Abstract
Tumor necrosis factor α (TNFα) regulates inflammation in metabolic diseases and probably aging-associated inflammation. Here, TNFα´s role in aging-related liver inflammation and fibrosis and underlying mechanisms was assessed in mice. In male C57BL/6J mice, aging increased hepatic inflammation, senescence markers p16 and p21 and Tnfa mRNA expression in liver tissue. In a second study, 4 and 24-month-old TNFα-/- and wild-type (WT) mice were compared for senescence, liver damage, intestinal barrier function, and microbiota composition. 24-month-old TNFα-/- mice were significantly protected from the aging-associated increase in hepatic senescence, inflammation and fibrosis found in WT mice. This protection was related with preserved stem cell marker expression, maintained small intestinal barrier function and lower bacterial endotoxin in portal blood. While differing from young mice, intestinal microbiota composition of old TNFα-/- mice differed markedly from age-matched WT mice. Also, TNFα was found to alter permeability and tight junction protein levels being reversed by the presence of an JNK inhibitor in an ex vivo intestinal tissue model. Taken together, our results suggest that TNFα plays a key role in the development of aging-related liver decline in male mice.
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Data availability
The original contributions presented in the study are included in the article/ Supplementary Material and raw sequences were deposited to the European Nucleotide Archive (ENA) under accession number PRJEB76497. Further inquiries can be directed to the corresponding author.
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Acknowledgements
This research was funded by the Herzfelder Family Foundation/ Austrian Science Fund FWF (10.55776/P35271 to IB) and the Austrian Science Fund FWF (10.55776/I4844 to IB) and in parts by the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no. 859890 (Smart-Age). For open access purposes, the author has applied a CC BY public copyright license to any author accepted manuscript version arising from this submission. We acknowledge the support of the HighPerformance and Cloud Computing Group at the Zentrum für Datenverarbeitung of the University of Tübingen, the state of Baden-Württemberg through bwHPC, and the GermanResearch Foundation (DFG) through grant no. INST 37/935-1FUGG. Graphics in Figure 3 and Graphical Abstract created with BioRender.com.
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Haktan Övül Bozkir: Formal analysis, investigation. Annette Brandt: Formal analysis, Investigation, writing—original draft, writing—review and editing, visualization. Katja Csarmann: Investigation. Anja Baumann: Investigation. Katharina Burger: Investigation, Timur Yergaliyev: Formal analysis, visualization. Tim Hendrikx: Investigation. Amélia Camarinha-Silva: Formal analysis, visualization. Ina Bergheim: Conceptualization, writing—original draft, writing—review and editing, supervision, funding acquisition.
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Bozkir, H.Ö., Brandt, A., Csarmann, K. et al. TNFα is a trigger of aging-associated liver inflammation in mice. npj Aging (2026). https://doi.org/10.1038/s41514-025-00326-w
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DOI: https://doi.org/10.1038/s41514-025-00326-w
