Men lose Y chromosomes as they age. It may be harming their hearts:

 As men get older, they don’t just lose their hair, muscle tone, and knee cartilage. They also start to lose Y chromosomes from their cells. Scientists have linked this vanishing to a long list of diseases and a higher risk of death, but the evidence has been circumstantial. Now, researchers report that when they removed the Y chromosome from male mice, the animals died earlier than their Y-carrying counterparts, likely because their hearts became stiffer.

“This is the best evidence to date” that losing the Y chromosome is detrimental to health, says John Perry, a human geneticist at the University of Cambridge. Perry led one of the biggest studies on the frequency of Y chromosome loss in men, but wasn’t connected to the new research.

Despite its macho reputation, the Y chromosome is a pipsqueak, carrying a mere 71 genes—less than one-tenth as many as the X chromosome. That may be why the chromosome sometimes doesn’t get passed on when a cell divides. Analyzing blood samples is the easiest way to detect loss of Y, and researchers have found the chromosome is missing from at least some white blood cells in about 40% of 70-year-olds and 57% of 93-year-olds. In some older men, more than 80% of the cells can be short a Y chromosome.

Cells can survive and reproduce without a Y, but men lacking the chromosome in some of their cells are more likely to suffer from heart disease, cancer, Alzheimer’s disease, and other aging-related ailments. Moreover, the condition could be a reason why men die on average about 5 years earlier than women in the United States, says molecular biologist Kenneth Walsh of the University of Virginia.

To test whether removing the Y chromosome harms health, Walsh and colleagues performed bone marrow transplants on 38 mice. They used the CRISPR-Cas9 gene-editing tool to delete the Y chromosome from mouse bone marrow cells and then inserted the altered cells into young male mice whose bone marrow had been removed. The swap didn’t banish the Y chromosome from the recipients, but it culled the chromosome from 49% to 81% of white blood cells—about the same percentage as in many humans with Y-chromosome loss. The 37 control mice for this experiment also received bone marrow transplants but retained the Y chromosome.

For nearly 2 years, the researchers followed both groups of animals. The Y-lacking rodents were more likely to die during this period—only about 40% of these mice survived for 600 days after the transplants, versus about 60% of the control rodents.

Mice that lost their Y chromosome also had weaker hearts. After about 15 months, the heart’s contraction strength had declined by close to 20%. In addition, the buildup of tough connective tissue, a process called fibrosis, surged in the hearts of mice missing the Y chromosome. This accumulation stiffens the heart and impairs its ability to pump blood.

The bone marrow transplants the researchers performed on the mice did not eliminate the Y chromosome from heart muscle cells. But the white blood cells called macrophages, which are born in the bone marrow, slip into the heart. The scientists found that many of the macrophages from mice lacking the Y chromosome began to promote fibrosis, stimulating other cells in the heart to spin more connective tissue.

Something similar may be going on in humans. Walsh and colleagues obtained DNA and survival information for more than 15,000 men from the UK Biobank, a huge health database. The team determined that men who had lost the Y chromosome from at least 40% of their white blood cells were 31% more likely to die from circulatory system diseases than those in which the chromosome was more abundant. When the scientists broke down the causes of death that correlated with the Y chromosome’s absence, they identified several cardiac conditions, including heart failure.

Losing  the Y chromosome spurs fibrosis in the heart, resulting in heart failure and an earlier death, the team concludes today in Science. Researchers have long downplayed the Y chromosome’s health impact because it sports so few genes, Walsh says, but the evidence suggests shedding it “leads to a staggering amount of years of life lost.”

Genetic epidemiologist Mitchell Machiela of the National Cancer Institute, who also wasn’t connected to the study, says the research provides “compelling evidence.” The discovery that macrophages in the Y-lacking mice change their “personality” and begin to foster fibrosis makes sense, adds collagen biologist Amy Bradshaw of the Medical University of South Carolina. This switch “is central to a lot of the fibrosis we see in the heart.”