Spontaneous onset of cellular markers of inflammation and genome instability during aging in the immune niche of the naturally short-lived turquoise killifish (Nothobranchius furzeri)

Turquoise killifish ( Nothobranchius furzeri ) are naturally short-lived vertebrates, with a lifespan in captivity ranging from 4 to 8 months. Aging in turquoise killifish recapitulates several aspects of human aging, including protein aggregation, telomere shortening, neurodegeneration, cellular senescence, increased cancer incidence, age-dependent gut dysbiosis, decline in antibody diversity, and more. The mechanistic causes or systemic aging in killifish are still poorly understood. Here we ask whether killifish undergo significant age-dependent changes in the main hematopoietic organ, which together could contribute to systemic aging. We employed single-cell RNA sequencing, proteomics and cytometry, and provide an R Shiny app (KIAMO) to visualize and compare omics changes occurring during killifish aging. We find that old killifish display increased inflammatory markers both in plasma and in the main hematopoietic organ (kidney marrow). Immune cells from adult killifish display increased markers of proliferation and replication-independent DNA repair in progenitor-like cell clusters, while progenitors from old killifish display extensive markers of DNA double-strand breaks. In less than 10 weeks, from adulthood to geriatric age, killifish recapitulate several markers of aging of the immune niche, which could be functionally linked with its extensive systemic aging and serve as a target for anti-aging interventions. ### Competing Interest Statement The authors have declared no competing interest.