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The immune cells of many older men lose their Y chromosomes, and this may contribute to men having a higher rate of heart disease than women.

Health risks from Y chromosome loss have long been suspected, but evidence from animals and people now adds more support to the idea 鈥� and may suggest a treatment for the damage caused to the heart.

DNA is packaged into chromosomes, with the cells of most men and transgender women carrying one X and one Y, and those of most women and transgender men carrying two Xs 鈥� although some people have other combinations, such as .

It was discovered several decades ago that in some people born with XY chromosomes, a proportion of the immune cells have no Y chromosome, a phenomenon that becomes more common with increasing age. For instance, 40 per cent of 70-year-old men have no Y in at least some of the immune cells found in their blood.

The reasons for this are unclear, but it could be because the Y chromosome is small and carries relatively few genes apart from those involved in sex determination and sperm production, so the stem cells that produce immune cells can survive if they happen to lose their Y when replicating their DNA. If they lose any other chromosomes, however, the cells would be more likely to die.

Loss of this Y chromosome in immune cells correlates with higher rates of health problems, including heart disease, cancer and Alzheimer鈥檚 disease. But it was unclear whether Y loss causes these conditions or if faulty DNA replication is behind both Y loss and the health issues, says at Uppsala University in Sweden.

To find out, Forsberg and his colleagues used the CRISPR gene-editing technique to remove the Y chromosome from about two-thirds of the immune cells of male mice to mimic the phenomenon.

These mice developed heart problems once they got to about 1 year of age, precipitated by their heart muscle becoming scarred. 鈥淲e show causality,鈥� says Forsberg. 鈥淲e can see that losing the Y chromosome in the blood causes disease in the heart.鈥�

The researchers also looked at how Y chromosome loss affected men in a large ongoing medical study called UK Biobank, which tracks participants鈥� health over time. They found that the more immune cells without a Y that the men had at the time of their enrolment, the higher their risk of dying from any type of heart disease over the following 12 years.

For instance, men who had lost the Y chromosome in more than 40 per cent of their immune cells had a 31 per cent higher risk of dying from any circulatory disease during the study period. Scarring of heart muscle can contribute to some common types of heart disease, such as heart failure, says Forsberg.

Further work on the mice uncovered clues about how immune cells cause heart scarring. When the animals were dissected, immune cells lacking a Y chromosome were found to have infiltrated heart muscle, triggering the release of an inflammatory signalling molecule called transforming growth factor beta.

Treating the mice with an antibody that blocks this growth factor reduced the harmful effects of the loss of the Y chromosome 鈥� although it is too soon to conclude the same approach would benefit men who are losing their Y chromosomes, says Forsberg. He is co-founder of a biotech firm called that is developing a blood test to tell people if they have loss of the Y chromosome in their immune cells.

鈥淭his is the best evidence I have seen for a direct effect of Y chromosome loss on a physiological process,鈥� says at the University of Cambridge.

In 2019, Perry and his colleagues published work suggesting that a propensity for Y chromosome loss is caused by , which could be why loss of the Y chromosome is linked with cancer.

Forsberg鈥檚 team next plans to investigate whether people born with XYY chromosomes experience different effects if they lose of one of their Y chromosomes.

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