Review Volume 13, Issue 19 pp 23416—23434

Impact of aging on primary liver cancer: epidemiology, pathogenesis and therapeutics

Rocio I.R. Macias1,5, , Maria J. Monte1,5, , Maria A. Serrano1,5, , Jesús M. González-Santiago2, , Isabel Martín-Arribas2, , André L. Simão3, , Rui E. Castro3, , Javier González-Gallego4,5, , José L. Mauriz4,5, , Jose J.G. Marin1,5, ,

  • 1 Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, Salamanca, Spain
  • 2 Department of Gastroenterology and Hepatology, University Hospital of Salamanca, IBSAL, Salamanca, Spain
  • 3 Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
  • 4 Institute of Biomedicine (IBIOMED), University of León, León, Spain
  • 5 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, Madrid, Spain

Received: May 24, 2021       Accepted: September 28, 2021       Published: October 11, 2021
How to Cite

Copyright: © 2021 Macias et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Aging involves progressive physiological and metabolic reprogramming to adapt to gradual deterioration of organs and functions. This includes mechanisms of defense against pre-malignant transformations. Thus, certain tumors are more prone to appear in elderly patients. This is the case of the two most frequent types of primary liver cancer, i.e., hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Accordingly, aging hallmarks, such as genomic instability, telomere attrition, epigenetic alterations, altered proteostasis, mitochondrial dysfunction, cellular senescence, exhaustion of stem cell niches, impaired intracellular communication, and deregulated nutrient sensing can play an important role in liver carcinogenesis in the elders. In addition, increased liver fragility determines a worse response to risk factors, which more frequently affect the aged population. This, together with the difficulty to carry out an early detection of HCC and iCCA, accounts for the late diagnosis of these tumors, which usually occurs in patients with approximately 60 and 70 years, respectively. Furthermore, there has been a considerable controversy on what treatment should be used in the management of HCC and iCCA in elderly patients. The consensus reached by numerous studies that have investigated the feasibility and safety of different curative and palliative therapeutic approaches in elders with liver tumors is that advanced age itself is not a contraindication for specific treatments, although the frequent presence of comorbidities in these individuals should be taken into consideration for their management.


CCA: cholangiocarcinoma; EGFR: epidermal growth factor receptor; HBV: hepatitis B virus; HCC: hepatocellular carcinoma; HCV: hepatitis C virus; NASH: non-alcoholic steatohepatitis; OS: overall survival; PFS: progression-free survival; RFA: radiofrequency ablation; ROS: reactive oxygen species; TACE: trans-arterial chemoembolization; TERC: telomerase RNA; TERT: telomere reverse transcriptase; TKI: tyrosine kinase inhibitor.