Dormant genes on the X chromosome may reawaken in old age, potentially giving the aging female brain a boost that the male brain doesn’t receive.
This phenomenon may help to explain why, on many measures, females show a higher level of cognitive resilience in old age than males do.
The findings come from a new study in lab mice, and the researchers also backed up the results with genetic data from humans. More research is still needed to confirm that the findings in mice translate to people, but overall, the work points to a potential difference in how female and male brains age.
Historically, “we simply haven’t looked at the X chrom[osome] very much,” said Rachel Buckley, an associate professor of neurology at Harvard Medical School who was not involved in the new study. “And now we’re starting to really shine a very, very big spotlight on it, and we’re starting to realize things that we had not fully appreciated” — namely, how sex chromosomes might influence how the brain ages.
“There are very important and potentially therapeutic targets that are coming out from these papers” that focus on the X chromosome, Buckley told Live Science.
The resilience of the female brain
There seem to be fundamental differences in how males and females age. When it comes to the brain, females have lower rates of various forms of dementia than males do, even though females live longer, on average. One exception is that females have higher rates of Alzheimer’s disease than males do, although females with Alzheimer’s tend to survive longer than males with the condition.
“There’s been a lot of documented trends where there’s resilience in cognitive aging in female populations, compared to males,” said study first author Margaret Gadek, an MD-PhD student at the University of California, San Francisco. “There’s a lot of reasons why these trends could be in place, but one thing we wanted to look into was the role of the X chromosome,” Gadek told Live Science.
Alongside hormones, the sex chromosomes — X and Y — are one of the starkest biological differences between males and females, and they could help provide biological explanations for why these differences emerge in aging.
Males typically carry one X and one Y in each cell; they inherit the X from their mother and the Y from their father. Females, on the other hand, usually carry two X chromosomes — one from mom and one from dad. But each cell needs only one X to be active, so in females, the second X is “silenced,” leaving only the maternal or paternal X switched on.
This is not a seamless process. Some genes on the silenced X chromosome escape that silencing process, and thus remain switched on, while additional genes may get switched back on as a person ages. Gadek and her colleagues wondered how these “reawakened” genes might factor into brain aging, especially given that this silencing is a uniquely female phenomenon.
Nearly two dozen “reawakened” genes
In their new study, published March 5 in the journal Science Advances, the researchers crossed two subspecies of lab mice — called Mus musculus and Mus castaneus — so that each of the rodents’ offspring would inherit one X from the former subspecies and one from the latter. The team also genetically tweaked the mice such that the X from M. castaneus was always silenced. Normally, the X that happens to be silenced in each cell is random.
This experimental setup made it easier to tell which chromosome an active gene belonged to and, therefore, whether it had “escaped” the silencing process, Gadek explained.
With their modified mice in hand, the team then examined the gene activity in four young mice and four old mice, the latter of which were 20 months old. (That’s about 65 in human years.)
They specifically zoomed in on gene activity in cells of the hippocampus, a key memory center in the brain that tends to shrink with normal aging and cognitive decline and is heavily impacted in dementia. They looked at over 40,000 cells in total, including both neurons and various types of glial cells, which help maintain and support neurons in the brain and also make an insulating substance, called myelin.
This analysis revealed that, with age, about 22 genes that were initially silenced got switched back on. Some of the same genes were reawakened across many the mice, while others were more variable, Gadek added.
“I was really shocked to see that we could be thinking about X-related inactivation escapism as a function of age,” Buckley said. “So as women get older, there’ll be more of it” — meaning X-linked gene activity — “and in fact some of it’s quite protective,” she added.
Importance of insulation in the brain
Among the 22 reawakened genes, one called PLP1 jumped out as interesting, in part because it was switched on in seven of the nine cell types studied, Gadek said.
PLP1 carries the instructions to make a key component of myelin, the fatty insulation that helps neurons send signals efficiently. It’s known that mutations in PLP1 can decrease the amount of myelin in the brain, resulting in intellectual disability. It’s also known that myelin can be compromised in aging and that loss of myelin function can contribute to cognitive decline.
To see if the reawakening of PLP1 might boost cognition, the scientists ran some experiments with male and female mice. In one, they confirmed that older female mice had more PLP1 activity in their hippocampi than the older male mice did. In the second experiment, the researchers artificially increased PLP1 using gene editing in both old males and old females, and they found that both sexes performed better on tests of learning and memory after that boost.
To see if any of the findings extended to humans, the team looked at data previously collected for a large study of human brain tissue. Data weren’t available for the hippocampus, but the brain tissue immediately surrounding the hippocampus showed more PLP1 activation in older women than in older men. So that hints that the same phenomenon might be unfolding in people.
Gadek said that, in the future, she’d be interested in looking at this reawakened gene in animal models of diseases like dementia, since the current mouse experiments looked at only healthy aging. Buckley added that it would also be interesting to investigate the phenomenon in the context of menopause.
Related: Faster brain aging tied to X chromosome inherited from Mom
In menopause, estrogen levels plummet. The hormone has many functions in the brain, including helping shuttle fuel from the blood into brain cells. Buckley pointed to research led by neuroscientist Roberta Brinton of the University of Arizona, which suggests that, as estrogen levels decline, the brain may break down some of its own myelin for fuel.
In reading the new study, Buckley connected the dots and wondered if the boost in myelin in later life could be a way of recovering from the hit taken earlier, during menopause. “That’s something that really made me sit up and take notice,” she said, although this idea is speculative for now.
Given the current study was primarily in mice, Buckley did note that more work is needed to see how this phenomenon unfolds in the human brain. And in the long term, it would behoove scientists to study the role of the Y chromosome in brain aging; although it carries far fewer genes than the X, it may still have an impact, she noted.
“One thing that this paper highlights is that studying sex chromosomes isn’t a niche woman’s health issue,” Gadek said. “It provides insights into cognitive aging and certainly other areas of health that could benefit males and females and everyone alike, because we all have an X chromosome.”
