Silent X chromosome awakens with age: New explanation for sex differences in age-related diseases

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Women age differently from men when it comes to health—particularly in conditions like cardiovascular disease and neurodegenerative disorders such as dementia and Parkinson's.

A research team proposed a new explanation for this. In aging female mice, genes on the previously silenced second X chromosome become active again. This mechanism might also influence women's health later in life. The study is published in the journal Nature Aging.

Unlike men, who carry one X and one Y chromosome, women have two X chromosomes in each cell. However, one of the two X chromosomes is effectively silenced. It folds into a compact structure known as the Barr body and can no longer be read. Without this mechanism, the genes on the X chromosome would be read twice as often in women as in men.

Scientists have known for some time that some genes can escape inactivation in the Barr body, resulting in higher gene activity in women. These genes are suspected to influence disease.

Researchers have now shown for the first time that with increasing age, more and more genes escape the inactivation of the Barr body.

The researchers examined the major organs of mice at different stages of life. In the older animals, the proportion of genes that had escaped was on average twice as high as in adult animals—6% instead of 3% of the genes on the X chromosome. In some organs, the numbers were even higher: in the kidneys, for instance, nearly 9%.

With aging, epigenetic processes gradually loosen the tightly packed structure of the inactive X chromosome. This mainly happens at the ends of the chromosome, allowing for genes located in those regions to be read again.

Many of the genes that become active again with age are associated with disease. These new findings are based on mice, but since the X chromosome is very similar in humans, the same may happen in aging women.

According to the researchers, this doubled gene activity could have positive effects in some cases and negative effects in others.

ACE2, for example—a gene that escapes in the lungs with age—can help limit pulmonary fibrosis. Increased activity of the gene TLR8 in old age, however, may play a role in autoimmune diseases such as late-onset lupus.

Sex differences in age-related disease are incredibly complex.

So far, scientific explanations have mostly focused on hormonal or lifestyle factors. While the role of the X chromosome and some escape genes have been studied before, the discovery that many genes on the inactive X can reactivate with age opens up entirely new lines of research.

Sarah Hoelzl et al, Aging promotes reactivation of the Barr body at distal chromosome regions, Nature Aging (2025). DOI: 10.1038/s43587-025-00856-8