Mosaic loss of the Y chromosome (LOY), a common age-related genetic change in men, is linked to increased risk of cardiovascular disease and shorter lifespan.
A landmark 2022 Science study showed that Y chromosome loss in immune cells can directly cause cardiac fibrosis and increase heart failure mortality.
The prevalence of Y chromosome loss rises significantly with age, affecting a substantial proportion of men over 60 years.
Smoking and age-related genomic instability are major risk factors that increase the likelihood of developing mosaic loss of the Y chromosome.
Scientists are investigating Y chromosome loss as a potential biomarker for predicting cardiovascular risk and improving early disease detection in men.
Men consistently show lower life expectancy compared to women across many populations. Recent genetic research suggests that age-related loss of the Y chromosome in blood cells, known as mosaic loss of Y (LOY) may contribute to this disparity. Studies indicate that LOY is associated with increased cardiovascular disease risk, organ fibrosis, and reduced overall survival.1
Although researchers had observed this phenomenon for decades, the 2022 study published in Science was among the first to demonstrate a direct causal role of Y chromosome loss in driving cardiac fibrosis and heart failure mortality, rather than merely showing an association. This helped establish LOY as a biologically active contributor to disease rather than a passive marker of aging.1
Mosaic loss of Y refers to the gradual disappearance of the Y chromosome in a proportion of white blood cells as men age. This is an acquired, somatic change and not an inherited mutation. The prevalence of LOY increases significantly after middle age, and by 70 years of age, a notable proportion of men exhibit detectable Y chromosome loss in circulating leukocytes.1
Smoking has been identified as a modifiable risk factor associated with a higher likelihood of developing LOY. Researchers consider LOY one of the most common acquired chromosomal alterations observed in aging men.
A 2022 study published in Science provided mechanistic evidence linking LOY to cardiovascular disease. Researchers used both large-scale human genetic data and mouse models to examine its biological effects.1
The study found that immune cells lacking the Y chromosome, particularly macrophages, adopted a profibrotic profile. This shift promoted tissue scarring, which can impair cardiac function and contribute to heart failure.1
Observational data in human cohorts have also shown that men with higher levels of LOY in blood cells face increased risks of cardiovascular disease and mortality. While association does not establish causation, combined experimental and epidemiological findings strengthen the biological plausibility of this relationship.
Importantly, the Science study showed that mice engineered to lack the Y chromosome in blood cells developed more severe cardiac fibrosis and reduced survival. These findings provided direct experimental evidence that LOY can actively drive disease processes rather than simply reflecting underlying aging or illness.1
Loss of Y occurs only in some cells, and their descendants never get it back. This creates a mosaic of cells with and without a Y in the body. Y-less cells grow faster than normal cells in culture, suggesting they may have an advantage in the body — and in tumors.
Jenny Graves, Geneticist, La Trobe University
For many years, scientists assumed that the loss of the Y chromosome had minimal biological consequences because it carries significantly fewer genes than other chromosomes and is primarily associated with male sex determination.
However, emerging research indicates that losing the Y chromosome may have broader systemic effects and could play a role in the development of age-related diseases.2
Jenny Graves, Geneticist at La Trobe University wrote in her analysis,
Evidence has mounted over the past few years that when people who have a Y chromosome lose it, the loss is associated with serious diseases throughout the body, contributing to a shorter lifespan.
Jenny Graves, Geneticist, La Trobe University
Researchers propose that genomic instability increases with aging, making chromosomes more susceptible to errors during cell division. The Y chromosome appears particularly vulnerable to loss in hematopoietic stem cells. Over time, affected cells expand clonally, increasing the proportion of circulating blood cells without the Y chromosome.1
Environmental factors such as smoking may accelerate this process. However, aging remains the strongest risk factor identified so far.
New techniques to detect Y chromosome genes show frequent loss of the Y in tissues of older men. The increase with age is clear: 40% of 60-year-old men show loss of Y, but 57% of 90-year-olds.
Jenny Graves, Geneticist, La Trobe University
LOY is measurable through genetic testing of blood samples. As evidence linking LOY to cardiovascular disease and mortality accumulates, researchers are exploring whether it could serve as a biomarker for disease risk stratification.
Recent research and renewed scientific interest have highlighted LOY as a potential predictive biomarker for age-related diseases, particularly cardiovascular disease. This has contributed to increased attention in medical literature and media, as researchers investigate whether detecting LOY could help identify men at higher risk for heart disease and premature mortality.2
Investigators are also examining whether antifibrotic therapies might reduce cardiac complications associated with Y chromosome loss, although clinical applications remain under investigation.
Understanding LOY may help explain persistent sex-based differences in chronic disease burden and lifespan. Further studies are needed to determine screening strategies, therapeutic interventions, and long-term population impact.
Sano, Soichi, et al. “Hematopoietic Loss of Y Chromosome Leads to Cardiac Fibrosis and Heart Failure Mortality.” Science 377, no. 6603 (2022): 292–297.
Live Science. “Many Men Lose Their Y Chromosomes as They Age. It May Shorten Their Lives.” Live Science, February 16, 2026. https://www.livescience.com/health/genetics/many-men-lose-their-y-chromosomes-as-they-age-it-may-shorten-their-lives
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