Genes inherited from our mothers make our brains age faster

The battle against brain aging has a surprising new player: the X chromosome we inherit from our mothers. Recent research reveals that this genetic hand-me-down could influence how quickly our brains age, particularly in women.

While we’ve long known that women have two X chromosomes compared to men’s single X, it turns out that which parent those X chromosomes come from might matter more than we thought.

X chromosome in brain function

The X chromosome has long been linked to brain health. Many intellectual disabilities stem from mutations in genes located on the X chromosome.

Women with Turner syndrome, a condition where only one X chromosome is present instead of two, often experience cognitive impairments. Scientists have suspected that the X chromosome plays a role in memory, learning, and susceptibility to neurodegenerative diseases such as Alzheimer’s.

Dr. Samira Abdulai-Saiku, a postdoctoral fellow at UCSF and first author of the study, emphasized the significance of these findings.

“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,” she said.

Why does X chromosome matter?

In females, every cell requires only one active X chromosome. To maintain balance, the body randomly inactivates one X chromosome in each cell.

Some cells use the maternal X chromosome, while others rely on the paternal X chromosome. This mosaic pattern of gene expression creates a unique genetic environment in women.

However, the process of X inactivation is not always perfectly balanced. Some women, purely by chance, may have more cells that activate the maternal X chromosome than the paternal one. This variation, known as X chromosome skewing, has been largely overlooked in brain aging research – until now.

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

“There has been little research on the potential consequences of this.”

Maternal X chromosome accelerates brain aging

To understand the effects of X chromosome activation, the UCSF research team bred female mice in a way that ensured some had only an active maternal X chromosome, while others retained a mix of maternal and paternal X chromosomes.

The results revealed that female mice with only a maternal X chromosome suffered from worse memory and learning abilities as they aged.

Further investigation showed that the hippocampus – a brain region essential for memory and learning – aged more rapidly in mice with only an active maternal X chromosome.

The researchers observed significant differences in gene expression, with certain genes on the maternal X chromosome being completely silenced, while they remained active on the paternal X chromosome.

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

Reactivating the silenced genes

To further explore the effects of X chromosome expression, the researchers turned to CRISPR gene-editing technology. By reactivating the silenced genes on the maternal X chromosome in older female mice, they were able to improve cognitive function.

The mice that underwent this genetic intervention demonstrated enhanced learning and memory, suggesting that reversing gene silencing could be a potential strategy for slowing brain aging.

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

An evolutionary tradeoff?

The study was not designed to determine why the maternal X chromosome accelerates brain aging compared to the paternal X chromosome.

However, Dubal proposed a possible evolutionary explanation. “It may be that this gene expression pattern is actually really beneficial to brain development, but then there is this tradeoff later in life,” she said.

This hypothesis raises important questions about the genetic mechanisms underlying aging and neurodegeneration.

If certain genes promote brain growth and function during youth but accelerate decline with age, understanding these tradeoffs could lead to interventions that extend cognitive health into old age.

Future research directions

Dubal and her team plan to continue their investigation into the role of the X chromosome in brain aging. Their findings could help explain why some people are more prone to cognitive decline than others and may offer new strategies for preventing diseases like Alzheimer’s.

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

The potential for reversing age-related cognitive decline by modifying gene expression is an exciting avenue for future research. If scientists can identify ways to balance X chromosome expression, it may open doors to new therapies for brain aging in both men and women.

This remarkable research not only deepens our understanding of the genetic factors influencing brain aging but also offers hope for innovative approaches to maintaining cognitive health across the lifespan.

The study is published in the journal Nature.

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