Research Paper Volume 13, Issue 6 pp 7800—7827

Chronic treatment with acetaminophen protects against liver aging by targeting inflammation and oxidative stress

Rocío Brea1, *, , Pilar Valdecantos1,2, *, , Patricia Rada1,2, *, , Rosa Alen1,2, , Carmelo García-Monzón3,6, , Lisardo Boscá1,4, , Marina Fuertes-Agudo5,6, , Marta Casado5,6, , Paloma Martín-Sanz1,6, #, , Ángela M. Valverde1,2, #, ,

  • 1 Instituto de Investigaciones Biomédicas “Alberto Sols”, (CSIC-UAM), Department of Metabolism and Cellular Signaling, Madrid 28029, Spain
  • 2 Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem) ISCIII, Madrid 28029, Spain
  • 3 Liver Research Unit, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa, Madrid 28009, Spain
  • 4 Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERcv) ISCIII, Madrid 28029, Spain
  • 5 Instituto de Biomedicina de Valencia (IBV-CSIC), Valencia 46010, Spain
  • 6 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) ISCIII, Madrid 28029, Spain
* Equal contribution
# Senior authorship

Received: September 22, 2020       Accepted: March 2, 2021       Published: March 29, 2021
How to Cite

Copyright: © 2021 Brea 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.


The liver exhibits a variety of functions that are well-preserved during aging. However, the cellular hallmarks of aging increase the risk of hepatic alterations and development of chronic liver diseases. Acetaminophen (APAP) is a first choice for relieving mild-to-moderate pain. Most of the knowledge about APAP-mediated hepatotoxicity arises from acute overdose studies due to massive oxidative stress and inflammation, but little is known about its effect in age-related liver inflammation after chronic exposure. Our results show that chronic treatment of wild-type mice on the B6D2JRcc/Hsd genetic background with APAP at an infratherapeutic dose reduces liver alterations during aging without affecting body weight. This intervention attenuates age-induced mild oxidative stress by increasing HO-1, MnSOD and NQO1 protein levels and reducing ERK1/2 and p38 MAPK phosphorylation. More importantly, APAP treatment counteracts the increase in Cd8+ and the reduction in Cd4+ T lymphocytes observed in the liver with age. This response was also found in peripheral blood mononuclear cells. In conclusion, chronic infratherapeutic APAP treatment protects mice from age-related liver alterations by attenuating oxidative stress and inflammation.


APAP: N-acetyl-p-aminophenol, acetaminophen or paracetamol; CRP: C-reactive Protein; ERK: extracellular-signal-regulated kinase; GLUT4: glucose transporter type 4; HO-1/Hmox1: heme oxygenase 1; IκBα: nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha; IL: interleukin; JNK: c-Jun N-terminal kinase; MCP1/Ccl2: monocyte chemoattractant protein 1; MGL1/Clec10a: macrophage galactose-type lectin 1; MnSOD/Sod2: manganese superoxide dismutase/superoxide dismutase 2; NK: natural killer; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; NQO1: NAD(P)H quinone dehydrogenase 1; NRF2/Nfe2l2: nuclear factor erythroid 2-related factor 2; p38-MAPK: p38 mitogen-activated protein kinases; sICAM-1: soluble intercellular adhesion molecule-1; SIRT1: sirtuin 1; sVCAM-1: soluble vascular cell adhesion molecule-1; TNF-α: tumor necrosis factor-α.

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