Y chromosome loss linked to premature death among men

Y chromosome
© iStock/Usis

Scientists may have identified why women live longer than men on average, discovering that losing the Y chromosome as men age drives diseases and causes premature death.

In the US, women tend to live around five years longer than men, a significant health disparity. New evidence from the University of Virginia (UVA) School of Medicine suggests that Y chromosome loss as men get older results in heart muscle scarring that leads to deadly heart failure.

Y chromosome loss is common – affecting around 40% of men over the age of 70. The researchers believe that an existing drug that targets tissue scarring, called pirfenidone, may help to mitigate the effects of Y chromosome loss.

Kenneth Walsh, PhD, the director of UVA’s Hematovascular Biology Center, commented: “Particularly past age 60, men die more rapidly than women. It’s as if they biologically age more quickly.

“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.”

The study is published in the journal Science.

How does Y chromosome loss affect male life expectancy?

Women have two X chromosomes, whereas men have an X and a Y. However, as some men age, they lose the Y chromosome in some cells, especially those who smoke. This mainly occurs in cells that undergo rapid turnover, such as blood cells.

Previous research illuminated that men who experience loss of this chromosome have an increased risk of premature death and age-related conditions like Alzheimer’s disease. However, this is the first study to identify that Y chromosome loss directly causes harmful impacts on men’s health.

The researchers utilised CRISPR gene-editing technology to design a mouse model to analyse the effects of Y chromosome loss in the blood, finding that the process accelerated age-related disease, increased the risk of heart scarring, and led to premature death.

The team determined that this was not the result of inflammation, with the mice suffering a complex series of immune system responses that lead to a process known as fibrosis throughout the body that exacerbates disease development.

Subsequently, the team examined the impacts of Y chromosome loss in human men, analysing data from the UK Biobank. The results highlighted that losing the chromosome was linked to cardiovascular disease and heart failure, and as the loss increased, so did the risk of death.

Life-extending treatment

The scientists explained that combatting Y chromosome loss with the FDA-approved pirfenidone could help men live longer. Pirfenidone is currently used to treat a type of lung scarring called idiopathic pulmonary fibrosis and is also being tested for heart failure and chronic kidney disease, two conditions characterised by tissue scarring.

The team believe that men suffering Y chromosome loss could benefit from this drug and other classes of antifibrotic medications, although more research is needed. Moreover, there is currently no simple method to locate chromosome loss in men. To overcome this, the team has designed an inexpensive polymerase chain reaction (PCR) test that can identify the condition that they are hoping to make commercially available.

Walsh concluded: “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 personalised therapy, maybe this becomes a routine diagnostic test.

“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 ageing process itself.

“Studies that examine Y chromosome loss and other acquired mutations have great promise for the development of personalised medicines that are tailored to these specific mutations.”

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