Previous research has shown that men, on average, die years earlier than women and that the gradual loss of Y chromosomes in their immune system’s white blood cells puts them at risk of developing diseases such as cancer and Alzheimer’s. Is.
A new study published Thursday in the journal Science found that white blood cells lacking the Y chromosome, known as mLOY (mosaic loss of Y), also increase the risk of dying from heart disease. The most common reason is this. Death in humans.
It was not yet known whether mLOY in leukocytes had a direct effect on disease progression in other organs, say the researchers, including researchers from Uppsala University in Sweden.
“The DNA of all of our cells inevitably accumulates mutations as we age. This includes the loss of the entire Y chromosome in a subset of cells in males. Understanding that the body is a mosaic of acquired mutations is important as we age. provides insight into diseases related to aging and the aging process itself,” said study co-author Kenneth Walsh of the University of Virginia.
In the new study, scientists used the CRISPR gene-editing tool to create mouse models with mLOY in their white blood cells.
They found that mLOY directly damaged the internal organs of mice and that mice with mLOY lived less than mice without mLOY.
“In the mouse models used in the study, the mouse Y chromosome was deleted to mimic the human mLOY condition, and we analyzed the results directly. Examination of mice with mLOY There was an increase in scarring of the heart, called fibrosis,” said study co-author Lars Forsberg of Uppsala University.
“We see that mLOY causes fibrosis, which leads to reduced heart function,” said Dr. Forsberg.
When the researchers compared the effect observed in mice with population-based studies in humans, they found that mLOY was a significant new risk factor for cardiovascular death in men.
The comparative study examined data from the UK Biobank, a database of genomic and health information from half a million normal elderly people aged between 40 and 70 when the study began.
The researchers found that men with mLOY blood levels at the start of the study had a nearly 30 percent increased risk of dying from heart failure and other cardiovascular diseases during about 11 years of follow-up.
“We also find that men who have a higher proportion of white blood cells with mLOY in their blood have a higher risk of dying from heart disease. This observation is consistent with results from the mouse model and suggests mLOY also has a direct physiological effect on humans,” said Dr. Forsberg.
The study showed that mLOY in a specific type of white blood cell in the mouse heart, called cardiac macrophages, activates a molecular pathway that leads to increased fibrosis.
It describes for the first time the mechanism by which mLOY in the blood causes disease in other organs, and suggests a possible treatment.
When the researchers blocked the molecular pathway, the pathological changes in the heart caused by mLOY could be reversed.
“The relationship between mLOY and fibrosis is very interesting, especially given the new treatment strategies for heart failure, pulmonary fibrosis, and some cancers aimed at counteracting the onset of fibrosis. One of the male patients with mLOY There may be groups that respond particularly well to such treatments,” said Dr. Forsberg.
“Research looking at Y-chromosome loss and other acquired mutations holds great promise for the development of personalized medicine tailored to these specific mutations,” added Dr. Walsh.