Senolytics reduce coronavirus-related mortality in old mice

Science. 2021 Jul 16;373(6552):eabe4832. doi: 10.1126/science.abe4832. Epub 2021 Jun 8.

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.

Publication types

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

MeSH terms

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

Substances

  • Flavonols
  • Lipopolysaccharides
  • Pathogen-Associated Molecular Pattern Molecules
  • Receptors, Coronavirus
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Quercetin
  • fisetin
  • Dasatinib

Supplementary concepts

  • COVID-19 drug treatment