Hematopoietic loss of Y chromosome activates immune checkpoints to impair senescent cell clearance contributing to renal disease

The accumulation of senescent cells contributes to morbidity and mortality; however, common mechanisms underpinning this age-associated phenomenon remain elusive. Notably, hematopoietic loss of the Y chromosome (LOY) is the most frequently acquired somatic mutation in males, and this condition has been associated with various age-associated diseases and reduced lifespan. Therefore, we investigated the role of hematopoietic LOY in promoting cellular senescence, focusing on kidney disease due to its well-documented connection with aging and senescence. Herein, a prospective cohort study revealed that LOY in blood is associated with an increased incidence of kidney diseases. Analyses of transcriptional signatures in human kidneys found that immune cell LOY is enriched in patients with kidney disease and associated with greater levels of cellular senescence. In mice, hematopoietic LOY led to renal dysfunction that was accompanied by senescent cell accumulation in models of kidney injury and advanced age. Accordingly, treatment with a senolytic agent promoted senolysis and preferentially inhibited the progression of renal dysfunction in LOY mice. The hematopoietic LOY condition led to the upregulation of multiple immune inhibitory receptors. Treatment with the combination of antibodies targeting PD-1 and SIRP reduced senescent cell accumulation and rescued the renal pathology conferred by hematopoietic LOY. These data indicate that hematopoietic LOY contributes to pathologic conditions by impairing the clearance of senescent cells through upregulation of immune checkpoint proteins.