It’s a provocative finding, one revealed in a groundbreaking recent study. These genes on the otherwise dormant X chromosome in females can reprogram later in life, possibly enhancing cognitive performance as women grow older. This discovery fills an important gap in understanding the intricate role that sex chromosomes play in the aging of the brain, with a notable emphasis on females. Margaret Gadek and her team at Johns Hopkins University performed the analysis. To understand how the reawakened genes could be affecting brain function in older females, they turned to laboratory mice.
Females are XX — they inherit one X chromosome from their mother and one from their father. Conversely, males typically possess one X and one Y chromosome. In females, one of the X chromosomes is typically silenced, leaving just the maternal or paternal X active. This genetic phenomenon allows one of the two X chromosomes possessed by females to be silenced. New research has shown that a subset of genes on the otherwise dormant X chromosome can in fact reactivate during old age. Such reactivation might provide a powerful morale booster to the aging female mind.
Unraveling the Mystery of the X Chromosome
Margaret Gadek and her collaborators initiated a study to understand the contribution of reawakened genes on the X chromosome. They were especially interested in how these genes could affect brain aging. To do this, they crossed two subspecies of laboratory mice, Mus musculus and Mus castaneus. This genetic cross made it possible for each offspring to receive one X chromosome from each subspecies. The researchers then examined gene activity in four young mice and four old mice, with the old mice being 20 months old, equivalent to approximately 65 human years.
Their results showed that around 22 genes, previously turned off, reactivated as the beings grew older. This was a big discovery because it opened a new avenue of research related to the role the X chromosome may play in cognitive aging. One gene, PLP1, was an outlier even before knowing anything about the biology, though, given its strong association with brain health. Mutations in PLP1 can cause a degradation of myelin in the brain, causing severe intellectual disabilities.
Implications for Female Brain Aging
The reactivation of dormant genes on the X chromosome could explain why some women experience resilience in cognitive aging compared to men. The study’s key findings show that as women get older, X-linked gene activity could be turned up. Even this small boost would go a long way toward engendering protective benefits for brain health.
Rachel Buckley, a researcher not involved in the study, expressed her surprise at these findings:
"I was really shocked to see that we could be thinking about X-related inactivation escapism as a function of age," – Rachel Buckley.
She further elaborated on the potential protective nature of these reactivated genes:
"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," – Rachel Buckley.
Buckley emphasized the growing recognition of how sex chromosomes might influence brain aging:
"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. – Rachel Buckley.
A Broader Perspective on Sex Chromosomes
As the study’s findings suggest, it is powerful to approach understanding sex chromosomes beyond traditional gender health issues. Margaret Gadek pointed out:
"One thing that this paper highlights is that studying sex chromosomes isn't a niche woman's health issue," – Margaret Gadek.
Gadek noted documented trends of cognitive resilience among females compared to males:
"There's been a lot of documented trends where there's resilience in cognitive aging in female populations, compared to males," – Margaret Gadek.
This study, therefore, underscores the need to investigate sex chromosomes. Going forward, we need to understand how they might modulate or mitigate age-related changes in the brain.
