How the Maternal X Chromosome Impacts Memory and Aging

What if the X chromosome you inherited from your mother could accelerate brain aging?

This intriguing question was explored by researchers at the University of California - San Francisco (UCSF), whose study, published in Nature, revealed that maternal X chromosome expression can lead to faster cognitive decline and hippocampal aging in female mice.

The X chromosome’s impact on brain health

The X chromosome plays an important role in genetic health, particularly concerning brain function. In females with two X chromosomes – one inherited from each parent – one of the two X chromosomes is randomly silenced in every cell through a process called X-inactivation. When this process occurs, cells express genes exclusively from either the maternal or paternal X chromosome. This random distribution ensures that both the maternal and paternal X chromosomes contribute to a woman's overall genetic expression.

The X chromosome is enriched with genes vital for neural function and disruptions in these X-linked genes often lead to intellectual impairments. For example, mutations in the FMR1 gene on the X chromosome cause fragile X syndrome, a condition associated with intellectual disability. Turner syndrome, a condition where females are born with only one X chromosome, is also linked to specific cognitive challenges. While individuals with Turner syndrome generally have normal intelligence, they may experience difficulties in areas such as visuospatial reasoning, executive function and social cognition.

During the formation of gametes (i.e., egg and sperm cells), chemical tags are added to specific genes on the chromosomes. These tags vary depending on whether the chromosome originates from the mother or father and influence which genes are activated in cells.

“Given the fact that the X chromosome is enriched for brain-related genes, it became very important for us to know what roles it might be playing in brain aging,” said first author Dr. Samira Abdulai-Saiku, a postdoctoral fellow from UCSF. 

The phenomenon of X-inactivation is not always a perfectly balanced process. In some individuals there is skewed X-inactivation, where a higher proportion of cells preferentially inactivate either the maternal or paternal X chromosome. This skewing can lead to differences in gene expression profiles, potentially impacting cognitive function and susceptibility to neurological conditions.

“Skewing of the X chromosome is common among humans. There are certainly women who are walking around with much higher or lower levels of maternal X chromosomes than others, just by chance,” said corresponding author Dr. Dena B. Dubal, a professor in neurology at UCSF.

Despite its potential implications, the consequences of skewed X-inactivation, especially favoring the maternal X chromosome, have not been extensively studied. Understanding these effects is essential, as they may shed light on variations in cognitive aging and the development of brain diseases among women.

Accelerated aging and cognitive decline

Dubal and Abdulai-Saiku bred two groups of genetically engineered female mice, expressing either only maternal X chromosomes or a mixture of maternal and paternal X chromosomes. The team then employed a combination of behavioral tests, gene expression analysis and advanced epigenetic techniques to measure cognitive abilities, hippocampal aging and patterns of gene silencing.

The female mice that expressed only the maternal X chromosome exhibited larger deficits in memory and learning abilities as they aged. The hippocampus also showed signs of biological aging – measured via changes in DNA methylation patterns – at a much faster rate in the maternal X chromosome group compared to the control group.

“What we showed is that these animals’ brains were aging faster than the brains of their genetically identical sisters who had both mom’s and dad’s X chromosomes turned on,” said Dubal.  

Reversing cognitive impairments with CRISPR

Detailed analyses identified specific genes silenced on the maternal X chromosome, including Sash3, Tlr7 and Cysltr1. These genes are known to play roles in cognitive processes, suggesting their silencing contributes to the observed impairments.

To further explore the role of these silenced genes, the researchers used CRISPR-mediated gene activation to reactivate them in neurons of aged female mice.

Surprisingly, reactivating these genes reversed some cognitive deficits, demonstrating that the silenced genes on the maternal X chromosome are key contributors to brain aging.

“Together, all these experiments suggested that the parental origin of an X chromosome can have a big impact on brain health,” said Abdulai-Saiku. 

Implications for human health

“These findings raise the possibility that some women who express more of their mom’s X chromosome, just by pure chance, may have more cognitive impairment with aging or an increased risk for diseases like Alzheimer’s. Ultimately, it could also help us find constructive strategies for slowing brain aging in both sexes,” said Dubal.

By identifying specific genes silenced on the maternal X chromosome, this research could lead to the future of novel precision medicine approaches. Using tools like CRISPR gene-editing, scientists may be able to reactivate these silenced genes, potentially reversing cognitive decline in aging populations.

Since X chromosome skewing is a natural phenomenon, understanding its patterns could also help identify individuals at higher risk for cognitive impairments, particularly as they relate to Alzheimer’s disease and other conditions that disproportionately affect women.

The implications extend beyond women’s health, raising questions about how the phenomenon might also affect men – who only inherit a maternal X chromosome. While men lack a second X chromosome, their Y chromosome and distinct hormonal profiles might interact differently with X-linked genes. Further research is needed to determine how maternal X chromosome silencing impacts cognitive aging in males.

These results also highlight a potential evolutionary tradeoff: “It may be that this gene expression pattern is beneficial to brain development, but then there is this tradeoff later in life,” said Dubal.

Silencing specific genes on the maternal X chromosome might confer advantages during early life, such as optimizing brain development or immune system regulation. However, these same mechanisms could accelerate aging processes in later years, leading to cognitive decline.

Future directions

Several questions remain. How does X chromosome skewing influence brain health across the lifespan in different populations? And can gene-editing technologies be safely applied to reverse silencing effects in humans?

“The X chromosome you inherited from your mom is turning off genes, accelerating aging and impairing cognition. Can we reverse this?” said Dubal.

The team plans to continue to study the role of X chromosomes in brain aging. They hope to develop targeted interventions that slow brain aging and improve cognitive outcomes for future generations.

Reference: Abdulai-Saiku S, Gupta S, Wang D, et al. The maternal X chromosome affects cognition and brain ageing in female mice. Nature. 2025. doi: 10.1038/s41586-024-08457-y

This article is a rework of a press release issued by the University of California - San Francisco. Material has been edited for length and content.