Scientists at the University of California, San Francisco (UCSF) may have uncovered a key reason why women tend to outlive men and maintain better cognitive function as they age.
Their research suggests that the female brain has a hidden advantage—one that comes from the second X chromosome.
For years, scientists believed that the second X chromosome in females was mostly inactive. In every cell, one X chromosome remains “silent,” forming a structure called the Barr body.
Since men have only one X chromosome, researchers didn’t think the extra one in women played much of a role.
However, this new study reveals that in older age, the supposedly inactive X chromosome “wakes up” and starts helping the brain, potentially slowing cognitive decline.
The study, led by Dr. Dena Dubal and published in Science Advances, provides the first clear evidence that this second X chromosome becomes active in older female brains, boosting brain function and resilience in aging.
The Silent X Comes Back to Life
To investigate whether the second X chromosome had any unexpected activity, the UCSF team designed an experiment using genetically engineered mice. They created female mice with two different types of X chromosomes, allowing them to track whether genes from the “silent” X were being expressed.
The researchers examined the hippocampus, a brain region crucial for learning and memory, in female mice that were around 20 months old—the equivalent of a 65-year-old human. They expected to see only the genes from the active X chromosome at work, but to their surprise, about 20 genes from the supposedly silent X chromosome were also active.
These genes included several that are important for brain development and function. The team believes this genetic activity may explain why women’s brains typically show fewer signs of cognitive decline than men’s as they age.
“Aging had awakened the sleeping X,” said Dr. Dubal.
Graduate student and first author of the study, Margaret Gadek, noted that this discovery could explain why women tend to have more cognitive resilience than men. “Men don’t have this extra X chromosome, so they wouldn’t have this benefit,” she said.
A Key Gene That Protects the Aging Brain
Among the genes that became active, one stood out: PLP1. This gene plays a crucial role in producing myelin, a fatty substance that insulates nerve fibers and helps brain signals travel efficiently. Myelin is essential for brain function, and as people age, their myelin levels decline, leading to slower thinking and memory problems.
The researchers found that older female mice had higher levels of PLP1 in their brains than older male mice, suggesting that the second X chromosome was giving them a protective boost.
To test whether PLP1 was responsible for the improved brain function, the scientists artificially increased PLP1 levels in the brains of both male and female older mice. The results were striking—both sexes performed better on learning and memory tests when they had more PLP1, confirming its role in brain resilience.
Could This Apply to Humans?
The next step for the researchers was to see if the same thing happens in human brains. To do this, they analyzed donated brain tissue from older men and women, with the help of Dr. Kaitlin Casaletto from the UCSF Memory and Aging Center. Their findings supported the mouse study—only women had elevated PLP1 levels in their brains.
This suggests that the second X chromosome may provide a natural advantage for cognitive aging in women. However, it also raises an exciting question: Could boosting PLP1 help men and women stay mentally sharp as they age?
What This Means for the Future
Cognitive decline is one of the biggest health challenges of aging, and this study opens the door to new possibilities. If researchers can figure out how to activate the beneficial genes on the X chromosome—like PLP1—they might be able to slow down memory loss in both men and women.
“Things are changeable in the aging brain,” said Dr. Dubal. “The X chromosome clearly has something to teach us about what’s possible.”
The team now hopes to explore whether specific treatments could enhance the protective effects of PLP1, potentially leading to new therapies for Alzheimer’s and other age-related brain conditions.
This discovery sheds light on an important biological difference between men and women and may help explain why women generally live longer and maintain their cognitive abilities better. With further research, scientists may be able to harness this natural advantage to help everyone age with a sharper mind.
If you care about Alzheimer’s, please read studies about the likely cause of Alzheimer’s disease , and new non-drug treatment that could help prevent Alzheimer’s.
For more information about brain health, please see recent studies about diet that may help prevent Alzheimer’s, and results showing some dementia cases could be prevented by changing these 12 things.
The study is published in Science Advances.
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