the first time, the researchers used time-lapse microscopy to image REC8 dynamics in mouse eggs at high resolution, showing exactly how cohesion changes as eggs prepare to divide.
Then, the researchers used protein degradation systems, which use molecules to bind to and break down specific proteins, to quickly and precisely remove REC8 and other components from the eggs. Using advanced 3D live imaging, they tracked chromosome movements in real-time and observed aging-like segregation errors, including chromatid splitting events that lead to aneuploidy.
Finally, by selectively disrupting two other parts of the cell - the actin cytoskeleton and the centromere protein A (CENP-A) - they found that each of those disruptions significantly increased error rates, closely resembling the phenomenon observed in naturally aged eggs.
Through their method, the researchers discovered that chromosomal abnormalities in aging eggs therefore result from a combination of failures, ranging from a drop in REC8 levels to the gradual breakdown of cellular parts that organize the spindle (a cellular structure that helps to separate chromosomes accurately) and the centromere (the region that links sister chromatids).
"These systems typically work together to ensure that each egg receives an exact copy of every chromosome," Mogessie said. "However, as they progressively decline with age, their failures tend to cluster within a narrow reproductive window, resulting in poor-quality eggs that are significantly less likely to support healthy embryo formation and growth."
These findings may help explain why fertility drops so sharply in a person's late 30s and early 40s rather than declining gradually over time. Ultimately, researchers say, this could guide strategies that extend the female reproductive lifespan, enabling more people to build families when they're ready, without being so limited by biology's timeline.
"In a world where infertility rates are rising and family planning is increasingly postponed, understanding and protecting the biology of the egg is not only a scientific challenge but also a societal one," Mogessie said.
For the researchers, the next steps include turning their "synthetic oocyte aging" system into a high-throughput screening platform (HTS), a drug discovery process often used in the pharmaceutical industry.
Other Yale authors include Jiyeon Leem and Tom Lemonnier, who are postdoctoral scientists in Mogessie's lab; Lei Tian and Xiaojun Xing, research associates in the Yale Genome Editing Center; and Suxia Bai and Timothy Nottoli, research scientists in the Department of Comparative Medicine at Yale School of Medicine.
Grants from the Wellcome Trust, the National Institutes of Health, the Human Frontier Science Program, and the National Research Foundation of Korea supported this study.
