Cellular senescence drives age-dependent hepatic steatosis

Mikolaj Ogrodnik, Satomi Miwa, Tamar Tchkonia, Dina Tiniakos, Caroline L. Wilson, Albert Lahat, Christoper P. Day, Alastair Burt, Allyson Palmer, Quentin M. Anstee, Sushma Nagaraja Grellscheid, Jan H J. Hoeijmakers, Sander Barnhoorn, Derek A. Mann, Thomas G. Bird, Wilbert P. Vermeij, James L. Kirkland, João F. Passos, Thomas von Zglinicki and Diana Jurk ()
Additional contact information
Mikolaj Ogrodnik: Newcastle University Institute for Ageing, Institute for Cell and Molecular Biosciences, Campus for Ageing and Vitality, Newcastle University
Satomi Miwa: Newcastle University Institute for Ageing, Institute for Cell and Molecular Biosciences, Campus for Ageing and Vitality, Newcastle University
Tamar Tchkonia: Robert and Arlene Kogod Center on Aging, Mayo Clinic
Dina Tiniakos: Institute of Cellular Medicine, Newcastle University
Caroline L. Wilson: Institute of Cellular Medicine, Newcastle University
Albert Lahat: Durham University
Christoper P. Day: Institute of Cellular Medicine, Newcastle University
Alastair Burt: Institute of Cellular Medicine, Newcastle University
Allyson Palmer: Robert and Arlene Kogod Center on Aging, Mayo Clinic
Quentin M. Anstee: Institute of Cellular Medicine, Newcastle University
Sushma Nagaraja Grellscheid: Durham University
Jan H J. Hoeijmakers: Erasmus University Medical Center
Sander Barnhoorn: Erasmus University Medical Center
Derek A. Mann: Institute of Cellular Medicine, Newcastle University
Thomas G. Bird: MRC Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh
Wilbert P. Vermeij: Erasmus University Medical Center
James L. Kirkland: Robert and Arlene Kogod Center on Aging, Mayo Clinic
João F. Passos: Newcastle University Institute for Ageing, Institute for Cell and Molecular Biosciences, Campus for Ageing and Vitality, Newcastle University
Thomas von Zglinicki: Newcastle University Institute for Ageing, Institute for Cell and Molecular Biosciences, Campus for Ageing and Vitality, Newcastle University
Diana Jurk: Newcastle University Institute for Ageing, Institute for Cell and Molecular Biosciences, Campus for Ageing and Vitality, Newcastle University

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15691

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