Errors in the human genome are part of life. As we age and DNA replicates, small errors are introduced into our genes (a letter out of place here or some erroneous repetition there) that can accumulate over time to create a “mosaic” of cells with unique codes throughout the body. Some cells may even lose entire chromosomes.
An example of this is a condition where white blood cells do not have the Y chromosome. Called mLOY (for the loss of the Y chromosome in mosaic), it is more common than you might think, which occurs in about 40 per one hundred men over 70 years of age.
Although the Y chromosome has long been considered a reduced genetic wasteland full of expendable pieces of DNA, the lack of a Y chromosome can have serious health consequences.
In epidemiological studies, mLOY has been associated with a shorter shelf life and an increased risk of age-related diseases, such as cancer and Alzheimer’s disease. Now, the condition could also be related to impaired heart function, according to a new study that mimics the human condition in mice.
For a time it is unclear how the loss of the Y chromosome from blood cells causes damage to organs and disease in other parts of the body, and increases the risk of age-related diseases, especially cardiovascular disease and stroke.
The team of researchers led by cardiovascular researcher Soichi Sano of Osaka Metropolitan University School of Medicine in Japan, delved into these questions and has shown how mLOY causes tissue damage leading to heart failure in mice and is related to cardiovascular disease.
In the study, the researchers used the famous CRISPR gene editing tool to design mice without Y chromosomes in their white blood cells to mimic the human mLOY condition.
CRISPR mice lived shorter lives than unaffected mice and had greater heart healing, a condition known as cardiac fibrosis that hardens heart tissue and is related to heart failure.
“We see this mLOY [in mice] it causes fibrosis which leads to a decrease in heart function, ”says geneticist and lead author Lars Forsberg of Uppsala University.
To test these findings with epidemiological data, the researchers analyzed data from the UK Biobank, a decade-long study that has captured genetic and health information from some half a million adults who typically age.
They found that men with mLOY in their blood at the start of the study had a higher risk of dying from heart failure and other types of cardiovascular disease during the 11-year follow-up average.
“This observation is in line with the results of the mouse model and suggests that mLOY has a direct physiological effect in humans as well,” says Forsberg.
Of course, more research is needed before we can trace the direct consequences of mLOY in humans. And keep in mind that Y chromosome loss is unlikely to be the only cause of age-related diseases that are linked to a lot of cellular processes that have gone wrong and a number of genetic changes that s ‘have accumulated over time.
As Cambridge University biologist John Perry told The Atlantic in 2019, after publishing a paper showing why some are more prone to mLOY than others, “Y chromosome loss is a manifestation of instability of the wider genome “. The instability that is characteristic of cancer and indicates that DNA has been accumulating errors faster than cells can fix them.
Chronic inflammation is another suspected culprit for many aging diseases, such as cancer and Alzheimer’s. Therefore, as Forsberg and colleagues point out, more work needs to be done to unravel the complex interaction between inflammation and fibrosis and the role of mLOY in both.
Returning to mouse models for one last hoorah, Forsberg and colleagues also identified a possible treatment to enhance the effects of mLOY. By blocking a signaling pathway that was activated in mice with Y chromosome-deficient immune cells, the researchers noted that subsequent fibrotic changes were partially reversed.
“The link between mLOY and fibrosis is very interesting, especially given the new strategies for treating heart failure, pulmonary fibrosis, and certain cancers that aim to counteract the onset of fibrosis,” says Forsberg.
While a possible therapy to counteract the loss of the Y chromosome in blood cells is still long, “men with mLOY could be a group of patients who respond particularly well to this treatment,” Forsberg added.
But knowing what we do now, quitting smoking would also be a good measure, as research also shows that men who smoke are more than three times more likely than non-smokers to show Y chromosome loss in their cells. blood.
The study was published in Science.