Posted: Jul 18, 2022
By Mark Terry
Chromosomally normal males have 46 chromosomes, two of which are sex chromosomes, one X and one Y (46, XY), and as males age they may lose some of these chromosomes. A new study published in Science found that loss of Y chromosomes in white blood cells is associated with an increased risk of dying from heart disease.
This type of Y chromosome loss is called mLOY (mosaic Loss Of Y). Mosaic refers to a mixture of chromosomally different cells, some being 46, XY and some being 45, X, -Y.
The Y chromosome is the smallest of the chromosomes and contains very few genes. However, as the authors note, “its functions are not fully understood. It has been observed, however, that the mosaic loss of the Y chromosome in blood cells occurs frequently with age, and this alteration is associated with various medical conditions.
In studies in mice, cells lacking the Y chromosome are more likely to develop fibrosis (scarring) and decreased heart function. However, they benefited from treatment with an antibody that neutralized transforming growth factor beta 1. In this study, working with male mice that had been reconstituted with bone marrow cells that lacked the Y chromosome, they found that they had increased mortality and age-related profibrotic symptoms, including reduced heart function.
Cardiac macrophages, a type of immune cell, which lacked Y chromosomes, tended toward more fibrosis. But treatment with a neutralizing antibody to transforming growth factor beta 1 improved heart function in mLOY mice.
They don’t know if 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,” said study co-author Kenneth Walsh, Ph.D. Walsh is a researcher at the University of Virginia. The study was conducted with researchers from Uppsala University in Sweden. “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 provides clues to age-related diseases and the aging process. -same.
The researcher exploited CRISPR-Cas9 gene editing to create mouse models with mLOY in their white blood cells. mLOY directly damaged the internal organs of the mice. Mice with mLOY did not survive as long as those without mLOY.
Lars Forsberg, Ph.D., co-author of the Uppsala study, said, “In the mouse models used in the study, the mouse Y chromosome was knocked out to mimic the human mLOY condition and we We analyzed the direct consequences that this had. . Examination of mice with mLOY showed increased scarring of the heart, known as fibrosis. We see that mLOY causes fibrosis which leads to a decline in heart function.
The study analyzed UK Biobank data from 500,000 people normally aging between 40 and 70 at the start of the study. Men with mLOY in their blood at the start of the study had a 30% increased risk of dying from heart failure and other types of cardiovascular disease over the 11 years of follow-up.
Forsberg said, “We also find 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 consistent with the results from the mouse model and suggests that mLOY has a direct physiological effect also in humans.
He went on to note, “The link between mLOY and fibrosis is very interesting, especially given new treatment strategies for heart failure, pulmonary fibrosis and certain cancers that aim to counteract the onset of fibrosis. . Males with mLOY might be a patient group that responds particularly well to such treatment.