It has been known for more than half a century that many men lose their Y chromosomes as they age. But no one knew if it really mattered. The loss of Y could simply be a sign of aging, such as gray hair, with no clinical relevance.
Now, however, researchers report that it may matter. Much.
A new study using male mice genetically modified to lose their Y chromosomes provides insight. Paper, published Thursday in the journal Sciencefound that when the Y chromosome disappeared from blood cells in those mice, scar tissue built up in the heart, leading to heart failure and a shorter lifespan.
Because there was a direct cause-and-effect relationship between the loss of Y and the ailments of aging in mice, the study reinforces the idea that the same may be true in human males. Researchers have documented an increased risk of chronic conditions such as heart disease and cancer linked to Y-chromosome loss in many studies over the years, including the new one, which used data from a large British population genetic study . The loss of Y might even explain some of the difference between the lifespans of men and women, the authors of the Science study say.
Other researchers not associated with the work were impressed.
“The authors really nailed it here,” said Dr. Ross Levine, associate physician-in-chief for translational research at Memorial Sloan Kettering Cancer Center. “It’s a super important job.”
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 started talking, and the professor told Dr. Forsberg that chromosomes And on fruit flies were more important than previously believed.
Dr. Forsberg was intrigued. I had never paid much attention to the loss of Y chromosomes. Males have an X and a Y (females have two Xs), and almost all genes used by male cells are genes on the X. Dr. Forsberg had shared the common opinion that the Y chromosome was practically a genetic wasteland.
At least 40 percent of men 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 sporadically lost from blood cells during cell division, when it is expelled from some cells and then disintegrates. The result is what the researchers call a mosaic loss of Y.
There is no way, short of smoking cessation, to reduce the risk of losing the Y chromosome. And the condition is not related to men having lower levels of testosterone in their bodies as they age. Taking testosterone supplements would not have any effect or reverse the consequences.
Curious about the idea his professor had proposed, Dr. Forsberg went back to his computer and looked at 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 was like, ‘Wow,'” Dr. Forsberg said. “I saw that men with Y loss in a large proportion of their blood cells survived only half as long, 5.5 years versus 11.1 years.”
“You can imagine my surprise,” he said. “Of course I redid everything.”
The finding stood and he published an article 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.
He quickly founded and became a shareholder in the company. Cray Innovation to test men for the loss of Y.
Other researchers began to publish similar analyses. Soon, around 20 separate papers showed associations between loss of the Y chromosome in blood cells and heart disease, shorter life expectancy, and various age-related diseases such as solid tumors and blood cancers.
At that point, Dr. Forsberg heard from Kenneth Walsh, director of the Center for Hematovascular Biology at the University of Virginia School of Medicine. Dr. Walsh became interested in Y chromosome loss because of his work on a different type of genetic loss that occurs with aging: an increase in cancerous mutations in blood cells called CHIP. People with CHIP are at increased risk for heart disease and cancer, which led Dr. Levine to establish a CHIP clinic at Sloan Kettering.
In January, Dr. Pradeep Natarajan, director of preventive cardiology at Massachusetts General Hospital, and others formed a company, Biography of TenSixteendevelop a cost-effective test for CHIP and study treatments to prevent its consequences.
But, noted Dr. Walsh, CHIP mutations are only a small part of the genetic alterations that occur with aging.
“What is the rest of this cake?” she asked. She wondered about 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. That led to his study with mice.
At first, the mice seemed fine, Dr. Walsh said, but “they aged poorly.” Their life expectancy shortened and they developed scar tissue in their heart, kidneys and lungs, including nonischemic 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 Dr. Forsberg, Dr. Walsh then examined UK Biobank data involving 223,173 men.
Men with mosaic loss of Y had a 41% increased risk of dying from any cause during a seven-year follow-up and a 31% increased risk of dying from any cardiovascular disease. The more cells that have lost their Y chromosomes, the greater the risk.
But the work also begs the question: What about the women? Do they lose one of their two X chromosomes? And 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 who lose their Y.
Women can lose an X chromosome as they age, Dr. Walsh said, but not as often as men lose their Y chromosome. Except for an association with lymphoid leukemiadata from the UK Biobank has shown no health risks for women who have lost an X. But more study is needed, Dr. Walsh said.
Turner syndrome is different. Women with the condition actually have some of the same health risks as men who have lost their Y chromosomes: cardiovascular abnormalities and nonischemic heart failure. Their average lifespan is shorter than that of women with two X’s.
It is too early to say what men should do, other than quit smoking, to protect themselves from losing their Y chromosomes or to alleviate the consequences.
Those in Dr. Walsh’s group found that they could protect the hearts of mice without Y chromosomes by blocking 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 mouse study was “really cool.” But he pointed out that there was no evidence yet that drugs to block TGF-beta were effective in men who lost their Y.
And, for now, it doesn’t make much sense to test men for Y loss, Dr. Chanock said, adding, “I am deeply concerned about over-interpreting these data for monetary purposes.”