Fight Aging!

Stochastic mutational damage is thought to be problematic where it occurs in stem cells and progenitor cells, and can thus spread widely. A more severe form of such damage is the loss of the entire Y chromosome in men. Researchers here provide evidence, using an engineered mouse lineage, for this to make macrophages more inflammatory, accelerating fibrosis and dysfunction in the heart. This in turn raises mortality, which might explain the observed association between loss of the Y chromosome and increased incidence of age-related disease in humans. Inflammation accelerates all of the common fatal age-related conditions, and dysfunction in immune cells is a real problem in this context.

Why a condition that frequently occurs in aging men, in which an increasing number of hematopoietic cells display a loss of the Y chromosome, is associated with increased risk of mortality and age-related diseases is now a little clearer, thanks to work in mice. This condition - known as mosaic loss of Y chromosome, or mLOY - is a major risk factor for heart failure and cardiac fibrosis in men growing older, according to the study, which includes prospective data from the UK Biobank. The study also revealed that a neutralizing antibody could reverse some cardiac impacts caused by mLOY.

The Y chromosome has been long considered a "genetic wasteland," and beyond biological sex determination, there is little understanding of its functional role. Nevertheless, mLOY in blood cells has been linked to increased risk for mortality, cardiovascular disease, and other age-related disorders. In human somatic cells, mLOY is the most commonly acquired mutation in the male's genome. However, a relationship between mLOY and pathogenesis has not yet been established.

Using CRISPR-Cas9, researchers developed a mouse model of hematopoietic mLOY by reconstituting their bone marrow with cells lacking the Y chromosome. They discovered that these mice displayed increased mortality and were more prone to age-related cardiac fibrosis and decreased cardiac function. According to the findings, bone marrow-derived mLOY macrophages that infiltrate the heart trigger high transforming growth factor β1 (TGF-β1) activity, which leads to fibroblast proliferation and accelerated cardiac tissue fibrosis. Treatment with a TGF-β1 neutralizing antibody was shown to ameliorate these harmful effects. What's more, a prospective study in human patients showed that those with mLOY in blood were also at a greater risk for cardiovascular dysfunction and associated mortality.

Link: https://www.eurekalert.org/news-releases/958410