Women inherit two X chromosomes, one from each parent. However, only one X chromosome functions in each cell. The other is inactivated. But recent research shows that when the X chromosome is expressed only from the mother, cognitive decline accelerates. UC San Francisco researchers uncovered this critical link in a study published in Nature.
This discovery might explain why some women experience faster cognitive aging. It may also shed light on the gender differences seen in conditions like Alzheimer’s disease.
THE ROLE OF X CHROMOSOMES IN BRAIN HEALTH
The X chromosome carries many genes essential for brain function. Mutations in these genes can lead to cognitive impairments. Women with only one functional X chromosome, as in Turner Syndrome, often have brain-related challenges. The X chromosome could also explain differences in cognition and the risk of neurological diseases.
Dr. Dena Dubal, a leading neurologist at UCSF, emphasizes the importance of understanding the effects of the X chromosome. This understanding is crucial for grasping cognitive aging. Her team focused on whether the origin of the X chromosome—whether maternal or paternal—matters for brain health.
THE PARENTAL ORIGIN OF X CHROMOSOMES: A KEY TO BRAIN AGING
The research team sought to determine if the maternal or paternal X chromosome impacts brain health differently. They knew that during the formation of egg and sperm cells, certain chemical tags are added to chromosomes. These marks are crucial, as they impact how genes are activated.
In this study, UCSF researchers bred female mice that expressed only the maternal X chromosome. They also bred mice that expressed both maternal and paternal X chromosomes. They found a significant difference in brain aging between these two groups of mice.
MATERNAL X CHROMOSOME ACCELERATES BRAIN AGING
The study revealed a crucial finding. Female mice with only a maternal X chromosome showed faster cognitive decline. This occurred compared to their genetically identical sisters who expressed both X chromosomes. These mice had poorer memory and learning abilities as they aged.
In the brains of these mice, the hippocampus—a region essential for memory and learning—showed signs of accelerated aging. “The brains of these mice aged faster than their sisters who had both maternal and paternal X chromosomes active,” explained Dr. Dubal.
GENE SILENCING AND ITS IMPACT ON COGNITIVE DECLINE
The researchers also identified specific genes that were silenced on the maternal X chromosome but active on the paternal one. These silenced genes are critical in aging and cognitive function.
To test the hypothesis, the team used CRISPR gene-editing technology to activate these silenced genes. When they did, the female mice’s cognitive abilities improved as they grew older. This suggested that the origin of the X chromosome has a direct effect on cognitive function and brain aging.
POSSIBLE EVOLUTIONARY TRADE-OFFS: THE MATERNAL X CHROMOSOME
Although the study did not explore the evolutionary reason behind this phenomenon, Dr. Dubal offered an insight. She hypothesized that the silenced genes on the maternal X chromosome might provide an advantage in early life. However, this advantage may come at a cost later in life, contributing to faster brain aging.
“Certain genes on the maternal X chromosome may benefit brain development early on. However, they might have negative effects as we age,” she explained.
IMPLICATIONS FOR WOMEN’S BRAIN HEALTH AND COGNITIVE DISEASES
This research could lead to new ways of understanding why women, on average, experience different cognitive aging processes than men. Dr. Dubal’s team is hopeful that their findings will eventually help identify women at higher risk for diseases like Alzheimer’s. In turn, this could lead to targeted strategies to slow brain aging in women and both sexes.
“Our work shows that the X chromosome you inherit from your mother might have a lasting impact on brain health,” said Dr. Dubal. “We’re looking for ways to reverse these effects and protect cognition as we age.”
THE FUTURE OF X CHROMOSOME RESEARCH IN AGING
The study is just the beginning. Dr. Dubal and her team plan to continue their research into the role of the X chromosome in aging. They aim to understand how this discovery could lead to new treatments for brain diseases, particularly in women.
With further investigation, scientists hope to find ways to mitigate the effects of the maternal X chromosome. This could open up possibilities for reducing the risk of Alzheimer’s and other age-related cognitive disorders.
