As the Y chromosomes disappear with age, heart risks can increase

It has been known for more than half a century that many men lose their chromosomes with age.

But no one knew if it really mattered.

Loss of Y could simply be a sign of aging, such as gray hair, without clinical relevance.

Now, however, the researchers report that it could be important.

Much.

A new study using genetically engineered male mice to lose their Y chromosomes provides insight.

The article, published Thursday in the magazine Sciencefound that when the Y chromosome disappeared from the blood cells in those mice, scar tissue built up in the heart, leading to heart failure and a shorter life span.

Because there was a direct cause and effect relationship between Y loss and aging disorders in mice, the study reinforces the idea that the same may be true in human males.

Researchers have documented an increased risk of chronic diseases such as heart disease and cancer linked to the loss of the Y chromosome in many studies over the years, including the new one, which used data from a large genetic study of the British population.

The loss of Y could also explain some of the difference between the lifespan of men and womensay the authors of the Science study.

Other researchers not associated with the work were impressed.

“The authors really nailed it here,” said Dr. Ross Levine, associate primary for translational research at Memorial Sloan Kettering Cancer Center in New York.

“It’s a very important job”.

The inspiration for the new research came when Lars Forsberg, a researcher at Uppsala University, met a former professor on a bus in Uppsala, Sweden, in 2013.

They started talking, and the professor told Forsberg that the fruit flies’ Y chromosomes were more important than previously estimated.

Forsberg was intrigued.

I had never paid much attention to the loss of Y chromosomes.

Males have one X and one Y (females have two Xs) and almost all of the genes used by male cells are genes on X.

Forsberg shared the common view that the Y chromosome was practically a genetic desert.

At least 40% of men lose the Y chromosome from some of their blood cells by age 70.

And by the age of 93, at least 57% have lost some of it.

The chromosome is sporadically lost by blood cells during cell division, when it is expelled from certain cells and then disintegrates.

The result is what the researchers call a Y mosaic loss.

There is no way, other than quitting smoking, to reduce the risk of losing the Y chromosome.

and the condition it is not related with men having lower testosterone levels in their bodies as they age.

Taking testosterone supplements would have no effect or negate the consequences.

Curious about his professor’s idea, Forsberg went back to his computer and examined data on 1,153 older men in a large Swedish study, the Uppsala Longitudinal Study of Older Men.

“I had the data in a few hours and I thought, ‘Wow’,” Forsberg said.

“I have seen that men with loss of Y in most of their blood cells only survived half, 5.5 years versus 11.1 years.

“You can imagine my surprise,” he said.

“Of course I did it all again.”

The discovery held and published an article in the journal Genetics of nature in 2014, reporting that increased death rates and cancer diagnoses were associated with a loss of the Y chromosome in blood cells.

He quickly founded and became a shareholder of the Cray Innovation company to test men for the loss of Y.

Other researchers have begun publishing similar analyzes.

Soon, around 20 separate papers showed associations between Y-chromosome loss in blood cells and heart disease, shorter life expectancy, and various age-related diseases such as solid tumors and blood cancers.

At that point, Forsberg heard from Kenneth Walsh, director of the Center for Hematovascular Biology at the University of Virginia School of Medicine.

Walsh became interested in the loss of Y chromosomes due to his work on a different type of genetic loss that occurs with aging:

an increase in cancerous mutations in blood cells called CHIPs.

People with CHIP are at increased risk for heart disease and cancer, prompting Levine to found a CHIP clinic in Sloan Kettering.

In January, Dr. Pradeep Natarajan, director of preventive cardiology at Massachusetts General Hospital, and others formed a company, TenSixteen Bio, to develop a cost-effective test for CHIP and study treatments to prevent its consequences.

But, Walsh noted, CHIP mutations are only a small fraction of the genetic alterations that occur with aging.

“What’s the rest of this cake?” I ask.

He questioned the Y chromosomes and began planning a way to see if there was a direct cause and effect between the loss of Y in blood cells and disease.

This led him to his study with mice.

At first the mice looked fine, Walsh said, but “they have aged badly“Their lifespan shrank and they developed scar tissue in their hearts, kidneys and lungs, including the non-ischemic heart failure, a type that is not the result of a heart attack and whose cause is poorly understood.

The animals’ mental abilities were also diminished.

Working with Forsberg, Walsh then looked at British biobank data involving 223,173 men.

Men with Y-mosaic loss had a 41% higher risk of dying from any cause during a seven-year follow-up and a 31% higher risk of dying from any cardiovascular disease.

The more cells that have lost their Y chromosomes, the greater the risk.

But the work also raises the question:

And the women?

Do they lose one of their two X chromosomes?

What about women with Turner syndrome?

They are born with a single X chromosome, making all of their cells the equivalent of the random pool of blood cells in men losing their Y.

Women can lose an X chromosome as they age, Walsh said, but not as often as men lose their Y.

Except for an association with the lymphoid leukemiaBritish biobank data showed no health risks for women who lost an X.

But more studies are needed, Walsh said.

Turner syndrome is different.

Women with this condition actually have some of the same health risks as men who have lost Y chromosomes:

cardiovascular anomalies and non-ischemic heart failure.

Their average lifespan is shorter than that of women with two Xs.

It is too early to say what men should do, besides quitting smoking, to protect themselves from the loss of Y chromosomes or to alleviate the consequences.

Those in Walsh’s group found that they could protect the hearts of mice without Y chromosomes by blocking them TGF-beta, a key molecule involved in the production of scar tissue.

Dr Stephen Chanock, director of the division of cancer epidemiology and genetics at the National Cancer Institute, said the study in mice was “really interesting.”

But he noted that there was still no evidence that drugs to block TGF-beta were effective in men who had lost their Y.

And, for now, it doesn’t make much sense to test men for the loss of Y, Chanock said, adding that “the excessive interpretation of this data for monetary purposes worries me deeply.”

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