Senolytics reduce coronavirus-related mortality in old mice.

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

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.