Younger deaths in men are related to Y chromosome loss with age

According to new research from the University of Virginia (UVA) 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. Published in the journal Science, the discovery might provide some insight into why males typically pass away at a younger age than women.

According to UVA researcher Kenneth Walsh, Ph.D., the director of UVA's Hematovascular Biology Center, the new finding shows that males who experience Y chromosome loss, which is believed to affect 40 percent of people over the age of 70, may benefit significantly from a current medication that combats hazardous tissue scarring. He believes the medication might help mitigate the negative effects of chromosomal loss, which could manifest not only in the heart but in other areas of the body as well.

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

"Particularly past age 60, men die more rapidly than women. It's as if they biologically age more quickly," explained Walsh. "There are more than 160 million males in the United States alone. The years of life lost due to the survival disadvantage of maleness are staggering. This new research provides clues as to why men have shorter lifespans than women," he added.

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. Interestingly, however, smokers seem be particularly vulnerable to this process.

The loss mostly affects blood cells and other cells that change quickly. Children of men 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 young and develop age-related diseases like Alzheimer's, 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.

The team developed a new model to discover the impact of male chromosome loss in mice

Walsh, of UVA's Division of Cardiovascular Medicine and the Robert M. Berne Cardiovascular Research Center, and his research 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 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 this immune system struggle could 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 U.K. 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 increased, so did the probability of mortality.

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 already approved by the federal Food and Drug Administration (FDA) 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 kidney disease, both of which are characterized by tissue scarring. According to Walsh's research, men with Y chromosomal deletion may respond particularly well to this medication and other types of antifibrotic medications that are now being researched, however more 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 collaborator Lars A. Forsberg of Uppsala University in Sweden, however, it is mostly used in Walsh and Forsberg's labs.

But Walsh sees a change coming, "if interest in this continues and it's shown to have utility in terms of being prognostic for men's disease and can lead to personalized therapy, maybe this becomes a routine diagnostic test," he said.

"The DNA of all our cells inevitably accumulate mutations as we age. This includes the loss of the entire Y chromosome within a subset of cells [in] men. Understanding that the body is a mosaic of acquired mutations provides clues about age-related diseases and the aging process itself," added Walsh. "Studies that examine Y chromosome loss and other acquired mutations have great promise for the development of personalized medicines that are tailored to these specific mutations."

You can read the entire study in the journal Science.

Study abstract:

During their lifetimes, organisms acquire somatic mutations in individual cells caused by genomic instability, endogenous DNA replication errors, or exposure to mutagens. When mutations occur in somatic stem cells, the mutation “spreads” in a mosaic manner, appearing in the progeny of mutated stem cells but not in cells from nonmutated stem cells. Mosaic loss of Y chromosome (mLOY) has been observed in peripheral leukocytes of aging men, reaching 40% of leukocytes in individuals over 70 years. LOY increases over time and correlates with clonal expansion of myeloid cells. LOY also correlates with increased risk for mortality, cardiovascular events, and other age-associated disorders, but a causal relationship has not been established. On page 292 of this issue, Sano et al. determine that mLOY in myeloid cells is a major risk factor for increased incidence of cardiovascular and fibrotic diseases during aging.