
Scientists have discovered that in females, the maternal X chromosome can have a negative effect on brain aging. During development, one of the two X chromosomes present in females is randomly “turned off.” When the maternal X chromosome becomes more active, it can accelerate brain aging, leading to memory and learning problems as a person ages. When these genes are activated, cognition improves.
Female mammalian cells have two X chromosomes, one inherited from the mother and one from the father. During embryonic development, one of these X chromosomes is randomly “turned off” in each cell, meaning that some cells will use the mother’s X chromosome (Xm), while others will use the father’s X chromosome (Xp).
This process creates a pattern known as “mosaicism,” in which the active chromosome can vary between different cells in the body. In some people, this mosaicism is balanced, meaning there is an equal proportion of cells using Xm and Xp.
In others, there may be a deviation, with most cells activating a single X chromosome (Xm or Xp).

This mosaicism is important because it contributes to genetic and epigenetic diversity, which can help protect against disease and the effects of aging.
However, when there is a skew toward a single active X chromosome, it can increase vulnerability to health problems. For example, a very strong skew toward Xm can affect the way the body and brain function, especially as we age.
This study investigated whether skew toward the active Xm chromosome could negatively impact important functions in female mice as they age.

Researchers at the University of California, San Francisco, USA, used mice as a model to understand the impact of a single X chromosome skew. They created two groups of genetically modified female mice:
1- Xm+Xp mice: These mice maintained the typical mosaicism, with a mix of cells activating Xm and Xp.
2- Xm mice: In these mice, the paternal X chromosome (Xp) was permanently switched off, leaving only the maternal X chromosome (Xm) active in all cells.
To create the Xm mice, the scientists used a genetic technique called Xist-loxP deletion. Essentially, they switched off a key gene needed for Xp to function, ensuring that only Xm was used.

This modification was passed down the germline to ensure that all the cells in the mouse had the same pattern.
The resulting mice were then compared to see if there were any differences in body and brain function, especially in middle age, when the effects of aging begin to show.
The researchers carefully checked to see if the cells in the Xm mice were actually using only the maternal X chromosome. They did this using immunofluorescence, a laboratory technique that allows them to visualize specific proteins in cells and confirm that the Xp was inactive.

Furthermore, the two groups of mice were nearly genetically identical, except for the difference in the active X chromosome. Thus, any differences observed between the two groups could be attributed to epigenetic effects, or how genes are regulated and expressed based on which X chromosome is active.
The results showed that females with only active Xm (Xm mice) had poorer cognitive performance (such as memory and learning) throughout their lives, especially as they aged.
These deficits were linked to faster brain aging, specifically in the hippocampus, an area crucial for learning and memory. The study revealed that in the Xm mice, several genes important for cognition were “silenced,” meaning they were not being used by brain cells.
Interestingly, the genes that were silenced in Xm included genes involved in immune function and the development of neural connections (synapses). This suggests that active Xm may impair the brain’s ability to adapt and function well over time.
To confirm this link, the researchers used a technique called CRISPR to “reactivate” these silenced genes in aging mice. When they did so, they observed significant improvements in cognition, showing that these genes play a key role in memory and learning.
The study suggests that women who have a natural shift toward the active Xm chromosome may be more prone to cognitive deficits or even neurodegenerative diseases, such as Alzheimer’s, as they age.

This is because certain genes important for brain function are located on the X chromosome, and an active Xm can silence some of these genes.
On the other hand, women with more balanced mosaicism (using both Xm and Xp) may be better protected, since cells that activate Xp can compensate for the loss of function in cells that use Xm.
In addition, understanding how Xm influences brain health may open up new possibilities for treatments. For example, future therapies could focus on reactivating genes silenced in Xm or manipulating these mechanisms to improve cognitive health and combat brain aging.
READ MORE:
The maternal X chromosome affects cognition and brain ageing in female mice
Samira Abdulai-Saiku, Shweta Gupta, Dan Wang, Francesca Marino, Arturo J. Moreno, Yu Huang, Deepak Srivastava, Barbara Panning & Dena B. Dubal
Nature (2025)
Abstract:
Female mammalian cells have two X chromosomes, one of maternal origin and one of paternal origin. During development, one X chromosome randomly becomes inactivated. This renders either the maternal X (Xm) chromosome or the paternal X (Xp) chromosome inactive, causing X mosaicism that varies between female individuals, with some showing considerable or complete skew of the X chromosome that remains active. Parent-of-X origin can modify epigenetics through DNA methylation and possibly gene expression; thus, mosaicism could buffer dysregulated processes in ageing and disease. However, whether X skew or its mosaicism alters functions in female individuals is largely unknown. Here we tested whether skew towards an active Xm chromosome influences the brain and body—and then delineated unique features of Xm neurons and Xp neurons. An active Xm chromosome impaired cognition in female mice throughout the lifespan and led to worsened cognition with age. Cognitive deficits were accompanied by Xm-mediated acceleration of biological or epigenetic ageing of the hippocampus, a key centre for learning and memory, in female mice. Several genes were imprinted on the Xm chromosome of hippocampal neurons, suggesting silenced cognitive loci. CRISPR-mediated activation of Xm-imprinted genes improved cognition in ageing female mice. Thus, the Xm chromosome impaired cognition, accelerated brain ageing and silenced genes that contribute to cognition in ageing. Understanding how Xm impairs brain function could lead to an improved understanding of heterogeneity in cognitive health in female individuals and to X-chromosome-derived pathways that protect against cognitive deficits and brain ageing.
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