Spontaneous aging-associated inflammation and genome instability in the immune system of turquoise killifish

Abstract Turquoise killifish ( Nothobranchius furzeri ) are naturally short-lived vertebrates that recapitulate key aspects of human aging. However, the molecular and cellular causes of systemic aging in killifish are poorly understood. Here we ask whether killifish undergo age-dependent changes in the main hematopoietic organ (kidney marrow), which may contribute to systemic aging. To characterize immune aging in killifish, we used single-cell RNA sequencing, cytometry and functional in vitro assays on kidney marrow cells from young-adult and old killifish, together with proteomic profiling of both kidney marrow-derived cells and plasma. We show that old killifish display increased markers of inflammation; while immune progenitor-like cell clusters from adult killifish display markers of active proliferation and replication-independent DNA repair, immune cell progenitors from old killifish display increased markers of DNA damage. Within less than 10 weeks, killifish exhibit age-related transformations within the immune system, underscoring the value of killifish for developing immune-system-targeted antiaging interventions.