The X chromosome passed from mother to offspring could accelerate brain aging, a new animal study suggests.
Research highlights a potential fundamental difference in how men’s and women’s brains age. The research was conducted on mice, but if the results translate to humans, they could point to sex-specific drivers of cognitive decline and, possibly, ways to prevent or treat them.
“Women demonstrate resilience in many measures of aging,” said the study’s lead author Dr Dena Dubalprofessor of neurology and David A. Coulter Chair in Aging and Neurodegenerative Diseases at the University of California, San Francisco (UCSF). For example, they tend to live longer than men and have rates of various forms of dementia. An exception is Alzheimer’s diseasewhich affects women at higher rates, but despite this, some studies suggest that women survive longer with Alzheimer’s disease than men.
Dubal and his colleagues wondered whether the sex chromosomes, X and Y, could help explain these differences. There is evidence of genes on the X chromosome that help protect against dementia, while others contribute to the risk of cognitive decline, said Rachel Buckleyassociate professor of neurology at Harvard Medical School who was not involved in the new study. The new study reveals a potential factor that could shape the influence of the X chromosome.
Related: 1 in 500 men may carry an extra sex chromosome (most without knowing it)
The origin of X matters
Typically, females have two chromosomes in each cell – one from their mother and one from their father. But one cell only needs one X to be active, so the other is “silenced.” The result is that females carry a mosaic of cells that have silenced their paternal or maternal X chromosome. Meanwhile, males – who usually carry an X and a Y – only inherit their X from their mother, and it is active in every cell.
“This makes us wonder about female resilience and whether this diversity of the X chromosome, having that of mom and dad, could contribute to resilience,” Dubal said.
To explore this idea, Dubal; Samira Abdulai-Saikupostdoctoral researcher at UCSF; and colleagues did experiments with female laboratory mice of different ages. Some experiments involved using a genetic trick to silence all paternal X chromosomes in some mice, leaving only the mother’s X active. These mice were compared to others that had a mixture of activated maternal and paternal Xs.
“I actually really liked that approach,” Buckley said. Comparing women to men would have introduced additional sex-related factors, such as hormonal differences, Buckley told Live Science.
The team also made sure that each parent’s X chromosomes were genetically identical, Dubal noted. So any differences that arise would be related to the parent who passed them on, not to differences in the genes themselves, she explained. This also allowed the team to identify differences in epigenetic – chemical tags that attach to DNA and control which genes can be activated.
Young “Mom-X” mice were cognitively similar to other young mice, performing about the same in maze-based tests. But at older ages, they presented a more marked cognitive decline, particularly in terms of their spatial memory and their spatial memory. working memory. “The analyzes showed quite a striking effect,” Dubal said.
The team wondered whether these declines were linked to changes in the seahorsea key memory center in the brain. To see this, they examined epigenetic markers on the DNA of the hippocampi of young and old mice. Epigenetic tags change throughout life, with certain patterns correlated with “higher” biological ages — in other words, a more advanced degree of aging. At higher chronological ages, Mom-X mice showed a greater degree of biological aging in the hippocampus than mice with both Xs.
The scientists then sorted the hippocampal neurons based on whether the mother’s or father’s X was active, so they could determine which genes were activated.
Three genes were silenced on the maternal X – Sash3, Tlr7 and Cysltr1 – but were highly active on the paternal X. CRISPR gene editing toolthey studied what would happen if they reactivated these genes in the brains of old mice with only maternal Xs. When tested, these mice showed improvements in spatial learning and memory.
What does this mean for humans?
Interestingly, in humans, these three genes are involved in immune protectionbut their exact roles in neurons are not fully understood, Dubal said. Future work could explore in more detail what genes do in neurons and other types of brain cells. It’s also unclear how or why X chromosomes from different parents undergo different epigenetic changes, she added.
The team also wants to study what these findings might mean for men, who carry only maternal X chromosomes – and could, in theory, then have higher rates of brain aging. “One can imagine” that the more active maternal Xs a person carries, the more pronounced the impact on brain aging, Dubal speculated. But this remains to be confirmed.
And, of course, because the current study was conducted only in mice, future research should examine human brain tissue to verify that the results hold up, Buckley said. “This is such unique and innovative work…but it’s a cautionary tale.”
In the long term, this line of research could help scientists understand the influence of sex on dementia risk, differentiating it from other factors, like education, that are more closely linked to sex, Buckley said. By identifying these biological factors of brain aging, researchers could better determine how to intervene and adapt treatments to each patient.
“For now, we’re going with a one-size-fits-all solution,” Buckley said. “And in reality, that’s not how we’re going to get things done.”