Loss of Y Chromosome Rewires Immune Cells and Triggers Abnormal X-Gene Activity in Aging Men

Loss of chromosome Y (LOY) in blood cells is the most common form of age-related genetic mosaicism in men, yet its precise effects on immune function have remained poorly understood. New research published in Aging Cell sheds important light on how this chromosomal loss reshapes immune cell behavior at the single-cell level, with implications for cardiovascular disease, fibrosis, and cancer risk.

Researchers analyzed single-cell RNA sequencing data from 416 male donors with a median age of 68, drawn from the OneK1K cohort. LOY was detected in nearly 9% of all cells examined, with the highest rates found in monocytes — key innate immune cells — where roughly 18% carried the deletion. Critically, LOY frequency declined progressively as monocytes transitioned from classical to nonclassical subtypes, suggesting LOY actively influences differentiation trajectories rather than accumulating passively.

In classical monocytes, LOY was associated with a profibrotic gene expression signature, including suppression of the inflammatory cytokine IL-1B and downregulation of MYC-regulated genes. This aligns with prior evidence that LOY-associated macrophages favor tissue scarring over inflammation in cardiac and pulmonary injury — a pattern that may help explain the elevated cardiovascular mortality seen in men with high LOY rates.

Perhaps most striking was the detection of aberrant XIST expression — an RNA molecule that normally silences one X chromosome in females and is not expressed in males — alongside upregulation of cancer-associated X-linked genes including KDM6A, DDX3X, KDM5C, and ZRSR2. This suggests LOY may destabilize normal sex-chromosome gene regulation in ways that promote malignancy.

Limitations include the observational, cross-sectional design and reliance on abstract-level data. Causal mechanisms remain to be established, and findings require replication in larger, longitudinal cohorts.