Maternal X Chromosome Speeds Up Brain Aging, Impacting Memory and Cognition

Scientists have discovered that the maternal X chromosome may accelerate cognitive decline by silencing key genes in the brain. This finding sheds light on why Alzheimer’s disease disproportionately affects women and opens new possibilities for reversing age-related cognitive decline.

Credit : nature publishers

In an unexpected twist, the fight against brain aging, researchers have now identified the maternal X chromosome as playing a critical role. Brain aging, researchers found, seems to be accelerated by the X chromosome inherited from mothers, possibly heightening the risk of cognitive diseases such as Alzheimer's.

Females carry two X chromosomes, while males inherit only one, paired with a Y chromosome.

In recent studies at the University of California, San Francisco, it has been found that much genetic information is located on the X chromosome—information which, when altered or mutated, greatly influences brain health. Although women generally outlive men and have lower dementia rates, Alzheimer's disease is known to affect more women. Interestingly, some studies have indicated that women tend to survive longer with the disease than men.

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The Effect of Maternal Chromosomes

To test this hypothesis, researchers at UCSF selectively bred female mice so that some retained only an active maternal X and others had a combination of the maternal and paternal X. When these mice aged, the memory and learning deficits were more pronounced in those with only the maternal X. The hippocampus, or brain region involved in the process of learning and memory, had characteristics of premature biological aging when the maternal X was solely active.

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

Through detailed analyses of brain cells, the research team identified specific genes that were completely silenced on the maternal X chromosome but remained active on the paternal X chromosome. When the researchers used CRISPR gene-editing technology to activate these silenced genes in female mice, the animals displayed improved cognitive function in old age.

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

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Refining big-data analytic approaches to reveal the many facets of brain aging.

(A) Smith et al. used a technique called independent component analysis (ICA) to analyze MRI and fMRI data on brain structure, connectivity or activity from more than 18,000 individuals over the age of 45. This enabled them to identify 62 modes. Most of these modes co-varied with age across the sample, thus potentially reflecting biological processes affected by aging. (B) Schematic matrix in which each row represents an individual and each column represents a mode. The color scale represents the brain-age delta, the difference between the actual age of the individual and what age would have been expected for this person given the value of the mode. (C) The 62 modes can be grouped into six mode-clusters, such as one which captures the microstructure of brain white-matter. (D) Smith et al. were able to relate the brain-age deltas for specific modes and the mode-clusters to various phenotypes (for instance health, genetics and cognition).

Image References : https://elifesciences.org/articles/56640

Evolutionary Roots?

The study was not designed to determine precisely why the maternal X chromosome accelerates brain aging compared to the paternal X chromosome. However, Dubal proposed a hypothesis: the genes silenced on the maternal X chromosome might provide an early-life advantage.

"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.

Dubal hopes to further investigate the role of the X chromosome in brain aging and whether it contributes to an individual’s risk of developing brain diseases or experiencing memory decline.

"The X chromosome you inherited from your mom is turning off genes, accelerating aging, and impairing cognition," she noted. "Can we reverse this?"

If these findings translate to humans, they could shed light on how cognitive decline is linked to biological sex, ultimately paving the way for new strategies to prevent or treat brain diseases in the future.

Citations:

Nature 638, 45-47 (2025)

DOI: https://doi.org/10.1038/d41586-025-00079-2

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