Related Experiment Video

Updated: Apr 18, 2026

Drug-Induced Senescence in Liver Cells Promotes M2 Macrophage Polarization: Implications for Tyrosine Kinase Inhibitor-Associated Hepatotoxicity
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Drug-Induced Senescence in Liver Cells Promotes M2 Macrophage Polarization: Implications for Tyrosine Kinase Inhibitor-Associated Hepatotoxicity

Published on: October 17, 2025

653

p21+TREM2+ senescent macrophages fuel inflammaging and metabolic dysfunction-associated steatotic liver disease

Ivan A Salladay-Perez1,2, Itzetl Avila1, Lizeth Estrada1

  • 1Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

Nature Aging
|April 16, 2026
PubMed

Insights

Senescent macrophages, marked by p21 and TREM2, drive aging-related inflammation. Targeting these senescent macrophages reduces liver inflammation and steatosis, offering a new therapeutic approach for aging and liver diseases.

Area of Science:

  • Immunology
  • Cell Biology
  • Geroscience

Background:

  • Cellular senescence contributes to aging-related chronic inflammation through the senescence-associated secretory phenotype.
  • The specific cell types driving this inflammation, particularly within the macrophage lineage, are not well understood.
  • Macrophages exhibit inflammatory properties, but their capacity to undergo senescence remains an open question.

Purpose of the Study:

  • To identify and characterize senescent macrophages as a source of inflammaging.
  • To investigate the molecular mechanisms underlying macrophage senescence.
  • To determine the role of senescent macrophages in aging and metabolic liver disease and evaluate senolytic therapy.

Main Methods:

  • Primary mouse and human macrophages were subjected to DNA damage and cholesterol-induced senescence.
  • Multi-omic profiling was employed to characterize senescent macrophages.
  • Senescent macrophage accumulation was assessed in aging and diseased liver tissues.
  • Senolytic treatment was administered to aged mice and mice with metabolic dysfunction-associated steatotic liver disease.

Main Results:

  • p21-positive, TREM2-positive senescent macrophages were identified as a major contributor to inflammaging.
  • Senescent macrophages display a unique p21-TREM2 expression profile and senescence-associated secretory phenotype.
  • Type I interferon signaling, triggered by cytosolic mitochondrial DNA, partially drives this phenotype.
  • Accumulation of senescent macrophages was observed in aging mouse livers and human cirrhotic liver tissues.
  • Senolytic treatment targeting senescent macrophages effectively reduced liver inflammation and steatosis.

Conclusions:

  • Macrophage senescence is a significant driver of chronic inflammation in aging and metabolic liver disease.
  • Senescent macrophages represent a promising therapeutic target for age-related inflammatory conditions and liver pathologies.
  • This study establishes senescent macrophages as key players in inflammaging and metabolic liver disease.

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