Aging individuals exhibit a pervasive decline in adaptive immune function, with important implications for health and lifespan. Previous studies have found a pervasive loss of immune-repertoire diversity in human peripheral blood during aging; however, little is known about repertoire aging in other immune compartments, or in species other than humans. Here, we perform the first study of immune-repertoire aging in an emerging model of vertebrate aging, the African turquoise killifish (Nothobranchius furzeri). Despite their extremely short lifespans, these killifish exhibit complex and individualized heavy-chain repertoires, with a generative process capable of producing millions of distinct productive sequences. Whole-body killifish repertoires decline rapidly in within-individual diversity with age, while between-individual variability increases. Large, expanded B-cell clones exhibit far greater diversity loss with age than small clones, suggesting important differences in how age affects different B cell populations. The immune repertoires of isolated intestinal samples exhibit especially dramatic age-related diversity loss, related to an elevated prevalence of expanded clones. Lower intestinal repertoire diversity was also associated with transcriptomic signatures of reduced B-cell activity, supporting a functional role for diversity changes in killifish immunosenescence. Our results highlight important differences in systemic vs. organ-specific aging dynamics in the adaptive immune system.

Lifespan is a remarkably diverse trait in nature, ranging from just hours in adult mayflies to hundreds of years in the Greenland shark and quahog clam. Great disparities in lifespan are often observed even among somewhat closely related species; for example, in the laboratory, wild-derived strains of the common house mouse have a maximum observed lifespan of approximately 6 years, while a similarly sized rodent, the naked mole rat, can live for over 30 years. Comparative biology of aging across the tree of life provides a tremendous opportunity for understanding the molecular and genetic basis underlying lifespan and aging. However, a lack of molecular and laboratory tools has limited the ability of researchers to take full advantage of the incredible diversity of aging phenotypes in nature. Recent developments in genomic technology have made it increasingly possible to study non-canonical model organisms for aging. One promising new genetic model organism amenable to a range of experimental interventions is the turquoise killifish (Nothobranchius furzeri). This fish species has a naturally short lifespan and undergoes a wide range of aging-related transformations. These fish have a fully sequenced genome and transcriptome, and killifish embryos are accessible to transgenesis and genome editing. Furthermore, different killifish species and populations show striking differences in lifespan, providing the opportunity for comparative analysis of aging. This Review introduces the natural life history of the turquoise killifish, its emerging applicability as an aging model system, the genetic tools that have been developed to study aging for this species and a summary of recent studies facilitated by these new tools.

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.