New Study Finds the 'Silent' X Chromosome in Mice Activates with Age

Researchers believe this discovery may explain why females, including humans, tend to live longer and retain higher level of cognitive resilience in old age than males

Hiya!

Despite all we’ve learned about our shared external reality, we have no idea how much we don’t know. Often, anything we learn is a layer of an answer rather than the entire answer. Usually, we can only reveal one layer at a time before we’re forced to stop and put further investigations on a back burner.

Thanks to technological advancements, scientists can now re-examine previously halted research to discover even more. For instance, it’s commonly known that females predominantly have two X sex chromosomes. However, one is “active” while the other is “inactive,” and scientists weren’t sure why — but a recent study may reveal at least part of the answer.

Brain Differences Between the Sexes While Aging

Research indicates there’s a fundamental difference in how males and females age, especially when it comes to their brains.

Perhaps the most well-known difference is that females typically live longer than men, in every country worldwide, even during severe epidemics and famines. The life expectancy gap between males and females in the United States widened during the COVID-19 pandemic between 2019 and 2021, with men dying almost six years earlier than women.

However, females don’t just typically live longer than males; their quality of life, including their cognitive abilities, is generally better, too. For instance, females tend to have lower rates of dementia than males. Although there’s one exception, Alzheimer’s disease, which is about twice as common in females as males, even then, females with the disease still typically live longer than males who have it.

Scientists have long wondered why females generally age better and live longer. There are plenty of theories to explain it — from lifestyle habits and environmental factors, to differences in immune systems and hormones.

However, Margaret Gadek, an MD-PhD student at the University of California, San Francisco, recently co-led research I’ll tell you about soon, investigating what, if any, role the inactive X sex chromosome might play. She told Nicoletta Lanese of Live Science:

"There's been a lot of documented trends where there's resilience in cognitive aging in female populations, compared to males. There's a lot of excuses why these trends could be in place, but one thing we wanted to look into was the role of the X chromosome.”

After all, along with our hormones, our sex chromosomes are one of the most significant biological differences between males and females, so it makes sense they might explain the difference between males and females as we age.

The Sex Chromosomes

Humans and most (but not all) other mammals have two sex chromosomes, X and Y, that determine the sex of an individual, along with their external genitalia.

To be clear, a person’s sex is different than their gender, which is socially constructed, and their gender identity, which is a person’s deep, internal, and unique experience of gender, which may or may not correspond to their physiology or designated sex at birth.

Anyway, males typically have one X chromosome, which they get from their biological mother, and a Y chromosome from their biological father. Meanwhile, females usually have two X chromosomes, one from each biological parent.

However, some people are described as intersex because they have sex chromosomes and reproductive anatomy that differs from the typical definitions of female or male.

For instance, some people have XXY or just X sex chromosomes, and some people with XX chromosomes can have male testes, while people with XY chromosomes can have ovaries. So far, over 30 medical terms exist for specific combinations of intersex traits.

The X chromosome is particularly interesting to scientists, since it carries about 5 percent of the human genome. Another reason scientists are curious about the X chromosome because within the female body, only one is active while the other is silenced.

Adding to the mystery is that which one becomes activated or inactivated appears to be completely random. Further, once an X chromosome is inactivated, it will remain inactive throughout the person’s lifetime — or so scientists thought.

There are a couple of flaws in this system, however, that intrigued Gadek and her colleagues: Some genes on the inactive X chromosome resist the silencing process and remain active, and some inactive genes become active again as a person ages.

Rachel Buckley, an Associate Professor of neurology at Harvard Medical School who was not involved in the new study, explained to Lanese that,

"We simply haven't looked at the X chrom[osome] very much, 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."

Gadek and her team grew curious about how these “reawakened” genes on the otherwise inactive X chromosome might affect brain aging, especially considering that the silencing effect is a uniquely female phenomenon. So, they conducted a study to find out.

The Study

For the the study, published on March 5, 2025, in Science Advances, Gadek teamed up with Dena Dubal, a neurologist and neuroscientist and the David A. Coulter Endowed Chair in Aging and Neurodegenerative Disease, Vijay Ramani, a genomics expert, professor, and investigator in the Gladstone Institute for Data Science & Biotechnology, and Barbara Panning, a professor of biochemistry, all at the University of California, San Francisco (UCSF).

To investigate inactive X chromosomes, the researchers cross-bred two subspecies of laboratory mice, Mus musculus and Mus castaneus, so that each offspring would inherit one X chromosome from each parental species.

The scientists also genetically altered the mice so that the X chromosome inherited from M. castaneus was always inactive. Remember, whichever X chromosome is silenced or activated in nature appears random.

Gadek told Lanese that such a setup made it easier for the team to determine which chromosome an active gene belonged to and whether it “escaped” the silencing process.

The Analysis

The team examined the gene activity of their genetically altered mice and compared four young mice to four mice aged 20 months, or about 65 in human years.

The researchers were particularly interested in gene activity within the cells of the mice’s hippocampus, a brain region highly involved in memory, learning, and emotional processing, among other things. The team was curious about this region because the hippocampus often shrinks with aging and cognitive decline, in humans and other animals, including mice, and is heavily impacted by dementia.

They analyzed over 40,000 cells in the mice’s hippocampus, including neurons and various glial cells, which help support and maintain neurons and make the insulating myelin sheath that protects them.

The Results

The researchers were stunned to discover that the supposed inactive X chromosome had 22 active genes within several types of hippocampus cells, many of which are involved in brain development and intellectual disabilities. Some genes reawakened across many of the mice, while others varied. Gadek, who is the paper’s first author, said in a news release by UCSF that,

“We immediately thought this might explain how women’s brains remain resilient in typical aging, because men wouldn’t have this extra X.”

In the same statement, Dubal explained:

“In typical aging, women have a brain that looks younger, with fewer cognitive deficits compared to men. These results show that the silent X in females actually reawakens late in life, probably helping to slow cognitive decline.”

Meanwhile, Buckley shared with Lanese that when she read the study,

"I was really shocked to see that we could be thinking about X-related inactivation escapism as a function of age. So as women get older, there'll be more of it [X-related gene activity] and in fact some of it's quite protective."

Such a discovery was exciting, but they weren’t done yet. One “escapee” gene stood out, and the team wanted to investigate it further.

Further Investigation

Of the 22 genes on the X chromosome that resisted being silenced, one called PLP1 is particularly intriguing because it helps produce the myelin that insulates the brain’s wires, or axons, so that they can transmit their signals.

It’s also known that myelin can be compromised during aging, and mutations in PLP1 can reduce myelin production in the brain, resulting in cognitive disabilities.

Yet, the older female mice had more PLP1 in their hippocampus than the older male mice.

To test their theory that PLP1 could explain the resilience of female brains, the researchers artificially boosted PLP1 in the hippocampus of the older female and male mice. They found that both groups performed better on tests involving memory and learning, suggesting that the bonus PLP1 in female brains from the second X chromosome makes a difference.

And they didn’t stop there.

The team wanted to know whether their research findings extend to humans, so they analyzed data of male and female brain tissue previously collected for an extensive study on human brain tissue by Kaitlin Casaletto and Rowan Saloner, both professors of neurology at the UCSF Memory and Aging Center.

Unfortunately, there wasn’t any data available for the hippocampus specifically, but the brain tissue immediately surrounding the region did have more PLP1 activations in older females compared to older males.

Such results suggest that the same phenomenon the researchers discovered in their mice study may also occur in the brains of female humans. Dubal said in the statement,

“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. 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?”

Buckley, who was not involved in the research, discussed another reason elevated PLP1 activation is intriguing, which concerns estrogen. The hormone has many roles in the brain, including shuttling fuel from the blood to brain cells, but during menopause, estrogen levels fall.

Buckley explained to Lanese that while reading the new study, she was reminded of earlier research suggesting that, as estrogen levels decrease, the brain may break down some of its myelin (which PLP1 helps produce) for fuel.

Considering the results of the two studies, Buckley wonders if perhaps the boost in myelin later in life might be a way the brain replenishes the myelin used during menopause. Her hypothesis is speculative for now, but she said the idea "really made me sit up and take notice."

In the end, the team concludes,

"The study of female-specific biology is historically underrepresented in science and medicine but is essential and expanding fervently,” and that, “What X activation broadly means for women's brain health – or for other systems of the body – is now a critical area of investigation."

And this line of research isn’t just beneficial for females. As Gadek points out,

"One thing that this paper highlights is that studying sex chromosomes isn't a niche woman's health issue. 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."

Future Research

Now that they’ve investigated reawakened X chromosome genes in the brains of healthy mice, Gadek told Lanese she’d like to research the PLP1 and other reawakened genes and how they relate to diseases like dementia in animal models next.

Buckley adds that, in the long term, it would be good for scientists to study what, if any, role the Y chromosome plays in an aging brain. Even though the Y chromosome is about three times smaller than the X chromosome, and contains around 100 genes compared to the 900-or-so genes on the X chromosome.

Perspective Shift

More research is needed, but the idea that the inactive X chromosome activates, or at least enough of its genes do, to positively impact cognition in aging female brains makes sense to me.

I remember learning that we only need one X chromosome, which is why only one activates in females while the other remains dormant, but I always thought it was strange. For one thing, Nature is nothing if not efficient and resourceful, so it doesn’t make sense that most females would evolve two X chromosomes but only have one with a purpose.

Further, some people are born with only one X chromosome, or one and a partial, resulting in a female-specific condition known as Turner’s Syndrome, which is the second most common genetic disorder, affecting roughly 1 in 2,000 females, and can result in any number of physical abnormalities.

Also, while it was once thought that female humans and various whale species were the only mammals to experience menopause, research now suggests that, while still relatively rare, menopause is likely more common among mammals, as long as they survive long enough to experience it. Still, this natural transition remains mysterious and is highly understudied.

Experts have attributed the purpose of menopause to the Grandmother hypothesis, which proposes that older females go through menopause to become grandmothers, to better serve their community by becoming caregivers, so the parents can focus on having more kids, or whatever community duties they may have. And it’s not just us. The grandmother effect has also been observed in orca whales and Asian elephant communities.

If there’s any truth to the Grandmother hypothesis, then it seems plausible that the not-so-inactive X chromosome may have something to do with it. Perhaps, the reawakening of dormant genes like the PLP1 helps keep aging female brains healthy so they can become the leaders and caregivers their communities need.

Or maybe not, who knows, but I’m excited to see what they learn next.

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Image by Megan Judge from Pixabay