The X Factor Behind Women's Brains Aging Differently

UCLA Health researchers have discovered a sex-chromosome-linked gene that causes inflammation in the female brain, providing insight into why women are disproportionately affected by conditions like Alzheimer's disease and multiple sclerosis (MS), as well as a potential target for intervention.

Women Are More Susceptible to Alzheimer's Disease and Multiple Sclerosis

The study, published in the journal Science Translational Medicine, used a mouse model of multiple sclerosis to uncover a gene on the X chromosome that causes inflammation in brain immune cells called microglia (1^✔ ✔Trusted Source
Deletion of the X-chromosomal gene Kdm6a in microglia of female mice ameliorates neuroinflammation and restores translatome profiles

Go to source). Females get a "double dose" of inflammation because they have two X chromosomes, whereas males only have one.

In female mice, deactivating the gene Kdm6a and its related protein significantly improved both multiple sclerosis-like illness and neuropathology.

Metformin's Anti-Aging Action Is More Effective in Women than Men

When first author Dr. Yuichiro Itoh of the Voskuhl lab genetically "knocked out" the gene Kdm6a in brain immune cells, the inflammatory molecules went from active to resting. In addition, the Voskuhl team used metformin to "knock down" the protein produced by this gene. Metformin is commonly used to treat diabetes, but it is also being studied for potential anti-aging qualities.

While these interventions were highly effective in female mice, they had little effect on males, according to Voskuhl.

"This is consistent with there being 'more to block' in females due to having two copies of the X-linked gene," said Voskuhl, a neurology professor at UCLA Health. "This is also why women are more likely than men to develop MS and Alzheimer's disease. This has ramifications for the clinic. Women may react differently to metformin medication than men."

According to Voskuhl, the findings could also help explain why healthy women experience brain fog after menopause.

Why Do Women Experience Brain Fog After Menopause?

"Sex chromosomes and sex hormones achieve a balance through evolution," the scientist stated. "There is a selection bias for doing so. Females have a balance of X-chromosome-driven inflammation, which can help them fight infections during childbearing age. This is regulated by estrogen, which is anti-inflammatory and neuroprotective. Menopause induces estrogen loss in women, which unleashes the proinflammatory and neurodegenerative consequences of this X chromosome, the brain immune cell.

According to Voskuhl, these findings may justify the use of brain-targeted estrogens to maintain balance and thereby protect the brain after menopause.

Reference:

1. Deletion of the X-chromosomal gene Kdm6a in microglia of female mice ameliorates neuroinflammation and restores translatome profiles - (https://www.science.org/doi/10.1126/scitranslmed.adq3401)

Source-Medindia