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.
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided. The raw data used in these analyses are available via NCBI (BioProject accession PRJNA662612). Processed data and code are freely available at https://github.com/willbradshaw/killifish-igseq/
Antibody repertoire sequencing reveals systemic and mucosal immunosenescence in the short-lived turquoise killifishNCBI BioProject, PRJNA662612.
- Dario Riccardo Valenzano
- Dario Riccardo Valenzano
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Matt Kaeberlein, University of Washington, United States
© 2022, Bradshaw et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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