Aging Cell. 2026 May;25(5):e70528. doi: 10.1111/acel.70528.
ABSTRACT
The loss of chromosome Y (LOY) in leukocytes is the most prevalent form of clonal mosaicism observed in older men. Previous studies provided multiple pieces of evidence for the effect of LOY on the immune system and connected LOY to elevated risk of all major causes of mortality, including cardiovascular diseases and cancer. Despite these associations, the dynamic effects of LOY across the developmental trajectories of immune cell populations remain unclear. We utilized single-cell RNA-sequencing data from the peripheral blood mononuclear cells of 416 male donors (median age = 68) from the OneK1K cohort. LOY was identified in 45,304 cells (8.76%) and exhibited cell type-specific effects on immune cells along the differentiation trajectories. The largest frequency was detected in monocytes (18.6% in classical and 17.1% in nonclassical) with a progressive decrease along the transition trajectory from 22.6% to 15.8% (padj = 2.00 × 10-11), and a gradual reduction in the expression of nonclassical markers LYPD2 and C1QA. LOY is associated with a profibrotic signature in classical monocytes marked by downregulation of IL1B (log FC = -0.22, pfdr = 2.84 × 10-6) and MYC-regulated genes (log FC = -0.25, pfdr = 2.22 × 10-5), consistent with previous observations that LOY-associated macrophages are polarized toward a fibrotic rather than inflammatory phenotype in cardiac and pulmonary injury. Notably, we detected aberrant expression of XIST, the essential X-chromosome-inactivation lncRNA that is not normally expressed in males, and upregulation of genes known to escape X-inactivation, including male-biased cancer-related genes KDM6A, DDX3X, KDM5C, and ZRSR2. Our results indicate associations between LOY and cell type-specific transcriptional changes, including aberrant X-inactivation features.
PMID:42070154 | DOI:10.1111/acel.70528