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Extensive age-dependent loss of antibody diversity in naturally short-lived turquoise killifish

William J Bradshaw, Michael Poeschla, Aleksandra Placzek, Samuel Kean, View ORCID ProfileDario Riccardo Valenzano
doi: https://doi.org/10.1101/2020.08.21.261248
William J Bradshaw
1Max Planck Institute for Biology of Aging, Joseph-Stelzmann-Str. 296, 50937 Cologne, Germany
2CECAD Research Center, University of Cologne, Joseph-Stelzmann-Straße 26, 50931 Cologne, Germany
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Michael Poeschla
1Max Planck Institute for Biology of Aging, Joseph-Stelzmann-Str. 296, 50937 Cologne, Germany
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Aleksandra Placzek
1Max Planck Institute for Biology of Aging, Joseph-Stelzmann-Str. 296, 50937 Cologne, Germany
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Samuel Kean
1Max Planck Institute for Biology of Aging, Joseph-Stelzmann-Str. 296, 50937 Cologne, Germany
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Dario Riccardo Valenzano
1Max Planck Institute for Biology of Aging, Joseph-Stelzmann-Str. 296, 50937 Cologne, Germany
2CECAD Research Center, University of Cologne, Joseph-Stelzmann-Straße 26, 50931 Cologne, Germany
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  • ORCID record for Dario Riccardo Valenzano
  • For correspondence: dvalenzano@age.mpg.de Dario.Valenzano@leibniz-fli.de
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Abstract

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.

Significance Statement Immune function declines dramatically with age, with important consequences for health in the elderly. Changes in the diversity and composition of the body’s antibody repertoire are an important contributor to this age-related dysfunction. However, studying repertoire aging at high spatial and temporal resolution is hampered by the long lifespans of humans and other vertebrate models, and the difficulty of acquiring human samples other than peripheral blood. Here, we characterize the aging of the antibody repertoire in a naturally short-lived vertebrate, the turquoise killifish (Nothobranchius furzeri). We found that aging killifish undergo rapid loss of repertoire diversity in both whole-body and intestinal samples within four months of hatching. Loss of repertoire diversity in the gut was also associated with broader gene-expression changes indicative of reduced B-cell activity. As such, killifish represent a powerful laboratory model to study adaptive immune aging.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 25, 2022.
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Extensive age-dependent loss of antibody diversity in naturally short-lived turquoise killifish
William J Bradshaw, Michael Poeschla, Aleksandra Placzek, Samuel Kean, Dario Riccardo Valenzano
bioRxiv 2020.08.21.261248; doi: https://doi.org/10.1101/2020.08.21.261248
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Extensive age-dependent loss of antibody diversity in naturally short-lived turquoise killifish
William J Bradshaw, Michael Poeschla, Aleksandra Placzek, Samuel Kean, Dario Riccardo Valenzano
bioRxiv 2020.08.21.261248; doi: https://doi.org/10.1101/2020.08.21.261248

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