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Many Men Lose the Male Sex Chromosome As They Age

Y chromosome (in red). Credit: Wikipedia

Did you know that a significant percentage of men lose the male sex chromosome in some of their cells as they age? About 40% of 70 year olds! This loss may explain why so many men die several years before women.

The loss of the male Y chromosome in some cells (mosaic loss) has health effects. It is associated with an increased risk of early death and some age-related diseases in men, such as heart disease and heart failure. This loss mainly happens in cells with a rapid turnover, such as blood cells, and does not happen in male reproductive cells.

A recent two part study in both mice and human males found that this Y chromosome loss resulted in heart muscle scarring (fibrosis), which led to increased risk of heart problems and heart failure. The researchers discuss a drug (pirfenidone) that may help with treatment.

Why is this happening? The researchers point out that as we age, more and more gene mutations are occurring, that is, the DNA of our cells accumulate mutations as we age. Some of them are due to our own choices, such as smoking, exposures to toxic chemicals, radiation, our lifestyle. Others are out of our control (e.g., aging).

From Science Daily: Loss of male sex chromosome leads to earlier death for men

The loss of the male sex chromosome as many men age causes the heart muscle to scar and can lead to deadly heart failure, new research from the University of Virginia School of Medicine shows. The finding may help explain why men die, on average, several years younger than women.

UVA researcher Kenneth Walsh, PhD, says the new discovery suggests that men who suffer Y chromosome loss -- estimated to include 40% of 70-year-olds -- may particularly benefit from an existing drug that targets dangerous tissue scarring. The drug, he suspects, may help counteract the harmful effects of the chromosome loss -- effects that may manifest not just in the heart but in other parts of the body as well.

On average, women live five years longer than men in the United States. The new finding, Walsh estimates, may explain nearly four of the five-year difference.

"Particularly past age 60, men die more rapidly than women. It's as if they biologically age more quickly," said Walsh, the director of UVA's Hematovascular Biology Center. "There are more than 160 million males in the United States alone. The years of life lost due to the survival disadvantage of maleness is staggering. This new research provides clues as to why men have shorter lifespans than women."

Chromosome Loss and Heart Health

While women have two X chromosomes, men have an X and a Y. But many men begin to lose their Y chromosome in a fraction of their cells as they age. This appears to be particularly true for smokers. The loss occurs predominantly 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 the children of men who exhibit Y chromosome loss.) Scientists previously observed that men who suffer Y chromosome loss are more likely to die at a younger age and suffer age-associated maladies such as Alzheimer's disease. Walsh's new research, however, is believed to be the first hard evidence that the chromosome loss directly causes harmful effects on men's health.

Walsh, of UVA's Division of Cardiovascular Medicine and the Robert M. Berne Cardiovascular Research Center, and his team used cutting-edge CRISPR gene-editing technology to develop a special mouse model to better understand the effects of Y chromosome loss in the blood. They found that the loss accelerated age-related diseases, made the mice more prone to heart scarring and led to earlier death. This wasn't the result of just inflammation, the scientists determined. Instead, the mice suffered a complex series of responses in the immune system, leading to a process referred to as fibrosis throughout the body. This tug-of-war within the immune system, the researchers believe, may accelerate disease development.

The scientists also looked at the effects of Y chromosome loss in human men. They conducted three analyses of data compiled from the UK Biobank, a massive biomedical database, and found that Y chromosome loss was associated with cardiovascular disease and heart failure. As chromosome loss increased, the scientists found, so did the risk of death.

Potential Treatment

The findings suggest that targeting the effects of Y chromosome loss could help men live longer, healthier lives. Walsh notes that one potential treatment option might be a drug, pirfenidone, that has already been approved by the federal Food and Drug Administration for the treatment of idiopathic pulmonary fibrosis, a form of lung scarring. The drug is also being tested for the treatment of heart failure and chronic kidney disease, two conditions for which tissue scarring is a hallmark. Based on his research, Walsh believes that men with Y chromosome loss could respond particularly well to this drug, and other classes of antifibrotic drugs that are being developed, though more research will be needed to determine that.

At the moment, doctors have no easy way to determine which men suffer Y chromosome loss.

"The DNA of all our cells inevitably accumulate mutations as we age. This includes the loss of the entire Y chromosome within a subset of cells within men. Understanding that the body is a mosaic of acquired mutations provides clues about age-related diseases and the aging process itself," said Walsh, a member of UVA's Department of Biochemistry and Molecular Genetics. 

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