Allele-specific, single-nucleus sequencing of cell varieties within the younger and ageing XX hippocampus. Credit score: Science Advances (2025). DOI: 10.1126/sciadv.ads8169
UCSF researchers could have found how the feminine mind stays resilient in ageing, answering an age-old query of how most girls outlive males and retain their cognitive talents longer.
Females carry two X chromosomes. One in all them is ensconced in a nook within the cell known as the Barr physique, the place it could’t specific many genes, and scientists thought it did not do a lot of something.
However the UCSF group found that as feminine mice reached the equal of about 65 human years, their ‘silent’ second X began expressing genes that bolster the mind’s connections, rising cognition.
“In typical aging, women have a brain that looks younger, with fewer cognitive deficits compared to men,” mentioned Dena Dubal, MD, Ph.D., a professor of neurology and the David A. Coulter Endowed Chair in Ageing and Neurodegenerative Illness at UCSF. She is the senior writer of the brand new paper, which seems on Mar. 5 in Science Advances. “These results show that the silent X in females actually reawakens late in life, probably helping to slow cognitive decline.”
Listening for whispers from the silent X
To trace whether or not any genes on the silent X would possibly, in reality, be energetic, Dubal collaborated with genomics skilled Vijay Ramani, Ph.D., professor at UCSF and investigator within the Gladstone Institute for Information Science & Biotechnology and Barbara Panning, Ph.D., professor of biochemistry at UCSF.
The scientists created hybrid mice from two completely different strains of laboratory mouse and engineered the X chromosome from one pressure to be silent. Since they knew the genetic code for every pressure, they might observe the supply of any expressed genes again to every X chromosome.
Then they measured gene expression within the hippocampus—a key mind area for studying and reminiscence that deteriorates throughout ageing—in 20-month-old feminine mice, which had been akin to 65-year-old people.
Surprisingly, in a number of completely different cell kinds of the hippocampus, the X chromosome that was alleged to be silent as an alternative expressed about 20 genes. A lot of them play a job in mind growth, in addition to mental incapacity.
“Aging had awakened the sleeping X,” Dubal mentioned.
“We immediately thought this might explain how women’s brains remain resilient in typical aging, because men wouldn’t have this extra X,” mentioned Margaret Gadek, a graduate scholar within the MD Ph.D. program at UCSF and first writer of the paper.
A not-so-silent X results in a brain-restoring issue
One of many 22 genes that had ‘escaped’ silencing on the X chromosome, PLP1, stood out to the researchers. PLP1 helps construct the neural insulation, or myelin, that surrounds the mind’s wires, to allow them to transmit their indicators.
Outdated feminine mice had extra PLP1 within the hippocampus than outdated male mice, suggesting that the additional PLP1 from the second X chromosome had made a distinction.
To check whether or not PLP1 may clarify the resilience of the feminine mind, the group artificially expressed PLP1 within the hippocampus of feminine and male outdated mice. The additional PLP1 supplied a mind enhance in each sexes, and these mice did higher on checks of studying and reminiscence.
Dubal and her colleagues are actually investigating whether or not the second X additionally could also be energetic in older girls. They’ve motive to imagine it’d: an evaluation of donated mind tissue from older women and men, facilitated by Katilin Casaletto, professor of neurology on the UCSF Reminiscence and Ageing Middle, discovered that solely girls had elevated PLP1.
“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 mentioned. “Are there interventions that can amplify genes like PLP1 from the X chromosome to slow the decline—for both women and men—as we age?”
Extra data:
Margaret Gadek et al, Ageing prompts escape of the silent X chromosome within the feminine mouse hippocampus, Science Advances (2025). DOI: 10.1126/sciadv.ads8169
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College of California, San Francisco
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The ‘silent’ X chromosome offers the ageing feminine mind a lift (2025, March 5)
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