Reawakened X chromosome may help protect aging female brain, study finds
A 3D illustration of an X chromosome showing its internal DNA structure. (Adobe Stock Photo)
A new study suggests that genes from the so-called silent X chromosome in women may reactivate later in life, potentially offering protection against cognitive decline.
The research may explain why women often experience slower cognitive aging than men and could lead to new strategies to preserve brain function.
The findings, led by researchers at the University of California, San Francisco (UCSF), were published in Science Advances on March 5. While the study was done in mice, supporting evidence from human brain tissue suggests the same process could occur in people.
X chromosome reactivation may explain women’s cognitive resilience
Unlike men, who carry one X and one Y chromosome, women typically have two X chromosomes.
- However, one X is silenced early in development to avoid excessive gene activity
- This inactive X, long believed to stay dormant, appears to come back to life as women age
- Researchers discovered that older female mice began expressing genes from the silent X chromosome in the hippocampus, a brain region critical for memory and learning
“Aging had awakened the sleeping X,” said Margaret Gadek, the study’s first author and a graduate student in UCSF’s MD-PhD program.
This reactivation may offer insight into why women generally maintain cognitive abilities longer than men, despite living longer.
Reawakened gene may support myelin, brain signal transmission
Among the 22 genes that became active again in older female mice, one stood out: PLP1.
- Why it matters: This gene plays a key role in producing myelin, a fatty substance that coats nerve fibers and allows brain signals to move quickly and efficiently.
- Study finding: Older female mice had higher levels of PLP1 in the hippocampus compared to older males
- Testing: To test its effect, scientists used gene therapy to increase PLP1 in both sexes
- Result: Better learning and memory performance in both male and female mice
The PLP1 gene was particularly active in oligodendrocytes, brain cells responsible for producing myelin. The study found that increasing PLP1 in these cells improved cognitive performance, even when introduced late in life.
Human brain tissue study shows higher PLP1 levels in older women
To see if this process occurs in humans, the researchers analyzed brain tissue from older adults.
They found that only women had elevated levels of PLP1 in brain regions near the hippocampus. This suggests that the same gene reactivation seen in mice could also happen in women.
Professor Dena Dubal, senior author of the study, explained, “Only women had elevated PLP1.” This supports the idea that the second X chromosome may continue to influence brain health throughout life.
Reactivation of silent X chromosome may impact female brain aging
The study adds to a growing understanding of how women’s brains age differently from men’s.
- The team found that the so-called silent X chromosome is not permanently off
- With age, it begins to express genes that play a role in brain development and cognitive function
In total, around 22 genes escaped X inactivation in the hippocampus of aged female mice. Many of these genes are linked to brain development and intellectual disability when mutated.
The researchers noted that the aging female brain had higher overall X chromosome expression due to this reactivation. As a result, women may have a biological advantage when it comes to resisting age-related cognitive decline.
Future research to explore gene-based therapies for cognitive aging
Scientists are now working to find out whether similar gene reactivation patterns occur in women with dementia or other brain conditions. They are also exploring whether treatments can enhance the expression of protective genes like PLP1.
Cognition is one of our biggest biomedical problems. Are there interventions that can amplify genes like PLP1 from the X chromosome to slow the decline—as we age?
Professor Dena Dubal said
While more research is needed to confirm these results in humans, the study offers a promising new perspective.
The reawakening of the silent X chromosome may play a critical role in brain aging, and understanding this process could lead to future breakthroughs in preventing cognitive decline.
