Over the past half century, many men have lost their Y chromosomes as they age. But no one knows if it really matters. The loss of Y may just be a sign of aging, like graying of hair, that is not clinically relevant.
Now, however, researchers report that it may be important. So many.
A new study using male mice genetically engineered to lose the Y chromosome provides insights. The paper, published Thursday in the journal Science, found that when the Y chromosome was no longer present in the blood cells in those mice, scar tissue built up in the heart, leading to heart failure and shortened lifespan. .
Because there is a direct cause-and-effect relationship between the loss of Y and aging disease in mice, the study reinforces the idea that the same could be said in male mice. Researchers have documented an increased risk of chronic diseases like heart disease and cancer associated with Y-chromosome loss in multiple studies over the years, including a new one, using the data. from a large genetic study of the British population. The study’s authors say that the loss of Y may even account for some of the differences between men’s and women’s lifespans.
Other investigators unrelated to the work were impressed.
“The authors really nailed it here,” said Dr. Ross Levine, associate physician in charge of translational research at Memorial Sloan Kettering Cancer Center. “It’s super important work.”
The inspiration for the new study came when Lars Forsberg, a researcher at Uppsala University, ran into an old professor on a bus in Uppsala, Sweden, in 2013. They started chatting and teaching. Professor told Dr. Forsberg that the Y chromosome in fruit. flies are more appreciated than before.
Dr. Forsberg was intrigued. He never cared much about the loss of the Y chromosome. Men have one X and one Y (females have two Xs), and nearly all the genes used by male cells are genes on the X. Forsberg shared the common view that the Y chromosome is a genetic wasteland.
At least 40% of men have lost a Y chromosome from some of their blood cells by age 70. And by age 93, at least 57% have lost some of these chromosomes.
Chromosomes are sporadically lost from blood cells during meiosis, when it is ejected from some cells and then disintegrated. The result is what the researchers call mosaic Y loss.
There’s no way, other than stopping smoking, to reduce the risk of losing a Y chromosome. And the condition isn’t linked to men having lower levels of testosterone in their bodies as they age. Taking testosterone supplements will have no effect, nor will it reverse the effects.
Curious about the idea his professor had suggested, Dr Forsberg went back to his computer and looked at data on 1,153 aging men in a large Swedish study, the Longitudinal Study of Uppsala’s aging men.
“I had the data for a few hours and I felt like, ‘Wow,’” Dr. Forsberg said. “I found that men who lost Y in a large percentage of their blood cells lived only half as long, 5.5 years versus 11.1 years.”
“You can imagine my surprise,” he said. “Of course I did everything again.”
This finding was confirmed, and he published a paper in Nature Genetics in 2014, reporting that increased mortality and cancer diagnoses were associated with the loss of the Y chromosome in health. blood cells.
He quickly founded and became a shareholder of the company Cray Innovation to examine the loss of Y of men.
Other researchers began publishing similar analyses. Soon, about 20 independent papers linked the loss of the Y chromosome in blood cells and heart disease, shortened life expectancy, and age-related diseases such as solid tumors and cancer. blood letter.
At that point, Dr. Forsberg heard from Kenneth Walsh, director of the Center for Hematology Biology at the University of Virginia School of Medicine. Dr. Walsh became interested in Y chromosome loss because of his research on another form of genetic loss that occurs with aging: an increase in a cancerous mutation in blood cells called CHIP. People with CHIP have a higher risk of heart disease and cancer, which prompted Dr. Levine to set up a CHIP clinic at Sloan Kettering.
In January, Dr. Pradeep Natarajan, director of preventive cardiology at Massachusetts General Hospital, and others founded a company, TenSixteen Bio, to develop a cost-effective test for CHIP and research treatments to prevent its consequences.
However, Dr. Walsh notes, CHIP mutations are only a small part of the genetic changes that occur with aging.
“What’s the rest of this cake?” he asks. He wondered about the Y chromosome and began planning to find 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 research with rats.
At first, the mice seemed fine, Dr. Walsh said, but “they aged very poorly.” Their life expectancy is shortened and they develop scar tissue in the heart, kidneys and lungs, including non-ischemic heart failure, a type that is not the result of a heart attack and the cause is not understood. clear. The animals’ mental abilities are also impaired.
Working with Dr Forsberg, Dr Walsh then examined data from the UK Biobank involving 223,173 men.
Men with mosaic Y impairment had a 41% increased risk of dying from any cause during the 7-year follow-up period and a 31% increased risk of dying from any cardiovascular disease. The more cells that have lost their Y chromosome, the greater the risk.
But the work also raises the question, What about women? Did they lose one of their two X chromosomes? What about women with Turner syndrome? They were born with only one X chromosome, making all their cells the equivalent of a random group of blood cells in men with a loss of Y.
Women can lose their X chromosomes as they age, but not as often as men, said Dr. Walsh. Except for the association with lymphoid leukemia, UK Biobank data do not show found health risks for women losing X. But more research is needed, Dr. Walsh said.
Turner syndrome is different. Women with the condition actually have some of the same health risks as men with a missing Y chromosome — cardiovascular abnormalities and non-ischemic heart failure. Their average life expectancy is shorter than that of women with two Xs.
It’s too early to say what men should do – other than stop smoking – to protect themselves from losing a Y chromosome or to lessen the consequences.
Dr. Walsh’s team found they could protect the hearts of mice without the Y chromosome by blocking TGF-beta, a key molecule involved in scar tissue production.
Dr Stephen Chanock, director of the division of cancer epidemiology and genetics at the National Cancer Institute, said the mouse study was “really amazing”. But he notes that there is still no evidence that drugs that block TGF-beta are effective in men who have lost Y.
And currently, there’s little point in examining whether men lose Y, adds Dr Chanock, “over-interpreting these data for monetary purposes makes me extremely nervous. “
