Age-related cardiovascular disease and mosaic hematopoietic loss of the Y chromosome

Abstract

Age is the strongest risk factor for cardiovascular morbidity and mortality, driven in part by aging leukocytes negatively impact cardiovascular health. This effect is particularly pronounced in men, who have a shorter average lifespan -approximately six years less than women, largely due to higher mortality rates in old age. One contributing factor is a male-specific aging blood phenotype characterized by the mosaic loss of the Y chromosome (mLOY), a condition in which a subset of blood cells lose the Y chromosome. mLOY is highly prevalent in elderly men, affecting 45% of those aged 70 and older. Recent studies have linked mLOY to increased early mortality, age-related pathologies, and cardiovascular disease, potentially explaining the observed sex discrepancy in life expectancy. Experimental studies have begun to uncover potential mechanisms related to leukocyte responses to cardiac injury and the polarization of macrophages that promote pro-fibrotic cytokine expression. Current evidence suggests that mLOY reflects an underlying aspect of biological aging related to genomic instability, which drives age-related diseases, including cardiovascular conditions. Although mLOY shares similarities with general age-related changes in the hematopoietic system, it may exert distinct effects on leukocytes that promote cardiovascular disease through enhanced tissue fibrosis pathways. These findings highlight that mLOY accumulates with age and contributes to cardiovascular disease through mechanisms that are independent of biological aging per se. Further investigation into mLOY-specific pathways in aging and age-related diseases may reveal novel therapeutic targets for a chronic condition that affects a large proportion of the elderly male population. This review discusses the current literature on mLOY and its connection to cardiovascular disease within the broader context of aging.

Keywords

Sex chromosome aneuploidy / mosaic Loss of Y chromosome / age-related cardiovascular disease / mosaic chromosomal alterations / clonal hematopoiesis

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