Study says Y chromosome loss raises heart risks

40 percent of men said to lose chromosome in some of their cells by the age of 70

It’s been known for more than a half-century that many men lose their Y chromosomes as they age. But no one knew if it really mattered. The loss of Y could just be a sign of aging, like gray hair, with no clinical relevance.

Now, though, researchers report that it can matter. Very much.

A new study using male mice genetically engineered to lose their Y chromosomes provides insight. The paper, published Thursday in the journal Science, found when the Y chromosome was gone from blood cells in those mice, scar tissue built up in the heart, leading to heart failure and a shortened life span.

Because there was a direct cause-and-effect relationship between the loss of Y and ailments of aging in the mice, the study bolsters the notion that the same thing can happen in human males. Researchers have documented an increase in risk for chronic diseases like heart disease and cancer related to 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 even account for some of the difference between the life spans of men and women, the authors of the Science study say.

Other investigators not associated with the work were impressed.

“The authors really nailed it here,” said Dr. Ross Levine, the deputy physician in chief for translational research at Memorial Sloan Kettering Cancer Center in New York. “It’s super important work.”

The inspiration for the new research came when Lars Forsberg, a researcher at Uppsala University, 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 appreciated.

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 chromosome is lost sporadically from blood cells during cell division, when it is kicked out of some cells and then disintegrates. The result is what researchers call a mosaic loss of Y.

Curious about the idea his professor had proposed, Forsberg went back to his computer and looked at 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.

At that point, Forsberg heard from Kenneth Walsh, director of the Hematovascular Biology Center at the University of Virginia School of Medicine. Walsh had become interested in the loss of Y chromosomes because of 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 risk of heart disease and cancer, which prompted Levine to set up a CHIP clinic at Sloan Kettering.

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 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 also were diminished.