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Senolytics reduce coronavirus-related mortality in old mice

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

Online: https://science.sciencemag.org/content/early/2021/06/07/science.abe4832.abstract

Issue: Science. 2021 Jun 8;eabe4832.


The COVID-19 pandemic has revealed the pronounced vulnerability of the elderly and chronically-ill to 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 (SnC) 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 anti-viral 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 using senolytic drugs before or after pathogen exposure significantly reduced mortality, cellular senescence, and inflammatory markers and increased anti-viral antibodies. Thus, reducing the SnC burden in diseased or aged individuals should enhance resilience and reduce mortality following viral infection, including SARS-CoV-2.