This study reveals a mechanistic link between loss of Y chromosome (LOY) in the male hematopoietic system and aging-related diseases such as renal disease. It demonstrates that LOY impairs the clearance of senescent cells by upregulating immune inhibitory receptors such as PD-1 and SIRPα, consequently promoting renal dysfunction. Using animal models and single-cell sequencing analysis, the study further validates the critical role of LOY in senescent cell accumulation and explores therapeutic strategies for clearing senescent cells, offering new molecular insights and treatment directions for renal disease and other aging-related disorders.
Literature Overview
This article titled 'Hematopoietic loss of Y chromosome activates immune checkpoints and contributes to impaired senescent cell clearance and renal disease' was published in the journal Science Translational Medicine. It reviews and summarizes the role of Y chromosome loss (LOY) in male aging-related renal disease, its impact on immune checkpoint activation and impaired clearance of senescent cells. The study also evaluates renal injury and cellular senescence phenotypes in an aging mouse model associated with LOY, and explores the therapeutic potential of targeting immune checkpoint inhibitors (ICIs) and senescent cell clearance agents such as ABT-263.
Background Knowledge
Loss of Y chromosome (LOY) is one of the most common somatic mutations in males, typically accumulating with age and associated with multiple aging-related diseases such as cardiovascular disease, cancer, and renal disease, as well as increased mortality risk. Cellular senescence refers to a permanent cell cycle arrest accompanied by the emergence of a senescence-associated secretory phenotype (SASP), which promotes tissue inflammation and fibrosis and is closely linked to organ dysfunction. Renal disease, as an aging-related condition, progresses in parallel with the accumulation of senescent cells and the failure of immune clearance mechanisms. However, whether LOY promotes senescent cell accumulation by impairing immune cell function remains incompletely understood. Using large population cohort analysis, single-cell transcriptomic sequencing, and mouse models, this study for the first time demonstrates that LOY impairs senescent cell clearance by upregulating immune inhibitory receptors such as PD-1 and SIRPα, thereby accelerating renal disease progression. It further evaluates the therapeutic potential of targeting immune checkpoints, providing new intervention strategies for renal disease and other aging-related disorders.
Research Methods and Experiments
Researchers first analyzed LOY status in over 210,000 male blood samples from the UK Biobank and assessed the risk of renal disease in conjunction with clinical data. Subsequently, single-cell RNA sequencing was used to examine LOY distribution in kidney tissues of healthy and diseased males, and its association with senescent cells. In mouse models, LOY bone marrow cells were generated using gene-editing techniques and transplanted into recipient mice to evaluate renal function and cellular senescence phenotypes in both natural aging and acute kidney injury models. Additionally, the study tested the therapeutic efficacy of senolytic agents such as ABT-263 and immune checkpoint inhibitors (ICIs) targeting PD-1 and SIRPα in LOY-associated renal disease.
Key Conclusions and Perspectives
Research Significance and Prospects
This study is the first to mechanistically link LOY with senescent cell accumulation and renal disease progression, revealing a novel mechanism by which LOY impairs senescent cell clearance through upregulation of immune inhibitory receptors. Future studies should further explore the role of LOY in promoting senescence in other tissues, such as the heart and lungs, and assess the translational potential of immune checkpoint-targeted therapies in humans. Moreover, as LOY is a male-specific and aging-associated genetic event, it may serve as a risk biomarker for renal disease and other aging-related disorders, providing a molecular basis for personalized therapeutic interventions.
Conclusion
This study systematically investigates the mechanisms underlying LOY-associated renal disease in aging males and identifies LOY as a driver of renal dysfunction through activation of immune checkpoints such as PD-1 and SIRPα, which impair senescent cell clearance. LOY accumulation is not only associated with renal disease but also with cellular senescence in other tissues, suggesting a broad impact on systemic aging. Pharmacological interventions with senescent cell clearance agents and immune checkpoint inhibitors effectively ameliorated LOY-associated kidney injury, offering novel therapeutic strategies for renal disease and other aging-related conditions. These findings provide a molecular framework for understanding LOY's role in aging and disease and lay a theoretical foundation for future clinical interventions.
