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The X Factor: How the Female Brain Resists Cognitive Decline

by Naina Bhargava on Mar 8 2025 1:59 PM
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The reactivation of the dormant X chromosome may explain slower cognitive aging in women, paving the way for potential brain aging treatments.

The X Factor: How the Female Brain Resists Cognitive Decline
The slower cognitive aging in female brains may be linked to the reactivation of the inactive X chromosome later in life, which activates genes that support the maintenance of healthy brain cell connections. This discovery, made by researchers at the University of California, San Francisco (UCSF), could open up new possibilities for treatments aimed at combating brain aging and diseases in both women and men (1 Trusted Source
Aging activates escape of the silent X chromosome in the female mouse hippocampus

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The study, conducted on mice and published in Science Advances under the title "Aging activates escape of the silent X chromosome in the female mouse hippocampus," reveals that when female mice reached an age equivalent to about 65 human years, their inactive second X chromosome (the Barr body) began to express genes that enhanced brain connections and improved cognition. This finding could help explain why older women generally experience fewer cognitive declines compared to older men, according to Dr. Dena Dubal, M.D., Ph.D., senior author of the study and a professor of neurology at UCSF. "These results demonstrate that the silent X chromosome in females reawakens late in life, likely helping to slow cognitive decline," she explained.


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Analysis of Gene Expression in the Hippocampus

To investigate this phenomenon, Dr. Dubal and her team created hybrid mice by crossing two different laboratory strains, with one strain having a silent X chromosome. Because they knew the genetic code for each strain, they could accurately trace any gene expression back to its respective X chromosome. The researchers then analyzed gene expression in the hippocampus of 20-month-old female mice, which are roughly equivalent to 65-year-old humans. The hippocampus, a crucial area for learning and memory, is known to decline with age.


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Impact of the Silent X Chromosome on Brain Function

The researchers discovered that in various hippocampal cell types, the silenced X chromosome began expressing around 20 genes, many of which are involved in brain development and intellectual disabilities. "We immediately thought this might explain how women’s brains remain resilient during typical aging, as men don’t have this extra X chromosome," said Margaret Gadek, a graduate student in the M.D.-Ph..D program at UCSF and the study's first author.


Gender Differences in PLP1 Expression

Upon further investigation, the researchers noticed that a gene called PLP1, which is involved in the formation of myelin, was particularly notable. In particular, older female mice had higher levels of PLP1 in their hippocampus compared to older male mice, likely due to the activation of the silent X chromosome.

To determine whether PLP1 could account for the resilience they observed, the team artificially expressed the gene in the hippocampus of both older female and male mice. In both groups, the increased gene activity improved brain function. Mice of both sexes that received the PLP1 boost performed better on memory and learning tests.

For their next steps, the team is further investigating the activity of the silent X chromosome and exploring potential interventions. As part of this work, they analyzed brain tissue donated by older men and women, finding that only women had elevated levels of PLP1. "Cognition is one of our biggest biomedical challenges, but the aging brain is adaptable, and the X chromosome clearly offers insights into what might be possible," Dubal said.

Reference:
  1. Aging activates escape of the silent X chromosome in the female mouse hippocampus - (https://www.science.org/doi/10.1126/sciadv.ads8169?)

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