Loss of male sex chromosome leads to earlier death for men


According to recent study from the University of Virginia School of Medicine, the loss of the male sex chromosome as men age causes the heart muscle to scar and can result in fatal heart failure. The discovery could provide some insight into why males often pass away at an earlier age than women.

The new finding, according to UVA researcher Kenneth Walsh, PhD, implies that males who experience Y chromosome loss—which is believed to affect 40% of people over the age of 70—may benefit significantly from a current medication that combats potentially harmful tissue scarring. He believes that the medication could help mitigate the negative effects of the chromosomal loss, which could emerge not only in the heart but in other areas of the body as well.

In the US, women typically live five more years than men do. According to Walsh, the new discovery may account for roughly four of the five-year discrepancy.

"Men tend to pass away sooner than women, especially beyond the age of 60. They appear to age physiologically more quickly "Walsh, the center's director for hematovascular biology at UVA, said. "In the US alone, there are more than 160 million men. The number of years lost owing to the male survival disadvantage is astounding. This new study sheds light on why males live shorter lives than women."

Loss of Chromosomes and Heart Health

Men have an X and a Y chromosome, whereas women have two X chromosomes. But as men age, a small percentage of their cells start to lose the Y chromosome. Smokers seem to be an exception to this rule. The loss mostly affects blood cells and other cells that change quickly. Children of males who demonstrate Y chromosome loss do not inherit it because Y chromosome loss does not occur in male reproductive cells. Men who lose their Y chromosome are more likely to die early and develop age-related diseases like Alzheimer's disease, according to earlier research. The latest study by Walsh, however, is thought to be the first concrete proof that chromosomal deletion directly has a negative impact on men's health.

Walsh, of UVA's Division of Cardiovascular Medicine and the Robert M. Berne Cardiovascular Research Center, and his group created a unique mouse model to better study the impact of Y chromosome deletion in the blood using cutting-edge CRISPR gene-editing technology. They discovered that the loss hastened age-related disorders, increased the mice's susceptibility to cardiac scarring, and accelerated their mortality. The investigators found that this wasn't only an inflammatory response. Instead, the mice experienced a complicated series of immune system reactions that resulted in a condition known as fibrosis across the body. The researchers hypothesize that this immune system struggle might hasten the onset of illness.

The repercussions of Y chromosome deletion in male humans were also studied by the researchers. They performed three studies on data taken from the UK Biobank, a huge biological database, and discovered that Y chromosome deletion was linked to heart failure and cardiovascular illness. The researchers discovered that as chromosomal loss rose, so did the probability of mortality.

Potential Therapy

The results show that males may live longer, healthier lives if the impacts of Y chromosome depletion are targeted. Walsh points out that pirfenidone, a medication currently approved by the US Food and Drug Administration for the treatment of idiopathic pulmonary fibrosis, a kind of lung scarring, may be a viable therapy option. Additionally, the medication is being evaluated for the treatment of heart failure and chronic renal disease, both of which are characterized by tissue scarring. According to Walsh's study, males with Y chromosomal deletion may respond particularly well to this medication and other types of antifibrotic medications that are now being researched, however further studies are required to confirm this.

There is currently no quick technique for doctors to identify which males lose their Y chromosomes. An affordable polymerase chain reaction (PCR) test, similar to those used for COVID-19 testing, has been created by Walsh's partner Lars A. Forsberg of Uppsala University in Sweden, however it is mostly utilized in Walsh and Forsberg's labs. But Walsh sees a change coming: "Maybe this becomes a common diagnostic test," he said. "If interest in this continues and it's demonstrated to have usefulness in terms of being predictive for men's illness and may lead to tailored therapy."

"All of our cells' DNA eventually develops mutations as we age. This involves the complete deletion of the Y chromosome in a subpopulation of male cells. Age-related disorders and the aging process itself can be better understood by realizing that the body is a mosaic of acquired mutations "said Walsh, a student at UVA's Biochemistry and Molecular Genetics Department. Research on Y chromosome deletion and other acquired abnormalities holds considerable potential for the creation of specialized medications that address these particular mutations.