Removal of senescent cells reduces the viral load and attenuates pulmonary and systemic inflammation in SARS-CoV-2-infected, aged hamsters

Older age is one of the strongest risk factors for coronavirus disease 2019 (COVID-19) morbidity and mortality. In an older adult, the chronic accumulation of senescent cells can interfere with the immune system and accentuate inflammation. Here, we sought to determine whether age-associated cellular senescence contributes to the severity of COVID-19 by studying the well-established golden hamster model of severe acute respiratory syndrome coronavirus (SARS-CoV-2)-driven lung disease. We found that aged hamsters (22 months of age) accumulate senescent cells in the lungs and that the senolytic drug ABT-263 (a Bcl-2-family inhibitor) depletes these cells at baseline and during a SARS-CoV-2 infection (when the senescent cell count is typically elevated). Relative to young hamsters (2 months of age), aged hamsters had a greater viral load during the acute phase of infection and displayed higher levels of fibrosis and worse body weight recovery during the post-acute phase. Interestingly, early treatment with ABT-263 was associated with a significantly lower pulmonary viral load and an amelioration of COVID-19-like lung disease in aged (but not young) animals. ABT-263 treatment of aged animals was also associated with lower pulmonary and systemic levels of senescence-associated secretory phenotype factors. We conclude that the removal of senescent cells via treatment with a senolytic reduces the pathologic severity of SARS-CoV-2 infection in aged hamsters. As several senolytics have recently moved into early-stage clinical trials, our present findings have clear clinical relevance.