Abstract
The liver is not oblivious to the passage of time, as ageing is a major risk factor for the development of acute and chronic liver diseases. Ageing produces alterations in all hepatic cells, affecting their phenotype and function and worsening the prognosis of liver disease. The ageing process also implies the accumulation of a cellular state characterized by a persistent proliferation arrest and a specific secretory phenotype named cellular senescence. Indeed, senescent cells have key roles in many physiological processes; however, their accumulation owing to ageing or pathological conditions contributes to the damage occurring in chronic diseases. The aim of this Review is to provide an updated description of the pathophysiological events in which hepatic senescent cells are involved and their role in liver disease progression. Finally, we discuss novel geroscience therapies that could be applied to prevent or improve liver diseases and age-mediated hepatic deregulations.
Key points
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Senescent hepatocytes undergo morphological changes and metabolic alterations, negatively affecting liver function and promoting disease progression.
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Structural and functional changes in senescent liver sinusoidal endothelial cells contribute to liver disease.
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In the initial stages of liver disease, hepatic stellate cells undergo senescence, facilitating liver regeneration and fibrosis regression. Conversely, during cirrhosis, the increase in their number induces inflammation, promoting hepatocellular carcinoma (HCC).
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Senescence has a role in the development and progression of metabolic dysfunction-associated steatotic liver disease and viral hepatitis, contributing to liver injury, inflammation, fibrosis and HCC.
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Senescence can protect against HCC, inhibiting the growth of damaged cells; it can also lead to HCC progression by promoting inflammation and creating a pro-tumoural microenvironment within the liver.
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Senotherapeutic strategies, drug repurposing, and lifestyle interventions hold potential as therapies for liver disease by targeting and eliminating senescent cells and counteracting the harmful effects of senescence and ageing.
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Acknowledgements
J.G.-S. is supported by the Instituto de Salud Carlos III (FIS PI23/00945 and DTS22/00010, co-funded by the European Union), the CIBEREHD, the Swiss National Science Foundation (320030_189252), the Novartis Foundation for Medical-Biological Research, the Foundation Suisse Contre le Cancer du Foie and the AGAUR-Generalitat de Catalunya (2021 SGR 01322 and 2021 PROD 00036). CIBEREHD is funded by the Instituto de Salud Carlos III. D.S.-R. acknowledges the support of the Spanish Ministry of Universities through the FPU fellowship FPU19/03098. A.G.-R. acknowledges the support of the Instituto de Salud Carlos III through the Sara Borrell fellowship CD22/00097.
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D.S.-R. and A.G.-R. researched data for the article. J.G.-S. conceptualized and coordinated the work. All authors contributed substantially to discussion of the content. All authors wrote the article. All authors reviewed and/or edited the manuscript before submission.
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Sanfeliu-Redondo, D., Gibert-Ramos, A. & Gracia-Sancho, J. Cell senescence in liver diseases: pathological mechanism and theranostic opportunity. Nat Rev Gastroenterol Hepatol (2024). https://doi.org/10.1038/s41575-024-00913-4
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DOI: https://doi.org/10.1038/s41575-024-00913-4
