It has been known for over 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 may simply be a sign of aging, like gray hair, with no clinical significance.
Now, however, researchers are reporting that it could make a difference. Lots of.
A new study using male mice genetically engineered to lose Y chromosomes provides insight. Paper, published Thursday in the journal Sciencefound that when the Y chromosome disappeared from the blood cells of these mice, scar tissue formed in the heart, leading to heart failure and reduced lifespan.
Since there was a direct causal relationship between Y loss and aging in mice, the study supports the notion that the same may be happening in males. Researchers have documented an increase in the risk of chronic diseases such as heart disease and cancer associated with Y-chromosome loss in many studies over the years, including a new one that used data from a large genetic study of the British population. The authors of the study say that the loss of Y may even explain some of the difference in life expectancy between men and women.
Other researchers not related to the work were impressed.
“The authors have really succeeded here,” the doctor said. Ross Levin, Associate Chief Medical Officer for Translational Research at Memorial Sloan Kettering Cancer Center. “This is a super important job.”
The inspiration for the new study came when Lars Forsberg, a researcher at Uppsala University, ran into a former professor on a bus in Uppsala, Sweden in 2013. Forsberg that Y chromosomes in fruit flies are more important than previously thought.
Dr. Forsberg was intrigued. He never paid much attention to the loss of the Y chromosome. Males have one X and one Y (females have two Xs), and almost all of the genes used by male cells are X genes. Forsberg shared the popular belief that the Y chromosome was a genetic wasteland.
At least 40 percent of men lose their Y chromosome from some blood cells by age 70. And by age 93, at least 57 percent lose some of it.
The chromosome is sporadically lost from blood cells during cell division, when it is ejected from some cells and then broken apart. The result is what researchers call mosaic Y loss.
There is no other way than to quit smoking, to reduce the risk of Y-chromosome loss. And this condition is not due to the fact that men have lower levels of testosterone in the body as they age. Taking testosterone supplements will not have any effect and will not change the effects.
Intrigued by the idea proposed by his professor, 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 Male Aging in Uppsala.
“I had the data a few hours later and I was like, ‘Wow,’” says the doctor. Forsberg said. “I saw that men with Y loss in a large proportion of their blood cells lived half as long, 5.5 years versus 11.1 years.”
“You can imagine my surprise,” he said. “Of course, I redid everything.”
The conclusion was confirmed, and he published article in the journal Nature Genetics in 2014, reporting that increases in deaths and cancer diagnoses were associated with the loss of the Y chromosome in blood cells.
He quickly founded and became a shareholder of the company. Cray Innovation check men for Y loss.
Other researchers have begun to publish similar analyses. Soon, about 20 independent articles showed a link between the loss of the Y chromosome in blood cells and heart disease, reduced life expectancy, and various age-related diseases such as solid tumors and blood cancer.
At that moment Dr. Forsberg heard from Kenneth Walsh, director of the Center for Hemovascular Biology at the University of Virginia School of Medicine. Dr. Walsh became interested in the loss of the Y chromosome because of his work on another type of genetic loss that occurs with age: an increase in the number of cancerous mutations in blood cells called CHIP. People with CHIP have a higher risk of heart disease and cancer, which prompted Dr. C. Levine to open the CHIP clinic in Sloan Kettering.
In January Dr. Pradeep Natarajan, director of preventive cardiology at Massachusetts General Hospital, and others formed a company Biographydevelop a cost-effective test for CHIP and explore treatments to prevent its consequences.
But, dr. Walsh noted that CHIP mutations are only a small part of the genetic changes that occur with aging.
“What’s left of this pie?” he asked. He 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. This led to its study with mice.
At first, the mice were fine. Walsh said, but “they didn’t age well.” Their life expectancy was shortened and they developed 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 of which is poorly understood. The mental abilities of the animals were also reduced.
Working with Dr. Forsberg, Dr. Walsh then examined data from the UK Biobank, which included 223,173 men.
Men with mosaic Y loss had a 41% increased risk of death from any cause during seven years of follow-up and a 31% increased risk of death from any cardiovascular disease. The more cells that have lost Y chromosomes, the higher the risk.
But the work also raises the question: what about women? Do they lose one of their two X chromosomes? What about women with Turner syndrome? They are born with only one X chromosome, making all their cells the equivalent of a random group of blood cells in men who have lost a Y.
Women can lose the X chromosome as they age, says Dr. Walsh, but not as often as men lose their Y. Except association with lymphoid leukemia, data from the British Biobank showed no health risk for women who lost X. But more research is needed, dr. Walsh said.
Turner syndrome is different. Women with this condition actually have some of the same health risks as men who have lost their Y chromosomes – cardiovascular abnormalities and non-ischemic heart failure. Their average life expectancy is shorter than that of women with two crosses.
It’s still too early to tell what men should do other than stop smoking to protect themselves from Y-chromosome loss or mitigate the consequences.
Those in Dr. Walsh’s group found that they could protect the hearts of mice lacking Y chromosomes by blocking TGF-beta, a key molecule involved in scar tissue formation.
Dr. Stephen Chanock, director of cancer epidemiology and genetics at the National Cancer Institute, said the mouse study was “really cool.” But he noted that there is no evidence yet that drugs to block TGF-beta will be effective in men who have lost Y.
And it doesn’t make much sense to test men for Y loss at this point, dr. Chanok said, adding, “I am deeply concerned about the over-interpretation of this data for monetary purposes.”