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As Y Chromosomes Vanish with Age, Heart Risks May Grow

By: Christina Mink

For years scientists have known that many men lose their Y chromosomes while aging, but only recently did they discover the true importance of this chromosome. It was assumed that losing the Y chromosome is merely a sign of aging, just like gray hair.

A new study using mice that were genetically engineered to lose their Y chromosomes proved that the loss of this chromosome could lead to heart failure. The paper, published on Thursday in Science, found that when the Y chromosome was removed from blood cells in those mice, scar tissue built up in the heart, leading to heart failure and a shortened life span.

The paper presented the notion that this may happen in humans too. Researchers using data from a large genetic study of the British population found that there was an increase in the risk of heart disease and cancer associated with the missing Y chromosome in human males. It also speculated that this may be attributed to women generally having longer lifespans than men.

At least 40 percent of males lose the Y chromosome from some of their blood cells by age 70. And by age 93, at least 57 percent have lost some of it. The Y chromosome is lost from blood cells during cell division, when it is kicked out of the cells and disintegrates. The only way to reduce the loss of Y chromosomes is to quit smoking.

Lars Forsberg, a researcher at Uppsala University, was inspired to run the study when he ran into a former professor on a bus in Uppsala, Sweden in 2013. They began talking, and the professor told Forsberg that the Y chromosomes in fruit flies were more important than previously realized. Fascinated by this, he immediately went on his computer and looked up data on 1,153 aging men in a large Swedish study, the Uppsala Longitudinal Study of Aging Men.

“I had the data in a few hours and I was like, ‘Wow,’” Forsberg said. “I saw that men with loss of Y in a large proportion of their blood cells survived only half as long, 5.5 years versus 11.1 years.”

He then published a paper in the journal “Nature Genetics” in 2014, reporting that increased death rates and cancer diagnoses were associated with a loss of the Y chromosome in blood cells. Many other papers were inspired by his work. Later, Forsberg founded the company Cray Innovation to test men for loss of Y.

Kenneth Walsh, the director of The Hematovascular Biology Center at the University of Virginia School of Medicine, reached out to Forsberg in relation to his work on a different type of genetic loss that occurs with aging: an increase in cancer mutations in blood cells called CHIP. People with CHIP have a greater chance of heart disease and cancer. But DWalsh noted that CHIP mutations are only a small part of genetic alterations associated with aging, inspiring his study with the mice.

At first the mice seemed fine, Walsh said, but “they aged poorly.” Their life spans were shortened and they developed scar tissue in their hearts, kidneys and lungs, including nonischemic heart failure, whose cause is poorly understood. Their mental abilities also diminished. Walsh and Forsberg studied data from the UK Biobank including 223,173 men.

They found that men with mosaic loss of Y had a 41 percent increased risk of dying from any cause within the following seven years, and a 31 percent increased chance of dying from any cardiovascular disease. The more cells that lost Y chromosomes, the greater the risk.

But what about women? Walsh says that women can lose X chromosomes as they age, but not as much as men. The US Biobank data has not shown health risks for women who lose X chromosomes, except those that have lymphoid leukemia. More studies are needed, Walsh said.

Those in Walsh’s group found they could protect the hearts of the mice without Y chromosomes by blocking TGF-beta, a key molecule involved in the production of scar tissue, but as of now, there is no evidence that this would help human men.

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