Senolytics reduce coronavirus-related mortality in old mice

Christina D. Camell, Matthew J. Yousefzadeh, Yi Zhu, Larissa G.P. Langhi Prata, Matthew A. Huggins, Mark Pierson, Lei Zhang, Ryan D. O’Kelly, Tamar Pirtskhalava, Pengcheng Xun, Keisuke Ejima, Ailing Xue, Utkarsh Tripathi, Jair Machado Espindola-Netto, Nino Giorgadze, Elizabeth J. Atkinson, Christina L. Inman, Kurt O. Johnson, Stephanie H. Cholensky, Timothy W. CarlsonNathan K. LeBrasseur, Sundeep Khosla, M. Gerard O’Sullivan, David B. Allison, Stephen C. Jameson, Alexander Meves, Ming Li, Y. S. Prakash, Sergio E. Chiarella, Sara E. Hamilton, Tamara Tchkonia, Laura J. Niedernhofer, James L. Kirkland, Paul D. Robbins

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

The COVID-19 pandemic has revealed the pronounced vulnerability of the elderly and chronically ill to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced morbidity and mortality. Cellular senescence contributes to inflammation, multiple chronic diseases, and age-related dysfunction, but effects on responses to viral infection are unclear. Here, we demonstrate that senescent cells (SnCs) become hyper-inflammatory in response to pathogen-associated molecular patterns (PAMPs), including SARS-CoV-2 spike protein-1, increasing expression of viral entry proteins and reducing antiviral gene expression in non-SnCs through a paracrine mechanism. Old mice acutely infected with pathogens that included a SARS-CoV-2-related mouse β-coronavirus experienced increased senescence and inflammation, with nearly 100% mortality. Targeting SnCs by using senolytic drugs before or after pathogen exposure significantly reduced mortality, cellular senescence, and inflammatory markers and increased antiviral antibodies. Thus, reducing the SnC burden in diseased or aged individuals should enhance resilience and reduce mortality after viral infection, including that of SARS-CoV-2.

Original languageEnglish (US)
Article numbereabe4832
JournalScience
Volume373
Issue number6552
DOIs
StatePublished - Jul 16 2021

Bibliographical note

Publisher Copyright:
© 2021 American Association for the Advancement of Science. All rights reserved.

Keywords

  • Aging
  • Animals
  • COVID-19/drug therapy
  • Cell Line
  • Cellular Senescence/drug effects
  • Coronavirus Infections/immunology
  • Dasatinib/pharmacology
  • Female
  • Flavonols/pharmacology
  • Gene Expression Regulation
  • Humans
  • Lipopolysaccharides
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Murine hepatitis virus/immunology
  • Pathogen-Associated Molecular Pattern Molecules/metabolism
  • Quercetin/pharmacology
  • Receptors, Coronavirus/genetics
  • Specific Pathogen-Free Organisms
  • Spike Glycoprotein, Coronavirus/metabolism

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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