Loss of the male sex chromosome, as men age, contributes to an increased risk of death from cardiovascular causes. According to research from the Faculty of Medicine of University of Virginia (USA) and the Uppsala University (Sweden), the disappearance of the Y chromosome in blood cells causes the development of fibrosis in the heart, impaired heart function and death from cardiovascular disease in men. The discovery, published in ‘Science’may help explain why men die, on average, many years earlier than women.
Men live less than women, a difference that previous studies have linked to the loss of the Y chromosome in men’s white blood cells. This genetic modification, which occurs during life, is called mLOY (for Mosaic Loss Of Y). It is very common and is detected in at least 20% of 60-year-old men and 40% of 70-year-old men..
Previous studies have shown that men with mLOY in their blood are at an increased risk of developing age-related diseases such as cancer and Alzheimer’s disease.
The current study establishes that men with mLOY in their white blood cells also have an increased risk of dying from cardiovascular disease, the most common cause of death in men.
The good news is that, according to the researcher Kenneth Walshof University of Virginia, the finding suggests that men suffering from Y-chromosome loss could particularly benefit from an existing drug that targets dangerous tissue scarring. The drug could help counteract the harmful effects of chromosome loss, effects that can manifest not only in the heart but also in other parts of the body.
“Especially after 60, men die faster than women. It’s as if we biologically age more quickly”, explains Walsh, director of the Hematovascular Biology Center of University of Virginia.
While women have two X chromosomes, men have an X and a Y. But many begin to lose their Y chromosome in a fraction of their cells as they age. And it’s much more common among smokers.
The loss occurs primarily in cells that undergo rapid turnover, such as blood cells. (Loss of the Y chromosome does not occur in male reproductive cells, so it is not inherited by sons of men who have lost the Y chromosome.)
Until now, it was unknown whether mLOY in white blood cells had a direct effect on disease progression in other organs.
The researchers used “genetic cut and paste”, CRISPR, to generate mouse models with mLOY in their white blood cells. They found that mLOY caused direct damage to the animals’ internal organs and that mice with mLOY lived less than mice without mLOY.
“In the models used, the mouse Y chromosome was deleted to mimic the human mLOY condition and we looked at the direct consequences of this. Examination of mLOY mice showed increased heart scarring or fibrosis. In other words, mLOY causes fibrosis which results in decreased heart function,” says Lars Forsberg from Uppsala University.
But they also looked at the effects of Y chromosome loss in men. They performed three analyzes of data collected from the UK Biobank, a huge biomedical database, and found that loss of the Y chromosome was associated with cardiovascular disease and heart failure. They found that as the loss of chromosomes increased, the risk of death also increased.
“We also see that men with a higher proportion of white blood cells with mLOY in the blood have a higher risk of dying due to cardiovascular disease. This observation is in line with the results of the mouse model and suggests that mLOY has a direct physiological effect also in humans”, adds Lars Forsberg.
A possible treatment option could be a drug, pirfenidone
Currently, there is no easy way to determine which males have Y chromosome loss. Forsberg has developed a PCR, like those used for Covid-19 tests, which can detect Y-chromosome loss, but for now it’s limited to his and Walsh’s lab.
However, Walsh expects that to change: “If interest in this test continues and its usefulness for the prognosis of male disease is demonstrated and may lead to a personalized therapy, perhaps it will become a routine diagnostic test,” he concludes.