A groundbreaking study by UCSF researchers may have unlocked the secret behind why women tend to outlive men and retain cognitive abilities longer as they age. The discovery sheds new light on brain resilience and aging, offering potential insights into neurodegenerative disease prevention.
The key lies in the two X chromosomes that females carry. One of these chromosomes typically remains inactive in a part of the cell called the Barr body, where it was long thought to have little function. However, UCSF scientists found that in aging female mice—equivalent to around 65 human years—this ‘silent’ second X chromosome begins expressing genes that strengthen brain connections, enhancing cognitive function.
This breakthrough could pave the way for new research into cognitive longevity and potential treatments for age-related brain decline.
“In typical aging, women have a brain that looks younger, with fewer cognitive deficits compared to men,” said Dena Dubal, MD, PhD, a professor of neurology and the David A. Coulter Endowed Chair in Aging and Neurodegenerative Disease at UCSF. She is the senior author of the new paper, which appears 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.”
Among 22 genes that avoided X chromosome silencing, PLP1 was particularly notable. PLP1 plays a critical role in myelin formation, the insulating sheath around nerve fibers that facilitates signal transmission in the brain. Researchers observed that aged female mice exhibited higher levels of PLP1 in the hippocampus compared to aged male mice, suggesting that the additional PLP1 from the second X chromosome contributed to this difference.
To determine if PLP1 was responsible for the observed resilience of the female brain, the team experimentally increased PLP1 expression in the hippocampus of both aged male and female mice. This manipulation resulted in improved cognitive function in both sexes, as evidenced by enhanced performance on learning and memory tests.
Building upon these findings, Dubal and her colleagues are now exploring whether the second X chromosome remains active in older women. Preliminary evidence supports this hypothesis: an analysis of donated brain tissue from older individuals, conducted in collaboration with Katilin Casaletto, professor of neurology at the UCSF Memory and Aging Center, revealed elevated PLP1 levels exclusively in women.
“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. “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?”
