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Rag1 immunodeficiency‐induced early aging and senescence in zebrafish are dependent on chronic inflammation and oxidative stress

AuthorsNovoa, Beatriz ; Pereiro, Patricia ; López-Muñoz, Azucena; Varela, Mónica ; Forn-Cuni, Gabriel ; Anchelin, Monique; Dios, S. ; Romero Jódar, Alejandro; Martínez-López, Alicia; Medina-Gali, Regla María; Collado, Manuel; Coll, Julio; Estepa, Amparo; Cayuela, María Luisa; Mulero, Victoriano; Figueras Huerta, Antonio
Issue Date2019
PublisherJohn Wiley & Sons
CitationAging Cell 18(5): e13020 (2019)
AbstractIn mammals, recombination activating gene 1 (RAG1) plays a crucial role in adaptive immunity, generating a vast range of immunoglobulins. Rag1−/− zebrafish (Danio rerio) are viable and reach adulthood without obvious signs of infectious disease in standard nonsterile conditions, suggesting that innate immunity could be enhanced to compensate for the lack of adaptive immunity. By using microarray analysis, we confirmed that the expression of immunity‐ and apoptosis‐related genes was increased in the rag1−/− fish. This tool also allows us to notice alterations of the DNA repair and cell cycle mechanisms in rag1−/− zebrafish. Several senescence and aging markers were analyzed. In addition to the lower lifespan of rag1−/− zebrafish compared to their wild‐type (wt) siblings, rag1−/− showed a higher incidence of cell cycle arrest and apoptosis, a greater amount of phosphorylated histone H2AX, oxidative stress and decline of the antioxidant mechanisms, an upregulated expression and activity of senescence‐related genes and senescence‐associated β‐galactosidase, respectively, diminished telomere length, and abnormal self‐renewal and repair capacities in the retina and liver. Metabolomic analysis also demonstrated clear differences between wt and rag1−/− fish, as was the deficiency of the antioxidant metabolite l‐acetylcarnitine (ALCAR) in rag1−/− fish. Therefore, Rag1 activity does not seem to be limited to
Description17 pages, 6 figures, 1 table.-- This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited
Publisher version (URL)http://dx.doi.org/10.1111/acel.13020
Appears in Collections:(IIM) Artículos
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