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As Y Chromosomes Vanish With Age, Heart Risks May Grow

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It has been known for more than half a century that many men lose the Y chromosome as they get older. But no one knew if it was really important. Loss of Y can be a sign of aging that is not clinically relevant, such as gray hair.

But now researchers are reporting that it can be a problem. very.

New studies using male mice genetically engineered to lose the Y chromosome provide insights. paper, Published in Journal Science on ThursdayFound that the loss of the Y chromosome from the blood cells of these mice causes the accumulation of scar tissue in the heart, leading to heart failure and shortened lifespan.

There was a direct causal link between the loss of Y in mice and the aging illness, so this study supports the idea that the same can happen in human males. Researchers have recorded an increased risk of chronic diseases such as heart disease and cancer associated with the loss of the Y chromosome in many studies, including new studies using data from large genetic studies of the UK population. I am. According to the authors of scientific studies, the loss of Y can even explain some of the differences in lifespan between men and women.

Other researchers unrelated to the work were impressed.

“The author really nailed it here,” said Dr. Ross Levine, Principal Doctor of Translational Research at the Memorial Sloan-Kettering Cancer Center. “It’s a very important job.”

The inspiration for the new research came in 2013 when Uppsala University researcher Lars Forceberg met a former professor of Bass in Uppsala, Sweden. They started talking and the professor told Dr. Forsburg about the Y chromosome of the fruit. Flies were more important than previously recognized.

Dr. Forsburg was intrigued. He did not pay much attention to the loss of the Y chromosome. Males have one X and one Y (female has two Xs), and almost all genes used by male cells are genes on X. Dr. Forsburg shared the common view that the Y chromosome is mostly a genetic wasteland.

By the age of 70, at least 40 percent of men lose the Y chromosome from some blood cells. And by the age of 93, at least 57 percent lost some of it.

Chromosomes are sporadically lost from blood cells during cell division and are expelled from some cells to collapse. The result is what researchers call Y’s mosaic loss.

The only way to reduce the risk of losing the Y chromosome is to quit smoking. And this condition is independent of men whose testosterone levels in the body decrease with age. Taking testosterone supplements has no effect and does not reverse the results.

Interested in the ideas proposed by the professor, Dr. Forsburg returned to the computer and examined data on 1,153 old men in a longitudinal study of old men in Uppsala, a large Swedish study.

“I got the data in a few hours, and I was like’wow’,” said Dr. Forsberg. “We found that men who lost Y in most of their blood cells survived only half the length of 11.1 years, 5.5 years.”

“You can imagine my surprise,” he said. “Of course I did everything over.”

The findings lasted, he announced Journal of Nature Genetics In 2014, we reported that increased mortality and cancer diagnosis were associated with the loss of the Y chromosome in blood cells.

He soon founded the company and became a shareholder of the company. Clay innovation Test men for loss of Y.

Other researchers have begun to publish similar analyzes. Soon, about 20 independent papers showed an association between the loss of the Y chromosome in blood cells and various age-related diseases such as heart disease, shortened lifespan, and solid tumors and blood cancers.

At that point, Dr. Forsburg spoke with Kenneth Walsh, director of the Center for Hematological and Vascular Biology, University of Virginia School of Medicine. Dr. Walsh was interested in another type of genetic loss that occurs with aging, the loss of the Y chromosome for his work on an increase in cancer mutations in blood cells called CHIP. Because people with CHIP are at increased risk of heart disease and cancer, Dr. Levine decided to set up a CHIP clinic in Sloan Kettering.

In January, Dr. Pradeep Natarajan, Dean of the Department of Preventive Heart Disease at Massachusetts General Hospital, founded the company. TenSixteen BioDevelop cost-effective tests for CHIP and study treatments to prevent the results.

However, Dr. Walsh pointed out that CHIP mutations are only a small part of the genetic changes that occur with aging.

“What’s the rest of this pie?” He asked. He wondered about the Y chromosome and began planning ways to see if there was a direct cause and effect between the loss of Y in blood cells and the disease. That led to his research in mice.

Dr. Walsh said the mice looked fine at first, but “aged poorly.” Their lifespan was shortened and scar tissue developed in the heart, kidneys, and lungs, including a type of non-ischemic heart failure of unknown cause, not the result of a heart attack. The mental abilities of the animals have also declined.

Later, in collaboration with Dr. Forsburg, Dr. Walsh examined data from UK Biobank, including 223,173 men.

Men with Y mosaic loss had a 41% increased risk of dying for any reason and a 31% increased chance of dying from cardiovascular disease during the 7-year follow-up period. The more cells that have lost the Y chromosome, the higher the risk.

But this work also raises the question, “What about women?” Do they lose one of the two X chromosomes? And what about women with Turner Syndrome? They are born on only one X chromosome and equate all cells with a random group of male blood cells that have lost Y.

According to Dr. Walsh, women can lose the X chromosome as they get older, but not as often as men lose Y. Association with lymphocytic leukemiaData from the UK Biobank do not show the health risk of women who have lost X. But more research is needed, Dr. Walsh said.

Turner syndrome is different. Women in this condition actually have some of the same health risks as men who have lost the Y chromosome. Cardiovascular abnormalities and non-ischemic heart failure. Their life expectancy is shorter than that of women with two Xs.

It’s too early to say what other than quitting smoking for men to protect themselves from losing the Y chromosome or to mitigate the consequences.

People in Dr. Walsh’s group have discovered that the heart of mice can be protected without the Y chromosome by blocking TGF-beta, an important molecule involved in the formation of scar tissue.

Dr. Stephen Channock, director of the Department of Cancer Epidemiology and Genetics at the National Cancer Institute, said mouse research is “really cool.” But he pointed out that there is still no evidence that drugs that block TGF-beta are effective in men who have lost Y.

And so far, it makes little sense to test men for the loss of Y, Dr. Channock said, “Over-interpretation of these data for financial purposes is deeply worrisome to me. I will do it. “

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