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. Loss of Y might just be a sign of aging, like gray hair, with no clinical relevance.
However, now researchers report that it may play a role. Very much.
A new study of male mice genetically engineered to lose their Y chromosomes sheds some light. The study, published Thursday in the journal Science, found that in these mice, when the Y chromosome was removed from blood cells, scar tissue built up in the heart, leading to heart failure and a shortened lifespan.
Because there was a direct cause-and-effect relationship between Y loss and senile symptoms in the mice, the study supports the notion that the same can happen in human males. Researchers have documented an increase in the risk of chronic diseases such as heart disease and cancer associated with 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 UK population. The loss of Y could even explain part of the difference in lifespans between men and women, say the authors of the Science study.
Other investigators unrelated to the work were impressed.
“The authors really nailed it here,” said Dr. Ross Levine, associate chief of translational research at Memorial Sloan Kettering Cancer Center. “It’s super important work.”
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 said Dr. Forsberg found that the Y chromosomes in fruit flies were more important than previously thought.
dr Forsberg was fascinated. He had never paid much attention to Y chromosome loss. Males have an X and a Y (females have two Xs), and nearly all genes used by male cells are genes on the X. Forsberg had shared the common view that the Y chromosome was pretty much a genetic wasteland.
At least 40 percent of men lose the Y chromosome in some of their blood cells by the age of 70. And by the age of 93, at least 57 percent have lost some of it.
The chromosome is sporadically lost from blood cells during cell division, when it is knocked out of some cells and then disintegrates. Researchers call the result a mosaic loss of Y.
There is no other option than quitting smoking to reduce the risk of losing the Y chromosome. And the condition has nothing to do with men having lower levels of testosterone in their bodies as they age. Taking testosterone supplements would have no effect, nor would it reverse the effects.
Curious about the idea his professor had proposed, Dr. Forsberg returned to his computer and looked at data from 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,'” said Dr. forsberg “I saw that men with Y loss in a large proportion of their blood cells survived half as long, 5.5 years versus 11.1 years.”
“You can imagine my surprise,” he said. “Of course I redid everything.”
The finding continued, 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 formed and became a part owner of the Cray Innovation company to test men for the loss of Y.
Other researchers began publishing similar analyses. About 20 independent papers were soon showing links between the loss of the Y chromosome in blood cells and heart disease, shortened life expectancy and various age-related diseases such as solid tumors and blood cancer.
At that point, Dr. Forsberg by Kenneth Walsh, director of the Hematovascular Biology Center at the University of Virginia School of Medicine. dr Walsh became interested in Y chromosome loss because of his work on another type of genetic loss that occurs with age: an increase in cancerous mutations in blood cells called CHIP. People with CHIP have a higher risk of heart disease and cancer, which Dr. Levine arranged for a CHIP clinic to be set up in Sloan Kettering.
In January, Dr. Pradeep Natarajan, director of preventive cardiology at Massachusetts General Hospital, and others set up TenSixteen Bio to develop an inexpensive test for CHIP and investigate treatments to prevent its consequences.
But, noted Dr. Walsh, CHIP mutations are just a small part of the genetic changes that occur with aging.
“What’s the rest of this cake?” he asked. He became concerned about Y chromosomes and began devising 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, said Dr. Walsh, but “they’ve aged badly.” Their lifespans 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 the cause of which is poorly understood. The mental abilities of the animals were also reduced.
In cooperation with dr. Forsberg examined Dr. Walsh then used data from the UK Biobank involving 223,173 men.
Men with mosaic loss of Y had a 41 percent increased risk of dying from any cause during a seven-year follow-up and a 31 percent increased chance of dying from cardiovascular disease. The more cells that have lost Y chromosomes, the greater the risk.
But the work also begs the question: What about women? Do you lose one of your two X chromosomes? And what about women with Turner syndrome? They are born with only one X chromosome, making all of their cells the equivalent of the random set of blood cells in males who lose their Y.
Women can lose an X chromosome as they age, said Dr. Walsh, but not as often as men lose their Y. Apart from an association with lymphoid leukemia, the UK Biobank data have shown no health risks for women who have lost an X. But more studies are needed, said Dr. Walsh.
Turner syndrome is different. Women with the condition actually share some of the same health risks as men who have lost their Y chromosomes – cardiovascular abnormalities and non-ischemic heart failure. Their average lifespan is shorter than that of women with two Xs.
It’s too early to tell what men should do – other than quit smoking – to protect themselves from, or mitigate, the loss of their Y chromosomes.
The members of Dr. Walsh’s group found that they could protect the hearts of mice lacking the Y chromosome 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.” However, he noted that there is still no evidence that drugs to block TGF-beta are effective in men who have lost their Y.
And right now there’s little point in testing men for Y loss, said Dr. Chanock, adding: “The over-interpretation of this data for monetary purposes worries me deeply.”