Based on Aging activates escape of the silent X chromosome in the female mouse hippocampus published in Science Advances 2025
Why do women’s brains age differently?
Women often live longer than men and tend to show slower mental decline as they age. While many
factors contribute to this, scientists are now focusing on a unique feature of female biology: the second X
chromosome. Men have only one X, but women have two — and while one of them (called the inactive X
or Xi) is mostly turned off, it still sits quietly in every cell. Recent research shows that this “silent” X isn’t
completely inactive. In fact, as women age, some genes on the Xi start to become active again, and this
could play a key role in protecting the brain.
What happens to the X with age?
A new study looked closely at how aging changes the activity of the X chromosomes in brain cells. Using
a powerful tool called allele-specific single-nucleus RNA sequencing, researchers studied brain cells in
aging female mice. They discovered that aging changes gene activity on both the active X and the
inactive X, especially in brain regions involved in learning and memory, like the hippocampus. Some
genes on the Xi — which are usually off — started to “escape” and turn back on. This reactivation was
seen in important areas like the dentate gyrus, which plays a key role in forming new memories.
Can this help the brain?
One of the genes that became active with age was Plp1, a gene involved in making myelin — the
protective coating around nerve cells. Myelin helps brain cells send signals quickly and efficiently, and it
tends to break down with age. When researchers increased Plp1 levels in the dentate gyrus of aging mice
(both male and female), the animals showed improved memory and learning abilities. This suggests that
turning on certain genes from the inactive X could actually help the aging brain work better.
Why does this matter?
The X chromosome holds many genes linked to brain health, memory, and cognitive function. If women
can “reactivate” some of these genes with age, it could give them an edge when it comes to resisting
age-related cognitive decline. This may help explain why women often have stronger memory in early
stages of diseases like Alzheimer’s. However, not all genes that escape from the inactive X are helpful.
Some may actually worsen brain inflammation or disease. That’s why researchers are working to figure
out which genes protect the brain — and which may cause harm.
DR HUNT’s opinion
These discoveries could one day lead to new ways to treat or prevent cognitive decline in both women
and men. If scientists can safely activate specific helpful genes, like Plp1, it may be possible to boost
brain function or slow the effects of aging. Since some of these genes are naturally reactivated in women
as they age, they could hold clues for new therapies. There’s still a lot to learn, but this research opens
the door to a completely new approach to brain aging — starting with the power of the “inactive” X.