Small but indispensable: As men age, they lose the Y chromosome in some of their body cells. Now a study confirms that this damages the heart and probably other organs as well, and may contribute to shorter lifespans in men. Because if the male sex chromosome is missing in white blood cells, they trigger an inflammatory reaction and scarring in the heart tissue, which weakens heart function, as researchers report in the journal Science.
Men have a Y chromosome instead of the second X chromosome. In the course of evolution, this has lost almost 90 percent of its original set of genes and is only a third the size of its female counterpart. The few genes that are still on the Y chromosome regulate sperm production and sex development, the rest is filled in by highly variable gene sections whose functions are only determined partly are known.
For a long time it was even assumed that the Y chromosome would one day be whole could die out. After all, this genetic material carrier can be lost through mutations in some of the man’s cells without the affected person dying as a result. In around 40 percent of all 70-year-old men, such a mosaic-like loss of the Y chromosome (mLOY) can be detected in body cells. The rapidly dividing blood cells, including white blood cells, are particularly affected.
Is the missing Y to blame for disease and early death?
But is this loss of the Y chromosome really harmless? “Epidemiological studies have shown that mLOY is associated with a shorter lifespan and an increased incidence of age-related diseases, including tumors and Alzheimer’s disease,” explain Soichi
Sano of the University of Virginia at Charlottesville and his colleagues. A connection with the increased risk of arteriosclerosis, heart attacks and strokes is also suspected.
So far, however, there has been no experimental evidence for this suspicion. Sano and his team have therefore examined the connection between Y chromosome loss and diseases more closely. For their study, they modified the genome of aging mice in such a way that two-thirds of their white blood cells lacked the Y chromosome – similar to mLOY. The researchers then tested whether and how this affected the function of the heart and other organs in the months that followed.
Increased scarring of heart tissue
In fact, there was an effect: unlike their untreated peers, the mLOY mice developed age-related heart failure more quickly and died earlier. More detailed analyzes showed that the animals suffered more from fibrosis – scarring of the heart that impairs the function of the heart muscle. The researchers also found increased fibrotic adhesions in the lungs and kidneys of the mLOY mice 15 months after the loss of the Y chromosome.
The mice showed symptoms and suffering similar to those that occur more often in older men with a mosaic-like loss of the Y chromosome. “These results indicate that the mice recapitulate typical aspects of the mLOY phenotype,” Sano and his team write. The loss of the Y chromosome in the white blood cells in these animals was enough to make them sicker as they aged.
But why? A closer examination of the heart tissue showed that the scarring is triggered by macrophages with chromosome loss: these white blood cells activate the growth factor TGF-beta1 in the heart tissue, which promotes inflammation and fibrosis. When the researchers blocked this growth factor with a monoclonal antibody, the scarring in the mLOY mice also decreased.
Also detectable in humans
But what does this mean for older men? Can these findings be extrapolated to humans? To check this, Sano and his team evaluated data from a British long-term study. In 223,338 UK Biobank participants aged over 50, they examined whether there was a link between the proportion of Y-chromosome-free white blood cells and the risk of cardiovascular disease and death.
The result: “Men with a higher proportion of white blood cells with mLOY have a higher risk of dying from cardiovascular disease,” reports co-author Lars Forsberg from Uppsala University in Sweden. “This agrees with the results in the mouse model and indicates that mLOY also has a direct physiological effect in humans.”
Starting point for prevention and therapy
Thus, this study provides experimental confirmation that the loss of the Y chromosome in blood cells can affect male health. “Our results suggest that mLOY contributes causally to fibrosis, cardiac dysfunction and mortality in men,” say Sano and his team. Hartmut Geiger from the University of Ulm sees it similarly: “A possible connection was suspected beforehand. What is new and very convincing about this study is that it was actually possible to prove a causal connection,” comments the physician, who is not part of the authoring team
Knowledge of the causal relationships now opens up new opportunities to prevent the harmful effects of Y chromosome loss. Sano and his team have already been able to use their mice to show that a drug that has already been approved for treating pulmonary fibrosis in humans also reduces scarring on the hearts of mLOY mice. The animals treated in this way lived longer. Clinical studies must now show whether this also works for men with mLOY.
Consequences also for other organs?
In their study, Sano and his team focused primarily on the effects of the loss of the Y chromosome on the heart – although they were also able to demonstrate consequences for the lungs and kidneys and possibly even the brain in their mice: Aging mLOY mice did themselves in Memory tests significantly harder than their peers.
According to Elisabeth Zeisberg from the University Medical Center Göttingen, this suggests that the loss of the male Y chromosome in blood cells can also cause damage elsewhere in the body: “It is quite possible that this study will be a pioneer study for many more and only those This is the tip of the iceberg when it comes to the role of mosaic chromosomal losses in stem cells in the pathogenesis of various organs,” comments the researcher, who was not involved in the study. (Science, 2022; doi: 10.1126/science.abn3100)
Quelle: University of Virginia Health System