Research by an international team of scientists headed by researchers at the University of Virginia (UVA) School of Medicine and Uppsala University, has found that loss of the Y chromosome in the white blood cells of men as they age causes the heart muscle to scar and can lead to deadly heart failure. The findings may help explain why men die, on average, several years younger than women.

On average, women live five years longer than men in the United States, and the new finding may explain nearly four of the five-year difference, suggests UVA research co-lead Kenneth Walsh, PhD. “Particularly past age 60, men die more rapidly than women. It’s as if they biologically age more quickly,” said Walsh, director of UVA’s Hematovascular Biology Center. “There are more than 160 million males in the United States alone. The years of life lost due to the survival disadvantage of maleness is staggering. This new research provides clues as to why men have shorter lifespans than women.”

The new discovery suggests that men who do exhibit Y chromosome loss—which is estimated to include 40% of 70-year-olds—may particularly benefit from an existing drug that targets dangerous tissue scarring, suggested UVA researcher Kenneth Walsh, PhD. The drug, Walsh suspects, may help counteract the harmful effects of the chromosome loss—effects that may manifest not just in the heart but in other parts of the body as well.

Walsh, together with co-senior author Lars A Forsberg, at Uppsala University, first author Soichi Sano, PhD, at UVA School of Medicine, and colleagues reported on their findings in Science, in a paper titled, “Hematopoietic loss of Y chromosome leads to cardiac fibrosis and heart failure mortality.”

The human male-specific Y chromosome is relatively small in size and contains a limited number of genes that regulate sex determination and spermatogenesis, the authors noted. But beyond sex determination, “… there is a paucity of information about the biological role of the Y chromosome.” Many men begin to lose their Y chromosome in a fraction of their cells as they age. This appears to be particularly true for smokers. The loss occurs predominantly in cells that undergo rapid turnover, such as blood cells. (Loss of the Y chromosome does not occur in male reproductive cells, so it is not inherited by the children of men who exhibit Y chromosome loss.)

Kenneth Walsh, PhD, of the University of Virginia School of Medicine, has found that the loss of the male sex chromosome as many men age causes the heart muscle to scar and can lead to deadly heart failure. The finding may help explain why men die, on average, several years younger than women. [Dan Addison|UVA Communications]
Scientists previously observed that men who suffer Y chromosome loss are more likely to die at a younger age and suffer age-associated maladies such as Alzheimer’s disease. “Hematopoietic mosaic loss of Y chromosome (mLOY) is associated with increased risk of mortality and age-related diseases in men, but the causal and mechanistic relationships have yet to be established,” the team continued. Loss of the Y chromosome is prevalent in blood cancers and may be relevant to disease prognosis. “Whereas most men with mLOY never progress to a hematologic cancer, epidemiological studies have shown that mLOY in blood is associated with shorter life span and increased incidence of various age-associated diseases, including solid tumors and Alzheimer’s disease,” they added. mLOY has also previously been linked with secondary major cardiovascular events in some patients.

The new research reported by Walsh et al., is believed to be the first hard evidence that the chromosome loss directly causes harmful effects on men’s health. Walsh, of UVA’s Division of Cardiovascular Medicine and the Robert M. Berne Cardiovascular Research Center, and his team used CRISPR-Cas9 gene editing technology to develop a mouse model of hematopoietic mLOY by reconstituting the animals’ bone marrow with cells lacking the Y chromosome. This model gave them a better understanding of the effects of Y chromosome loss in the blood. They found that Y chromosome loss accelerated age-related diseases, made the mice more prone to heart scarring, and led to an earlier death. This wasn’t the result of just inflammation, the scientists determined. Instead, the mice suffered a complex series of responses in the immune system, leading to fibrosis throughout the body. The findings suggested that bone marrow-derived mLOY macrophages that infiltrate the heart trigger high transforming growth factor β(TGF-β1) activity, which leads to fibroblast proliferation and accelerated cardiac tissue fibrosis.

This tug-of-war within the immune system, the researchers believe, may accelerate disease development. “In the mouse models used in the study, the mouse Y chromosome was eliminated to mimic the human mLOY condition and we analyzed the direct consequences that this had,” commented co-research lead Lars Forsberg, PhD, associate professor at the department of immunology, genetics and pathology at Uppsala University. “Examination of mice with mLOY showed an increased scarring of the heart, known as fibrosis. We see that mLOY causes the fibrosis which leads to a decline in heart function.”

The authors further stated that their findings “provide evidence in mouse models that supports a causal link between hematopoietic mLOY and age-dependent cardiac dysfunction and heart failure in men. We report that Y chromosome–deficient cardiac macrophages overactivate a profibrotic signaling network, leading to cardiac fibroblast proliferation and activation, excessive matrix production, and diminished heart function.

The scientists looked at the effects of Y chromosome loss in human men. They conducted three analyses of data compiled from the UK Biobank, and found that Y chromosome loss was associated with cardiovascular disease and heart failure. As chromosome loss increased, the scientists found, so did the risk of death. Men with mLOY in their blood at the start of the study displayed an approximately 30% increased risk of dying from heart failure and other types of cardiovascular disease during approximately 11 years of follow-up. “We also see that men with a higher proportion of white blood cells with mLOY in the blood have a greater risk of dying from cardiovascular disease. This observation is in line with the results from the mouse model and suggests that mLOY has a direct physiological effect also in humans,” said Forsberg.

Along with describing for the first time a mechanism by which mLOY in blood causes disease in other organs the study further identified a possible treatment. In the mouse models, treatment with a TGF-βneutralizing antibody was shown to ameliorate the harmful effects of Y chromosome loss “… our experimental studies also found that a neutralizing TGFβ1 antibody could reverse the pathological cardiac phenotypes caused by mLOY,” the team wrote. The findings suggest that targeting the effects of Y chromosome loss could help men live longer, healthier lives. “In view of recent efforts to treat heart failure, idiopathic pulmonary fibrosis, and some cancers with antifibrotic approaches, men with mLOY could represent a patient subpopulation that exhibits a superior response to this class of therapeutic agents.”

In a related perspective in the same issue of Science, Andreas Zeiher, PhD, at Goethe University, and Thomas Braun, PhD, at the Max Planck Institute for Heart and Lung Research, commented, “… several unexpected links between the Y chromosome, immune system, and complex polygenic traits have been discovered, suggesting an influence of the Y chromosome on immune and inflammatory responses in men … The study of Sano et al., reinforces this view and uncovers a crucial function of the Y chromosome in maintaining a healthy innate immune system, but further research is required to elucidate the mechanisms.”

Walsh noted that one potential treatment option might be a drug, pirfenidone, which has already been approved by FDA for the treatment of idiopathic pulmonary fibrosis, a form of lung scarring. The drug is also being tested for the treatment of heart failure and chronic kidney disease, two conditions for which tissue scarring is a hallmark. Based on his research, Walsh believes that men with Y chromosome loss could respond particularly well to this drug, and other classes of antifibrotic drugs that are being developed, though more research will be needed to determine that. “The link between mLOY and fibrosis is very interesting, especially given the new treatment strategies for heart failure, pulmonary fibrosis, and certain cancers that aim to counteract the onset of fibrosis,” Forsberg added. “Men with mLOY could be a patient group that responds particularly well to such treatment.”

At present, doctors have no easy way to determine which men suffer Y chromosome loss. Forsberg developed an inexpensive polymerase chain reaction (PCR) test—such as those used for COVID-19 testing, that can detect Y chromosome loss—but the test is largely confined to his and Walsh’s labs.

Walsh, however, can foresee that changing: “If interest in this continues and it’s shown to have utility in terms of being prognostic for men’s disease and can lead to personalized therapy, maybe this becomes a routine diagnostic test,” he said. “The DNA of all our cells inevitably accumulate mutations as we age. This includes the loss of the entire Y chromosome within a subset of cells in men. Understanding that the body is a mosaic of acquired mutations provides clues about age-related diseases and the aging process itself,” said Walsh, a member of UVA’s department of biochemistry and molecular genetics. “Studies that examine Y chromosome loss and other acquired mutations have great promise for the development of personalized medicines that are tailored to these specific mutations.”