Aging and metabolic dysfunction-associated steatotic liver disease: a bidirectional relationship

Chen Chen , Lin Wang

Front. Med. ›› 2025, Vol. 19 ›› Issue (3) : 427 -438.

PDF (1547KB)
Front. Med. ›› 2025, Vol. 19 ›› Issue (3) : 427 -438. DOI: 10.1007/s11684-025-1133-7
REVIEW

Aging and metabolic dysfunction-associated steatotic liver disease: a bidirectional relationship

Author information +
History +
PDF (1547KB)

Abstract

In recent years, aging and cellular senescence have triggered an increased interest in corresponding research fields. Evidence shows that the complex aging process is involved in the development of many chronic liver diseases, such as metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). In fact, aging has a tremendous effect on the liver, leading to a gradual decline in the metabolism, detoxification and immune functions of the liver, which in turn increases the risk of liver disease. These changes can be based on the aging of liver cells (hepatocytes, liver sinusoidal endothelial cells, hepatic stellate cells, and Kupffer cells). Similarly, patients with liver diseases exhibit increases in the aging phenotype and aging cells, often manifesting as faster physical functional decline, which is closely related to the promoting effect of liver disease on aging. This review summarizes the interplay between MASLD/MASH development and aging, aiming to reveal the complex relationships that exacerbate one another. Moreover, the corresponding schemes for delaying aging or treating diseases are discussed to provide a basis for the development of effective prevention and treatment strategies in the future.

Keywords

cell senescence / aging / metabolic dysfunction-associated steatotic liver disease / metabolic dysfunction-associated steatohepatitis

Cite this article

Download citation ▾
Chen Chen, Lin Wang. Aging and metabolic dysfunction-associated steatotic liver disease: a bidirectional relationship. Front. Med., 2025, 19(3): 427-438 DOI:10.1007/s11684-025-1133-7

登录浏览全文

4963

注册一个新账户 忘记密码

References

[1]

Wong VW, Ekstedt M, Wong GL, Hagstrom H. Changing epidemiology, global trends and implications for outcomes of NAFLD. J Hepatol 2023; 79(3): 842–852

[2]

Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med 2018; 24(7): 908–922

[3]

GBD 2017 Cirrhosis Collaborators. The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol 2020; 5(3): 245–266

[4]

Rui L. Energy metabolism in the liver. Compr Physiol 2014; 4(1): 177–197

[5]

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. Cellular senescence drives age-dependent hepatic steatosis. Nat Commun 2017; 8(1): 15691

[6]

Campisi J, d’Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 2007; 8(9): 729–740

[7]

Collado M, Blasco MA, Serrano M. Cellular senescence in cancer and aging. Cell 2007; 130(2): 223–233

[8]

Wynne HA, Cope LH, Mutch E, Rawlins MD, Woodhouse KW, James OF. The effect of age upon liver volume and apparent liver blood flow in healthy man. Hepatology 1989; 9(2): 297–301

[9]

Ghosh PM, Shu ZJ, Zhu B, Lu Z, Ikeno Y, Barnes JL, Yeh CK, Zhang BX, Katz MS, Kamat A. Role of β-adrenergic receptors in regulation of hepatic fat accumulation during aging. J Endocrinol 2012; 213(3): 251–261

[10]

Frith J, Jones D, Newton JL. Chronic liver disease in an ageing population. Age Ageing 2009; 38(1): 11–18

[11]

Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, DiPietro L, Cline GW, Shulman GI. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 2003; 300(5622): 1140–1142

[12]

Gabriely I, Ma XH, Yang XM, Rossetti L, Barzilai N. Leptin resistance during aging is independent of fat mass. Diabetes 2002; 51(4): 1016–1021

[13]

Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science 2011; 332(6037): 1519–1523

[14]

Kwok R, Choi KC, Wong GL, Zhang Y, Chan HL, Luk AO, Shu SS, Chan AW, Yeung MW, Chan JC, Kong AP, Wong VW. Screening diabetic patients for non-alcoholic fatty liver disease with controlled attenuation parameter and liver stiffness measurements: a prospective cohort study. Gut 2016; 65(8): 1359–1368

[15]

Ballestri S, Zona S, Targher G, Romagnoli D, Baldelli E, Nascimbeni F, Roverato A, Guaraldi G, Lonardo A. Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis. J Gastroenterol Hepatol 2016; 31(5): 936–944

[16]

Cikes D, Leutner M, Cronin SJF, Novatchkova M, Pfleger L, Klepochová R, Lair B, Lac M, Bergoglio C, Viguerie N, Dürnberger G, Roitinger E, Grivej M, Rullman E, Gustafsson T, Hagelkruys A, Tavernier G, Bourlier V, Knauf C, Krebs M, Kautzky-Willer A, Moro C, Krssak M, Orthofer M, Penninger JM. Gpcpd1-GPC metabolic pathway is dysfunctional in aging and its deficiency severely perturbs glucose metabolism. Nat Aging 2024; 4(1): 80–94

[17]

Chia CW, Egan JM, Ferrucci L. Age-related changes in glucose metabolism, hyperglycemia, and cardiovascular risk. Circ Res 2018; 123(7): 886–904

[18]

Seo E, Kang H, Choi H, Choi W, Jun HS. Reactive oxygen species-induced changes in glucose and lipid metabolism contribute to the accumulation of cholesterol in the liver during aging. Aging Cell 2019; 18(2): e12895

[19]

Bugianesi E, McCullough AJ, Marchesini G. Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology 2005; 42(5): 987–1000

[20]

Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, Luketic VA, Shiffman ML, Clore JN. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 2001; 120(5): 1183–1192

[21]

Baboota RK, Rawshani A, Bonnet L, Li X, Yang H, Mardinoglu A, Tchkonia T, Kirkland JL, Hoffmann A, Dietrich A, Boucher J, Blüher M, Smith U. BMP4 and Gremlin 1 regulate hepatic cell senescence during clinical progression of NAFLD/NASH. Nat Metab 2022; 4(8): 1007–1021

[22]

Minamino T, Orimo M, Shimizu I, Kunieda T, Yokoyama M, Ito T, Nojima A, Nabetani A, Oike Y, Matsubara H, Ishikawa F, Komuro I. A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat Med 2009; 15(9): 1082–1087

[23]

Lomonaco R, Ortiz-Lopez C, Orsak B, Webb A, Hardies J, Darland C, Finch J, Gastaldelli A, Harrison S, Tio F, Cusi K. Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with nonalcoholic fatty liver disease. Hepatology 2012; 55(5): 1389–1397

[24]

Imajo K, Fujita K, Yoneda M, Nozaki Y, Ogawa Y, Shinohara Y, Kato S, Mawatari H, Shibata W, Kitani H, Ikejima K, Kirikoshi H, Nakajima N, Saito S, Maeyama S, Watanabe S, Wada K, Nakajima A. Hyperresponsivity to low-dose endotoxin during progression to nonalcoholic steatohepatitis is regulated by leptin-mediated signaling. Cell Metab 2012; 16(1): 44–54

[25]

Lindström P. The physiology of obese-hyperglycemic mice. Scientific World Journal 2007; 7: 666–685

[26]

Schmucker DL. Age-related changes in liver structure and function: implications for disease. Exp Gerontol 2005; 40(8–9): 650–659

[27]

Koehler EM, Schouten JN, Hansen BE, van Rooij FJ, Hofman A, Stricker BH, Janssen HL. Prevalence and risk factors of non-alcoholic fatty liver disease in the elderly: results from the Rotterdam study. J Hepatol 2012; 57(6): 1305–1311

[28]

Gagliano N, Grizzi F, Annoni G. Mechanisms of aging and liver functions. Dig Dis 2007; 25(2): 118–123

[29]

Dhiman RK, Jain S, Maheshwari U, Bhalla A, Sharma N, Ahluwalia J, Duseja A, Chawla Y. Early indicators of prognosis in fulminant hepatic failure: an assessment of the Model for End-Stage Liver Disease (MELD) and King’s College Hospital criteria. Liver Transpl 2007; 13(6): 814–821

[30]

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

[31]

Bird TG, Müller M, Boulter L, Vincent DF, Ridgway RA, Lopez-Guadamillas E, Lu WY, Jamieson T, Govaere O, Campbell AD, Ferreira-Gonzalez S, Cole AM, Hay T, Simpson KJ, Clark W, Hedley A, Clarke M, Gentaz P, Nixon C, Bryce S, Kiourtis C, Sprangers J, Nibbs RJB, Van Rooijen N, Bartholin L, McGreal SR, Apte U, Barry ST, Iredale JP, Clarke AR, Serrano M, Roskams TA, Sansom OJ, Forbes SJ. TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence. Sci Transl Med 2018; 10(454): eaan1230

[32]

Krupczak-Hollis K, Wang X, Dennewitz MB, Costa RH. Growth hormone stimulates proliferation of old-aged regenerating liver through forkhead box m1b. Hepatology 2003; 38(6): 1552–1562

[33]

Timchenko NA. Aging and liver regeneration. Trends Endocrinol Metab 2009; 20(4): 171–176

[34]

Iakova P, Awad SS, Timchenko NA. Aging reduces proliferative capacities of liver by switching pathways of C/EBPα growth arrest. Cell 2003; 113(4): 495–506

[35]

Conboy IM, Conboy MJ, Wagers AJ, Girma ER, Weissman IL, Rando TA. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 2005; 433(7027): 760–764

[36]

Bertolotti M. Nonalcoholic fatty liver disease and aging: epidemiology to management. World J Gastroenterol 2014; 20(39): 14185

[37]

Noureddin M, Yates KP, Vaughn IA, Neuschwander-Tetri BA, Sanyal AJ, McCullough A, Merriman R, Hameed B, Doo E, Kleiner DE, Behling C, Loomba R, Nash CRN. Clinical and histological determinants of nonalcoholic steatohepatitis and advanced fibrosis in elderly patients. Hepatology 2013; 58(5): 1644–1654

[38]

Angulo P, Keach JC, Batts KP, Lindor KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999; 30(6): 1356–1362

[39]

Ratziu V, Giral P, Charlotte F, Bruckert E, Thibault V, Theodorou I, Khalil L, Turpin G, Opolon P, Poynard T. Liver fibrosis in overweight patients. Gastroenterology 2000; 118(6): 1117–1123

[40]

Wan J, Wu X, Chen H, Xia X, Song X, Chen S, Lu X, Jin J, Su Q, Cai D, Liu B, Li B. Aging-induced aberrant RAGE/PPARα axis promotes hepatic steatosis via dysfunctional mitochondrial beta oxidation. Aging Cell 2020; 19(10): e13238

[41]

Duan JL, Liu JJ, Ruan B, Ding J, Fang ZQ, Xu H, Song P, Xu C, Li ZW, Du W, Xu M, Ling YW, He F, Wang L. Age-related liver endothelial zonation triggers steatohepatitis by inactivating pericentral endothelium-derived C-kit. Nat Aging 2023; 3(3): 258–274

[42]

Tchkonia T, Morbeck DE, Von Zglinicki T, Van Deursen J, Lustgarten J, Scrable H, Khosla S, Jensen MD, Kirkland JL. Fat tissue, aging, and cellular senescence. Aging Cell 2010; 9(5): 667–684

[43]

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(5): G558–G564

[44]

Aravinthan A, Scarpini C, Tachtatzis P, Verma S, Penrhyn-Lowe S, Harvey R, Davies SE, Allison M, Coleman N, Alexander G. Hepatocyte senescence predicts progression in non-alcohol-related fatty liver disease. J Hepatol 2013; 58(3): 549–556

[45]

Aravinthan A, Challis B, Shannon N, Hoare M, Heaney J, Alexander GJM. Selective insulin resistance in hepatocyte senescence. Exp Cell Res 2015; 331(1): 38–45

[46]

Richardson MM, Jonsson JR, Powell EE, Brunt EM, Neuschwander-Tetri BA, Bhathal PS, Dixon JB, Weltman MD, Tilg H, Moschen AR, Purdie DM, Demetris AJ, Clouston AD. Progressive fibrosis in nonalcoholic steatohepatitis: association with altered regeneration and a ductular reaction. Gastroenterology 2007; 133(1): 80–90

[47]

Yang S, Koteish A, Lin H, Huang J, Roskams T, Dawson V, Diehl AM. Oval cells compensate for damage and replicative senescence of mature hepatocytes in mice with fatty liver disease. Hepatology 2004; 39(2): 403–411

[48]

Aravinthan A, Pietrosi G, Hoare M, Jupp J, Marshall A, Verrill C, Davies S, Bateman A, Sheron N, Allison M, Alexander GJ. 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(9): e72904

[49]

Liu P, Tang Q, Chen M, Chen W, Lu Y, Liu Z, He Z. Hepatocellular senescence: immunosurveillance and future senescence-induced therapy in hepatocellular carcinoma. Front Oncol 2020; 10: 589908

[50]

Hoare M, Das T, Alexander G. Ageing, telomeres, senescence, and liver injury. J Hepatol 2010; 53(5): 950–961

[51]

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(6): 557–560

[52]

Nakajima T, Nakashima T, Okada Y, Jo M, Nishikawa T, Mitsumoto Y, Katagishi T, Kimura H, Itoh Y, Kagawa K, Yoshikawa T. 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(3): 175–183

[53]

Yin K, Büttner M, Deligiannis IK, Strzelecki M, Zhang L, Talavera-López C, Theis F, Odom DT, Martinez-Jimenez CP. Polyploidisation pleiotropically buffers ageing in hepatocytes. J Hepatol 2024; 81(2): 289–302

[54]

Schmucker DL, Mooney JS, Jones AL. Stereological analysis of hepatic fine structure in the Fischer 344 rat. Influence of sublobular location and animal age. J Cell Biol 1978; 78(2): 319–337

[55]

Gasek NS, Kuchel GA, Kirkland JL, Xu M. Strategies for targeting senescent cells in human disease. Nat Aging 2021; 1(10): 870–879

[56]

Hoare M, Narita M. Transmitting senescence to the cell neighbourhood. Nat Cell Biol 2013; 15(8): 887–889

[57]

Kuilman T, Michaloglou C, Vredeveld LC, Douma S, van Doorn R, Desmet CJ, Aarden LA, Mooi WJ, Peeper DS. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 2008; 133(6): 1019–1031

[58]

Coppé JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol 2010; 5(1): 99–118

[59]

Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol 2013; 75(1): 685–705

[60]

Zhang X, Fan L, Wu J, Xu H, Leung WY, Fu K, Wu J, Liu K, Man K, Yang X, Han J, Ren J, Yu J. Macrophage p38α promotes nutritional steatohepatitis through M1 polarization. J Hepatol 2019; 71(1): 163–174

[61]

Park J, Zhao Y, Zhang F, Zhang S, Kwong AC, Zhang Y, Hoffmann HH, Bushweller L, Wu X, Ashbrook AW, Stefanovic B, Chen S, Branch AD, Mason CE, Jung JU, Rice CM, Wu X. IL-6/STAT3 axis dictates the PNPLA3-mediated susceptibility to non-alcoholic fatty liver disease. J Hepatol 2023; 78(1): 45–56

[62]

Hou X, Yin S, Ren R, Liu S, Yong L, Liu Y, Li Y, Zheng MH, Kunos G, Gao B, Wang H. Myeloid-cell-specific IL-6 signaling promotes microRNA-223-enriched exosome production to attenuate NAFLD-associated fibrosis. Hepatology 2021; 74(1): 116–132

[63]

Loo TM, Kamachi F, Watanabe Y, Yoshimoto S, Kanda H, Arai Y, Nakajima-Takagi Y, Iwama A, Koga T, Sugimoto Y, Ozawa T, Nakamura M, Kumagai M, Watashi K, Taketo MM, Aoki T, Narumiya S, Oshima M, Arita M, Hara E, Ohtani N. Gut microbiota promotes obesity-associated liver cancer through PGE2-mediated suppression of antitumor immunity. Cancer Discov 2017; 7(5): 522–538

[64]

Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, Iwakura Y, Oshima K, Morita H, Hattori M, Honda K, Ishikawa Y, Hara E, Ohtani N. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 2013; 499(7456): 97–101

[65]

Grosse L, Wagner N, Emelyanov A, Molina C, Lacas-Gervais S, Wagner KD, Bulavin DV. Defined p16High senescent cell types are indispensable for mouse healthspan. Cell Metab 2020; 32(1): 87–99.e6

[66]

Omori S, Wang TW, Johmura Y, Kanai T, Nakano Y, Kido T, Susaki EA, Nakajima T, Shichino S, Ueha S, Ozawa M, Yokote K, Kumamoto S, Nishiyama A, Sakamoto T, Yamaguchi K, Hatakeyama S, Shimizu E, Katayama K, Yamada Y, Yamazaki S, Iwasaki K, Miyoshi C, Funato H, Yanagisawa M, Ueno H, Imoto S, Furukawa Y, Yoshida N, Matsushima K, Ueda HR, Miyajima A, Nakanishi M. Generation of a p16 reporter mouse and its use to characterize and target p16high cells in vivo. Cell Metab 2020; 32(5): 814–28.e6

[67]

Le Couteur DG, Fraser R, Cogger VC, McLean AJ. Hepatic pseudocapillarisation and atherosclerosis in ageing. Lancet 2002; 359(9317): 1612–1615

[68]

Le Couteur DG, Cogger VC, Markus AM, Harvey PJ, Yin ZL, Ansselin AD, McLean AJ. Pseudocapillarization and associated energy limitation in the aged rat liver. Hepatology 2001; 33(3): 537–543

[69]

Maeso-Díaz R, Ortega-Ribera M, Fernández-Iglesias A, Hide D, Muñoz L, Hessheimer AJ, Vila S, Francés R, Fondevila C, Albillos A, Peralta C, Bosch J, Tacke F, Cogger VC, Gracia-Sancho J. Effects of aging on liver microcirculatory function and sinusoidal phenotype. Aging Cell 2018; 17(6): e12829

[70]

McLean AJ, Cogger VC, Chong GC, Warren A, Markus AM, Dahlstrom JE, Le Couteur DG. Age-related pseudocapillarization of the human liver. J Pathol 2003; 200(1): 112–117

[71]

Cogger VC, Svistounov D, Warren A, Zykova S, Melvin RG, Solon-Biet SM, O’Reilly JN, McMahon AC, Ballard JW, De Cabo R, Le Couteur DG, Lebel M. Liver aging and pseudocapillarization in a Werner syndrome mouse model. J Gerontol A Biol Sci Med Sci 2014; 69(9): 1076–1086

[72]

Smedsrød B, Le Couteur D, Ikejima K, Jaeschke H, Kawada N, Naito M, Knolle P, Nagy L, Senoo H, Vidal-Vanaclocha F, Yamaguchi N. Hepatic sinusoidal cells in health and disease: update from the 14th International Symposium. Liver Int 2009; 29(4): 490–501

[73]

Simon-Santamaria J, Malovic I, Warren A, Oteiza A, Le Couteur D, Smedsrød B, McCourt P, Sørensen KK. Age-related changes in scavenger receptor-mediated endocytosis in rat liver sinusoidal endothelial cells. J Gerontol A Biol Sci Med Sci 2010; 65(9): 951–960

[74]

Hilmer SN, Cogger VC, Fraser R, McLean AJ, Sullivan D, Le Couteur DG. Age-related changes in the hepatic sinusoidal endothelium impede lipoprotein transfer in the rat. Hepatology 2005; 42(6): 1349–1354

[75]

Kus E, Kaczara P, Czyzynska-Cichon I, Szafranska K, Zapotoczny B, Kij A, Sowinska A, Kotlinowski J, Mateuszuk L, Czarnowska E, Szymonski M, Chlopicki S. LSEC fenestrae are preserved despite pro-inflammatory phenotype of liver sinusoidal endothelial cells in mice on high fat diet. Front Physiol 2019; 10: 6

[76]

Mohamad M, Mitchell SJ, Wu LE, White MY, Cordwell SJ, Mach J, Solon-Biet SM, Boyer D, Nines D, Das A, Catherine Li SY, Warren A, Hilmer SN, Fraser R, Sinclair DA, Simpson SJ, de Cabo R, Le Couteur DG, Cogger VC. Ultrastructure of the liver microcirculation influences hepatic and systemic insulin activity and provides a mechanism for age-related insulin resistance. Aging Cell 2016; 15(4): 706–715

[77]

Hunt NJ, McCourt PAG, Le Couteur DG, Cogger VC. Novel targets for delaying aging: The importance of the liver and advances in drug delivery. Adv Drug Deliv Rev 2018; 135: 39–49

[78]

Ito Y, Sørensen KK, Bethea NW, Svistounov D, McCuskey MK, Smedsrød BH, McCuskey RS. Age-related changes in the hepatic microcirculation in mice. Exp Gerontol 2007; 42(8): 789–797

[79]

Hunt NJ, Lockwood GP, Warren A, Mao H, McCourt PAG, Le Couteur DG, Cogger VC. Manipulating fenestrations in young and old liver sinusoidal endothelial cells. Am J Physiol Gastrointest Liver Physiol 2019; 316(1): G144–G154

[80]

Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, Gomes AP, Ward TM, Minor RK, Blouin MJ, Schwab M, Pollak M, Zhang Y, Yu Y, Becker KG, Bohr VA, Ingram DK, Sinclair DA, Wolf NS, Spindler SR, Bernier M, de Cabo R. Metformin improves healthspan and lifespan in mice. Nat Commun 2013; 4(1): 2192

[81]

Yin K, Patten D, Gough S, de Barros Gonçalves S, Chan A, Olan I, Cassidy L, Poblocka M, Zhu H, Lun A, Schuijs M, Young A, Martinez-Jimenez C, Halim TYF, Shetty S, Narita M, Hoare M. Senescence-induced endothelial phenotypes underpin immune-mediated senescence surveillance. Genes Dev 2022; 36(9–10): 533–549

[82]

Fujio K, Hu Z, Evarts RP, Marsden ER, Niu CH, Thorgeirsson SS. Coexpression of stem cell factor and c-kit in embryonic and adult liver. Exp Cell Res 1996; 224(2): 243–250

[83]

Duan JL, Zhou ZY, Ruan B, Fang ZQ, Ding J, Liu JJ, Song P, Xu H, Xu C, Yue ZS, Han H, Dou GR, Wang L. Notch-regulated c-kit-positive liver sinusoidal endothelial cells contribute to liver zonation and regeneration. Cell Mol Gastroenterol Hepatol 2022; 13(6): 1741–1756

[84]

Duan JL, Ruan B, Song P, Fang ZQ, Yue ZS, Liu JJ, Dou GR, Han H, Wang L. Shear stress-induced cellular senescence blunts liver regeneration through Notch-sirtuin 1–P21/P16 axis. Hepatology 2022; 75(3): 584–599

[85]

Higashi T, Friedman SL, Hoshida Y. Hepatic stellate cells as key target in liver fibrosis. Adv Drug Deliv Rev 2017; 121: 27–42

[86]

Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol 2017; 14(7): 397–411

[87]

Cogger VC, Warren A, Fraser R, Ngu M, McLean AJ, Le Couteur DG. Hepatic sinusoidal pseudocapillarization with aging in the non-human primate. Exp Gerontol 2003; 38(10): 1101–1107

[88]

Krizhanovsky V, Yon M, Dickins RA, Hearn S, Simon J, Miething C, Yee H, Zender L, Lowe SW. Senescence of activated stellate cells limits liver fibrosis. Cell 2008; 134(4): 657–667

[89]

Cordero-Espinoza L, Huch M. The balancing act of the liver: tissue regeneration versus fibrosis. J Clin Invest 2018; 128(1): 85–96

[90]

Schnabl B, Purbeck CA, Choi YH, Hagedorn CH, Brenner D. Replicative senescence of activated human hepatic stellate cells is accompanied by a pronounced inflammatory but less fibrogenic phenotype. Hepatology 2003; 37(3): 653–664

[91]

Handayaningsih AE, Takahashi M, Fukuoka H, Iguchi G, Nishizawa H, Yamamoto M, Suda K, Takahashi Y. IGF-I enhances cellular senescence via the reactive oxygen species-p53 pathway. Biochem Biophys Res Commun 2012; 425(2): 478–484

[92]

Matsumoto R, Fukuoka H, Iguchi G, Odake Y, Yoshida K, Bando H, Suda K, Nishizawa H, Takahashi M, Yamada S, Ogawa W, Takahashi Y. Accelerated telomere shortening in acromegaly; IGF-I induces telomere shortening and cellular senescence. PLoS One 2015; 10(10): e0140189

[93]

Nishizawa H, Iguchi G, Fukuoka H, Takahashi M, Suda K, Bando H, Matsumoto R, Yoshida K, Odake Y, Ogawa W, Takahashi Y. IGF-I induces senescence of hepatic stellate cells and limits fibrosis in a p53-dependent manner. Sci Rep 2016; 6(1): 34605

[94]

Jin H, Jia Y, Yao Z, Huang J, Hao M, Yao S, Lian N, Zhang F, Zhang C, Chen X, Bian M, Shao J, Wu L, Chen A, Zheng S. Hepatic stellate cell interferes with NK cell regulation of fibrogenesis via curcumin induced senescence of hepatic stellate cell. Cell Signal 2017; 33: 79–85

[95]

Raulet DH, Vance RE. Self-tolerance of natural killer cells. Nat Rev Immunol 2006; 6(7): 520–531

[96]

Kong X, Feng D, Wang H, Hong F, Bertola A, Wang FS, Gao B. Interleukin-22 induces hepatic stellate cell senescence and restricts liver fibrosis in mice. Hepatology 2012; 56(3): 1150–1159

[97]

Chen E, Cen Y, Lu D, Luo W, Jiang H. IL-22 inactivates hepatic stellate cells via downregulation of the TGF-β1/Notch signaling pathway. Mol Med Rep 2018; 17(4): 5449–5453

[98]

Lujambio A, Akkari L, Simon J, Grace D, Tschaharganeh DF, Bolden JE, Zhao Z, Thapar V, Joyce JA, Krizhanovsky V, Lowe SW. Non-cell-autonomous tumor suppression by p53. Cell 2013; 153(2): 449–460

[99]

Cheng N, Kim KH, Lau LF. Senescent hepatic stellate cells promote liver regeneration through IL-6 and ligands of CXCR2. JCI Insight 2022; 7(14): e158207

[100]

Hilmer SN, Cogger VC, Le Couteur DG. Basal activity of Kupffer cells increases with old age. J Gerontol A Biol Sci Med Sci 2007; 62(9): 973–978

[101]

Singh P, Coskun ZZ, Goode C, Dean A, Thompson-Snipes L, Darlington G. Lymphoid neogenesis and immune infiltration in aged liver. Hepatology 2008; 47(5): 1680–1690

[102]

Stahl EC, Haschak MJ, Popovic B, Brown BN. Macrophages in the aging liver and age-related liver disease. Front Immunol 2018; 9: 2795

[103]

Yang X, Liang L, Zong C, Lai F, Zhu P, Liu Y, Jiang J, Yang Y, Gao L, Ye F, Zhao Q, Li R, Han Z, Wei L. Kupffer cells-dependent inflammation in the injured liver increases recruitment of mesenchymal stem cells in aging mice. Oncotarget 2016; 7(2): 1084–1095

[104]

Stranks AJ, Hansen AL, Panse I, Mortensen M, Ferguson DJ, Puleston DJ, Shenderov K, Watson AS, Veldhoen M, Phadwal K, Cerundolo V, Simon AK. Autophagy controls acquisition of aging features in macrophages. J Innate Immun 2015; 7(4): 375–391

[105]

Brouwer A, Knook DL. The reticuloendothelial system and aging: a review. Mech Ageing Dev 1983; 21(3–4): 205–228

[106]

Wan J, Benkdane M, Alons E, Lotersztajn S, Pavoine C. M2 kupffer cells promote hepatocyte senescence: an IL-6-dependent protective mechanism against alcoholic liver disease. Am J Pathol 2014; 184(6): 1763–1772

[107]

Fontana L, Zhao E, Amir M, Dong H, Tanaka K, Czaja MJ. Aging promotes the development of diet-induced murine steatohepatitis but not steatosis. Hepatology 2013; 57(3): 995–1004

[108]

Wu R, Nakatsu G, Zhang X, Yu J. Pathophysiological mechanisms and therapeutic potentials of macrophages in non-alcoholic steatohepatitis. Expert Opin Ther Targets 2016; 20(5): 615–626

[109]

Reid DT, Reyes JL, McDonald BA, Vo T, Reimer RA, Eksteen B. Kupffer cells undergo fundamental changes during the development of experimental NASH and are critical in initiating liver damage and inflammation. PLoS One 2016; 11(7): e0159524

[110]

Huang W, Metlakunta A, Dedousis N, Zhang P, Sipula I, Dube JJ, Scott DK, O’Doherty RM. Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance. Diabetes 2010; 59(2): 347–357

[111]

Zhang X, Han J, Man K, Li X, Du J, Chu ES, Go MY, Sung JJ, Yu J. CXC chemokine receptor 3 promotes steatohepatitis in mice through mediating inflammatory cytokines, macrophages and autophagy. J Hepatol 2016; 64(1): 160–170

[112]

Kazankov K, Barrera F, Møller HJ, Rosso C, Bugianesi E, David E, Younes R, Esmaili S, Eslam M, McLeod D, Bibby BM, Vilstrup H, George J, Grønbaek H. The macrophage activation marker sCD163 is associated with morphological disease stages in patients with non-alcoholic fatty liver disease. Liver Int 2016; 36(10): 1549–1557

[113]

Kazankov K, Møller HJ, Lange A, Birkebaek NH, Holland-Fischer P, Solvig J, Hørlyck A, Kristensen K, Rittig S, Handberg A, Vilstrup H, Grønbaek H. The macrophage activation marker sCD163 is associated with changes in NAFLD and metabolic profile during lifestyle intervention in obese children. Pediatr Obes 2015; 10(3): 226–233

[114]

Tomita K, Freeman BL, Bronk SF, LeBrasseur NK, White TA, Hirsova P, Ibrahim SH. CXCL10-mediates macrophage, but not other innate immune cells-associated inflammation in murine nonalcoholic steatohepatitis. Sci Rep 2016; 6(1): 28786

[115]

Alzaid F, Lagadec F, Albuquerque M, Ballaire R, Orliaguet L, Hainault I, Blugeon C, Lemoine S, Lehuen A, Saliba DG, Udalova IA, Paradis V, Foufelle F, Venteclef N. IRF5 governs liver macrophage activation that promotes hepatic fibrosis in mice and humans. JCI Insight 2016; 1(20): e88689

[116]

Pignolo RJ, Passos JF, Khosla S, Tchkonia T, Kirkland JL. Reducing senescent cell burden in aging and disease. Trends Mol Med 2020; 26(7): 630–638

[117]

Khosla S, Farr JN, Tchkonia T, Kirkland JL. The role of cellular senescence in ageing and endocrine disease. Nat Rev Endocrinol 2020; 16(5): 263–275

[118]

Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, Palmer AK, Ikeno Y, Hubbard GB, Lenburg M, O’Hara SP, LaRusso NF, Miller JD, Roos CM, Verzosa GC, LeBrasseur NK, Wren JD, Farr JN, Khosla S, Stout MB, McGowan SJ, Fuhrmann-Stroissnigg H, Gurkar AU, Zhao J, Colangelo D, Dorronsoro A, Ling YY, Barghouthy AS, Navarro DC, Sano T, Robbins PD, Niedernhofer LJ, Kirkland JL. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 2015; 14(4): 644–658

[119]

Palmer AK, Xu M, Zhu Y, Pirtskhalava T, Weivoda MM, Hachfeld CM, Prata LG, van Dijk TH, Verkade E, Casaclang-Verzosa G, Johnson KO, Cubro H, Doornebal EJ, Ogrodnik M, Jurk D, Jensen MD, Chini EN, Miller JD, Matveyenko A, Stout MB, Schafer MJ, White TA, Hickson LJ, Demaria M, Garovic V, Grande J, Arriaga EA, Kuipers F, von Zglinicki T, LeBrasseur NK, Campisi J, Tchkonia T, Kirkland JL. Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell 2019; 18(3): e12950

[120]

Hari P, Millar FR, Tarrats N, Birch J, Quintanilla A, Rink CJ, Fernández-Duran I, Muir M, Finch AJ, Brunton VG, Passos JF, Morton JP, Boulter L, Acosta JC. The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype. Sci Adv 2019; 5(6): eaaw0254

[121]

Ritschka B, Knauer-Meyer T, Gonçalves DS, Mas A, Plassat JL, Durik M, Jacobs H, Pedone E, Di Vicino U, Cosma MP, Keyes WM. The senotherapeutic drug ABT-737 disrupts aberrant p21 expression to restore liver regeneration in adult mice. Genes Dev 2020; 34(7–8): 489–494

[122]

Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H, Dai HM, Ling YY, Stout MB, Pirtskhalava T, Giorgadze N, Johnson KO, Giles CB, Wren JD, Niedernhofer LJ, Robbins PD, Kirkland JL. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell 2016; 15(3): 428–435

[123]

Suda M, Shimizu I, Katsuumi G, Yoshida Y, Hayashi Y, Ikegami R, Matsumoto N, Yoshida Y, Mikawa R, Katayama A, Wada J, Seki M, Suzuki Y, Iwama A, Nakagami H, Nagasawa A, Morishita R, Sugimoto M, Okuda S, Tsuchida M, Ozaki K, Nakanishi-Matsui M, Minamino T. Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice. Nat Aging 2021; 1(12): 1117–1126

[124]

Maeso-Díaz R, Du K, Pan C, Guy CD, Oh SH, Chen T, Wang L, Ko DC, Tang L, Dutta RK, Jun JH, Suzuki A, Abdelmalek MF, Wang XF, Diehl AM. Targeting senescent hepatocytes using the thrombomodulin-PAR1 inhibitor vorapaxar ameliorates NAFLD progression. Hepatology 2023; 78(4): 1209–1222

[125]

Massemin A, Goehrig D, Flaman JM, Jaber S, Griveau A, Djebali S, Marcos E, Payen L, Marvel J, Parent R, Adnot S, Bertolino P, Rieusset J, Tortereau A, Vindrieux D, Bernard D. Loss of Pla2r1 decreases cellular senescence and age-related alterations caused by aging and Western diets. Aging Cell 2023; 22(11): e13971

[126]

Gao Y, Zhang W, Zeng LQ, Bai H, Li J, Zhou J, Zhou GY, Fang CW, Wang F, Qin XJ. Exercise and dietary intervention ameliorate high-fat diet-induced NAFLD and liver aging by inducing lipophagy. Redox Biol 2020; 36: 101635

[127]

Boulé NG, Haddad E, Kenny GP, Wells GA, Sigal RJ. Effects of exercise on glycemic control and body mass in type 2 diabetes mellitus: a meta-analysis of controlled clinical trials. JAMA 2001; 286(10): 1218–1227

[128]

Umpierre D, Ribeiro PA, Kramer CK, Leitão CB, Zucatti AT, Azevedo MJ, Gross JL, Ribeiro JP, Schaan BD. Physical activity advice only or structured exercise training and association with HbA1c levels in type 2 diabetes: a systematic review and meta-analysis. JAMA 2011; 305(17): 1790–1799

[129]

Shah K, Stufflebam A, Hilton TN, Sinacore DR, Klein S, Villareal DT. Diet and exercise interventions reduce intrahepatic fat content and improve insulin sensitivity in obese older adults. Obesity (Silver Spring) 2009; 17(12): 2162–2168

[130]

Demaria M, Ohtani N, Youssef SA, Rodier F, Toussaint W, Mitchell JR, Laberge RM, Vijg J, Van Steeg H, Dollé ME, Hoeijmakers JH, de Bruin A, Hara E, Campisi J. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell 2014; 31(6): 722–733

[131]

He S, Sharpless NE. Senescence in health and disease. Cell 2017; 169(6): 1000–1011

RIGHTS & PERMISSIONS

Higher Education Press

AI Summary AI Mindmap
PDF (1547KB)

1020

Accesses

0

Citation

Detail

Sections
Recommended

AI思维导图

/