Highlights
- Mosaic loss of Y chromosome (mLOY) prevalence increases with age and is linked to poorer pulmonary function and structural lung damage in men.
- mLOY correlates with accelerated decline in FEV1, progression to chronic obstructive pulmonary disease (COPD), and higher CT-quantified emphysema burden.
- Epigenetic analyses reveal that mLOY associates with a faster pace of biological aging, independent of clonal hematopoiesis and telomere length.
- mLOY emerges as a potential biomarker of respiratory aging and disease susceptibility, meriting further exploration for risk stratification and targeted interventions.
Background
Chronic obstructive pulmonary disease (COPD) and emphysema represent globally significant health burdens characterized by progressive airflow obstruction and lung parenchymal destruction, predominately afflicting older adults. Identification of novel biomarkers linked to pulmonary aging could inform early risk assessment and personalized management strategies. Mosaic loss of Y chromosome (mLOY) is an age-related somatic chromosomal mosaicism event occurring in hematopoietic cells of men, characterized by partial or complete loss of the Y chromosome in a subpopulation of peripheral leukocytes. Emerging evidence implicates mLOY as a risk factor for multiple age-related diseases, including cancer and cardiovascular conditions. However, its relationship with respiratory health and lung aging has been undercharacterized until recently.
Key Content
Evidence Chronology and Cohort Design
The pivotal study by Saw et al. (2026) evaluated over 12,000 men from the COPDGene Study (N=5097) and six additional cohorts in the NHLBI Trans-Omics for Precision Medicine (TOPMed) program (N=7235) to interrogate mLOY’s impact on lung function, emphysema, and epigenetic aging. Using a threshold of mosaic Y chromosome cell fraction ≥5%, they conducted cross-sectional, longitudinal, and prospective analyses adjusting for confounders including smoking, clonal hematopoiesis, and telomere length.
Associations with Lung Function and Emphysema
Cross-sectional data demonstrated a significant association between mLOY presence and airflow obstruction, with mean decrease in FEV1/FVC ratio of about 0.018-0.020 in both COPDGene and TOPMed cohorts (p < 0.01). CT imaging-based quantification showed increased emphysema in men with mLOY, suggesting a structural correlate to functional decline. Longitudinally, mLOY-positive men experienced a faster decline in FEV1 (~55 mL/year) compared to mLOY-negative counterparts (~38 mL/year), highlighting accelerated lung function deterioration.
Prospective Risk of COPD and PRISm
Among men with initially normal spirometry, mLOY conferred higher prospective odds of developing COPD (OR=1.84, 95% CI 1.10-3.07) and preserved ratio impaired spirometry (PRISm) (OR=2.87, 95% CI 1.09-7.56). This indicates mLOY’s utility as an early predictor of pulmonary impairment and heterogeneous COPD phenotypes.
Epigenetic Aging and Mechanistic Insights
By employing epigenetic clock models to assess biological aging, the study identified mLOY as a correlate of accelerated epigenetic aging pace. This relationship persisted after controlling for clonal hematopoiesis of indeterminate potential and telomere attrition, suggesting distinct pathways linking mLOY to systemic and pulmonary aging. Mechanistically, mLOY may contribute to altered immune regulation and impaired cellular maintenance, exacerbating lung tissue susceptibility to injury and remodeling.
Comparison and Integration with Related Literature
Prior works have implicated clonal hematopoiesis and telomere shortening in COPD pathogenesis; however, mLOY emerges as an independent biomarker with specific relevance to male respiratory aging. Although literature remains nascent, the convergence of large-scale cohort analyses substantiates the association between mLOY and respiratory decline. Future meta-analyses and mechanistic studies are needed to delineate causal pathways and validate mLOY as a clinical tool.
Expert Commentary
The robust multi-cohort evidence linking mLOY to spirometric decline, emphysema severity, and epigenetic aging advances our understanding of sex-specific molecular aging processes influencing pulmonary health. The specificity of mLOY to men highlights its potential role in explaining sex disparities observed in COPD epidemiology and progression. Current COPD guidelines do not include somatic mosaicism markers; integrating mLOY assessment could enhance risk stratification, especially in aging male populations with smoking exposure.
Nevertheless, limitations must be acknowledged: cross-sectional designs cannot definitively establish causality, and residual confounding from unmeasured environmental or genetic factors remains possible. Moreover, mLOY detection methods vary, and standardization is essential for clinical translation. The biological mechanisms by which hematopoietic mLOY impacts lung tissue warrant further experimental elucidation, including potential contributions to immune senescence or inflammatory milieu alterations.
The intersection of somatic mosaicism, epigenetic aging, and chronic respiratory disease represents a promising frontier, blending genomics and precision medicine approaches. Targeted interventions may emerge from understanding mLOY-mediated pathways, including anti-inflammatory or regenerative strategies tailored to mosaicism profiles.
Conclusion
Mosaic loss of Y chromosome constitutes a significant, age-related biomarker associated with accelerated lung function decline, emphysema development, and epigenetic aging in men. Its detection could inform early identification of individuals at heightened COPD risk and facilitate personalized prevention strategies. Continuing research should focus on mechanistic validation, methodological standardization for mLOY detection, and integration into multi-omic models of respiratory aging. Translational efforts may ultimately enable therapeutic modulation of mLOY-related pathways to mitigate pulmonary aging and disease progression in men.
References
- Saw WY, Kim K, Huang Y, et al. Mosaic loss of Y chromosome associates with lung function, emphysema, and epigenetic aging. Am J Respir Crit Care Med. 2026;212(7):1483-1494. PMID: 42085243.
- Feigin M, et al. Somatic mosaicism and age-related disease. Nat Rev Genet. 2020;21(10):659-672. PMID: 32905044.
- Zhang Q, et al. Clonal hematopoiesis and risk of COPD: a population-based study. Am J Respir Crit Care Med. 2021;204(5):594-604. PMID: 34020706.
- Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;14(10):R115. PMID: 24138928.
