Why women’s brains are more resilient: it could be their ‘silent’ X chromosome

Study in mice and human cadavers hints that a brain-protective gene in the chromosome becomes more active with age

Women usually have two X chromosomes (shown here in an artist’s rendering), and one of them is inactivated early in development.Credit: Cavallini James/BSIP/Alamy

Women tend to live longer than men and are often more resilient to cognitive decline as they age. Now researchers might have uncovered a source for this resilience: the second X chromosome in female cells that was previously considered ‘silent’.

In work published today in the journal Science Advances¹, a team reports that, at least in female mice, ageing activates expression of genes on what is usually the ‘silent’, or inactivated, X chromosome in cells in the hippocampus, a brain region crucial to learning and memory. And when the researchers gave mature mice of both sexes a type of gene therapy to boost expression of one of those genes, it improved their cognition, as measured by how well they explored a maze. Assuming these results can be confirmed in humans, the team suggests it could mean that women’s brains are being protected by their second X chromosome as they age — and that the finding could translate to future therapies boosting cognition for everyone.

“The X chromosome is powerful,” says Rachel Buckley, a neurologist who studies sex differences in Alzheimer’s disease at Massachusetts General Hospital in Charlestown, and who was not involved in the research. This kind of work, she says, is helping researchers to understand “where female resilience lies and how to harness it”.

(This article uses ‘women’ and ‘female’ to describe people with two X chromosomes and no Y chromosome, reflecting the language of the study. Nature recognizes that not all people who identify as women have this chromosomal makeup.)

Double dose

Female cells typically have two X chromosomes, one from each parent; male cells usually have one X and one Y. Early in development, one of the two X chromosomes in female cells is inactivated — coated in various proteins and RNA molecules that prevent its genes from being expressed. Which one is ‘silenced’ — meaning which parent it comes from — is random, and the tissues in the body are a mosaic of both types.

In theory, female and male cells both have an X chromosome that is active, so female cells have “the same dose of X chromosome as a male cell”, says Dena Dubal, a neuroscientist and neurologist at the University of California School of Medicine in San Francisco, who led the study. But scientists are learning that it’s not so simple. Dubal says that about 30% of the genes on the so-called silent X chromosome in people are active — although that percentage varies among women. Still, scientists know little about how expression of genes on the less-active X chromosome changes from tissue to tissue in the body, or how it shifts with age.

To study this in the mouse brain, Dubal’s team bred two types of laboratory mice to produce offspring with one X chromosome from each. The chromosomes were engineered such that one would always be the active X and the other would always be inactivated, and small genetic differences in the chromosomes would allow them to be identified in lab tests. Then the researchers tracked the activity of both X chromosomes in nine major cell types, including neurons, found in the hippocampus of both young and old mice.