Loss of male sex chromosome leads to shortened longevity for men

The loss can cause potentially deadly heart scarring, although an existing drug may offer treatment possibility.

New research shows that, as many men age, the loss of the male sex chromosome causes the heart muscle to scar and can lead to deadly heart failure. The findings, from the University of Virginia School of Medicine, may help explain why men die, on average, several years younger than women.

Longevity.Technology: Human cells contain 23 pairs of chromosomes, including a pair of sex chromosomes. While biologically female individuals have two X chromosomes (XX), people who are biologically male have one X and one Y chromosome (XY). Despite originating from the same pair of autosomes (non-sex chromosomes) genetic decay has played havoc with the Y chromosome, meaning that the X chromosome is now about three times the size of the Y chromosome and contains approximately 900 genes; the smaller Y chromosome has only about 55 genes, having lost approximately 97% of its ancestral genes.

As biological males age, some of their cells lose their Y chromosomes. A 2019 study of UK Biobank data estimated that 20% of 205,011 men had lost Y chromosomes from some white blood cells; by age 70, this figure had shot up to 43.6% [1]. Loss of the Y chromosome in blood has been linked to cancer, heart disease and other disorders, although it does not occur in male reproductive cells, so it is not a heritable characteristic.

UVA researcher Kenneth Walsh, PhD, says the new discovery suggests that men who suffer Y chromosome loss – the estimated to 40% of 70-year-olds indicated above – may particularly benefit from an existing drug that targets dangerous tissue scarring. The drug, he suspects, may help counteract the harmful effects of the chromosome loss – effects that may manifest not just in the heart but in other parts of the body as well.

On average, women live five years longer than men in the US. The new finding, Walsh estimates, may explain nearly four of the five-year difference.

“Particularly past age 60, men die more rapidly than women. It’s as if they biologically age more quickly,” said Walsh, the director of UVA’s Hematovascular Biology Center. “There are more than 160 million males in the United States alone. The years of life lost due to the survival disadvantage of maleness is staggering. This new research provides clues as to why men have shorter lifespans than women [2].”

Chromosome loss and heart health

The loss of the Y chromosome appears to be particularly true for smokers and in occurs predominantly in cells that undergo rapid turnover, such as blood cells. Scientists previously observed that men who suffer Y chromosome loss are more likely to die at a younger age and suffer age-associated maladies such as Alzheimer’s disease. Walsh’s new research, however, is believed to be the first hard evidence that the chromosome loss directly causes harmful effects on men’s health [3].

Walsh and his team used cutting-edge CRISPR gene-editing technology to develop a special mouse model to better understand the effects of Y chromosome loss in the blood. They found that the loss accelerated age-related diseases, made the mice more prone to heart scarring and led to earlier death. This wasn’t the result of just inflammation, the scientists determined; instead, the mice suffered a complex series of responses in the immune system, leading to a process referred to as fibrosis throughout the body. This tug-of-war within the immune system, the researchers believe, may accelerate disease development.

The scientists also looked at the effects of Y chromosome loss in human men. They conducted three analyses of data compiled from the UK Biobank, a massive biomedical database, and found that Y chromosome loss was associated with cardiovascular disease and heart failure. As chromosome loss increased, the scientists found, so did the risk of death [3].

Potential treatment

The findings suggest that targeting the effects of Y chromosome loss could help men live longer, healthier lives. Walsh notes that one potential treatment option might be a drug, pirfenidone, that has already been approved by the FDA for the treatment of idiopathic pulmonary fibrosis, a form of lung scarring. The drug is also being tested for the treatment of heart failure and chronic kidney disease, two conditions for which tissue scarring is a hallmark. Based on his research, Walsh believes that men with Y chromosome loss could respond particularly well to this drug, and other classes of antifibrotic drugs that are being developed, though more research will be needed to determine if that is indeed the case.

At the moment, doctors have no easy way to determine which men suffer Y chromosome loss. Walsh’s collaborator, Lars A Forsberg, of Uppsala University in Sweden, has developed an inexpensive polymerase chain reaction (PCR) test, like those used for COVID-19 testing, that can detect Y chromosome loss, but the test is largely confined to his and Walsh’s labs. Walsh, however, can foresee that changing: “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 [2].

“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 within men. Understanding that the body is a mosaic of acquired mutations provides clues about age-related diseases and the aging process itself,” said 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 [2].”

[1] https://pubmed.ncbi.nlm.nih.gov/31748747/
[2] https://newsroom.uvahealth.com/2022/07/14/
[3] https://www.science.org/doi/10.1126/science.abn3100

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