The loss of the Y chromosome in the blood cells of men as they age can cause impaired heart function and death from cardiovascular disease, according to a new study that may lead to new therapies to treat heart disease.
Previous research has shown that men, on average, die several years younger than women, with the gradual loss of the Y chromosome in the white blood cells of their immune system linked to a higher risk of developing diseases such as cancer and Alzheimer’s.
The new research, published in the journal Sciences on Thursday, found that those with such a loss of the Y chromosome, called mLOY (mosaic loss of Y) in white blood cells also have a higher risk of dying from heart disease, the most common cause of death in humans.
The researchers, including those at Uppsala University in Sweden, say it was previously unknown whether mLOY in white blood cells has a direct effect on disease progression in other organs.
“The DNA in all of our cells inevitably accumulates mutations as we age. This includes the loss of the entire Y chromosome within a subset of cells within males. Understanding that the body is a mosaic of acquired mutations provides clues about age-related diseases and the aging process itself,” said study co-author Kenneth Walsh of the University of Virginia.
In the new study, the scientists used the Crispr gene-editing tool to generate mouse models with mLOY in their white blood cells.
They found that mLOY caused direct damage to the internal organs of rodents and that mice with mLOY had shorter survival than those without mLOY.
“In the mouse models used in the study, the mouse Y chromosome was deleted to mimic the human mLOY condition and we looked at the direct consequences this had. Examination of mLOY mice showed increased scarring of the heart, known as fibrosis,” Lars Forsberg, a co-author of the study at Uppsala University, said in a statement.
“We see that mLOY causes fibrosis that leads to decreased heart function,” said Dr. Forsberg.
When the researchers compared the effect seen in mice with human population studies, they found that mLOY was a significant new risk factor for death from cardiovascular disease in men.
The comparative study evaluated data from the UK Biobank, a database of genomic and health information on half a million normally aged people who were between the ages of 40 and 70 at the start of the study.
The scientists found that men with mLOY in their blood at the start of the study had about a 30 percent increased risk of dying from heart failure and other types of cardiovascular disease during about 11 years of follow-up.
“We also see that men with a higher proportion of mLOY white blood cells in their blood have a higher 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 in humans as well,” said Dr. Forsberg.
The study suggests that mLOY in a certain type of white blood cell in the heart of mice, known as cardiac macrophages, stimulates a molecular pathway that leads to increased fibrosis.
It describes for the first time a mechanism by which mLOY in the blood causes disease in other organs and also identifies a possible treatment.
When the researchers blocked the molecular pathway, the pathological changes in the heart caused by mLOY could be reversed.
“The link between mLOY and fibrosis is very interesting, especially given new treatment strategies for heart failure, pulmonary fibrosis, and certain types of cancer that aim to counteract the onset of fibrosis. Men with mLOY could be a group of patients that responds particularly well to such treatment,” said Dr. Forsberg.
“Studies examining Y-chromosome loss and other acquired mutations hold great promise for the development of personalized drugs that are tailored to these specific mutations,” added Dr. Walsh.