Women hear the loaded reminders far too often: if you want to have children, you’d better do it before it’s too late. But why is it that eggs get less fertile as time passes?
“Even if a woman is still ovulating, the quality of the egg decreases with age,” says Greg Fitzharris at the University of Montreal, Canada. “The best proof of that is that if you have donor eggs from younger women, all of a sudden fertility is increased.”
Women are thought to be born with all their eggs, but these undergo several further cell divisions to create an embryo. Previous studies have shown that in ageing eggs, chromosomes stick together less well. This reduced cohesion causes them to prematurely separate during cell division, creating eggs that don’t have the right number of chromosomes – a state called aneuploidy – which usually renders them infertile.
“When loss of cohesion was suggested as a cause of female infertility, people thought, that’s it, we found the one cause,” Fitzharris says. “But there are certain types of aneuploidy that are well explained by cohesion loss. And there are other types that are harder to explain.”
Now Fitzharris’s team has identified a second reason why the eggs of female mammals become less fertile with age. Comparing cells from young and old mice, they discovered that the first phase of egg division in older eggs was chaotic.
This was caused by microtubules, the structures that direct the movement and traffic of a cell’s contents when a cell is replicating. Microtubules normally corral chromosomes to opposite ends of a dividing cell, so that they can be split evenly in two. But in half the cells taken from old mice, the team observed microtubules sending chromosomes in different directions, causing clumps in three or four different spots, instead of just to two opposite camps.
Later on, these cells began to look more normal, but the damage has already been done, says Fitzharris – when division is complete, the egg is more likely to have the wrong number of chromosomes.
Swapping the nuclei of young eggs with those from old eggs showed that it is the age of the egg cell itself, and not the chromosomes inside the nucleus, that seems to cause this problem. When given a young nucleus, older cells still had dysfunctional microtubules, and younger eggs hosting the older nuclei didn’t show chaotic cell division.
“Since they didn’t have a problem, it implies that there’s something about that aged cytoplasm, the big volume of that cell, that’s not able to direct the chromosome segregation machinery,” says Francesca Duncan, a reproductive biologist at Northwestern University, Illinois.
Forming correctly arranged microtubules and segregating chromosomes requires energy, so it could be due to ageing mitochondria – the powerhouses of the cell – which are known to produce less energy.
“Understanding why mis-segregation of chromosomes is taking place might equip us to do experiments where we can make older eggs behave like younger ones, but that’s in a distant future,” Fitzharris says.
Journal reference: Current Biology, DOI: 10.1016/j.cub.2017.02.025