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"According to a study ... a lack of the Y chromosome in bone marrow cells causes heart failure. ...
Their team zeroed in on mosaic loss of Y chromosome (mLOY), a condition where some of a male’s somatic cells, particularly white blood cells, lose the Y chromosome. This condition, which is heavily associated with tobacco smoking, affects more than 40 percent of 70-year-old men in the UK Biobank cohort and is associated with a long list of illnesses, including Alzheimer’s disease. ...
The team knocked out the chromosome in mice’s bone marrow cells by deleting its centromere with CRISPR, mirroring the degeneration of the Y chromosome in male humans. The modification successfully induced blood chimerism—a condition where an individual has two sets of genetically different cells, in this case one with and one without the Y chromosome—in 81 percent of the mice. The researchers report that this scenario is consistent with the level of mosaic loss of Y chromosome (mLOY) in men that has been linked with Alzheimer’s disease. In the study, the team observed that these mice had a shorter lifespan than unmodified controls. ..."
The team knocked out the chromosome in mice’s bone marrow cells by deleting its centromere with CRISPR, mirroring the degeneration of the Y chromosome in male humans. The modification successfully induced blood chimerism—a condition where an individual has two sets of genetically different cells, in this case one with and one without the Y chromosome—in 81 percent of the mice. The researchers report that this scenario is consistent with the level of mosaic loss of Y chromosome (mLOY) in men that has been linked with Alzheimer’s disease. In the study, the team observed that these mice had a shorter lifespan than unmodified controls. ..."
"Although the Y chromosome is the smallest and contains few genes, its functions are not fully understood. It has been observed, however, that mosaic loss of the Y chromosome in blood cells frequently occurs with age, and this alteration is associated with various medical conditions. Sano et al. modeled this process in mice by reconstituting their bone marrow with cells lacking the Y chromosome (see the Perspective by Zeiher and Braun). The resulting mice were prone to fibrosis and decreased cardiac function, especially in the setting of pressure overload, but they benefited from treatment with a transforming growth factor β1–neutralizing antibody. Human patients with loss of chromosome Y in their blood were also at greater risk of cardiac pathology, supporting the clinical relevance of these findings."
"During their lifetimes, organisms acquire somatic mutations in individual cells caused by genomic instability, endogenous DNA replication errors, or exposure to mutagens. When mutations occur in somatic stem cells, the mutation “spreads” in a mosaic manner, appearing in the progeny of mutated stem cells but not in cells from nonmutated stem cells. Mosaic loss of Y chromosome (mLOY) has been observed in peripheral leukocytes of aging men, reaching 40% of leukocytes in individuals over 70 years. LOY increases over time and correlates with clonal expansion of myeloid cells. LOY also correlates with increased risk for mortality, cardiovascular events, and other age-associated disorders, but a causal relationship has not been established. ..."
From the abstract:
"Hematopoietic mosaic loss of Y chromosome (mLOY) is associated with increased risk of mortality and age-related diseases in men, but the causal and mechanistic relationships have yet to be established. Here, we show that male mice reconstituted with bone marrow cells lacking the Y chromosome display increased mortality and age-related profibrotic pathologies including reduced cardiac function. Cardiac macrophages lacking the Y chromosome exhibited polarization toward a more fibrotic phenotype, and treatment with a transforming growth factor β1–neutralizing antibody ameliorated cardiac dysfunction in mLOY mice. A prospective study revealed that mLOY in blood is associated with an increased risk for cardiovascular disease and heart failure–associated mortality. Together, these results indicate that hematopoietic mLOY causally contributes to fibrosis, cardiac dysfunction, and mortality in men."
Mosaic loss of Y chromosome during aging Spread of Y chromosome aneuploidy in myeloid cells with age promotes cardiac fibrosis
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