My Lovely Wife is five years younger than me, but I’ve come to believe that her brain may be even younger. It’s not just that she’s smarter than I am; I’ve known that forever (though it took me a while to admit it). But she also tends to absorb and retain information more reliably as she grows older than my own aging gray matter can manage. My memory often fails me at crucial junctures, like the other day when I returned from the grocery store with the wrong flavor of ramen noodles for our finicky grandson. No big deal, really, but it does sometimes make a guy wonder what’s going on upstairs.
To hear Dena Dubal, MD, PhD, tell it, this divergence of cognitive capabilities shouldn’t be surprising: It’s all about our chromosomes. Dubal, a professor of neurology at the University of California, San Francisco (UCSF), argues that the two X chromosomes women typically harbor may give them a distinct cerebral advantage over their male counterparts, who generally carry an X and a Y — especially as we age. Volumes of research over the years have shown that women’s brains age more slowly than those of men, but Dubal and her team set out to determine why that might be the case.
Their study, published last month in Science Advances, leans on the activity — and inactivity — of one of those two chromosomes women host. Prior to birth, a process known as X chromosome inactivation “silences” one of the two Xs (Xi), leaving the other one (Xa) activated. But certain Xi genes “escape” the process and eventually reactivate to supercharge the cognitive capabilities of aging women, which could potentially explain the “sex bias in cognitive resilience,” Dubal explains.
To test their hypothesis, Dubal and her team created two strains of genetically identical hybrid mice and silenced one of the two X chromosomes in one of the strains. They knew the genetic code for each strain of mice, so they could track which X chromosome hosted any expressed genes.
Observing the hippocampi of the female mice at 20 months (about equal to 65 years of human life), they discovered some 20 Xi genes — including Plp1 — had indeed been reactivated. Plp1 produces a protein integral to the composition and maintenance of the myelin sheath that protects nerve cells and facilitates information flow in the brain. And the females displayed more of this protein than the males.
“We immediately thought this might explain how women’s brains remain resilient in typical aging, because men wouldn’t have this extra X,” says study coauthor Margaret Gadek, BS, a UCSF graduate student.
They then used gene therapy to insert the Plp1 gene into the hippocampi of older male mice and found that their memory and overall cognitive abilities improved. In the older female mice, the procedure boosted their already superior braininess.
Because the Plp1 procedure produced immediate effects in these older mice, the study suggests that similar interventions may help older humans retain — or regain — memory and other cognitive skills. “This is important because treatments for cognitive aging, and for neurodegenerative diseases like [Alzheimer’s disease], will require treatment late in life, and perhaps after symptoms emerge,” the authors explain.
And though Dubal acknowledges much more research will be required before her team’s findings lead to any practical interventions for cognitive dysfunction, she’s confident that we’ll get there eventually. “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,” she says. “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?”
It’s an intriguing question, one that will surely inspire some modicum of hope among dementia sufferers and their loved ones in the years to come. But even My Lovely Wife will admit that my cognitive bungling hasn’t quite reached that level. So, rather than pine for some genetic magic to cure my occasional forgetfulness, I’ll have to be content with more banal remedies — like taking a list with me next time I go to the store to buy some ramen.
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