Antibody repertoire sequencing reveals systemic and mucosal immunosenescence in the short-lived turquoise killifish

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; 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 individualised heavy-chain repertoires, with a generative process capable of producing millions of productive receptor 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 an important difference in the age-sensitivity of different B-cell populations. Compared to the whole body, the immune repertoires of isolated intestinal samples exhibit much more dramatic age-related phenotypes, apparently due to an elevated prevalence of age-sensitive expanded clones. Our results highlight the importance of organ-specific dynamics in adaptive immunosenescence.