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Nat Commun. 2017 Jun 13;8:15691. doi: 10.1038/ncomms15691.

Cellular senescence drives age-dependent hepatic steatosis.

Author information

1
Newcastle University Institute for Ageing, Institute for Cell and Molecular Biosciences, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE4 5PL, UK.
2
Robert and Arlene Kogod Center on Aging, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA.
3
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
4
Department of Pathology, Aretaieio Hospital, Medical School, National &Kapodistrian University of Athens, Athens 11528, Greece.
5
Department of Biosciences, Durham University, Durham DH1 3LE, UK.
6
Liver Unit, Newcastle upon Tyne Hospitals NHS Trust, Freeman Hospital, Newcastle upon Tyne NE7 7DN, UK.
7
The University of Adelaide, Faculty of Health Science, North Terrace, Adelaide, South Australia 5005, Australia.
8
Department of Molecular Genetics, Erasmus University Medical Center, PO Box 2040, Rotterdam 3000 CA, The Netherlands.
9
CECAD Forschungszentrum, Universität zu Köln, Joseph-Stelzmann-Straße 26, Köln 50931, Germany.
10
MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
11
Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.

Abstract

The incidence of non-alcoholic fatty liver disease (NAFLD) increases with age. Cellular senescence refers to a state of irreversible cell-cycle arrest combined with the secretion of proinflammatory cytokines and mitochondrial dysfunction. Senescent cells contribute to age-related tissue degeneration. Here we show that the accumulation of senescent cells promotes hepatic fat accumulation and steatosis. We report a close correlation between hepatic fat accumulation and markers of hepatocyte senescence. The elimination of senescent cells by suicide gene-meditated ablation of p16Ink4a-expressing senescent cells in INK-ATTAC mice or by treatment with a combination of the senolytic drugs dasatinib and quercetin (D+Q) reduces overall hepatic steatosis. Conversely, inducing hepatocyte senescence promotes fat accumulation in vitro and in vivo. Mechanistically, we show that mitochondria in senescent cells lose the ability to metabolize fatty acids efficiently. Our study demonstrates that cellular senescence drives hepatic steatosis and elimination of senescent cells may be a novel therapeutic strategy to reduce steatosis.

PMID:
28608850
PMCID:
PMC5474745
DOI:
10.1038/ncomms15691
[Indexed for MEDLINE]
Free PMC Article

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