The Journal is included in Russian and International Library and Abstract Databases
Russain Science Index (Russia)
DOI Registration Agency (USA)



I. Mesheriakova(1); A. Ilina(1, 2); N. Linkova(1, 3), Doctor of Biological Sciences; M. Koroleva(3), Candidate of Medical Sciences; Professor V. Khavinson(1, 4), Corresponding Member of RAS (1)Saint Petersburg Bioregulation and Gerontology Institute (2)Institute of biomedical systems and biotechnologies, Peter the Great Saint Petersburg Polytechnic University (3)Academy of Postgraduate Education under Federal Scientific and Clinical Center for Specialized types Medical Assistance and Medical Technologies of the FMBA, Moscow (4)Pavlov Institute of Physiology Russian Academy of Sciences, Saint Petersburg

Age-associated liver disease is one of the leading causes of reduced ability to work and the development of polymorbidity syndrome. The incidence of non-alcoholic fatty liver disease (NAFLD) and hepatitis increases with age and is about 20% in the working-age population of developed countries. The purpose of the review is to analyze the molecular mechanisms of development of age-related liver involution in normal and pathological conditions and to search for promising methods of differential diagnosis. The review describes the role of cell aging proteins and apoptosis (p16ink4a, p21, p53) and factors that regulate the hepatocyte cell cycle (Cdk1, Skp2, Ccne2, pRb, survivin, Ssu72) in the development of liver pathology. Blood plasma proteins (CYP450, GLDH, SDH, K18, GST), sulfitoxidase, cytokeratin 18, etc. are considered as new markers of liver damage. Serum triglycerides, miRNA-122, miRNA-10b, miRNA-33 are specific biomarkers of NAFLD also methylation status MT-ND6. A possible way of steatohepatitis diagnostic to influence the signaling of FXR, FGF19, PPARα, YAP / TAZ. It is assumed that the targets for the action of new generation hepatoprotectors in case of age-related liver pathology may be cytokines (TGF, TNF, IL-6) and vascular endothelial growth factor (VEGF).

non-alcoholic fatty liver disease
non-alcoholic steatohepatitis
molecular markers

  1. Schwabe R.F., Tabas I., Pajvani U.B. Mechanisms of Fibrosis Development in Nonalcoholic Steatohepatitis. Gastroenterology. 2020; pii: S0016-5085(20)30169-4. DOI: 10.1053/j.gastro.2019.11.311
  2. Tajir K., Shimizu Y. Liver physiology and liver diseases in the elderly. World J Gastroenterol. 2013; 19 (5): 8459–67. DOI: 10.3748/wjg.v19.i46.8459
  3. Kim I.H., Kisseleva T., Brenner D.A. Aging and liver disease. Curr Opin Gastroenterol. 2015; 31 (3): 184–91. DOI: 10.1097/MOG.0000000000000176
  4. Schmucker D.L., Sanchez H. Liver regeneration and aging: A current perspective. Curr Gerontol Geriatr Res. 2011; 2011: 526379. DOI: 10.1155/2011/526379
  5. Basseri S., Austin R.C. Endoplasmic reticulum stress and lipid metabolism: mechanisms and therapeutic potential. Biochem Res Int. 2012; 2012: 841362. DOI: 10.1155/2012/841362
  6. Gong Z., Tas E., Yakar S. et al. Hepatic lipid metabolism and non-alcoholic fatty liver disease in aging. Mol Cell Endocrinol. 2017; 455: 115–30. DOI: 10.1016/j.mce.2016.12.022
  7. Schmucker D.L. Age-related changes in liver structure and function: Implications for disease? Exp Gerontol. 2005; 40 (8–9): 650–9. DOI: 10.1016/j.exger.2005.06.009
  8. Schoenfelder K.P., Fox D.T. The expanding implications of polyploidy. J Cell Biol. 2015; 209 (4): 485–91. DOI: 10.1083/jcb.201502016
  9. Celton-Morizur S., Merlen G., Couton D. et al. The insulin/Akt pathway controls a specific cell division program that leads to generation of binucleated tetraploid liver cells in rodents. J Clin Invest. 2009; 119 (7): 1880–7. DOI: 10.1172/jci38677
  10. Banales J.M., Huebert R.C., Karlsen T. et al. Cholangiocyte pathobiology. Nat Rev Gastroenterol Hepatol. 2019; 16 (5): 69–281. DOI: 10.1038/s41575-019-0125-y
  11. Jensen K., Marzioni M., Munshi K. et al. Autocrine regulation of biliary pathology by activated cholangiocytes. Am J Physiol Gastrointest Liver Physiol. 2012; 302 (5): G473–83. DOI: 10.1152/ajpgi.00482.2011
  12. O’Hara S.P., Splinter P.L., Trussoni C.E. 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 (4): 18698–713. DOI: 10.1074/jbc.RA119.010176
  13. Maeso-Diaz R., Ortega-Ribera M., Fernández-Iglesias A. et al. Effects of aging on liver microcirculatory function and sinusoidal phenotype. Aging Cell. 2018; 17 (6): e12829. DOI: 10.1111/acel.12829
  14. Mysore K.R., Leung D.H. Hepatitis B and C. Clin Liver Dis. 2018; 22 (4): 703–22. DOI: 10.1016/j.cld.2018.06.002
  15. Beyoǧlu D., Idle J.R. The metabolomic window into hepatobiliary disease. J Hepatol. 2013; 59 (4): 842–58. DOI: 10.1016/j.jhep.2013.05.030
  16. Fu S., Wu D., Jiang W. et al. Molecular Biomarkers in Drug-Induced Liver Injury: Challenges and Future Perspectives. Front Pharmacol. 2020; 10 :1667. DOI: 10.3389/fphar.2019.01667
  17. Luedde T., Kaplowitz N., Schwabe R.F. Cell death and cell death responses in liver disease: mechanisms and clinical relevance. Gastroenterology. 2014; 147 (4): 765–83.e4. DOI: 10.1053/j.gastro.2014.07.018
  18. Danjuma M.I., Sajid J., Fatima H. et al. Novel biomarkers for potential risk stratification of drug induced liver injury (DILI): A narrative perspective on current trends. Medicine (Baltimore). 2019; 98 (50): e18322. DOI: 10.1097/MD.0000000000018322
  19. Church R.J., Watkins P.B. The transformation in biomarker detection and management of drug-induced liver injury. Liver Int. 2017; 37 (11): 1582–90. DOI: 10.1111/liv.13441
  20. Ku N.O., Strnad P., Bantel H. et al. Keratins: Biomarkers and modulators of apoptotic and necrotic cell death in the liver. Hepatology. 2016; 64 (3): 966–6. DOI: 10.1002/hep.28493
  21. An J., Kim J.W., Shim J.H. et al. Chronic hepatitis B infection and nonhepatocellular cancers: A hospital registry-based, case-control study. PLoS One. 2018; 13 (3): e0193232. DOI: 10.1371/journal.pone.0193232
  22. Harrill A.H., Roach J., Fier I. et al. The effects of heparins on the liver: Application of mechanistic serum biomarkers in a randomized study in healthy volunteers. Clin Pharmacol Ther. 2012; 92 (2): 214–20. DOI: 10.1038/clpt.2012.40
  23. Metushi I., Uetrecht J., Phillips E. Mechanism of isoniazid-induced hepatotoxicity: Then and now. Br J Clin Pharmacol. 2016; 81 (6): 1030–6. DOI: 10.1038/clpt.2012.40
  24. Li S., Xue F., Zheng Y. et al. GSTM1 and GSTT1 null genotype increase the risk of hepatocellular carcinoma: evidence based on 46 studies. Cancer Cell Int. 2019; 19 (1): 76. DOI: 10.1186/s12935-019-0792-3
  25. Park W.J., Kim S.Y., Kim Y.R. et al. Bortezomib alleviates drug-induced liver injury by regulating CYP2E1 gene transcription. Int J Mol Med. 2016; 37 (3): 613–22. DOI: 10.3892/ijmm.2016.2461
  26. Li L., Li D., Heyward S. et al. Transcriptional regulation of CYP2B6 expression by hepatocyte nuclear factor 3β in human liver cells. PLoS One. 2016; 11 (3): e0150587. DOI: 10.1371/journal.pone.0150587
  27. Wang D., Lu R., Rempala G. et al. Ligand-free estrogen receptor α (ESR1) as master regulator for the expression of CYP3A4 and other cytochrome P450 enzymes in the human liver. Mol Pharmacol. 2019; 96 (4): 430–40. DOI: 10.1124/mol.119.116897
  28. Gao Y., Cao Z., Yang X. et al. Proteomic analysis of acetaminophen-induced hepatotoxicity and identification of heme oxygenase 1 as a potential plasma biomarker of liver injury. Proteomics Clin Appl. 2017; 11 (1–2). doi: 10.1002/prca.201600123
  29. Bruschi F.V., Tardelli M., Herac M. et al. Metabolic regulation of hepatic PNPLA3 expression and severity of liver fibrosis in patients with NASH. Liver Int. 2020; 40 (5):1098–110. DOI: 10.1111/liv.1440
  30. Annegowda V.M., Devi H.U., Rao K. et al. Immunohistochemical study of alpha-smooth muscle actin in odontogenic cysts and tumors. J Oral Maxillofac Pathol. 2018; 22 (2): 188–92. DOI: 10.4103/jomfp.JOMFP_31_18
  31. Krützfeldt J., Rajewsky N., Braich R. et al. Silencing of microRNAs in vivo with «antagomirs». Nature. 2005; 438 (7068): 685–9. DOI: 10.1038/nature04303
  32. Pawlak M., Lefebvre P., Staels B. Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. J Hepatol. 2015; 62 (3): 720–33. DOI: 10.1016/j.jhep.2014.10.039
  33. Yu J., Peng J., Luan Z. et al. MicroRNAs as a novel tool in the diagnosis of liver lipid dysregulation and fatty liver disease. Molecules. 2019; 24 (2): pii: E230. DOI: 10.3390/molecules24020230
  34. Sulaiman S.A., Muhsin N.I.A., Jamal R. Regulatory non-coding RNAs network in non-alcoholic fatty liver disease. Front Physiol. 2019; 10: 279. DOI: 10.3389/fphys.2019.00279
  35. Sun C., Fan J.G., Qiao L. Potential epigenetic mechanism in non-alcoholic fatty liver disease. Int J Mol Sci. 2015; 16 (3): 5161–79. DOI: 10.3390/ijms16035161
  36. Dadrich M., Nicolay N.H., Flechsig P. et al. Combined inhibition of TGFβ and PDGF signaling attenuates radiation-induced pulmonary fibrosis. Oncoimmunology. 2016; 5 (5): e1123366. DOI: 10.1080/2162402X.2015.1123366
  37. Noguchi S., Saito A., Nagase T. YAP/TAZ signaling as a molecular link between fibrosis and cancer. Int J Mol Sci. 2018; 19 (11): pii: e3674. DOI: 10.3390/ijms19113674
  38. Dupont S. Role of YAP/TAZ in cell-matrix adhesion-mediated signalling and mechanotransduction. Exp Cell Res. 2016; 343 (1): 42–53. DOI: 10.1016/j.yexcr.2015.10.034
  39. Tsuchida T., Friedman S.L. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol. 2017; 14 (7): 397–411. DOI: 10.1038/nrgastro.2017.38
  40. Zhu C., Kim K., Wang X. et al. Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis. Sci Transl Med. 2018; 10 (468): eaat0344. DOI: 10.1126/scitranslmed.aat0344