Removal of senescent cells reduces the viral load and attenuates pulmonary and systemic inflammation in SARS-CoV-2-infected, aged hamsters
Lou Delval, Aline Hantute-Ghesquier, Valentin Sencio, Jean‐Michel Flaman, Cyril Robil, Fabiola Silva Angulo, Larissa Lipskaia, Özmen Çobanoglu, Anne‐Sophie Lacoste, Arnaud Machelart, Adeline Danneels, Mathieu Corbin, Lucie Deruyter, Séverine Heumel, Thierry Idziorek, Karin Séron, Florent Sauvé, Antonino Bongiovanni, Vincent Prévot, Isabelle Wolowczuk, Sandrine Belouzard, Jean‐Michel Saliou, Philippe Gosset, David Bernard, Yves Rouillé, Serge Adnot, Martine Duterque‐Coquillaud, François Trottein
Abstract
Older age is one of the strongest risk factors for severe COVID-19. In this study, we determined whether age-associated cellular senescence contributes to the severity of experimental COVID-19. Aged golden hamsters accumulate senescent cells in the lungs, and the senolytic drug ABT-263, a BCL-2 inhibitor, depletes these cells at baseline and during SARS-CoV-2 infection. Relative to young hamsters, aged hamsters had a greater viral load during the acute phase of infection and displayed higher levels of sequelae during the post-acute phase. Early treatment with ABT-263 lowered pulmonary viral load in aged (but not young) animals, an effect associated with lower expression of ACE2, the receptor for SARS-CoV-2. ABT-263 treatment also led to lower pulmonary and systemic levels of senescence-associated secretory phenotype factors and to amelioration of early and late lung disease. These data demonstrate the causative role of age-associated pre-existing senescent cells on COVID-19 severity and have clear clinical relevance.