The Aging Human Liver: The Weal and Woe of Evolutionary Legacy

Dedication

This contribution is dedicated to the memory of the one who started it all: Nancy Leslie Rutherford Bucher, M.D. (1913 – 2017)

Abstract

Aging is characterized by the progressive decline of biological integrity and its compensatory mechanisms as well as immunological dysregulation. This goes along with an increasing risk of frailty and disease. Against this background, we here specifically focus on the aging of the human liver. For the first time, we shed light on the intertwining evolutionary underpinnings of the liver’s declining regenerative capacity, the phenomenon of inflammaging, and the biotransformation capacity in the process of aging. In addition, we discuss how aging influences the risk for developing nonalcoholic fatty liver disease, hepatocellular carcinoma, and/or autoimmune hepatitis, and we describe chronic diseases as accelerators of biological aging.

Zusammenfassung

Altern ist gekennzeichnet durch die progrediente Abnahme der biologischen Integrität und ihrer kompensatorischen Mechanismen sowie immunologische Dysregulation. Dies geht mit einem zunehmenden Risiko für Gebrechlichkeit und Krankheit einher. Vor diesem Hintergrund fokussieren wir auf die Alterung der menschlichen Leber. Dabei beleuchten wir erstmals die ineinandergreifenden evolutiven Fundamente der abnehmenden Leberregenerationsfähigkeit, des Inflammaging-Phänomens und der Biotransformationskapazität im Alterungsprozess. Zudem diskutieren wir den Einfluss des Alterns auf das Risko, eine nichtalkoholische Fettlebererkrankung, ein Hepatozelluläres Karzinom und/oder eine Autoimmunhepatitis zu entwickeln, und wir beschreiben chronische Erkrankungen als Beschleuniger des biologischen Alterns.

Schlüsselwörter

Leberregeneration - Inflammaging - Biotransformation - nicht-alkoholische Fettlebererkrankung - Hepatozelluläres Karzinom - Horvath clock

Keywords

liver regeneration - inflammaging - biotransformation - nonalcoholic fatty liver disease - hepatocellular carcinoma - Horvath clock

Publication History

Received: 26 September 2022

Accepted after revision: 04 December 2022

Article published online:
09 January 2023

• References

• 1 Gilbert SF. Developmental Biology. 6th ed. Sunderland, MA. USA: Sinauer Associates; 2000
• 2 Canbay A, Kachru N, Haas JS. et al. Patterns and predictors of mortality and disease progression among patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2020; 52: 1185-1194
• 3 Ramanathan R, Ali AH, Ibdah JA. Mitochondrial Dysfunction Plays Central Role in Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2022; 23: 7280 DOI: 10.3390/ijms23137280. (PMID: 35806284)
• 4 Powell EE, Wong VW, Rinella M. Non-alcoholic fatty liver disease. Lancet 2021; 397: 2212-2224 DOI: 10.1016/S0140-6736(20)32511-3. (PMID: 33894145)
• 5 Maluccio M, Covey A. Recent progress in understanding, diagnosing, and treating hepatocellular carcinoma. CA Cancer J Clin 2012; 62: 394-399 DOI: 10.3322/caac.21161. (PMID: 23070690)
• 6 Sung H, Ferlay J, Siegel RL. et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021; 71: 209-249 DOI: 10.3322/caac.21660. (PMID: 33538338)
• 7 Delgado-Coello B. Liver regeneration observed across the different classes of vertebrates from an evolutionary perspective. Heliyon 2021; 7: e06449 DOI: 10.1016/j.heliyon.2021.e06449. (PMID: 33748499)
• 8 Columbano A, Shinosuka H. Liver regeneration versus direct hyperplasia. FASEB J 1996; 10: 1118-1128
• 9 Fausto N. Liver regeneration. J Hepatol 2000; 32 (Suppl. 01) 19-31 DOI: 10.1002/hep.20969. (PMID: 16447274)
• 10 Rosselló RA, Chen CC, Dai R. et al. Mammalian genes induce partially reprogrammed pluripotent stem cells in nonmammalian vertebrate and invertebrate species. eLife 2013; 2: e00036 DOI: 10.7554/eLife.00036. (PMID: 24015354)
• 11 Khyeam S, Lee S, Huang GN. Genetic, Epigenetic, and Post-Transcriptional Basis of Divergent Tissue Regenerative Capacities Among Vertebrates. Adv Genet (Hoboken) 2021; 2: e10042 DOI: 10.1002/ggn2.10042.
• 12 Cox AG, Goessling W. The lure of zebrafish in liver research: regulation of hepatic growth in development and regeneration. Curr Opin Genet Dev 2015; 32: 153-161 DOI: 10.1016/j.gde.2015.03.002. (PMID: 25863341)
• 13 Khan S, Saxena R. Regression of Hepatic Fibrosis and Evolution of Cirrhosis: A Concise Review. Adv Anat Pathol 2021; 28: 408-414 DOI: 10.1097/PAP.0000000000000312. (PMID: 34326286)
• 14 Starzl TE. Peter Brian Medawar: father of transplantation. J Am Coll Surg 1995; 180: 332-336 (PMID: 7874344)
• 15 Medawar PB. Chapter 2: An Unsolved Problem of Biology. In: Medawar PB. The Uniqueness of the Individual. New York: Basic Books; 1952: 44-70
• 16 Turan ZG, Parvizi P, Dönertaş HM. et al. Molecular footprint of Medawar's mutation accumulation process in mammalian aging. Aging Cell 2019; 18: e12965 DOI: 10.1111/acel.12965. (PMID: 31062469)
• 17 Barth E, Srivastava A, Stojiljkovic M. et al. Conserved aging-related signatures of senescence and inflammation in different tissues and species. Aging (Albany NY) 2019; 11: 8556-8572 DOI: 10.18632/aging.102345. (PMID: 31606727)
• 18 Sheedfar F, Di Biase S, Koonen D. et al. Liver diseases and aging: friends or foes?. Aging Cell 2013; 12: 950-954 DOI: 10.1111/acel.12128. (PMID: 23815295)
• 19 Michalopoulos GK, Bhushan B. Liver regeneration: Biological and pathological mechanisms and implications. Nat. Rev. Gastroenterol. Hepatol 2021; 18: 40-55 DOI: 10.1038/s41575-020-0342-4. (PMID: 32764740)
• 20 Yagi S, Hirata M, Miyachi Y. et al. Liver Regeneration after Hepatectomy and Partial Liver Transplantation. Int J Mol Sci 2020; 21: 8414 DOI: 10.3390/ijms21218414. (PMID: 33182515)
• 21 Michalopoulos GK. Liver regeneration. J Cell Physiol 2007; 213: 286-300 DOI: 10.1038/s41575-020-0342-4. (PMID: 32764740)
• 22 Bucher NLR, Swaffield MN, DiTroia JF. The Influence of Age upon the Incorporation of Thymidine-2-C14 into the DNA of Regenerating Rat Liver. Cancer Res 1964; 24: 509-512
• 23 Timchenko NA. Aging and liver regeneration. Trends Endocrinol Metab 2009; 20: 171-176 DOI: 10.1016/j.tem.2009.01.005. (PMID: 19359195)
• 24 Feuda R, Dohrmann M, Pett W. et al. Improved Modeling of Compositional Heterogeneity Supports Sponges as Sister to All Other Animals. Curr Biol 2017; 27: 3864-3870.e4
• 25 Müller WE, Wang X, Schröder HC. Paleoclimate and evolution: emergence of sponges during the neoproterozoic. Prog Mol Subcell Biol 2009; 47: 55-77 DOI: 10.1007/978-3-540-88552-8_3. (PMID: 19198773)
• 26 Schuster A, Vargas S, Knapp IS. et al. Divergence times in demosponges (Porifera): first insights from new mitogenomes and the inclusion of fossils in a birth-death clock model. BMC Evol Biol 2018; 18: 114 DOI: 10.1186/s12862-018-1230-1.
• 27 Elvington M, Liszewski MK, Atkinson JP. Evolution of the complement system: from defense of the single cell to guardian of the intravascular space. Immunol Rev 2016; 274: 9-15 DOI: 10.1111/imr.12474. (PMID: 27782327)
• 28 Markiewski MM, Mastellos D, Tudoran R. et al. C3a and C3b activation products of the third component of complement (C3) are critical for normal liver recovery after toxic injury. J Immunol 2004; 173: 747-754 DOI: 10.4049/jimmunol.173.2.747. (PMID: 15240660)
• 29 Clark A, Weymann A, Hartman E. et al. Evidence for non-traditional activation of complement factor C3 during murine liver regeneration. Mol Immunol 2008; 45: 3125-3132
• 30 DeAngelis RA, Markiewski MM, Kourtzelis I. et al. A complement–IL-4 regulatory circuit controls liver regeneration. J Immunol 2012; 188: 641-648 DOI: 10.4049/jimmunol.1101925. (PMID: 22184721)
• 31 Min JS, DeAngelis RA, Reis ES. et al. Systems Analysis of the Complement-Induced Priming Phase of Liver Regeneration. J Immunol 2016; 197: 2500-2508 DOI: 10.4049/jimmunol.1600628. (PMID: 27511733)
• 32 Markiewski MM, DeAngelis RA, Strey CW. et al. The regulation of liver cell survival by complement. J Immunol 2009; 182: 5412-5418 DOI: 10.4049/jimmunol.0804179. (PMID: 19380788)
• 33 Ahne W. Evidence for the early appearance of interleukins and tumor necrosis factor in the phylogenesis of vertebrates. Immunol Today 1994; 15: 137 DOI: 10.1016/0167-5699(94)90158-9. (PMID: 8172647)
• 34 Quistad SD, Stotland A, Barott KL. et al. Evolution of TNF-induced apoptosis reveals 550 My of functional conservation. Proc Natl Acad Sci U S A 2014; 111: 9567-9572 DOI: 10.1073/pnas.1405912111. (PMID: 24927546)
• 35 Evans SS, Repasky EA, Fisher DT. Fever and the thermal regulation of immunity: the immune system feels the heat. Nat Rev Immunol 2015; 15: 335-349 DOI: 10.1038/nri3843. (PMID: 25976513)
• 36 Strey CW, Markiewski M, Mastellos D. et al. The proinflammatory mediators C3a and C5a are essential for liver regeneration. J Exp Med 2003; 198: 913-923 DOI: 10.1084/jem.20030374. (PMID: 12975457)
• 37 De Angelis RA, Markiewski MM, Lambris JD. Liver regeneration: a link to inflammation through complement. Adv Exp Med Biol 2006; 586: 17-34 DOI: 10.1007/0-387-34134-X_2. (PMID: 16893062)
• 38 Albrecht JH. MET and epidermal growth factor signaling: The pillars of liver regeneration?. Hepatology 2016; 64: 1427-1429 DOI: 10.1002/hep.28822. (PMID: 27632053)
• 39 Donate LE, Gherardi E, Srinivasan N. et al. Molecular evolution and domain structure of plasminogen-related growth factors (HGF/SF and HGF1/MSP). Protein Sci 1994; 3: 2378-2394 DOI: 10.1002/pro.5560031222. (PMID: 7756992)
• 40 Barberán S, Martín-Durán JM, Cebrià F. Evolution of the EGFR pathway in Metazoa and its diversification in the planarian Schmidtea mediterranea. Sci Rep 2016; 6: 28071 DOI: 10.1038/srep28071. (PMID: 27325311)
• 41 Lindroos PM, Zarnegar R, Michalopoulos GK. Hepatocyte growth factor (hepatopoietin A) rapidly increases in plasma before DNA synthesis and liver regeneration stimulated by partial hepatectomy and carbon tetrachloride administration. Hepatology 1991; 13: 743-750 (PMID: 1826282)
• 42 Mars WM, Liu ML, Kitson RP. et al. Immediate early detection of urokinase receptor after partial hepatectomy and its implications for initiation of liver regeneration. Hepatology 1995; 21: 1695-1701 (PMID: 7768515)
• 43 Kirkegaard P, Olsen PS, Poulsen SS. et al. Exocrine secretion of epidermal growth factor from Brunner’s glands. Stimulation by VIP and acetylcholine. Regul Pept 1983; 7: 367-372
• 44 Krause WJ. Brunner’s glands: a structural, histochemical and pathological profile. Prog Histochem Cytochem 2000; 35: 259-367 (PMID: 11148980)
• 45 Paranjpe S, Bowen WC, Mars WM. et al. Combined systemic elimination of MET and epidermal growth factor receptor signaling completely abolishes liver regeneration and leads to liver decompensation. Hepatology 2016; 64: 1711-1724 DOI: 10.1002/hep.28721. (PMID: 27397846)
• 46 Huminiecki L, Goldovsky L, Freilich S. et al. Emergence, development and diversification of the TGF-β signaling pathway within the animal kingdom. BMC Evol Biol 2009; 9: 28 DOI: 10.1186/1471-2148-9-28.
• 47 Zheng S, Long J, Liu Z. et al. Identification and evolution of TGF-β signaling pathway members in twenty-four animal species and expression in Tilapia.. Int J Mol Sci 2018; 19: 1154 DOI: 10.3390/ijms19041154.
• 48 Tao Y, Wang M, Chen E. et al. Liver Regeneration: Analysis of the Main Relevant Signaling Molecules. Mediators Inflamm 2017; 2017: 4256352 DOI: 10.1155/2017/4256352. (PMID: 28947857)
• 49 Molven A, Njølstad PR, Fjose A. Genomic structure and restricted neural expression of the zebrafish wnt-1 (int-1) gene. EMBO J 1991; 10: 799-807 DOI: 10.1002/j.1460-2075.1991.tb08012.x. (PMID: 2009859)
• 50 Liu H, Fergusson MM, Castilho RM. et al. Augmented Wnt signaling in a mammalian model of accelerated aging. Science 2007; 317: 803-806 DOI: 10.1126/science.1143578. (PMID: 17690294)
• 51 He S, Tang S. WNT/β-catenin signaling in the development of liver cancers. Biomed Pharmacother 2020; 132: 110851 DOI: 10.1016/j.biopha.2020.110851. (PMID: 33080466)
• 52 Agrawal A, Gupta S. Impact of aging on dendritic cell functions in humans. Ageing Res Rev 2011; 10: 336-345 DOI: 10.1016/j.arr.2010.06.004. (PMID: 20619360)
• 53 Tajiri K, Shimizu Y. Liver physiology and liver diseases in the elderly. World J Gastroenterol 2013; 19: 8459-8467 DOI: 10.3748/wjg.v19.i46.8459. (PMID: 24379563)
• 54 Franceschi C, Bonafè M, Valensin S. et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 2000; 908: 244-254 DOI: 10.1111/j.1749-6632.2000.tb06651.x. (PMID: 10911963)
• 55 Rizvi S, Gawrieh S. Autoimmune Hepatitis in the Elderly: Diagnosis and Pharmacologic Management. Drugs Aging 2018; 35: 589-602 DOI: 10.1007/s40266-018-0556-0. (PMID: 29971609)
• 56 Fried LP, Tangen CM, Walston J. et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001; 56 (03) M146-56 DOI: 10.1093/gerona/56.3.m146. (PMID: 11253156)
• 57 Marcos-Pérez D, Sánchez-Flores M, Proietti S. et al. Association of inflammatory mediators with frailty status in older adults: results from a systematic review and meta-analysis. Geroscience 2020; 42: 1451-1473 DOI: 10.1007/s11357-020-00247-4. (PMID: 32803650)
• 58 Peters JH, Gieseler R, Thiele B. et al. Dendritic cells: from ontogenetic orphans to myelomonocytic descendants. Immunol Today 1996; 17: 273-278
• 59 Gieseler R, Heise D, Soruri A. et al. In-vitro differentiation of mature dendritic cells from human blood monocytes. Dev Immunol 1998; 6: 25-39
• 60 Collin M, Bigley V, Haniffa M. et al. Human dendritic cell deficiency: the missing ID?. Nat Rev Immunol 2011; 11: 575-583 DOI: 10.1038/nri3046. (PMID: 21852794)
• 61 Agrawal A, Gupta S. Impact of aging on dendritic cell functions in humans. Ageing Res Rev 2011; 10: 336-345 DOI: 10.1016/j.arr.2010.06.004. (PMID: 20619360)
• 62 Ross EA, Devitt A, Johnson JR. Macrophages: The Good, the Bad, and the Gluttony. Front Immunol 2021; 12: 708186 DOI: 10.3389/fimmu.2021.708186. (PMID: 34456917)
• 63 Gale RP, Sparkes RS, Golde DW. Bone marrow origin of hepatic macrophages (Kupffer cells) in humans. Science 1978; 201: 937-938 DOI: 10.1126/science.356266. (PMID: 356266)
• 64 Schulz C, Gomez Perdiguero E, Chorro L. et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 2012; 336: 86-90
• 65 Gomez Perdiguero E, Klapproth K, Schulz C. et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 2015; 518: 547-551
• 66 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: e12829 DOI: 10.1111/acel.12829. (PMID: 30260562)
• 67 Wang X, Rao H, Zhao J. et al. STING expression in monocyte-derived macrophages is associated with the progression of liver inflammation and fibrosis in patients with nonalcoholic fatty liver disease. Lab Invest 2020; 100: 542-552
• 68 Ye Y, Guo J, Xiao P. et al. Macrophages-induced long noncoding RNA H19 up-regulation triggers and activates the miR-193b/MAPK1 axis and promotes cell aggressiveness in hepatocellular carcinoma. Cancer Lett 2020; 469: 310-322 DOI: 10.1016/j.canlet.2019.11.001. (PMID: 31705929)
• 69 Mohammed S, Thadathil N, Selvarani R. et al. Necroptosis contributes to chronic inflammation and fibrosis in aging liver. Aging Cell 2021; 20: e13512 DOI: 10.1111/acel.13512. (PMID: 34761505)
• 70 Wan Y, Li X, Slevin E. et al. Endothelial dysfunction in pathological processes of chronic liver disease during aging. FASEB J 2022; 36: e22125 DOI: 10.1096/fj.202101426R.
• 71 Trivedi P, Wang S, Friedman SL. The Power of Plasticity-Metabolic Regulation of Hepatic Stellate Cells. Cell Metab 2021; 33: 242-257 DOI: 10.1016/j.cmet.2020.10.026. (PMID: 33232666)
• 72 Saile B, Ramadori G. Inflammation, damage repair and liver fibrosis – role of cytokines and different cell types. Z Gastroenterol 2007; 45: 77-86 DOI: 10.1055/s-2006-927395. (PMID: 17236124)
• 73 Anantharaju A, Feller A, Chedid A. Aging Liver. A review. Gerontology 2002; 48: 343-353 DOI: 10.1159/000065506. (PMID: 12393949)
• 74 Yang TY, Gao Z, Liang NC. Sex-Dependent Wheel Running Effects on High Fat Diet Preference, Metabolic Outcomes, and Performance on the Barnes Maze in Rats. Nutrients 2020; 12: 2721 DOI: 10.3390/nu12092721. (PMID: 32899519)
• 75 Von Bank H, Kirsh C, Simcox J. Aging adipose: Depot location dictates age-associated expansion and dysfunction. Ageing Res Rev 2021; 67: 101259 DOI: 10.1016/j.arr.2021.101259. (PMID: 33515751)
• 76 Zamboni M, Nori N, Brunelli A. et al. How does adipose tissue contribute to inflammageing?. Exp Gerontol 2021; 143: 111162 DOI: 10.1016/j.exger.2020.111162.
• 77 Cheng Y, An B, Jiang M. et al. Association of Tumor Necrosis Factor-alpha Polymorphisms and Risk of Coronary Artery Disease in Patients With Non-alcoholic Fatty Liver Disease. Hepat Mon 2015; 15: e26818 DOI: 10.5812/hepatmon.26818.
• 78 Simon TG, Trejo MEP, McClelland R. et al. Circulating Interleukin-6 is a biomarker for coronary atherosclerosis in nonalcoholic fatty liver disease: Results from the Multi-Ethnic Study of Atherosclerosis. Int J Cardiol 2018; 259: 198-204
• 79 Cazac GD, Lăcătușu CM, Mihai C. et al. New Insights into Non-Alcoholic Fatty Liver Disease and Coronary Artery Disease: The Liver-Heart Axis. Life (Basel) 2022; 12: 1189 DOI: 10.3390/life12081189.
• 80 Leven AS, Gieseler RK, Schlattjan M. et al. Association of cell death mechanisms and fibrosis in visceral white adipose tissue with pathological alterations in the liver of morbidly obese patients with NAFLD. Adipocyte 2021; 10: 558-573
• 81 Baars T, Gieseler RK, Patsalis PC. et al. Towards harnessing the value of organokine crosstalk to predict the risk for cardiovascular disease in non-alcoholic fatty liver disease. Metabolism 2022; 130: 155179 DOI: 10.1016/j.metabol.2022.155179. (PMID: 35283187)
• 82 Amsterdam D, Ostrov BE. The Impact of the Microbiome on Immunosenescence. Immunol Invest 2018; 47: 801-811 DOI: 10.1080/08820139.2018.1537570. (PMID: 31282802)
• 83 Del Giudice G, Goronzy JJ, Grubeck-Loebenstein B. et al. Fighting Against a Protean Enemy: Immunosenescence, Vaccines, and Healthy Aging. NPJ Aging Mech Dis 2018; 4: 1 DOI: 10.1038/s41514-017-0020-0. (PMID: 29285399)
• 84 Azman KF, Safdar A, Zakaria R. D-galactose-induced liver aging model: Its underlying mechanisms and potential therapeutic interventions. Exp Gerontol 2021; 150: 111372 DOI: 10.1016/j.exger.2021.111372. (PMID: 33905879)
• 85 Morsiani C, Bacalini MG, Santoro A. et al. The peculiar aging of human liver: A geroscience perspective within transplant context. Ageing Res Rev 2019; 51: 24-34
• 86 Schreiter T, Gieseler RK, Vílchez-Vargas R. et al. Transcriptome-Wide Analysis of Human Liver Reveals Age-Related Differences in the Expression of Select Functional Gene Clusters and Evidence for a PPP1R10-Governed ‘Aging Cascade’. Pharmaceutics 2021; 13: 2009 DOI: 10.3390/pharmaceutics13122009. (PMID: 34959291)
• 87 Capri M, Olivieri F, Lanzarini C. et al. Identification of miR-31–5p, miR-141–3p, miR-200c-3p, and GLT1 as human liver aging markers sensitive to donor-recipient age-mismatch in transplants. Aging Cell 2017; 16: 262-272 DOI: 10.1111/acel.12549. (PMID: 27995756)
• 88 Palacios-Pedrero MÁ, Osterhaus ADME, Becker T. et al. Aging and Options to Halt Declining Immunity to Virus Infections. Front Immunol 2021; 12: 681449 DOI: 10.3389/fimmu.2021.681449..
• 89 Anderson N, Borlak J. Molecular mechanisms and therapeutic targets in steatosis and steatohepatitis. Pharmacol Rev 2008; 60: 311-357 DOI: 10.1124/pr.108.00001. (PMID: 18922966)
• 90 Ramadori G, Armbrust T. Cytokines in the liver. Eur J Gastroenterol Hepatol 2001; 13: 777-784 DOI: 10.1097/00042737-200107000-00004. (PMID: 11474306)
• 91 Joshi-Barve S, Barve S, Amancherla K. et al. Palmitic acid induces production of proinflammatory cytokine interleukin-8 from hepatocytes. Hepatology 2007; 46: 823-830
• 92 Gómez-Hurtado I, Gallego-Durán R, Zapater P. et al. Bacterial antigen translocation and age as BMI-independent contributing factors on systemic inflammation in NAFLD patients. Liver Int 2020; 40: 2182-2193 DOI: 10.1111/liv.14571. (PMID: 32559006)
• 93 Sheedfar F, Di Biase S, Koonen D. et al. Liver diseases and aging: friends or foes?. Aging Cell 2013; 12: 950-954 DOI: 10.1111/acel.12128. (PMID: 23815295)
• 94 Wang Y, Fu Z, Li X. et al. Cytoplasmic DNA sensing by KU complex in aged CD4+ T cell potentiates T cell activation and aging-related autoimmune inflammation. Immunity 2021; 54: 632-647 DOI: 10.1016/j.immuni.2021.02.003. (PMID: 33667382)
• 95 Gindin Y, Gaggar A, Lok AS. et al. DNA Methylation and Immune Cell Markers Demonstrate Evidence of Accelerated Aging in Patients with Chronic Hepatitis B Virus or Hepatitis C Virus, with or without Human Immunodeficienct Virus Co-infection. Clin Infect Dis 2021; 73: e184-e190 DOI: 10.1007/978-3-642-27340-7_4. (PMID: 23463198)
• 96 Horvath S. DNA methylation age of human tissues and cell types. Genome Biol 2013; 14: R115 DOI: 10.1186/gb-2013-14-10-r115. (PMID: 24138928)
• 97 Horvath S, Pirazzini C, Bacalini MG. et al. Decreased epigenetic age of PBMCs from Italian semi-supercentenarians and their offspring. Aging (Albany NY) 2015; 7: 1159-1170
• 98 Loomba R, Gindin Y, Jiang Z. et al. DNA methylation signatures reflect aging in patients with nonalcoholic steatohepatitis. JCI Insight 2018; 3: 1-9
• 99 Tanaka M, Miyajima A. Liver regeneration and fibrosis after inflammation. Inflamm Regen 2016; 36: 19 DOI: 10.1186/s41232-016-0025-2. (PMID: 29259692)
• 100 Schmucker DL. Aging and the liver: an update. J Gerontol A Biol Sci Med Sci 1998; 53: B315-B320 DOI: 10.1093/gerona/53a.5.b315. (PMID: 9754128)
• 101 Lucena MI, Sanabria J, García-Cortes M. et al. Drug-induced liver injury in older people. Lancet Gastroenterol Hepatol 2020; 5: 862-874 DOI: 10.1016/S2468-1253(20)30006-6. (PMID: 32818465)
• 102 Sameri S, Samadi P, Dehghan R. et al. Stem Cell Aging in Lifespan and Disease: A State-of-the-Art Review. Curr Stem Cell Res Ther 2020; 15: 362-378 DOI: 10.2174/1574888X15666200213105155. (PMID: 32053079)
• 103 Xu F, Hua C, Tautenhahn HM. et al. The Role of Autophagy for the Regeneration of the Aging Liver. Int J Mol Sci 2020; 21: 3606 DOI: 10.3390/ijms21103606. (PMID: 32443776)
• 104 Bellanti F, Vendemiale G. The Aging Liver: Redox Biology and Liver Regeneration. Antioxid Redox Signal 2021; 35 (10) 832-847 DOI: 10.1089/ars.2021.0048. (PMID: 33789448)
• 105 Kundu D, Kennedy L, Meadows V. et al. The Dynamic Interplay Between Mast Cells, Aging/Cellular Senescence, and Liver Disease. Gene Expr 2020; 20: 77-88
• 106 Liu Y, Wang J, Huang Z. et al. Environmental pollutants exposure: A potential contributor for aging and age-related diseases. Environ Toxicol Pharmacol 2021; 83: 103575 DOI: 10.1016/j.etap.2020.103575. (PMID: 33385577)
• 107 Shen J, Tower J. Effects of light on aging and longevity. Ageing Res Rev 2019; 53: 100913 DOI: 10.1016/j.arr.2019.100913. (PMID: 31154014)
• 108 Stern K, Hinds EG, Askonas BA. Ageing and detoxication; studies in hippuric acid synthesis during psychoses of the involutional and old age group. Am J Psychiatry 1945; 102: 325-329 DOI: 10.1176/ajp.102.3.325. (PMID: 21007679)
• 109 Probstein JG, Londe S. Studies of liver function by means of Quick’s hippuric acid test. Ann Surg 1940; 111: 230-245 DOI: 10.1097/00000658-194002000-00004. (PMID: 17857533)
• 110 Hunt NJ, Kang SWS, Lockwood GP. et al. Hallmarks of Aging in the Liver. Comput Struct Biotechnol J 2019; 17: 1151-1161 DOI: 10.1016/j.csbj.2019.07.021. (PMID: 31462971)
• 111 Chung HS, Choi KM. Organokines in disease. Adv Clin Chem 2020; 94: 261-321 DOI: 10.1016/bs.acc.2019.07.012. (PMID: 31952573)
• 112 Pallister T, Jackson MA, Martin TC. et al. Hippurate as a metabolomic marker of gut microbiome diversity: Modulation by diet and relationship to metabolic syndrome. Sci Rep 2017; 7: 13670 DOI: 10.1038/s41598-017-13722-4. (PMID: 29057986)
• 113 Hoyles L, Fernández-Real JM, Federici M. et al. Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women. Nat Med 2018; 24: 1070-1080 DOI: 10.1038/s41591-018-0061-3. (PMID: 29942096)
• 114 Brial F, Chilloux J, Nielsen T. et al. Human and preclinical studies of the host–gut microbiome co-metabolite hippurate as a marker and mediator of metabolic health. Gut 2021; 70: 2105-2114 DOI: 10.1136/gutjnl-2020-323314. (PMID: 33975870)
• 115 Lee KS, Cho Y, Kim H. et al. Association of Metabolomic Change and Treatment Response in Patients with Non-Alcoholic Fatty Liver Disease. Biomedicines 2022; 10: 1216 DOI: 10.3390/biomedicines10061216.
• 116 Rikans LE. Influence of aging on chemically induced hepatotoxicity: role of age-related changes in metabolism. Drug Metab Rev 1989; 20: 87-110 DOI: 10.3109/03602538908994145. (PMID: 2653764)
• 117 Sowa JP, Heider D, Bechmann LP. et al. Novel algorithm for non-invasive assessment of fibrosis in NAFLD. PLoS One 2013; 8: e62439 DOI: 10.1371/journal.pone.0062439. (PMID: 23638085)
• 118 Sowa JP, Atmaca Ö, Kahraman A. et al. Non-invasive separation of alcoholic and non-alcoholic liver disease with predictive modeling. PLoS One 2014; 9: e101444 DOI: 10.1371/journal.pone.0101444.
• 119 Canbay A, Kälsch J, Neumann U. et al. Non-invasive assessment of NAFLD as systemic disease – A machine learning perspective. PLoS One 2019; 14: e0214436 DOI: 10.1371/journal.pone.0214436. (PMID: 30913263)
• 120 Spänig S, Emberger-Klein A, Sowa JP. et al. The virtual doctor: An interactive clinical-decision-support system based on deep learning for non-invasive prediction of diabetes. Artif Intell Med 2019; 100: 101706 DOI: 10.1016/j.artmed.2019.101706. (PMID: 31607340)
• 121 Ghahramani Z. Probabilistic machine learning and artificial intelligence. Nature 2015; 521: 452-459 DOI: 10.1038/nature14541. (PMID: 26017444)
• 122 Schadinger SE, Bucher NLR, Schreiber BM. et al. PPARγ2 regulates lipogenesis and lipid accumulation in steatotic hepatocytes. Am J Physiol Endocrinol Metab 2005; 288: E1195-E1205
• 123 NN. Dr. Nancy L.R. Bucher (1913–2017). American Academy of Arts and Sciences. Last Updated: March 2022. Source:. Accessed September 23, 2022 at: https://www.amacad.org/person/nancy-lr-bucher