Summary: Age-related loss of the Y chromosome in men is linked to heart muscle scarring and an increased risk of heart failure, a study has found. The findings explain why men die an average of seven years younger than women.

Source: University of Virginia

As many men age, the loss of a male sex chromosome can lead to scarring of the heart muscle and potentially fatal heart attacks, according to a new study at the University of Virginia School of Medicine. The finding may help explain why men die, on average, several years younger than women.

UVA researcher Kenneth Walsh, Ph.D., said the new findings suggest that those who experience Y chromosome loss — an estimated 40% of people over the age of 70 — may benefit from an existing drug that targets particularly dangerous scar tissue.

He suspects that the drug may help counteract the damaging effects of chromosomal loss.

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

“Men die faster than women, especially before age 60. It’s like biologically aging faster, says Walsh, director of UVA’s Center for Hematovascular Biology.

“There are over 160 million men in the United States alone. The years of life lost as a result of male survival trauma are staggering. This new study sheds light on why men live longer than women.

Chromosomal loss and heart health

While females have two X chromosomes, males have an X and a Y. But as most men age, they begin to lose the Y chromosome in a fraction of their cells. This seems to be especially true for smokers.

The loss occurs mainly in rapidly changing cells such as blood cells. (The loss of the Y chromosome does not occur in male reproductive cells, so it is not inherited by boys who show the loss of the Y chromosome.)

Scientists have previously observed that men with Y chromosome loss are more likely to die at a younger age and suffer from age-related diseases such as Alzheimer’s disease. Walsh’s new research, however, is believed to be the first solid evidence that chromosomal loss directly affects men’s health.

Walsh, UVA’s Division of Cardiovascular Medicine and the Robert M. Bern Center for Cardiovascular Research and his team used CRISPR gene editing technology to develop a unique mouse model to understand the effects of the loss of the Y chromosome in the blood.

They found that the loss accelerated age-related diseases, leaving the mice prone to heart scarring and early death.

Scientists determined that this was not just an effect of pain. Instead, the mice experienced a complex series of reactions in the body’s immune system, leading to a process called fibrosis in the body. Researchers believe that this battle in the immune system accelerates the progression of disease.

This is a picture of a young man and an old man.
As men age, they lose their Y chromosome – and this is taking a toll on their health. Credit: Katriel E. Cho

The scientists also looked at the effects of the loss of the Y chromosome on humans. They performed three analyzes of data collected from the UK Biobank’s huge biomedical database and found that Y chromosome loss is associated with cardiovascular disease and heart failure. As the loss of chromosomes increases, scientists have found, so does the risk of death.

Potential treatment

The findings suggest that targeting the effects of Y chromosome loss may help men live longer and healthier lives.

According to Walsh, one possible treatment option may be the drug pirfenidone, which is approved by the federal Food and Drug Administration for the treatment of idiopathic pulmonary fibrosis. The drug is being tested for the treatment of heart failure and chronic kidney disease, both of which are characterized by tissue scarring.

Based on his research, Walsh believes that men with Y chromosome abnormalities may respond well to this drug and other anti-fibrotic drugs being developed, although more research is needed to determine that.

Currently, doctors do not have an easy way to determine which men have a Y chromosome loss. Lars A. Forsberg, Walsh’s collaborator at Sweden’s Uppsala University, developed an inexpensive polymerase chain reaction (PCR) test, similar to the one used for testing for Covid-19, that can detect Y chromosome loss, but the test was largely developed in his and Walsh’s labs.

But Walsh can foresee that change: “If the interest in this continues and it proves to be useful in terms of predicting disease in men and it can lead to personalized treatment, maybe this will become a routine diagnostic test,” Walsh said.

watch out

This shows a pair of glasses

“The DNA of our cells inevitably accumulates mutations as we age. This includes the loss of the entire Y chromosome in a subset of cells in males. “Understanding that the body is a mosaic of acquired mutations provides clues to age-related diseases and the aging process,” said Walsh, a member of UVA’s Department of Biochemistry and Molecular Genetics.

“Studies examining Y chromosome deletions and other acquired mutations hold great promise for the development of personalized medicines tailored to these specific mutations.”

So genetics and mortality research news

Author: Press office
Source: University of Virginia
Contact: Press Office – University of Virginia
Image: Image credits to Catryl E. Cho.

Preliminary study: Closed access.
Hematopoietic loss of the Y chromosome causes cardiac fibrosis and death from heart failure“In Sochi Sano et al. Science


Draft

Hematopoietic loss of the Y chromosome causes cardiac fibrosis and death from heart failure

Hematopoietic mosaic loss of the Y chromosome (mLOY) is associated with an increased risk of male mortality and age-related diseases, but the causal and mechanistic relationships have not yet been established.

Here, we show that male mice have been recombined with bone marrow cells that lack Y chromosome expression.

showed that cardiac macrophages lacking the Y chromosome shifted to a fibrotic phenotype and that treatment with a transforming growth factor β1-neutralizing antibody ameliorated cardiac dysfunction in mLOY mice.

A prospective study showed that serum mLOY increased the risk of cardiovascular disease and heart failure-related death.

Together, these results indicate that hematopoietic mLOY contributes causally to fibrosis, heart failure, and mortality in men.



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