In a new study, Yale researchers found aging weakens the structures that help eggs reduce their chromosome numbers accurately.
Super-resolution image of the intricate chromosome division machinery in a young mouse oocyte. At metaphase I, homologous chromosomes (green) are positioned within the spindle’s network of microtubules (orange). Centromeres (magenta) mark the sites where chromosomes connect to this machinery, helping ensure that the egg receives the correct number of chromosomes. Image courtesy of Binyam Mogessie / Yale University
As many as 1 in 6 adults face fertility difficulties worldwide, research has shown, and the challenge become harder as they age. Starting around age 35, the risk of eggs carrying an abnormal number of chromosomes rises steeply, contributing to declining fertility and increasing miscarriage rates. Understanding why these errors occur is essential for improving reproductive outcomes.
A new Yale study offers new insights that could improve outcomes for these individuals and families.
According to their findings, the structures that help eggs reduce chromosome numbers accurately before fertilization become weaker as people age. This is problematic because eggs must halve their chromosome number to assure that fusion with a sperm restores the correct number needed for health embryo development.
The researchers also identified how three proteins cooperate to maintain these critical structures. Restoring one of these components to the structures that anchor chromosomes improved chromosome positioning in aged eggs, they found, revealing a contributor to declining egg quality and a potential direction for research into preserving reproductive health.
“By identifying a previously unknown contributor to chromosome errors, our findings open a direction for research into preserving egg quality and improving assisted reproduction, including in vitro fertilization,” said Binyam Mogessie, an assistant professor of molecular, cellular and developmental biology in Yale’s Faculty of Arts and Sciences, assistant professor of obstetrics, gynecology and reproductive sciences at Yale School of Medicine, and senior author of the study.
The study was published in the Journal of Cell Biology.
Essential connections
Mogessie’s lab has long studied why eggs lose their ability to divide accurately with age, with consequences for fertility, miscarriage, and embryo development.
For the new study, he and his team wanted to understand how aging affects the connection between chromosomes and the machinery that propels them during division. Centromeres — the specialized chromosome regions that connect chromosomes to the machinery that separates them — build this essential connection, making their deterioration a potential source of chromosome errors and an important target for understanding reproductive aging.
Before the new study, the Yale team knew that aging weakens the molecular glue that holds chromosomes together, increasing the risk of eggs receiving the wrong number of chromosomes. How additional molecular defects combine with this weakened glue and accelerate chromosome abnormalities has remained poorly understood, Mogessie said. It’s also been difficult to test directly in naturally aged eggs, where many changes occur simultaneously.
For the study, the researchers investigated whether weakening centromeres could be an additional cause of chromosome errors in aging eggs. They focused on three proteins — CENP-A, CENP-B, and CENP-C — that are components of centromeres.
They combined studies of naturally aged eggs from mice with experiments that recreate specific features of aging in young eggs within hours. First, they measured centromere proteins in young and aged eggs. Then they used targeted protein degradation, a technique that directs the cell to remove a selected protein, to reduce CENP-A in the young eggs. With quantitative, high-resolution live microscopy, they tracked how chromosomes moved, lined up, and separated during division.
To test whether they could correct the resulting defects, the researchers supplied additional CENP-C. They repeated this experiment in eggs lacking CENP-B to determine whether the improvement depended on cooperation between these proteins. Finally, they supplied additional CENP-C to eggs collected from older mice to test whether the same approach could improve chromosome positioning.
Restoring chromosome positioning
The researchers found that naturally aged eggs have lower levels of CENP-A and CENP-C proteins at their centromeres. Reducing CENP-A in young eggs by the same amount lost during natural aging caused chromosomes to become incorrectly positioned and lag behind during division. In separate rescue experiments, additional CENP-C partially corrected defects caused by CENP-A depletion, provided CENP-B was present. This revealed how the three proteins cooperate to support accurate chromosome separation. Increasing CENP-C also improved chromosome positioning in naturally aged eggs.
Together, these findings establish a functional link between centromere weakening and chromosome errors, identifying a contributor to the decline in egg quality over time and showing that an aspect of this age-related dysfunction can be improved experimentally.
“Understanding how centromere weakening interacts with other age-related changes could help researchers develop treatments that address several sources of dysfunction together, with the long-term goal of reducing chromosome abnormalities and improving the chances of a healthy pregnancy,” Mogessie said.
The findings also speak to a broader challenge in women’s health, he added. The reproductive window narrows as many women are establishing careers or seeking the circumstances in which they want to start a family.
“Extending healthy reproductive life by even a few years could give people greater freedom to decide whether and when to have children,” Mogessie said. “Understanding the cellular causes of reproductive aging is essential to achieving that goal.”
Source: Yale University