A team of researchers at the University of California, San Francisco (UCSF) has uncovered surprising evidence that the so-called “inactive” X chromosome in older female mice isn’t so inactive after all. Their new study, published in Science Advances on March 5, 2025, suggests that certain genes once thought to be completely silent can “wake up” in the aging female brain—potentially offering insights into why women tend to live longer and often fare better on memory tests than men.
A Closer Look at the X Factor
Traditionally, scientists believed females (XX) keep one entire X chromosome shut down to balance out males (XY), who have only a single X. But this latest work shows that in older female mice, many genes on the inactive X begin to switch on—especially in the hippocampus, a key center for learning and memory. According to the study’s authors, led by Dena B. Dubal, Barbara Panning, and colleagues (including Margaret Gadek, Cayce K. Shaw, and others), this partial reactivation of the silent X chromosome could be a hidden factor helping females maintain better brain function later in life.
Standout Gene: Plp1
Among the newly awakened genes is Plp1, which helps produce myelin—the fatty insulation around nerve fibers that supports faster, more efficient brain signals. In experiments, boosting Plp1 in the hippocampus of older mice (both male and female) improved their performance on memory tasks. That finding hints at the possibility of developing future therapies, for both sexes, that harness or mimic this “extra” X chromosome activity to slow cognitive decline.
Why It Matters
Women worldwide typically outlive men, and many maintain sharper cognitive skills into old age. This study points to one possible explanation: when genes on the second X chromosome are unleashed, they might give female brains an added layer of resilience. The discovery could spur more research into how specific X-linked genes affect aging, potentially paving the way for new interventions against Alzheimer’s and other age-related brain diseases.
Research Study Source
“Aging activates escape of the silent X chromosome in the female mouse hippocampus,” by Margaret Gadek, Cayce K. Shaw, Samira Abdulai-Saiku, Rowan Saloner, Francesca Marino, Dan Wang, Luke W. Bonham, Jennifer S. Yokoyama, Barbara Panning, Dena B. Dubal, et al., published in Science Advances, Volume 11, Issue 10, March 5, 2025.
