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; Diana Jurk

doi:10.1038/ncomms15691

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, Diana Jurk

Research output: Contribution to journal › Article › peer-review

272 Scopus citations

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 p16^Ink4a-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.

Original language	English (US)
Article number	15691
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms15691
State	Published - Jun 13 2017

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
General
Physics and Astronomy(all)

Access to Document

10.1038/ncomms15691

Cite this

Ogrodnik, M., Miwa, S., Tchkonia, T., Tiniakos, D., Wilson, C. L., Lahat, A., Day, C. P., Burt, A., Palmer, A., Anstee, Q. M., Grellscheid, S. N., Hoeijmakers, J. H. J., Barnhoorn, S., Mann, D. A., Bird, T. G., Vermeij, W. P., Kirkland, J. L., Passos, J. F., Von Zglinicki, T., & Jurk, D. (2017). Cellular senescence drives age-dependent hepatic steatosis. Nature communications, 8, [15691]. https://doi.org/10.1038/ncomms15691

Ogrodnik, M, Miwa, S, Tchkonia, T, Tiniakos, D, Wilson, CL, Lahat, A, Day, CP, Burt, A, Palmer, A, Anstee, QM, Grellscheid, SN, Hoeijmakers, JHJ, Barnhoorn, S, Mann, DA, Bird, TG, Vermeij, WP, Kirkland, JL , Passos, JF, Von Zglinicki, T & Jurk, D 2017, 'Cellular senescence drives age-dependent hepatic steatosis', Nature communications, vol. 8, 15691. https://doi.org/10.1038/ncomms15691

@article{ecfabd0b8b874583af4abc4729327a32,

title = "Cellular senescence drives age-dependent hepatic steatosis",

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.",

author = "Mikolaj Ogrodnik and Satomi Miwa and Tamar Tchkonia and Dina Tiniakos and Wilson, {Caroline L.} and Albert Lahat and Day, {Christoper P.} and Alastair Burt and Allyson Palmer and Anstee, {Quentin M.} and Grellscheid, {Sushma Nagaraja} and Hoeijmakers, {Jan H.J.} and Sander Barnhoorn and Mann, {Derek A.} and Bird, {Thomas G.} and Vermeij, {Wilbert P.} and Kirkland, {James L.} and Passos, {Jo{\~a}o F.} and {Von Zglinicki}, Thomas and Diana Jurk",

note = "Funding Information: D.J. is funded by a Newcastle University Faculty of Medical Sciences Fellowship. C.P.D. is supported by the the National Institute for Health Research. J.F.P. is funded by a David Phillips BBSRC fellowship BB/H022384/1 and BBSRC grant BB/K017314/1. T.T., A.P. and J.L.K. were supported by NIH grant R37 AG013925 (J.L.K.), the Connor Group and the Noaber Foundation. D.A.M. is funded by Centre for Ageing & Vitality MR/M501700, MK/K001949/1 and MRC G0700890. T.G.B. is funded by a Wellcome Trust Intermediate Clinical Fellowship (WT107492). The study was supported by BBSRC (grants BB/C008200/1 and BB/I020748/1 to T.v.Z.) and grants from NUIA (D.J.) and the Newcastle Biomedical Research Centre (T.v.Z.). Financial support for J.H.J.H. was obtained from the National Institute of Health (NIH)/National Institute of Ageing (NIA) (PO1 AG017242), European Research Council Advanced Grant DamAge and Proof of Concept Grant Dementia, the KWO Dutch Cancer Society (5030), SFB628 and the Royal Academy of Arts and Sciences of the Netherlands (academia professorship to J.H.J.H.). We thank Dr Kerry Cameron for support with the mouse experiments, Professor Fiona Oakley for helpful comments and the Histology Services at the CRUK Beatson Institute for assistance with p21 immunohistochemistry. Publisher Copyright: {\textcopyright} The Author(s) 2017.",

year = "2017",

month = jun,

day = "13",

doi = "10.1038/ncomms15691",

language = "English (US)",

volume = "8",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Cellular senescence drives age-dependent hepatic steatosis

AU - Ogrodnik, Mikolaj

AU - Miwa, Satomi

AU - Tchkonia, Tamar

AU - Tiniakos, Dina

AU - Wilson, Caroline L.

AU - Lahat, Albert

AU - Day, Christoper P.

AU - Burt, Alastair

AU - Palmer, Allyson

AU - Anstee, Quentin M.

AU - Grellscheid, Sushma Nagaraja

AU - Hoeijmakers, Jan H.J.

AU - Barnhoorn, Sander

AU - Mann, Derek A.

AU - Bird, Thomas G.

AU - Vermeij, Wilbert P.

AU - Kirkland, James L.

AU - Passos, João F.

AU - Von Zglinicki, Thomas

AU - Jurk, Diana

N1 - Funding Information: D.J. is funded by a Newcastle University Faculty of Medical Sciences Fellowship. C.P.D. is supported by the the National Institute for Health Research. J.F.P. is funded by a David Phillips BBSRC fellowship BB/H022384/1 and BBSRC grant BB/K017314/1. T.T., A.P. and J.L.K. were supported by NIH grant R37 AG013925 (J.L.K.), the Connor Group and the Noaber Foundation. D.A.M. is funded by Centre for Ageing & Vitality MR/M501700, MK/K001949/1 and MRC G0700890. T.G.B. is funded by a Wellcome Trust Intermediate Clinical Fellowship (WT107492). The study was supported by BBSRC (grants BB/C008200/1 and BB/I020748/1 to T.v.Z.) and grants from NUIA (D.J.) and the Newcastle Biomedical Research Centre (T.v.Z.). Financial support for J.H.J.H. was obtained from the National Institute of Health (NIH)/National Institute of Ageing (NIA) (PO1 AG017242), European Research Council Advanced Grant DamAge and Proof of Concept Grant Dementia, the KWO Dutch Cancer Society (5030), SFB628 and the Royal Academy of Arts and Sciences of the Netherlands (academia professorship to J.H.J.H.). We thank Dr Kerry Cameron for support with the mouse experiments, Professor Fiona Oakley for helpful comments and the Histology Services at the CRUK Beatson Institute for assistance with p21 immunohistochemistry. Publisher Copyright: © The Author(s) 2017.

PY - 2017/6/13

Y1 - 2017/6/13

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85020726721&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85020726721&partnerID=8YFLogxK

U2 - 10.1038/ncomms15691

DO - 10.1038/ncomms15691

M3 - Article

C2 - 28608850

AN - SCOPUS:85020726721

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

M1 - 15691

ER -

Cellular senescence drives age-dependent hepatic steatosis

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this