The reason female brains have less cognitive aging may be due to the reawakening of the dormant X chromosome late in life, which turns on genes that help sustain healthy brain cell connections. This finding, from a team of scientists at the University of California, San Francisco (UCSF), could lead to novel targets for interventions that counter brain aging and disease in both females and males.
Details of this study done in mice have been published in a Science Advances paper titled, “Aging activates escape of the silent X chromosome in the female mouse hippocampus.” In it, the researchers report that when female mice reached the equivalent of about 65 human years, their inactive second X chromosome, also called the Barr body, began expressing genes that bolstered brain connections and increased cognition. It may help explain why older women typically have fewer cognitive deficits compared to older men, said Dena Dubal, MD, PhD, senior author on the study and a professor of neurology at UCSF. “These results show that the silent X in females actually reawakens late in life, probably helping to slow cognitive decline.”
To study this phenomenon, Dubal and her colleagues generated hybrid mice from two different laboratory strains and engineered the X chromosome from one strain to be silent. Since they knew the genetic code for each strain, they could easily track the source of any expressed genes back to each X chromosome. They then measured gene expression in the hippocampus in 20-month-old female mice, which are akin to 65-year-old humans. The hippocampus is a key region for learning and memory that deteriorates during aging.
What they found was that in several different hippocampal cell types, the silenced X chromosome expressed about 20 genes. Many of these play a role in brain development as well as intellectual disabilities.“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 on the paper.
Looking a little deeper, a gene called PLP1, which plays a role in building myelin, stood out to the researchers. Specifically, old female mice had more PLP1 in their hippocampus than old male mice likely due to the activity from the silent X chromosome.
To test whether PLP1 could explain the resilience they observed, the team artificially expressed the gene in the hippocampus of both old female and male mice. In both cases, the extra gene activity boosted brain function in both sexes. Both male and female mice that received the boost did better on memory and learning tests.
For their next steps, the team is looking deeper into the activity of the silent X chromosome and thinking through possible interventions. As part of those efforts, they analyzed donated brain tissue from older men and women and found that only women had elevated levels of 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 said.