Ribosomal S6 kinase 1 regulates inflammaging via the senescence secretome.

Autor: Gallage S; Medical Research Council Laboratory of Medical Sciences (LMS), London, UK.; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK.; Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.; University of Tübingen, Faculty of Medicine, Institute for Interdisciplinary Research on Cancer Metabolism and Chronic Inflammation, M3-Research Center for Malignome, Metabolome and Microbiome, Tübingen, Germany., Irvine EE; Medical Research Council Laboratory of Medical Sciences (LMS), London, UK.; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK., Barragan Avila JE; Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany., Reen V; Medical Research Council Laboratory of Medical Sciences (LMS), London, UK.; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK., Pedroni SMA; Medical Research Council Laboratory of Medical Sciences (LMS), London, UK.; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK., Duran I; Medical Research Council Laboratory of Medical Sciences (LMS), London, UK.; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK., Ranvir V; Emmy Noether Research Group, Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Epigenetic Machineries and Cancer, Heidelberg, Germany., Khadayate S; Medical Research Council Laboratory of Medical Sciences (LMS), London, UK.; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK., Pombo J; Medical Research Council Laboratory of Medical Sciences (LMS), London, UK.; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK., Brookes S; Medical Research Council Laboratory of Medical Sciences (LMS), London, UK.; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK., Heide D; Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany., Dharmalingham G; Medical Research Council Laboratory of Medical Sciences (LMS), London, UK.; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK., Choudhury AI; Medical Research Council Laboratory of Medical Sciences (LMS), London, UK.; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK., Singh I; Emmy Noether Research Group, Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Epigenetic Machineries and Cancer, Heidelberg, Germany., Herranz N; Medical Research Council Laboratory of Medical Sciences (LMS), London, UK.; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK., Vernia S; Medical Research Council Laboratory of Medical Sciences (LMS), London, UK.; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK., Heikenwalder M; Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. m.heikenwaelder@dkfz-heidelberg.de.; University of Tübingen, Faculty of Medicine, Institute for Interdisciplinary Research on Cancer Metabolism and Chronic Inflammation, M3-Research Center for Malignome, Metabolome and Microbiome, Tübingen, Germany. m.heikenwaelder@dkfz-heidelberg.de., Gil J; Medical Research Council Laboratory of Medical Sciences (LMS), London, UK. jesus.gil@imperial.ac.uk.; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK. jesus.gil@imperial.ac.uk., Withers DJ; Medical Research Council Laboratory of Medical Sciences (LMS), London, UK. d.withers@imperial.ac.uk.; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK. d.withers@imperial.ac.uk.
Jazyk: angličtina
Zdroj: Nature aging [Nat Aging] 2024 Nov; Vol. 4 (11), pp. 1544-1561. Date of Electronic Publication: 2024 Aug 29.
DOI: 10.1038/s43587-024-00695-z
Abstrakt: Inhibition of S6 kinase 1 (S6K1) extends lifespan and improves healthspan in mice, but the underlying mechanisms are unclear. Cellular senescence is a stable growth arrest accompanied by an inflammatory senescence-associated secretory phenotype (SASP). Cellular senescence and SASP-mediated chronic inflammation contribute to age-related pathology, but the specific role of S6K1 has not been determined. Here we show that S6K1 deletion does not reduce senescence but ameliorates inflammation in aged mouse livers. Using human and mouse models of senescence, we demonstrate that reduced inflammation is a liver-intrinsic effect associated with S6K deletion. Specifically, we show that S6K1 deletion results in reduced IRF3 activation; impaired production of cytokines, such as IL1β; and reduced immune infiltration. Using either liver-specific or myeloid-specific S6K knockout mice, we also demonstrate that reduced immune infiltration and clearance of senescent cells is a hepatocyte-intrinsic phenomenon. Overall, deletion of S6K reduces inflammation in the liver, suggesting that suppression of the inflammatory SASP by loss of S6K could underlie the beneficial effects of inhibiting this pathway on healthspan and lifespan.
Competing Interests: Competing interests J.G. has been a consultant for Unity Biotechnology, Geras Bio, Myricx Pharma and Merck KGaA. Pfizer and Unity Biotechnology have funded research in J.G.’s laboratory (unrelated to the work presented here). J.G. owns equity in Geras Bio. J.G. is a named inventor in Medical Research Council and Imperial College patents, both related to senolytic therapies (the patents are not related to the work presented here). The remaining authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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