Using a mouse model, researchers from UCSF have found that the genes that become activated on the silent X chromosome might explain some sex-dependent differences in cognitive abilities during aging [1].
XX and XY
It is widely known that women live longer than men [2]. Women also show differences in cognitive aging [3]. “In typical aging, women have a brain that looks younger, with fewer cognitive deficits compared to men,” said the senior author of this study, Dena Dubal, MD, PhD, a professor of neurology and the David A. Coulter Endowed Chair in Aging and Neurodegenerative Disease at UCSF.
This study’s authors link the genetic differences between sexes, specifically the X chromosome, of which women have two and men have one, to cognitive aging differences. “Cognition is one of our biggest biomedical problems, but things are changeable in the aging brain, and the X chromosome clearly can teach us what’s possible,” Dubal said.
Controlled inactivation
Even though women have two X chromosomes, they don’t simply express twice as many X-linked genes; instead, one X chromosome in each female cell is kept inactive or silent. However, some genes escape the inactivation of the second X chromosome. Such escapees from the silent X chromosome might be a part of sex-dependent differences, possibly those affecting cognition.
The inactivation of the X chromosome is a random process, and some cells in the same body might have an inactive maternal chromosome, while in others, the paternal X chromosome is inactive.
In experiments, it is challenging to distinguish whether a gene was expressed from the maternal or paternal chromosome. Therefore, the researchers crossed two mouse strains– Mus musculus and Mus castaneus. M. musculus is genetically modified to make the X chromosome from this strain always active, while the M. castaneus-derived X chromosome is inactive in every cell. Any gene expression that comes from M. castaneus, which can be assessed based on genetic differences, must be from the silent chromosome.
Changes on the X chromosome
The researchers used single-nucleus RNA sequencing to analyze the gene expression in 40,000 nuclei derived from different cell types in hippocampi taken from four young and four old female mice. The hippocampus is the the brain structure responsible for learning and memory.
An analysis of X chromosome-linked aging-impacted gene expression across hippocampal cell types uncovered that aging remodeled this expression from both X chromosomes in a cell-type-specific manner, suggesting differential responses to aging in different cells. Among the notable changes were several genes whose expression was activated from the silent X chromosome only in aged animals. “These results show that the silent X in females actually reawakens late in life, probably helping to slow cognitive decline,” said Dubal.
Many of these activated genes from the silent X chromosomes had neural-related functions. Additionally, nearly half of those genes are related to human X-linked conditions of intellectual disability, typically in males, who do not have the second X. In females, the second X can compensate for the mutation in a single X chromosome, suggesting the importance of those genes in cognitive functioning.
Female biology helping everyone
Among the identified genes, the researchers focused on the gene Plp1, which is activated on the silent X chromosome, and its expression increases with aging in a few cell types. Its protein, PLP1, is a component of myelin, the neuronal protective sheath essential for transmitting signals, and it is linked to Pelizaeus-Merzbacher disease, which results in intellectual disability.
A comparison of young and old mice’s hippocampi showed that Plp1 levels increased in aged female mice but not in the male parahippocampus, a region that surrounds the hippocampus and is involved in spatial memory, information, and context. These results were confirmed by measuring Plp1 expression in the aging human parahippocampus. Specifically, PLP1 levels were higher in older women than men in the parahippocampus but not in other tested brain regions.
To further test Plp1‘s effect on cognition in aging, the researchers created a genetically engineered virus that overexpressed Plp1 in oligodendrocytes. The focus on oligodendrocytes, cells that produce myelin, stems from the observation that “the highest overall expression and most robust aging-induced increase in Plp1” was in oligodendrocytes.
The researchers injected the dentate gyrus, one of the hippocampus regions, of mice of both sexes with the engineered virus expressing Plp1 or a control virus, which was identical except for the lack of Plp1 expression. The researchers chose the dentate gyrus because this brain region is essential for cognitive functions like spatial memory, and it exhibited the most differentially expressed genes in their analysis, suggesting sensitivity to aging.
Overexpression of Plp1 in oligodendrocytes of the hippocampi of aging mice didn’t change anxiety-like behaviors and total activity, but it improved learning and memory in both sexes.
These positive changes were observed in mice that received the treatment in relatively old age, showing that long-term treatment is not necessary. This is promising for developing future therapies for neurodegenerative diseases that occur later in life.
Understanding the biology
The authors discuss that the aging-induced activation of the silent X chromosome increases the dose of genes activated in the female hippocampus. They speculate that since the X chromosome is enriched in cognition-related genes, the increased dose of those genes might benefit cognitive abilities. “We immediately thought this might explain how women’s brains remain resilient in typical aging, because men wouldn’t have this extra X,” said Margaret Gadek, a graduate student in the MD PhD program at UCSF and the first author of the paper.
The authors suggest that aging-related epigenetic alterations, specifically methylation, might be responsible for making the chromatin more accessible, thus allowing some genes to be active on the silent X chromosome, but this still needs to be tested.
This research adds to a better understanding of sex-dependent differences in aging and what pathways and molecular processes are responsible for those differences. Understanding those differences might help find targets for interventions to increase both sexes’ healthspan and lifespan.
Literature
[1] Gadek, M., Shaw, C. K., Abdulai-Saiku, S., Saloner, R., Marino, F., Wang, D., Bonham, L. W., Yokoyama, J. S., Panning, B., Benayoun, B. A., Casaletto, K. B., Ramani, V., & Dubal, D. B. (2025). Aging activates escape of the silent X chromosome in the female mouse hippocampus. Science advances, 11(10), eads8169.
[2] Zarulli, V., Barthold Jones, J. A., Oksuzyan, A., Lindahl-Jacobsen, R., Christensen, K., & Vaupel, J. W. (2018). Women live longer than men even during severe famines and epidemics. Proceedings of the National Academy of Sciences of the United States of America, 115(4), E832–E840.
[3] McCarrey, A. C., An, Y., Kitner-Triolo, M. H., Ferrucci, L., & Resnick, S. M. (2016). Sex differences in cognitive trajectories in clinically normal older adults. Psychology and aging, 31(2), 166–175.
