Why do men die earlier on average than women? One explanation for this could be that the Y chromosome is lost in some body cells with increasing age. Researchers have previously suggested that this could increase the risk of cancer, Alzheimer’s and cardiovascular disease. A new study provides the first direct evidence of how cells without a Y chromosome damage the heart and other organs. In addition, the researchers propose a possible drug treatment that has shown promising results in mice.
During embryonic development, the sex chromosomes determine whether the embryo develops male or female sexual characteristics. Females have two X chromosomes, males have an X and a Y chromosome. While the Y chromosome is present in male reproductive cells for life, according to previous findings, it degrades in other body cells in some men with increasing age. Since this results in a mosaic-like mixture of cells with and without a Y chromosome, this is referred to as a mosaic loss of the Y chromosome (mLOY, mosaic loss of chromosome Y). Around 20 percent of 60-year-old and 40 percent of 70-year-old men are affected.
Data from humans and mice
“Previous research has shown that mLOY is associated with increased mortality in men and with various diseases of old age, but a causal relationship has not yet been established,” reports a research team led by Soichi Sano from the University of Virginia School of Medicine in the USA. To find out if and how the loss of the Y chromosome actually affects the risk of death in men, the researchers took a two-pronged approach.
On the one hand, they genetically manipulated mice in such a way that around two thirds of their blood stem cells did not carry a Y chromosome – similar to men with mLOY. The researchers observe how long these mLOY mice lived compared to the control group, what diseases they developed and what mechanisms were behind them. On the other hand, they compared the results with health data from human men. To do this, they used the UK Biobank, an extensive biomedical database with long-term data from around 500,000 participants.
influence on the immune system
The result: The mice with mLOY died earlier on average and had more heart diseases and reduced heart function. “Examination of the mLOY mice showed increased scarring of the heart, which is referred to as fibrosis,” reports co-author Lars Forsberg from Uppsala University in Sweden. “We see that mLOY causes the fibrosis that leads to deterioration in heart function.” At a mechanistic level, the researchers found that white blood cells called macrophages, which lack the Y chromosome, activate the growth factor TGF-beta1 in the heart . This signaling substance is involved in inflammatory responses and when overactive causes the observed scarring of heart tissue.
The evaluation of the data from the UK Biobank confirmed these results. “The data show that men with a higher percentage of white blood cells with mLOY in their blood have a higher risk of dying from cardiovascular disease,” said Forsberg. “This observation is consistent with the results from the mouse model and indicates that mLOY also has a direct physiological effect in humans.”
Possible therapy?
From the researchers’ point of view, their findings can help to find a therapy to mitigate the effects of the Y chromosome loss with medication in the future. A drug that slows down the overactivity of TGF-beta1 has already been approved. The drug has so far been used for chronic pulmonary fibrosis, scarring of the lung tissue. Sano and his colleagues experimentally administered the drug to some of their mLOY mice – and indeed: The animals treated in this way showed less scarring of the heart and lived longer than their untreated conspecifics.
“If similar mechanisms are responsible for the increase in mortality risk in men, anti-inflammatory therapy, in particular inhibition of TGF-beta1, could reduce the development of the disease in persons at risk – i.e. in men who have a high proportion of blood cells with Y-chromosome loss” , comments Lenhard Rudolph, head of the stem cell aging research group at the Leibniz Institute for Age Research in Jena, who was not involved in the study. However, before a corresponding therapy can actually be considered in humans, further studies are required.
Source: Soichi Sano (University of Virginia School of Medicine, USA) et al., Science, doi: 10.1126/science.abn3100