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Senolytics reduce coronavirus-related mortality in old mice
Science ( IF 56.9 ) Pub Date : 2021-07-16 , DOI: 10.1126/science.abe4832
Christina D Camell 1 , Matthew J Yousefzadeh 1 , Yi Zhu 2, 3 , Larissa G P Langhi Prata 2 , Matthew A Huggins 4 , Mark Pierson 4 , Lei Zhang 1 , Ryan D O'Kelly 1 , Tamar Pirtskhalava 2 , Pengcheng Xun 5 , Keisuke Ejima 5 , Ailing Xue 2 , Utkarsh Tripathi 2 , Jair Machado Espindola-Netto 2 , Nino Giorgadze 2 , Elizabeth J Atkinson 2, 6 , Christina L Inman 2 , Kurt O Johnson 2 , Stephanie H Cholensky 1 , Timothy W Carlson 7, 8 , Nathan K LeBrasseur 2, 9 , Sundeep Khosla 2, 10 , M Gerard O'Sullivan 7, 8 , David B Allison 5 , Stephen C Jameson 4 , Alexander Meves 11 , Ming Li 11 , Y S Prakash 3, 12 , Sergio E Chiarella 13 , Sara E Hamilton 4 , Tamara Tchkonia 2, 3 , Laura J Niedernhofer 1 , James L Kirkland 2, 3, 14 , Paul D Robbins 1
Affiliation  

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.



中文翻译:

Senolytics 可降低老年小鼠与冠状病毒相关的死亡率

COVID-19 大流行揭示了老年人和慢性病患者对严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 引起的发病率和死亡率的明显脆弱性。细胞衰老会导致炎症、多种慢性疾病和与年龄相关的功能障碍,但对病毒感染反应的影响尚不清楚。在这里,我们证明衰老细胞 (SnCs) 响应病原体相关分子模式 (PAMPs) 变得过度炎症,包括 SARS-CoV-2 刺突蛋白-1,增加病毒进入蛋白的表达并降低非病毒基因的抗病毒基因表达。 -SnCs 通过旁分泌机制。急性感染包括 SARS-CoV-2 相关小鼠 β 冠状病毒在内的病原体的老年小鼠衰老和炎症增加,死亡率接近 100%。在病原体暴露之前或之后使用抗衰老药物靶向 SnCs 可显着降低死亡率、细胞衰老和炎症标志物,并增加抗病毒抗体。因此,减少患病或老年人的 SnC 负担应增强复原力并降低病毒感染后的死亡率,包括 SARS-CoV-2。

更新日期:2021-07-16
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