Download PDF
CC BY 4.0 · Semin Liver Dis 2021; 41(01): 050-066
DOI: 10.1055/s-0040-1722262
Review Article

Cellular Senescence in Liver Disease and Regeneration

Sofia Ferreira-Gonzalez
1   MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom
,
Daniel Rodrigo-Torres
1   MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom
,
Victoria L. Gadd
1   MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom
,
Stuart J. Forbes
1   MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom
› Author Affiliations Funding This study was supported by Research Councils UK and Medical Research Council (MR/P016839/1, UKRMP, and MR/R015635/1).
› Further Information
   Permissions and Reprints

Abstract

Cellular senescence is an irreversible cell cycle arrest implemented by the cell as a result of stressful insults. Characterized by phenotypic alterations, including secretome changes and genomic instability, senescence is capable of exerting both detrimental and beneficial processes. Accumulating evidence has shown that cellular senescence plays a relevant role in the occurrence and development of liver disease, as a mechanism to contain damage and promote regeneration, but also characterizing the onset and correlating with the extent of damage. The evidence of senescent mechanisms acting on the cell populations of the liver will be described including the role of markers to detect cellular senescence. Overall, this review intends to summarize the role of senescence in liver homeostasis, injury, disease, and regeneration.

Keywords

senescence - liver disease - liver regeneration


Publication History

Article published online:
09 February 2021

© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Kirkwood TB. Where will it all end?. Lancet 2001; 357 (9256): 576
    CrossrefPubMedGoogle Scholar
  • 2 Source: Office for National Statistics, UK. Accessed February 11, 2020 at: https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/lifeexpectancies/articles/howhaslifeexpectancychangedovertime/2015-09-09
  • 3 Kirkwood TB, Austad SN. Why do we age?. Nature 2000; 408 (6809): 233-238
    CrossrefPubMedGoogle Scholar
  • 4 Carrel A. On the permanent life of tissue outside of the organism. J Exp Med 1912; 15 (05) 516-528
    CrossrefPubMedGoogle Scholar
  • 5 Friedman DM. The Immortalists: Charles Lindbergh, Dr Alexis Carrel, and Their Daring Quest to Live Forever. 2nd ed.. New York, NY: Harper Collins; 2008: 12
    Google Scholar
  • 6 Shay JW, Wright WE. Hayflick, his limit, and cellular ageing. Nat Rev Mol Cell Biol 2000; 1 (01) 72-76
    CrossrefPubMedGoogle Scholar
  • 7 Campisi J. Replicative senescence: an old lives' tale?. Cell 1996; 84 (04) 497-500
    CrossrefPubMedGoogle Scholar
  • 8 Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res 1961; 25: 585-621
    CrossrefPubMedGoogle Scholar
  • 9 Forbes SJ, Newsome PN. Liver regeneration - mechanisms and models to clinical application. Nat Rev Gastroenterol Hepatol 2016; 13 (08) 473-485
    CrossrefPubMedGoogle Scholar
  • 10 Childs BG, Baker DJ, Kirkland JL, Campisi J, van Deursen JM. Senescence and apoptosis: dueling or complementary cell fates?. EMBO Rep 2014; 15 (11) 1139-1153
    CrossrefPubMedGoogle Scholar
  • 11 Gorgoulis V, Adams PD, Alimonti A. et al. Cellular senescence: defining a path forward. Cell 2019; 179 (04) 813-827
    CrossrefPubMedGoogle Scholar
  • 12 Wang Y, Xu Q, Sack L, Kang C, Elledge SJ. A gain-of-function senescence bypass screen identifies the homeobox transcription factor DLX2 as a regulator of ATM-p53 signaling. Genes Dev 2016; 30 (03) 293-306
    CrossrefPubMedGoogle Scholar
  • 13 Lee S, Schmitt CA. The dynamic nature of senescence in cancer. Nat Cell Biol 2019; 21 (01) 94-101
    CrossrefPubMedGoogle Scholar
  • 14 Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144 (05) 646-674
    CrossrefPubMedGoogle Scholar
  • 15 Muñoz-Espín D, Serrano M. Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol 2014; 15 (07) 482-496
    CrossrefPubMedGoogle Scholar
  • 16 Demaria M, Ohtani N, Youssef SA. et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell 2014; 31 (06) 722-733
    CrossrefPubMedGoogle Scholar
  • 17 Mosteiro L, Pantoja C, Alcazar N. et al. Tissue damage and senescence provide critical signals for cellular reprogramming in vivo. Science 2016; 354 (6315): 1020-1030
    CrossrefPubMedGoogle Scholar
  • 18 Ritschka B, Storer M, Mas A. et al. The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes Dev 2017; 31 (02) 172-183
    CrossrefPubMedGoogle Scholar
  • 19 Krizhanovsky V, Yon M, Dickins RA. et al. Senescence of activated stellate cells limits liver fibrosis. Cell 2008; 134 (04) 657-667
    CrossrefPubMedGoogle Scholar
  • 20 Kim KH, Chen CC, Monzon RI, Lau LF. Matricellular protein CCN1 promotes regression of liver fibrosis through induction of cellular senescence in hepatic myofibroblasts. Mol Cell Biol 2013; 33 (10) 2078-2090
    CrossrefPubMedGoogle Scholar
  • 21 Wolstein JM, Lee DH, Michaud J, Buot V, Stefanchik B, Plotkin MD. INK4a knockout mice exhibit increased fibrosis under normal conditions and in response to unilateral ureteral obstruction. Am J Physiol Renal Physiol 2010; 299 (06) F1486-F1495
    CrossrefPubMedGoogle Scholar
  • 22 Zhu F, Li Y, Zhang J. et al. Senescent cardiac fibroblast is critical for cardiac fibrosis after myocardial infarction. PLoS One 2013; 8 (09) e74535
    CrossrefPubMedGoogle Scholar
  • 23 Jun JI, Lau LF. Cellular senescence controls fibrosis in wound healing. Aging (Albany NY) 2010; 2 (09) 627-631
    CrossrefPubMedGoogle Scholar
  • 24 Besancenot R, Chaligné R, Tonetti C. et al. A senescence-like cell-cycle arrest occurs during megakaryocytic maturation: implications for physiological and pathological megakaryocytic proliferation. PLoS Biol 2010; 8 (09) e1000476
    CrossrefPubMedGoogle Scholar
  • 25 Rajagopalan S, Long EO. Cellular senescence induced by CD158d reprograms natural killer cells to promote vascular remodeling. Proc Natl Acad Sci U S A 2012; 109 (50) 20596-20601
    CrossrefPubMedGoogle Scholar
  • 26 Chuprin A, Gal H, Biron-Shental T. et al. Cell fusion induced by ERVWE1 or measles virus causes cellular senescence. Genes Dev 2013; 27 (21) 2356-2366
    CrossrefPubMedGoogle Scholar
  • 27 Muñoz-Espín D, Cañamero M, Maraver A. et al. Programmed cell senescence during mammalian embryonic development. Cell 2013; 155 (05) 1104-1118
    CrossrefPubMedGoogle Scholar
  • 28 Storer M, Mas A, Robert-Moreno A. et al. Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell 2013; 155 (05) 1119-1130
    CrossrefPubMedGoogle Scholar
  • 29 Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci 2014; 69 (Suppl. 01) S4-S9
    CrossrefPubMedGoogle Scholar
  • 30 Hall BM, Balan V, Gleiberman AS. et al. Aging of mice is associated with p16(Ink4a)- and β-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells. Aging (Albany NY) 2016; 8 (07) 1294-1315
    CrossrefPubMedGoogle Scholar
  • 31 Coppé JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol 2010; 5 (01) 99-118
    CrossrefPubMedGoogle Scholar
  • 32 Childs BG, Baker DJ, Wijshake T, Conover CA, Campisi J, van Deursen JM. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 2016; 354 (6311): 472-477
    CrossrefPubMedGoogle Scholar
  • 33 Thompson PJ, Shah A, Ntranos V, Van Gool F, Atkinson M, Bhushan A. Targeted elimination of senescent beta cells prevents type 1 diabetes. Cell Metab 2019; 29 (05) 1045.e10-1060.e10
    CrossrefPubMedGoogle Scholar
  • 34 Jeon OH, Kim C, Laberge RM. et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med 2017; 23 (06) 775-781
    CrossrefPubMedGoogle Scholar
  • 35 Palmer AK, Xu M, Zhu Y. et al. Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell 2019; 18 (03) e12950
    CrossrefPubMedGoogle Scholar
  • 36 Bussian TJ, Aziz A, Meyer CF, Swenson BL, van Deursen JM, Baker DJ. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 2018; 562 (7728): 578-582
    CrossrefPubMedGoogle Scholar
  • 37 López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell 2013; 153 (06) 1194-1217
    CrossrefPubMedGoogle Scholar
  • 38 Dimri GP, Lee X, Basile G. et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A 1995; 92 (20) 9363-9367
    CrossrefPubMedGoogle Scholar
  • 39 Paradis V, Youssef N, Dargère D. et al. Replicative senescence in normal liver, chronic hepatitis C, and hepatocellular carcinomas. Hum Pathol 2001; 32 (03) 327-332
    CrossrefPubMedGoogle Scholar
  • 40 Melk A, Schmidt BM, Braun H. et al. Effects of donor age and cell senescence on kidney allograft survival. Am J Transplant 2009; 9 (01) 114-123
    CrossrefPubMedGoogle Scholar
  • 41 Erusalimsky JD, Kurz DJ. Cellular senescence in vivo: its relevance in ageing and cardiovascular disease. Exp Gerontol 2005; 40 (8-9): 634-642
    CrossrefPubMedGoogle Scholar
  • 42 Jeyapalan JC, Ferreira M, Sedivy JM, Herbig U. Accumulation of senescent cells in mitotic tissue of aging primates. Mech Ageing Dev 2007; 128 (01) 36-44
    CrossrefPubMedGoogle Scholar
  • 43 Rodier F, Campisi J. Four faces of cellular senescence. J Cell Biol 2011; 192 (04) 547-556
    CrossrefPubMedGoogle Scholar
  • 44 Beauséjour CM, Krtolica A, Galimi F. et al. Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J 2003; 22 (16) 4212-4222
    CrossrefPubMedGoogle Scholar
  • 45 Sharpless NE, Sherr CJ. Forging a signature of in vivo senescence. Nat Rev Cancer 2015; 15 (07) 397-408
    CrossrefPubMedGoogle Scholar
  • 46 Yosef R, Pilpel N, Tokarsky-Amiel R. et al. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat Commun 2016; 7: 11190
    CrossrefPubMedGoogle Scholar
  • 47 d'Adda di Fagagna F, Reaper PM, Clay-Farrace L. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 2003; 426 (6963): 194-198
    CrossrefPubMedGoogle Scholar
  • 48 d'Adda di Fagagna F. Living on a break: cellular senescence as a DNA-damage response. Nat Rev Cancer 2008; 8 (07) 512-522
    CrossrefPubMedGoogle Scholar
  • 49 Rodier F, Coppé JP, Patil CK. et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol 2009; 11 (08) 973-979
    CrossrefPubMedGoogle Scholar
  • 50 Ivanov A, Pawlikowski J, Manoharan I. et al. Lysosome-mediated processing of chromatin in senescence. J Cell Biol 2013; 202 (01) 129-143
    CrossrefPubMedGoogle Scholar
  • 51 Li T, Chen ZJ. The cGAS-cGAMP-STING pathway connects DNA damage to inflammation, senescence, and cancer. J Exp Med 2018; 215 (05) 1287-1299
    CrossrefPubMedGoogle Scholar
  • 52 Narita M, Nũnez S, Heard E. et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 2003; 113 (06) 703-716
    CrossrefPubMedGoogle Scholar
  • 53 Di Micco R, Sulli G, Dobreva M. et al. Interplay between oncogene-induced DNA damage response and heterochromatin in senescence and cancer. Nat Cell Biol 2011; 13 (03) 292-302
    CrossrefPubMedGoogle Scholar
  • 54 Aird KM, Zhang R. Detection of senescence-associated heterochromatin foci (SAHF). Methods Mol Biol 2013; 965: 185-196
    CrossrefPubMedGoogle Scholar
  • 55 Swanson EC, Manning B, Zhang H, Lawrence JB. Higher-order unfolding of satellite heterochromatin is a consistent and early event in cell senescence. J Cell Biol 2013; 203 (06) 929-942
    CrossrefPubMedGoogle Scholar
  • 56 Kuilman T, Michaloglou C, Mooi WJ, Peeper DS. The essence of senescence. Genes Dev 2010; 24 (22) 2463-2479
    CrossrefPubMedGoogle Scholar
  • 57 Dou Z, Ghosh K, Vizioli MG. et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 2017; 550 (7676): 402-406
    CrossrefPubMedGoogle Scholar
  • 58 Podrimaj-Bytyqi A, Borovečki A, Selimi Q, Manxhuka-Kerliu S, Gashi G, Elezaj IR. The frequencies of micronuclei, nucleoplasmic bridges and nuclear buds as biomarkers of genomic instability in patients with urothelial cell carcinoma. Sci Rep 2018; 8 (01) 17873
    CrossrefPubMedGoogle Scholar
  • 59 Shimi T, Butin-Israeli V, Adam SA. et al. The role of nuclear lamin B1 in cell proliferation and senescence. Genes Dev 2011; 25 (24) 2579-2593
    CrossrefPubMedGoogle Scholar
  • 60 Freund A, Laberge RM, Demaria M, Campisi J. Lamin B1 loss is a senescence-associated biomarker. Mol Biol Cell 2012; 23 (11) 2066-2075
    CrossrefPubMedGoogle Scholar
  • 61 Shay JW, Wright WE. Telomeres and telomerase: three decades of progress. Nat Rev Genet 2019; 20 (05) 299-309
    CrossrefPubMedGoogle Scholar
  • 62 Victorelli S, Passos JF. Telomeres and Cell senescence – size matters not. EBioMedicine 2017; 21: 14-20
    CrossrefPubMedGoogle Scholar
  • 63 Muñoz-Lorente MA, Cano-Martin AC, Blasco MA. Mice with hyper-long telomeres show less metabolic aging and longer lifespans. Nat Commun 2019; 10 (01) 4723
    CrossrefPubMedGoogle Scholar
  • 64 Passos JF, Nelson G, Wang C. et al. Feedback between p21 and reactive oxygen production is necessary for cell senescence. Mol Syst Biol 2010; 6: 347
    CrossrefPubMedGoogle Scholar
  • 65 Correia-Melo C, Marques FDM, Anderson R. et al. Mitochondria are required for pro-ageing features of the senescent phenotype. EMBO J 2016; 35 (07) 724-742
    CrossrefPubMedGoogle Scholar
  • 66 Birch J, Victorelli S, Rahmatika D. et al. Telomere dysfunction and senescence-associated pathways in bronchiectasis. Am J Respir Crit Care Med 2016; 193 (08) 929-932
    CrossrefPubMedGoogle Scholar
  • 67 Jung T, Bader N, Grune T. Lipofuscin: formation, distribution, and metabolic consequences. Ann N Y Acad Sci 2007; 1119: 97-111
    CrossrefPubMedGoogle Scholar
  • 68 Nardella C, Clohessy JG, Alimonti A, Pandolfi PP. Pro-senescence therapy for cancer treatment. Nat Rev Cancer 2011; 11 (07) 503-511
    CrossrefPubMedGoogle Scholar
  • 69 Debacq-Chainiaux F, Erusalimsky JD, Campisi J, Toussaint O. Protocols to detect senescence-associated beta-galactosidase (SA-betagal) activity, a biomarker of senescent cells in culture and in vivo. Nat Protoc 2009; 4 (12) 1798-1806
    CrossrefPubMedGoogle Scholar
  • 70 Georgakopoulou EA, Tsimaratou K, Evangelou K. et al. Specific lipofuscin staining as a novel biomarker to detect replicative and stress-induced senescence. A method applicable in cryo-preserved and archival tissues. Aging (Albany NY) 2013; 5 (01) 37-50
    CrossrefPubMedGoogle Scholar
  • 71 Evangelou K, Lougiakis N, Rizou SV. et al. Robust, universal biomarker assay to detect senescent cells in biological specimens. Aging Cell 2017; 16 (01) 192-197
    CrossrefPubMedGoogle Scholar
  • 72 Haugstetter AM, Loddenkemper C, Lenze D. et al. Cellular senescence predicts treatment outcome in metastasised colorectal cancer. Br J Cancer 2010; 103 (04) 505-509
    CrossrefPubMedGoogle Scholar
  • 73 Deschênes-Simard X, Gaumont-Leclerc MF, Bourdeau V. et al. Tumor suppressor activity of the ERK/MAPK pathway by promoting selective protein degradation. Genes Dev 2013; 27 (08) 900-915
    CrossrefPubMedGoogle Scholar
  • 74 Karisch R, Fernandez M, Taylor P. et al. Global proteomic assessment of the classical protein-tyrosine phosphatome and “Redoxome”. Cell 2011; 146 (05) 826-840
    CrossrefPubMedGoogle Scholar
  • 75 Nyström T. Role of oxidative carbonylation in protein quality control and senescence. EMBO J 2005; 24 (07) 1311-1317
    CrossrefPubMedGoogle Scholar
  • 76 Ogrodnik M, Salmonowicz H, Gladyshev VN. Integrating cellular senescence with the concept of damage accumulation in aging: Relevance for clearance of senescent cells. Aging Cell 2019; 18 (01) e12841
    CrossrefPubMedGoogle Scholar
  • 77 Vernier M, Bourdeau V, Gaumont-Leclerc MF. et al. Regulation of E2Fs and senescence by PML nuclear bodies. Genes Dev 2011; 25 (01) 41-50
    CrossrefPubMedGoogle Scholar
  • 78 Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of cellular senescence. Trends Cell Biol 2018; 28 (06) 436-453
    CrossrefPubMedGoogle Scholar
  • 79 Campisi J, d'Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 2007; 8 (09) 729-740
    CrossrefPubMedGoogle Scholar
  • 80 Aravinthan A, Verma S, Coleman N, Davies S, Allison M, Alexander G. Vacuolation in hepatocyte nuclei is a marker of senescence. J Clin Pathol 2012; 65 (06) 557-560
    CrossrefPubMedGoogle Scholar
  • 81 Ademowo OS, Dias HKI, Burton DGA, Griffiths HR. Lipid (per) oxidation in mitochondria: an emerging target in the ageing process?. Biogerontology 2017; 18 (06) 859-879
    CrossrefPubMedGoogle Scholar
  • 82 Ogrodnik M, Miwa S, Tchkonia T. et al. Cellular senescence drives age-dependent hepatic steatosis. Nat Commun 2017; 8: 15691
    CrossrefPubMedGoogle Scholar
  • 83 Kaplon J, Zheng L, Meissl K. et al. A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature 2013; 498 (7452): 109-112
    CrossrefPubMedGoogle Scholar
  • 84 Korolchuk VI, Miwa S, Carroll B, von Zglinicki T. Mitochondria in cell senescence: is mitophagy the weakest link?. EBioMedicine 2017; 21: 7-13
    CrossrefPubMedGoogle Scholar
  • 85 Passos JF, Saretzki G, Ahmed S. et al. Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence. PLoS Biol 2007; 5 (05) e110
    CrossrefPubMedGoogle Scholar
  • 86 Acosta JC, O'Loghlen A, Banito A. et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 2008; 133 (06) 1006-1018
    CrossrefPubMedGoogle Scholar
  • 87 Kuilman T, Peeper DS. Senescence-messaging secretome: SMS-ing cellular stress. Nat Rev Cancer 2009; 9 (02) 81-94
    CrossrefPubMedGoogle Scholar
  • 88 Hoare M, Ito Y, Kang TW. et al. NOTCH1 mediates a switch between two distinct secretomes during senescence. Nat Cell Biol 2016; 18 (09) 979-992
    CrossrefPubMedGoogle Scholar
  • 89 Basisty N, Kale A, Jeon OH. et al. A proteomic atlas of senescence-associated secretomes for aging biomarker development. PLoS Biol 2020; 18 (01) e3000599
    CrossrefPubMedGoogle Scholar
  • 90 Biran A, Perelmutter M, Gal H. et al. Senescent cells communicate via intercellular protein transfer. Genes Dev 2015; 29 (08) 791-802
    CrossrefPubMedGoogle Scholar
  • 91 Borghesan M, Fafián-Labora J, Eleftheriadou O. et al. Small extracellular vesicles are key regulators of non-cell autonomous intercellular communication in senescence via the interferon protein IFITM3. Cell Rep 2019; 27 (13) 3956.e6-3971.e6
    CrossrefPubMedGoogle Scholar
  • 92 Kang TW, Yevsa T, Woller N. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 2011; 479 (7374): 547-551
    Google Scholar
  • 93 Xue W, Zender L, Miething C. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 2007; 445 (7128): 656-660
    CrossrefPubMedGoogle Scholar
  • 94 Rakhra K, Bachireddy P, Zabuawala T. et al. CD4(+) T cells contribute to the remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation. Cancer Cell 2010; 18 (05) 485-498
    CrossrefPubMedGoogle Scholar
  • 95 Lunz III JG, Contrucci S, Ruppert K. et al. Replicative senescence of biliary epithelial cells precedes bile duct loss in chronic liver allograft rejection: increased expression of p21(WAF1/Cip1) as a disease marker and the influence of immunosuppressive drugs. Am J Pathol 2001; 158 (04) 1379-1390
    CrossrefPubMedGoogle Scholar
  • 96 Sasaki M, Ikeda H, Haga H, Manabe T, Nakanuma Y. Frequent cellular senescence in small bile ducts in primary biliary cirrhosis: a possible role in bile duct loss. J Pathol 2005; 205 (04) 451-459
    CrossrefPubMedGoogle Scholar
  • 97 Brain JG, Robertson H, Thompson E. et al. Biliary epithelial senescence and plasticity in acute cellular rejection. Am J Transplant 2013; 13 (07) 1688-1702
    CrossrefPubMedGoogle Scholar
  • 98 Demirci G, Nashan B, Pichlmayr R. Fibrosis in chronic rejection of human liver allografts: expression patterns of transforming growth factor-TGFbeta1 and TGF-beta3. Transplantation 1996; 62 (12) 1776-1783
    CrossrefPubMedGoogle Scholar
  • 99 Gutierrez-Reyes G, del Carmen Garcia de Leon M, Varela-Fascinetto G. et al. Cellular senescence in livers from children with end stage liver disease. PLoS One 2010; 5 (04) e10231
    CrossrefPubMedGoogle Scholar
  • 100 Sanada Y, Kawano Y, Miki A. et al. Maternal grafts protect daughter recipients from acute cellular rejection after pediatric living donor liver transplantation for biliary atresia. Transpl Int 2014; 27 (04) 383-390
    CrossrefPubMedGoogle Scholar
  • 101 Dyson JK, Beuers U, Jones DEJ, Lohse AW, Hudson M. Primary sclerosing cholangitis. Lancet 2018; 391 (10139): 2547-2559
    CrossrefPubMedGoogle Scholar
  • 102 Tabibian JH, O'Hara SP, Splinter PL, Trussoni CE, LaRusso NF. Cholangiocyte senescence by way of N-ras activation is a characteristic of primary sclerosing cholangitis. Hepatology 2014; 59 (06) 2263-2275
    Google Scholar
  • 103 Ferreira-Gonzalez S, Lu WY, Raven A. et al. Paracrine cellular senescence exacerbates biliary injury and impairs regeneration. Nat Commun 2018; 9 (01) 1020
    CrossrefPubMedGoogle Scholar
  • 104 Sasaki M, Ikeda H, Sato Y, Nakanuma Y. Decreased expression of Bmi1 is closely associated with cellular senescence in small bile ducts in primary biliary cirrhosis. Am J Pathol 2006; 169 (03) 831-845
    CrossrefPubMedGoogle Scholar
  • 105 Loarca L, De Assuncao TM, Jalan-Sakrikar N. et al. Development and characterization of cholangioids from normal and diseased human cholangiocytes as an in vitro model to study primary sclerosing cholangitis. Lab Invest 2017; 97 (11) 1385-1396
    CrossrefPubMedGoogle Scholar
  • 106 Moncsek A, Al-Suraih MS, Trussoni CE. et al. Targeting senescent cholangiocytes and activated fibroblasts with B-cell lymphoma-extra large inhibitors ameliorates fibrosis in multidrug resistance 2 gene knockout (Mdr2-/- ) mice. Hepatology 2018; 67 (01) 247-259
    CrossrefPubMedGoogle Scholar
  • 107 O'Hara SP, Splinter PL, Trussoni CE. et al. The transcription factor ETS1 promotes apoptosis resistance of senescent cholangiocytes by epigenetically up-regulating the apoptosis suppressor BCL2L1. J Biol Chem 2019; 294 (49) 18698-18713
    CrossrefPubMedGoogle Scholar
  • 108 Popov Y, Patsenker E, Fickert P, Trauner M, Schuppan D. Mdr2 (Abcb4)-/- mice spontaneously develop severe biliary fibrosis via massive dysregulation of pro- and antifibrogenic genes. J Hepatol 2005; 43 (06) 1045-1054
    CrossrefPubMedGoogle Scholar
  • 109 Lukivskaya O, Zavodnik L, Knas M, Buko V. Antioxidant mechanism of hepatoprotection by ursodeoxycholic acid in experimental alcoholic steatohepatitis. Adv Med Sci 2006; 51: 54-59
    PubMedGoogle Scholar
  • 110 Tabibian JH, O'Hara SP, Trussoni CE. et al. Absence of the intestinal microbiota exacerbates hepatobiliary disease in a murine model of primary sclerosing cholangitis. Hepatology 2016; 63 (01) 185-196
    CrossrefPubMedGoogle Scholar
  • 111 Zhou T, Wu N, Meng F. et al. Knockout of secretin receptor reduces biliary damage and liver fibrosis in Mdr2-/- mice by diminishing senescence of cholangiocytes. Lab Invest 2018; 98 (11) 1449-1464
    CrossrefPubMedGoogle Scholar
  • 112 Carey EJ, Ali AH, Lindor KD. Primary biliary cirrhosis. Lancet 2015; 386 (10003): 1565-1575
    CrossrefPubMedGoogle Scholar
  • 113 Harada K, Furubo S, Ozaki S, Hiramatsu K, Sudo Y, Nakanuma Y. Increased expression of WAF1 in intrahepatic bile ducts in primary biliary cirrhosis relates to apoptosis. J Hepatol 2001; 34 (04) 500-506
    CrossrefPubMedGoogle Scholar
  • 114 Sasaki M, Ikeda H, Yamaguchi J, Nakada S, Nakanuma Y. Telomere shortening in the damaged small bile ducts in primary biliary cirrhosis reflects ongoing cellular senescence. Hepatology 2008; 48 (01) 186-195
    Google Scholar
  • 115 Sasaki M, Miyakoshi M, Sato Y, Nakanuma Y. Modulation of the microenvironment by senescent biliary epithelial cells may be involved in the pathogenesis of primary biliary cirrhosis. J Hepatol 2010; 53 (02) 318-325
    CrossrefPubMedGoogle Scholar
  • 116 Sasaki M, Ikeda H, Yamaguchi J, Miyakoshi M, Sato Y, Nakanuma Y. Bile ductular cells undergoing cellular senescence increase in chronic liver diseases along with fibrous progression. Am J Clin Pathol 2010; 133 (02) 212-223
    CrossrefPubMedGoogle Scholar
  • 117 Sasaki M, Miyakoshi M, Sato Y, Nakanuma Y. Chemokine-chemokine receptor CCL2-CCR2 and CX3CL1-CX3CR1 axis may play a role in the aggravated inflammation in primary biliary cirrhosis. Dig Dis Sci 2014; 59 (02) 358-364
    CrossrefPubMedGoogle Scholar
  • 118 Sasaki M, Miyakoshi M, Sato Y, Nakanuma Y. Increased expression of mitochondrial proteins associated with autophagy in biliary epithelial lesions in primary biliary cirrhosis. Liver Int 2013; 33 (02) 312-320
    CrossrefPubMedGoogle Scholar
  • 119 Sasaki M, Kakuda Y, Miyakoshi M, Sato Y, Nakanuma Y. Infiltration of inflammatory cells expressing mitochondrial proteins around bile ducts and in biliary epithelial layer may be involved in the pathogenesis in primary biliary cirrhosis. J Clin Pathol 2014; 67 (06) 470-476
    CrossrefPubMedGoogle Scholar
  • 120 Young ARJ, Narita M, Ferreira M. et al. Autophagy mediates the mitotic senescence transition. Genes Dev 2009; 23 (07) 798-803
    CrossrefPubMedGoogle Scholar
  • 121 Sasaki M, Miyakoshi M, Sato Y, Nakanuma Y. A possible involvement of p62/sequestosome-1 in the process of biliary epithelial autophagy and senescence in primary biliary cirrhosis. Liver Int 2012; 32 (03) 487-499
    PubMedGoogle Scholar
  • 122 Sasaki M, Miyakoshi M, Sato Y, Nakanuma Y. Autophagy mediates the process of cellular senescence characterizing bile duct damages in primary biliary cirrhosis. Lab Invest 2010; 90 (06) 835-843
    CrossrefPubMedGoogle Scholar
  • 123 Davalli P, Mitic T, Caporali A, Lauriola A, D'Arca D. ROS, cell senescence, and novel molecular mechanisms in aging and age-related diseases. Oxid Med Cell Longev 2016; 2016: 3565127
    CrossrefPubMedGoogle Scholar
  • 124 Liguori I, Russo G, Curcio F. et al. Oxidative stress, aging, and diseases. Clin Interv Aging 2018; 13: 757-772
    CrossrefPubMedGoogle Scholar
  • 125 Strazzabosco M, Spirlí C, Okolicsanyi L. Pathophysiology of the intrahepatic biliary epithelium. J Gastroenterol Hepatol 2000; 15 (03) 244-253
    CrossrefPubMedGoogle Scholar
  • 126 Abe Y, Hines IN, Zibari G. et al. Mouse model of liver ischemia and reperfusion injury: method for studying reactive oxygen and nitrogen metabolites in vivo. Free Radic Biol Med 2009; 46 (01) 1-7
    CrossrefPubMedGoogle Scholar
  • 127 Hoare M, Das T, Alexander G. Ageing, telomeres, senescence, and liver injury. J Hepatol 2010; 53 (05) 950-961
    CrossrefPubMedGoogle Scholar
  • 128 Schmucker DL. Age-related changes in liver structure and function: Implications for disease?. Exp Gerontol 2005; 40 (8-9): 650-659
    CrossrefPubMedGoogle Scholar
  • 129 Wang MJ, Chen F, Li JX. et al. Reversal of hepatocyte senescence after continuous in vivo cell proliferation. Hepatology 2014; 60 (01) 349-361
    CrossrefPubMedGoogle Scholar
  • 130 Verma S, Tachtatzis P, Penrhyn-Lowe S. et al. Sustained telomere length in hepatocytes and cholangiocytes with increasing age in normal liver. Hepatology 2012; 56 (04) 1510-1520
    CrossrefPubMedGoogle Scholar
  • 131 Wang C, Chen WJ, Wu YF. et al. The extent of liver injury determines hepatocyte fate toward senescence or cancer. Cell Death Dis 2018; 9 (05) 575
    CrossrefPubMedGoogle Scholar
  • 132 Bird TG, Müller M, Boulter L. et al. TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence. Sci Transl Med 2018; 10 (454) eaan1230
    CrossrefPubMedGoogle Scholar
  • 133 Wiemann SU, Satyanarayana A, Tsahuridu M. et al. Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. FASEB J 2002; 16 (09) 935-942
    CrossrefPubMedGoogle Scholar
  • 134 Ikeda H, Sasaki M, Sato Y. et al. Large cell change of hepatocytes in chronic viral hepatitis represents a senescent-related lesion. Hum Pathol 2009; 40 (12) 1774-1782
    CrossrefPubMedGoogle Scholar
  • 135 Aravinthan A, Scarpini C, Tachtatzis P. et al. Hepatocyte senescence predicts progression in non-alcohol-related fatty liver disease. J Hepatol 2013; 58 (03) 549-556
    CrossrefPubMedGoogle Scholar
  • 136 Calado RT, Brudno J, Mehta P. et al. Constitutional telomerase mutations are genetic risk factors for cirrhosis. Hepatology 2011; 53 (05) 1600-1607
    CrossrefPubMedGoogle Scholar
  • 137 Hartmann D, Srivastava U, Thaler M. et al. Telomerase gene mutations are associated with cirrhosis formation. Hepatology 2011; 53 (05) 1608-1617
    CrossrefPubMedGoogle Scholar
  • 138 Rudolph KL, Chang S, Millard M, Schreiber-Agus N, DePinho RA. Inhibition of experimental liver cirrhosis in mice by telomerase gene delivery. Science 2000; 287 (5456): 1253-1258
    CrossrefPubMedGoogle Scholar
  • 139 Wiemann SU, Satyanarayana A, Buer J, Kamino K, Manns MP, Rudolph KL. Contrasting effects of telomere shortening on organ homeostasis, tumor suppression, and survival during chronic liver damage. Oncogene 2005; 24 (09) 1501-1509
    CrossrefPubMedGoogle Scholar
  • 140 Yosef R, Pilpel N, Papismadov N. et al. p21 maintains senescent cell viability under persistent DNA damage response by restraining JNK and caspase signaling. EMBO J 2017; 36 (15) 2280-2295
    CrossrefPubMedGoogle Scholar
  • 141 Marshall A, Rushbrook S, Davies SE. et al. Relation between hepatocyte G1 arrest, impaired hepatic regeneration, and fibrosis in chronic hepatitis C virus infection. Gastroenterology 2005; 128 (01) 33-42
    CrossrefPubMedGoogle Scholar
  • 142 Sekoguchi S, Nakajima T, Moriguchi M. et al. Role of cell-cycle turnover and oxidative stress in telomere shortening and cellular senescence in patients with chronic hepatitis C. J Gastroenterol Hepatol 2007; 22 (02) 182-190
    CrossrefPubMedGoogle Scholar
  • 143 Tachtatzis PM, Marshall A, Arvinthan A. et al. Chronic hepatitis B virus infection: the relation between hepatitis B antigen expression, telomere length, senescence, inflammation and fibrosis. PLoS One 2015; 10 (05) e0127511
    CrossrefPubMedGoogle Scholar
  • 144 Wan Y, McDaniel K, Wu N. et al. Regulation of cellular senescence by miR-34a in alcoholic liver injury. Am J Pathol 2017; 187 (12) 2788-2798
    CrossrefPubMedGoogle Scholar
  • 145 Meng F, Ramos-Lorenzo S, Francis H. et al. Characterization of cellular senescence mechanisms in alcoholic liver injury. FASEB J 2017;31(Suppl 1):804.3
    Google Scholar
  • 146 Aravinthan AD, Alexander GJM. Senescence in chronic liver disease: Is the future in aging?. J Hepatol 2016; 65 (04) 825-834
    CrossrefPubMedGoogle Scholar
  • 147 Papatheodoridi AM, Chrysavgis L, Koutsilieris M, Chatzigeorgiou A. The role of senescence in the development of nonalcoholic fatty liver disease and progression to nonalcoholic steatohepatitis. Hepatology 2020; 71 (01) 363-374
    CrossrefPubMedGoogle Scholar
  • 148 Wood MJ, Gadd VL, Powell LW, Ramm GA, Clouston AD. Ductular reaction in hereditary hemochromatosis: the link between hepatocyte senescence and fibrosis progression. Hepatology 2014; 59 (03) 848-857
    Google Scholar
  • 149 Wandrer F, Han B, Liebig S. et al. Senescence mirrors the extent of liver fibrosis in chronic hepatitis C virus infection. Aliment Pharmacol Ther 2018; 48 (03) 270-280
    CrossrefPubMedGoogle Scholar
  • 150 Aravinthan A, Pietrosi G, Hoare M. et al. Hepatocyte expression of the senescence marker p21 is linked to fibrosis and an adverse liver-related outcome in alcohol-related liver disease. PLoS One 2013; 8 (09) e72904
    CrossrefPubMedGoogle Scholar
  • 151 Tomita K, Teratani T, Suzuki T. et al. p53/p66Shc-mediated signaling contributes to the progression of non-alcoholic steatohepatitis in humans and mice. J Hepatol 2012; 57 (04) 837-843
    CrossrefPubMedGoogle Scholar
  • 152 Zhang X, Zhou D, Strakovsky R, Zhang Y, Pan YX. Hepatic cellular senescence pathway genes are induced through histone modifications in a diet-induced obese rat model. Am J Physiol Gastrointest Liver Physiol 2012; 302 (05) G558-G564
    CrossrefPubMedGoogle Scholar
  • 153 Richardson MM, Jonsson JR, Powell EE. et al. Progressive fibrosis in nonalcoholic steatohepatitis: association with altered regeneration and a ductular reaction. Gastroenterology 2007; 133 (01) 80-90
    CrossrefPubMedGoogle Scholar
  • 154 Laish I, Mannasse-Green B, Hadary R. et al. Telomere dysfunction in nonalcoholic fatty liver disease and cryptogenic cirrhosis. Cytogenet Genome Res 2016; 150 (02) 93-99
    CrossrefPubMedGoogle Scholar
  • 155 Ping F, Li ZY, Lv K. et al. Deoxyribonucleic acid telomere length shortening can predict the incidence of non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus. J Diabetes Investig 2017; 8 (02) 174-180
    CrossrefPubMedGoogle Scholar
  • 156 Nguyen P, Valanejad L, Cast A. et al. Elimination of age-associated hepatic steatosis and correction of aging phenotype by inhibition of cdk4-C/EBPα-p300 axis. Cell Rep 2018; 24 (06) 1597-1609
    CrossrefPubMedGoogle Scholar
  • 157 Aravinthan A, Mells G, Allison M. et al. Gene polymorphisms of cellular senescence marker p21 and disease progression in non-alcohol-related fatty liver disease. Cell Cycle 2014; 13 (09) 1489-1494
    CrossrefPubMedGoogle Scholar
  • 158 Karaman H, Karaman A, Donmez-Altuntas H. et al. Investigation of genome instability in patients with non-alcoholic steatohepatitis. World J Gastroenterol 2013; 19 (32) 5295-5301
    CrossrefPubMedGoogle Scholar
  • 159 Nishida N, Yada N, Hagiwara S, Sakurai T, Kitano M, Kudo M. Unique features associated with hepatic oxidative DNA damage and DNA methylation in non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2016; 31 (09) 1646-1653
    CrossrefPubMedGoogle Scholar
  • 160 Hardy T, Zeybel M, Day CP. et al. Plasma DNA methylation: a potential biomarker for stratification of liver fibrosis in non-alcoholic fatty liver disease. Gut 2017; 66 (07) 1321-1328
    CrossrefPubMedGoogle Scholar
  • 161 Hotta K, Kitamoto A, Kitamoto T. et al. Identification of differentially methylated region (DMR) networks associated with progression of nonalcoholic fatty liver disease. Sci Rep 2018; 8 (01) 13567
    CrossrefPubMedGoogle Scholar
  • 162 Nano J, Ghanbari M, Wang W. et al; BIOS consortium. Epigenome-wide association study identifies methylation sites associated with liver enzymes and hepatic steatosis. Gastroenterology 2017; 153 (04) 1096-1106.e2
    CrossrefPubMedGoogle Scholar
  • 163 Murphy SK, Yang H, Moylan CA. et al. Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease. Gastroenterology 2013; 145 (05) 1076-1087
    CrossrefPubMedGoogle Scholar
  • 164 Nakajima T, Nakashima T, Okada Y. et al. Nuclear size measurement is a simple method for the assessment of hepatocellular aging in non-alcoholic fatty liver disease: comparison with telomere-specific quantitative FISH and p21 immunohistochemistry. Pathol Int 2010; 60 (03) 175-183
    CrossrefPubMedGoogle Scholar
  • 165 Arun P, Aleti V, Parikh K, Manne V, Chilukuri N. Senescence marker protein 30 (SMP30) expression in eukaryotic cells: existence of multiple species and membrane localization. PLoS One 2011; 6 (02) e16545
    CrossrefPubMedGoogle Scholar
  • 166 Park H, Ishigami A, Shima T. et al. Hepatic senescence marker protein-30 is involved in the progression of nonalcoholic fatty liver disease. J Gastroenterol 2010; 45 (04) 426-434
    CrossrefPubMedGoogle Scholar
  • 167 Ishigami A, Fujita T, Handa S. et al. Senescence marker protein-30 knockout mouse liver is highly susceptible to tumor necrosis factor-alpha- and Fas-mediated apoptosis. Am J Pathol 2002; 161 (04) 1273-1281
    CrossrefPubMedGoogle Scholar
  • 168 Kondo Y, Hasegawa G, Okada H. et al. Lepr(db/db) Mice with senescence marker protein-30 knockout (Lepr(db/db)Smp30(Y/-)) exhibit increases in small dense-LDL and severe fatty liver despite being fed a standard diet. PLoS One 2013; 8 (06) e65698
    CrossrefPubMedGoogle Scholar
  • 169 Kondo Y, Masutomi H, Noda Y. et al. Senescence marker protein-30/superoxide dismutase 1 double knockout mice exhibit increased oxidative stress and hepatic steatosis. FEBS Open Bio 2014; 4: 522-532
    CrossrefPubMedGoogle Scholar
  • 170 Barnhoorn S, Uittenboogaard LM, Jaarsma D. et al. Cell-autonomous progeroid changes in conditional mouse models for repair endonuclease XPG deficiency. PLoS Genet 2014; 10 (10) e1004686
    CrossrefPubMedGoogle Scholar
  • 171 Trak-Smayra V, Paradis V, Massart J, Nasser S, Jebara V, Fromenty B. Pathology of the liver in obese and diabetic ob/ob and db/db mice fed a standard or high-calorie diet. Int J Exp Pathol 2011; 92 (06) 413-421
    CrossrefPubMedGoogle Scholar
  • 172 Poli G. Pathogenesis of liver fibrosis: role of oxidative stress. Mol Aspects Med 2000; 21 (03) 49-98
    CrossrefPubMedGoogle Scholar
  • 173 Lohr K, Pachl F, Moghaddas Gholami A. et al. Reduced mitochondrial mass and function add to age-related susceptibility toward diet-induced fatty liver in C57BL/6J mice. Physiol Rep 2016; 4 (19) e12988
    CrossrefPubMedGoogle Scholar
  • 174 Kumar A, Sharma A, Duseja A. et al. Patients with nonalcoholic fatty liver disease (NAFLD) have higher oxidative stress in comparison to chronic viral hepatitis. J Clin Exp Hepatol 2013; 3 (01) 12-18
    CrossrefPubMedGoogle Scholar
  • 175 Okuda M, Li K, Beard MR. et al. Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein. Gastroenterology 2002; 122 (02) 366-375
    CrossrefPubMedGoogle Scholar
  • 176 Satyanarayana A, Greenberg RA, Schaetzlein S. et al. Mitogen stimulation cooperates with telomere shortening to activate DNA damage responses and senescence signaling. Mol Cell Biol 2004; 24 (12) 5459-5474
    CrossrefPubMedGoogle Scholar
  • 177 Kong X, Feng D, Wang H. et al. Interleukin-22 induces hepatic stellate cell senescence and restricts liver fibrosis in mice. Hepatology 2012; 56 (03) 1150-1159
    CrossrefPubMedGoogle Scholar
  • 178 Nishizawa H, Iguchi G, Fukuoka H. et al. IGF-I induces senescence of hepatic stellate cells and limits fibrosis in a p53-dependent manner. Sci Rep 2016; 6: 34605
    Google Scholar
  • 179 Jin H, Lian N, Zhang F. et al. Activation of PPARγ/P53 signaling is required for curcumin to induce hepatic stellate cell senescence. Cell Death Dis 2016; 7: e2189
    CrossrefPubMedGoogle Scholar
  • 180 Wan Y, Meng F, Wu N. et al. Substance P increases liver fibrosis by differential changes in senescence of cholangiocytes and hepatic stellate cells. Hepatology 2017; 66 (02) 528-541
    CrossrefPubMedGoogle Scholar
  • 181 Yoshimoto S, Loo TM, Atarashi K. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 2013; 499 (7456): 97-101
    CrossrefPubMedGoogle Scholar
  • 182 Hoare M, Gelson WTH, Das A. et al. CD4+ T-lymphocyte telomere length is related to fibrosis stage, clinical outcome and treatment response in chronic hepatitis C virus infection. J Hepatol 2010; 53 (02) 252-260
    CrossrefPubMedGoogle Scholar
  • 183 Barathan M, Mohamed R, Saeidi A. et al. Increased frequency of late-senescent T cells lacking CD127 in chronic hepatitis C disease. Eur J Clin Invest 2015; 45 (05) 466-474
    CrossrefPubMedGoogle Scholar
  • 184 Zhou Y, Li GY, Ren JP. et al. Protection of CD4+ T cells from hepatitis C virus infection-associated senescence via ΔNp63-miR-181a-Sirt1 pathway. J Leukoc Biol 2016; 100 (05) 1201-1211
    CrossrefPubMedGoogle Scholar
  • 185 Schirdewahn T, Grabowski J, Owusu Sekyere S. et al. The third signal cytokine interleukin 12 rather than immune checkpoint inhibitors contributes to the functional restoration of hepatitis D virus-specific T cells. J Infect Dis 2017; 215 (01) 139-149
    CrossrefPubMedGoogle Scholar
  • 186 Gelson W, Hoare M, Vowler S. et al. Features of immune senescence in liver transplant recipients with established grafts. Liver Transpl 2010; 16 (05) 577-587
    CrossrefPubMedGoogle Scholar
  • 187 Sagiv A, Burton DGA, Moshayev Z. et al. NKG2D ligands mediate immunosurveillance of senescent cells. Aging (Albany NY) 2016; 8 (02) 328-344
    CrossrefPubMedGoogle Scholar
  • 188 Ovadya Y, Krizhanovsky V. Senescent cells: SASPected drivers of age-related pathologies. Biogerontology 2014; 15 (06) 627-642
    CrossrefPubMedGoogle Scholar
  • 189 Kwon Y, Kim JW, Jeoung JA, Kim MS, Kang C. Autophagy is pro-senescence when seen in close-up, but anti-senescence in long-shot. Mol Cells 2017; 40 (09) 607-612
    PubMedGoogle Scholar
  • 190 Grosse L, Wagner N, Emelyanov A. et al. Defined p16High senescent cell types are indispensable for mouse healthspan. Cell Metab 2020; S1550–4131 (20) 30241-30242
    PubMedGoogle Scholar
  • 191 Maeso-Díaz R, Ortega-Ribera M, Fernández-Iglesias A. et al. Effects of aging on liver microcirculatory function and sinusoidal phenotype. Aging Cell 2018; 17 (06) e12829
    CrossrefPubMedGoogle Scholar
  • 192 Koudelkova P, Weber G, Mikulits W. Liver sinusoidal endothelial cells escape senescence by loss of p19ARF. PLoS One 2015; 10 (11) e0142134
    CrossrefPubMedGoogle Scholar
  • 193 Eggert T, Wolter K, Ji J. et al. Distinct functions of senescence-associated immune responses in liver tumor surveillance and tumor progression. Cancer Cell 2016; 30 (04) 533-547
    CrossrefPubMedGoogle Scholar
  • 194 Yang D, Li L, Liu H. et al. Induction of autophagy and senescence by knockdown of ROC1 E3 ubiquitin ligase to suppress the growth of liver cancer cells. Cell Death Differ 2013; 20 (02) 235-247
    CrossrefPubMedGoogle Scholar
  • 195 Zhu R, Mok MT, Kang W. et al. Truncated HBx-dependent silencing of GAS2 promotes hepatocarcinogenesis through deregulation of cell cycle, senescence and p53-mediated apoptosis. J Pathol 2015; 237 (01) 38-49
    CrossrefPubMedGoogle Scholar
  • 196 Sasaki M, Nakanuma Y. New concept: cellular senescence in pathophysiology of cholangiocarcinoma. Expert Rev Gastroenterol Hepatol 2016; 10 (05) 625-638
    CrossrefPubMedGoogle Scholar
  • 197 Plentz RR, Park YN, Lechel A. et al. Telomere shortening and inactivation of cell cycle checkpoints characterize human hepatocarcinogenesis. Hepatology 2007; 45 (04) 968-976
    CrossrefPubMedGoogle Scholar
  • 198 MacDonald RA. “Lifespan” of liver cells. Autoradio-graphic study using tritiated thymidine in normal, cirrhotic, and partially hepatectomized rats. Arch Intern Med 1961; 107: 335-343
    CrossrefPubMedGoogle Scholar
  • 199 Michalopoulos GK, DeFrances MC. Liver regeneration. Science 1997; 276 (5309): 60-66
    CrossrefPubMedGoogle Scholar
  • 200 Ritschka B, Knauer-Meyer T, Gonçalves DS. et al. The senotherapeutic drug ABT-737 disrupts aberrant p21 expression to restore liver regeneration in adult mice. Genes Dev 2020; 34 (7-8): 489-494
    CrossrefPubMedGoogle Scholar
  • 201 Sanz N, Díez-Fernández C, Alvarez AM, Fernández-Simón L, Cascales M. Age-related changes on parameters of experimentally-induced liver injury and regeneration. Toxicol Appl Pharmacol 1999; 154 (01) 40-49
    CrossrefPubMedGoogle Scholar
  • 202 Tsukamoto I, Nakata R, Kojo S. Effect of ageing on rat liver regeneration after partial hepatectomy. Biochem Mol Biol Int 1993; 30 (04) 773-778
    PubMedGoogle Scholar
  • 203 Fry M, Silber J, Loeb LA, Martin GM. Delayed and reduced cell replication and diminishing levels of DNA polymerase-alpha in regenerating liver of aging mice. J Cell Physiol 1984; 118 (03) 225-232
    CrossrefPubMedGoogle Scholar
  • 204 Albrecht JH, Meyer AH, Hu MY. Regulation of cyclin-dependent kinase inhibitor p21(WAF1/Cip1/Sdi1) gene expression in hepatic regeneration. Hepatology 1997; 25 (03) 557-563
    CrossrefPubMedGoogle Scholar
  • 205 Albrecht JH, Poon RY, Ahonen CL, Rieland BM, Deng C, Crary GS. Involvement of p21 and p27 in the regulation of CDK activity and cell cycle progression in the regenerating liver. Oncogene 1998; 16 (16) 2141-2150
    CrossrefPubMedGoogle Scholar
  • 206 Pujol MJ, Jaime M, Serratosa J, Jaumot M, Agell N, Bachs O. Differential association of p21Cip1 and p27Kip1 with cyclin E-CDK2 during rat liver regeneration. J Hepatol 2000; 33 (02) 266-274
    CrossrefPubMedGoogle Scholar
  • 207 Jaime M, Pujol MJ, Serratosa J. et al. The p21(Cip1) protein, a cyclin inhibitor, regulates the levels and the intracellular localization of CDC25A in mice regenerating livers. Hepatology 2002; 35 (05) 1063-1071
    CrossrefPubMedGoogle Scholar
  • 208 Lu WY, Bird TG, Boulter L. et al. Hepatic progenitor cells of biliary origin with liver repopulation capacity. Nat Cell Biol 2015; 17 (08) 971-983
    CrossrefPubMedGoogle Scholar
  • 209 Raven A, Lu WY, Man TY. et al. Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration. Nature 2017; 547 (7663): 350-354
    Google Scholar
  • 210 Jin H, Lian N, Zhang F. et al. Inhibition of YAP signaling contributes to senescence of hepatic stellate cells induced by tetramethylpyrazine. Eur J Pharm Sci 2017; 96: 323-333
    CrossrefPubMedGoogle Scholar
  • 211 Panebianco C, Oben JA, Vinciguerra M, Pazienza V. Senescence in hepatic stellate cells as a mechanism of liver fibrosis reversal: a putative synergy between retinoic acid and PPAR-gamma signalings. Clin Exp Med 2017; 17 (03) 269-280
    CrossrefPubMedGoogle Scholar
  • 212 Zhang Z, Yao Z, Zhao S. et al. Interaction between autophagy and senescence is required for dihydroartemisinin to alleviate liver fibrosis. Cell Death Dis 2017; 8 (06) e2886
    CrossrefPubMedGoogle Scholar
  • 213 Wang C, Vegna S, Jin H. et al. Inducing and exploiting vulnerabilities for the treatment of liver cancer. Nature 2019; 574 (7777): 268-272
    CrossrefPubMedGoogle Scholar
  • 214 Ovadya Y, Krizhanovsky V. Strategies targeting cellular senescence. J Clin Invest 2018; 128 (04) 1247-1254
    CrossrefPubMedGoogle Scholar
  • 215 Fontana L, Nehme J, Demaria M. Caloric restriction and cellular senescence. Mech Ageing Dev 2018; 176: 19-23
    CrossrefPubMedGoogle Scholar
  • 216 Munoz-Espin D. Nanocarriers targeting senescent cells. Transl Med Aging. 2019; 3: 1-5
    CrossrefPubMedGoogle Scholar
  • 217 Sidler C, Kovalchuk O, Kovalchuk I. Epigenetic regulation of cellular senescence and aging. Front Genet 2017; 8: 138
    CrossrefPubMedGoogle Scholar
  • 218 Yang N, Sen P. The senescent cell epigenome. Aging (Albany NY) 2018; 10 (11) 3590-3609
    CrossrefPubMedGoogle Scholar
  • 219 Horvath S, Erhart W, Brosch M. et al. Obesity accelerates epigenetic aging of human liver. Proc Natl Acad Sci U S A 2014; 111 (43) 15538-15543
    CrossrefPubMedGoogle Scholar
  • 220 Prattichizzo F, Bonafè M, Olivieri F, Franceschi C. Senescence associated macrophages and “macroph-aging”: are they pieces of the same puzzle?. Aging (Albany NY) 2016; 8 (12) 3159-3160
    CrossrefPubMedGoogle Scholar
  • 221 Goto M. Inflammaging (inflammation + aging): a driving force for human aging based on an evolutionarily antagonistic pleiotropy theory?. Biosci Trends 2008; 2 (06) 218-230
    PubMedGoogle Scholar
  • 222 Baylis D, Bartlett DB, Patel HP, Roberts HC. Understanding how we age: insights into inflammaging. Longev Healthspan 2013; 2 (01) 8
    CrossrefPubMedGoogle Scholar