Loss of the Y chromosome from a subset of cells may explain why males die an average of five years younger than females in the United States. According to a new study in the journal Science, the gradual disappearance of this chromosome with age leads to scarring of the cardiac tissue and increases the chances of deadly heart failure.
“Particularly past age 60, men die more rapidly than women. It’s as if they biologically age more quickly,” said study author Kenneth Walsh in a statement. “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.”
All humans have 23 pairs of chromosomes, 22 of which are autosomes, meaning they look the same in both males and females. The other pair comprises the sex chromosomes, and consists of two X chromosomes for females and one X and one Y chromosome in the case of males.
However, as males age, they lose their Y chromosome in some of their cells. This appears to occur at a particularly high rate in cells that are frequently replaced, such as blood cells. Previous work has hinted at a connection between Y chromosome loss and age-related pathologies and death in males, although a mechanism underlying this proposed link had until now eluded scientists.
To investigate, the study authors used CRISPR gene-editing technology to remove the Y chromosome from the bone marrow cells of male mice. This resulted in the production of white blood cells with no Y chromosome, some of which traveled to the animals’ hearts and activated “a profibrotic signaling network.”
This, in turn, led to an increase in fibrosis – or tissue scaring – within the heart, ultimately reducing cardiac function and condemning the mice to an early death.
Commenting on the significance of this observation, the authors note that “tissue fibrosis is a hallmark of aging and is estimated to contribute to 45% of deaths in industrialized countries.” The fact their experiment triggered fibrosis in mice, therefore, suggests that many of these deaths may indeed be related to Y chromosome loss.
To determine how this applies to male humans, the researchers analyzed data from the UK Biobank and found that Y chromosome loss was associated with higher rates of heart disease and an increased risk of death.
Explaining how an entire chromosome can simply vanish, Walsh remarked that “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.”
As troubling as this may sound, the researchers do come bearing some slightly better news too: when mice were treated with an antibody that blocks the activity of white blood cells, cardiac dysfunction was relieved. This raises the possibility that drugs designed to treat fibrosis may help males stay healthy as they age and limit the chances of developing deadly heart disease.
One such drug, pirfenidone, has already been approved by the US Food and Drug Administration (FDA) for the treatment of fibrosis in the lungs, although more research is needed in order to determine whether the medication can attenuate the impact of Y chromosome loss.
“In view of recent efforts to treat heart failure, idiopathic pulmonary fibrosis, and some cancers with antifibrotic approaches, men with [Y chromosome loss] could represent a patient subpopulation that exhibits a superior response to this class of therapeutic agents,” conclude the authors.