TY - JOUR
T1 - Senolytics reduce coronavirus-related mortality in old mice
AU - Camell, Christina D.
AU - Yousefzadeh, Matthew J.
AU - Zhu, Yi
AU - Langhi Prata, Larissa G.P.
AU - Huggins, Matthew A.
AU - Pierson, Mark
AU - Zhang, Lei
AU - O’Kelly, Ryan D.
AU - Pirtskhalava, Tamar
AU - Xun, Pengcheng
AU - Ejima, Keisuke
AU - Xue, Ailing
AU - Tripathi, Utkarsh
AU - Espindola-Netto, Jair Machado
AU - Giorgadze, Nino
AU - Atkinson, Elizabeth J.
AU - Inman, Christina L.
AU - Johnson, Kurt O.
AU - Cholensky, Stephanie H.
AU - Carlson, Timothy W.
AU - LeBrasseur, Nathan K.
AU - Khosla, Sundeep
AU - Gerard O’Sullivan, M.
AU - Allison, David B.
AU - Jameson, Stephen C.
AU - Meves, Alexander
AU - Li, Ming
AU - Prakash, Y. S.
AU - Chiarella, Sergio E.
AU - Hamilton, Sara E.
AU - Tchkonia, Tamara
AU - Niedernhofer, Laura J.
AU - Kirkland, James L.
AU - Robbins, Paul D.
N1 - Publisher Copyright:
© 2021 American Association for the Advancement of Science. All rights reserved.
PY - 2021/7/16
Y1 - 2021/7/16
N2 - 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 b-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.
AB - 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 b-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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85110446410&partnerID=8YFLogxK
U2 - 10.1126/science.abe4832
DO - 10.1126/science.abe4832
M3 - Article
C2 - 34103349
AN - SCOPUS:85110446410
SN - 0036-8075
VL - 373
JO - Science
JF - Science
IS - 6552
M1 - eabe4832
ER -
