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Cellular senescence in gastrointestinal diseases: from pathogenesis to therapeutics

Key Points

  • Senescence is a durable cell cycle arrest induced in response to various stress factors such as telomere erosion, DNA damage or the aberrant activation of oncogenes; the senescence response counteracts tumorigenesis

  • Senescence plays important physiological roles in nondisease settings such as embryonic development, wound healing, tissue repair and ageing

  • Senescent cells secrete various cytokines, chemokines, matrix remodelling proteases and growth factors, forming the senescence-associated secretory phenotype

  • Senescence-associated secreted factors evoke immune responses, which, depending on the pathophysiological context, can either prevent or fuel disease progression

  • Senescence plays a key part in the pathogenesis of many gastrointestinal and hepatobiliary diseases

Abstract

Senescence is a durable cell cycle arrest that can be induced in response to various stress factors, such as telomere erosion, DNA damage or the aberrant activation of oncogenes. In addition to its well-established role as a stress response programme, research has revealed important physiological roles of senescence in nondisease settings, such as embryonic development, wound healing, tissue repair and ageing. Senescent cells secrete various cytokines, chemokines, matrix remodelling proteases and growth factors, a phenotype collectively referred to as the senescence-associated secretory phenotype. These factors evoke immune responses that, depending on the pathophysiological context, can either prevent or even fuel disease and tumorigenesis. Remarkably, even the gut microbiota can influence senescence in various organs. In this Review, we provide an introduction to cellular senescence, addressed particularly to gastroenterologists and hepatologists, and discuss the implications of senescence for the pathogenesis of malignant and nonmalignant gastrointestinal and hepatobiliary diseases. We conclude with an outlook on how modulation of cellular senescence might be used for therapeutic purposes.

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Figure 1: The hallmarks of cellular senescence.
Figure 2: Overview of the molecular mechanisms that lead to senescence induction.
Figure 3: The SASP as a double-edged sword in tumourigenesis.
Figure 4: Involvement of senescence in the pathogenesis of gastrointestinal and hepatobiliary diseases.

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Acknowledgements

The authors' work was supported by the German Research Foundation (DFG) grants FOR2314 (L.Z.), SFB685 (L.Z.) and SFB/TR 209 (L.Z. and M.B.), the Gottfried Wilhelm Leibniz Program (L.Z.), the European Research Council (projects 'CholangioConcept' (L.Z.) and 'Heptromic' (L.Z.)), the German Ministry for Education and Research (BMBF) (eMed [Multiscale HCC]) (L.Z., M.B.), the German Universities Excellence Initiative (third funding line: 'future concept') (L.Z.), the German Centre for Translational Cancer Research (DKTK) (L.Z.) and the German-Israeli Cooperation in Cancer Research (DKFZ-MOST) (L.Z.).

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L.Z. and M.B. researched data for the article. M.B., L.Z. and N.F. wrote the manuscript. All authors discussed the outline and content of the manuscript.

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Correspondence to Lars Zender or Michael Bitzer.

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Frey, N., Venturelli, S., Zender, L. et al. Cellular senescence in gastrointestinal diseases: from pathogenesis to therapeutics. Nat Rev Gastroenterol Hepatol 15, 81–95 (2018). https://doi.org/10.1038/nrgastro.2017.146

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