tetano
Editor, Senior Moderator
Science
. 2021 Jun 8;eabe4832.
doi: 10.1126/science.abe4832. Online ahead of print.
Senolytics reduce coronavirus-related mortality in old mice
Christina D Camell[SUP] #[/SUP][SUP] 1 [/SUP], Matthew J Yousefzadeh[SUP] #[/SUP][SUP] 1 [/SUP], Yi Zhu[SUP] #[/SUP][SUP] 2 3 [/SUP], Larissa G P Langhi Prata[SUP] #[/SUP][SUP] 2 [/SUP], Matthew A Huggins[SUP] 4 [/SUP], Mark Pierson[SUP] 4 [/SUP], Lei Zhang[SUP] 1 [/SUP], Ryan D O'Kelly[SUP] 1 [/SUP], Tamar Pirtskhalava[SUP] 2 [/SUP], Pengcheng Xun[SUP] 5 [/SUP], Keisuke Ejima[SUP] 5 [/SUP], Ailing Xue[SUP] 2 [/SUP], Utkarsh Tripathi[SUP] 2 [/SUP], Jair Machado Espindola-Netto[SUP] 2 [/SUP], Nino Giorgadze[SUP] 2 [/SUP], Elizabeth J Atkinson[SUP] 2 6 [/SUP], Christina L Inman[SUP] 2 [/SUP], Kurt O Johnson[SUP] 2 [/SUP], Stephanie H Cholensky[SUP] 1 [/SUP], Timothy W Carlson[SUP] 5 [/SUP], Nathan K LeBrasseur[SUP] 2 3 [/SUP], Sundeep Khosla[SUP] 2 7 [/SUP], M Gerard O'Sullivan[SUP] 8 9 [/SUP], David B Allison[SUP] 5 [/SUP], Stephen C Jameson[SUP] 4 [/SUP], Alexander Meves[SUP] 10 [/SUP], Ming Li[SUP] 10 [/SUP], Y S Prakash[SUP] 3 11 [/SUP], Sergio E Chiarella[SUP] 12 [/SUP], Sara E Hamilton[SUP] 13 [/SUP], Tamara Tchkonia[SUP] 14 3 [/SUP], Laura J Niedernhofer[SUP] 15 [/SUP], James L Kirkland[SUP] 14 3 16 [/SUP], Paul D Robbins[SUP] 15 [/SUP]
Affiliations
Abstract
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.
. 2021 Jun 8;eabe4832.
doi: 10.1126/science.abe4832. Online ahead of print.
Senolytics reduce coronavirus-related mortality in old mice
Christina D Camell[SUP] #[/SUP][SUP] 1 [/SUP], Matthew J Yousefzadeh[SUP] #[/SUP][SUP] 1 [/SUP], Yi Zhu[SUP] #[/SUP][SUP] 2 3 [/SUP], Larissa G P Langhi Prata[SUP] #[/SUP][SUP] 2 [/SUP], Matthew A Huggins[SUP] 4 [/SUP], Mark Pierson[SUP] 4 [/SUP], Lei Zhang[SUP] 1 [/SUP], Ryan D O'Kelly[SUP] 1 [/SUP], Tamar Pirtskhalava[SUP] 2 [/SUP], Pengcheng Xun[SUP] 5 [/SUP], Keisuke Ejima[SUP] 5 [/SUP], Ailing Xue[SUP] 2 [/SUP], Utkarsh Tripathi[SUP] 2 [/SUP], Jair Machado Espindola-Netto[SUP] 2 [/SUP], Nino Giorgadze[SUP] 2 [/SUP], Elizabeth J Atkinson[SUP] 2 6 [/SUP], Christina L Inman[SUP] 2 [/SUP], Kurt O Johnson[SUP] 2 [/SUP], Stephanie H Cholensky[SUP] 1 [/SUP], Timothy W Carlson[SUP] 5 [/SUP], Nathan K LeBrasseur[SUP] 2 3 [/SUP], Sundeep Khosla[SUP] 2 7 [/SUP], M Gerard O'Sullivan[SUP] 8 9 [/SUP], David B Allison[SUP] 5 [/SUP], Stephen C Jameson[SUP] 4 [/SUP], Alexander Meves[SUP] 10 [/SUP], Ming Li[SUP] 10 [/SUP], Y S Prakash[SUP] 3 11 [/SUP], Sergio E Chiarella[SUP] 12 [/SUP], Sara E Hamilton[SUP] 13 [/SUP], Tamara Tchkonia[SUP] 14 3 [/SUP], Laura J Niedernhofer[SUP] 15 [/SUP], James L Kirkland[SUP] 14 3 16 [/SUP], Paul D Robbins[SUP] 15 [/SUP]
Affiliations
- PMID: 34103349
- DOI: 10.1126/science.abe4832
Abstract
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.