As the COVID-19 pandemic ran its course, and it became clear that mortality in the old and the obese was the result of a cytokine storm, there was some speculation that the use of senolytics to clear senescent cells from old tissues would be an appropriate treatment to reduce mortality. Here, researchers provide supporting evidence for this view, showing that senolytic treatment in old mice reduces coronavirus mortality, as well as mortality due to other viral infections.
The risk of suffering a fatal inflammatory event as the result of infection is higher in individuals with an existing high level of systemic inflammation - due to, for example, the accumulation of senescent cells in the body that occurs in later life. Senescent cells secrete pro-inflammatory signals that are an important contributing cause of the chronic inflammation of old age, as well as the raised inflammation that accompanies obesity.
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 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-senescent cells 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 senescent cells using senolytic drugs before or after pathogen exposure significantly reduced mortality, cellular senescence, and inflammatory markers and increased anti-viral antibodies. Thus, reducing the senescent cell burden in diseased or aged individuals should enhance resilience and reduce mortality following viral infection, including SARS-CoV-2.