The elderly and chronically ill have been the most vulnerable to COVID-19 since the start of the pandemic. In a new study, researchers demonstrate how cellular senescence may contribute to SARS-CoV-2 infection. In addition, they show that senolytic drugs (which selectively remove senescent cells from the body) significantly reduced mortality in older mice upon infection from a beta-coronavirus closely related to SARS-CoV-2. These findings could reveal a possible new approach to preventing death and severe disease in elderly people infected with SARS-CoV-2.
This work is published in Science in the paper, “Senolytics reduce coronavirus-related mortality in old mice.”
Senescence is a cell state in which affected cells cease dividing and undergo genetic and metabolic changes, including the secretion of a variety of inflammatory factors, proteases, chemokines, and other bioactive compounds. These compounds can, in turn, induce senescence in neighboring cells, causing the cells to accumulate in ever-higher numbers. Cellular senescence contributes to inflammation, multiple chronic diseases, and age-related dysfunction, but effects on responses to viral infection have remained unclear.
The researchers hypothesized that senescent cells play a role in COVID-19 and that removing them with senolytics would dial back inflammation and enable an improved response to viral infection.
“We wanted to determine if therapeutically targeting fundamental aging mechanisms, such as cellular senescence, could reduce morbidity and mortality following viral infection,” said Christina Camell, PhD, an assistant professor in the department of biochemistry, molecular biology, and biophysics at the University of Minnesota, Minneapolis, and a first author of the study.
The team first verified in human cell lines that senescent cells are especially sensitive to the SARS-CoV-2 Spike protein S1, noting that exposure to S1 antigen prompted the cells to accelerate their secretion of inflammatory factors while suppressing their viral defense mechanisms.
Senescent cells, the authors wrote, “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.”
They then exposed aged, sterile mice to pathogens present in pet-store mice, including mouse hepatitis virus (MHV), a close relative of SARS-CoV and SARS-CoV-2, and saw that the mice were hypersensitive to infection. In particular, the older mice were unable to clear MHV—100% of the mice died in less than two weeks—and by the time of death, the mice were positive for MHV but not the other pathogens. In addition, although older mice exposed for the first time to the mouse beta-coronavirus experienced nearly 100% mortality, young mice barely got sick.
When the older mice were treated with senolytic drugs following infection, their survival rate increased to 50%. Treatment with the senolytic compound fisetin, which targets senescent cells, substantially reduced inflammation and mortality in the mice while increasing their levels of antiviral antibodies.
“We have been working on a new approach to help the elderly remain healthy, which is to find therapeutics to treat aging rather than treating each individual disease associated with old age. The fact that senolytics worked to protect old organisms from a viral infection proves that approach is accurate,” Robbins said. “By getting rid of a piece of aging biology, senescent cells, with senolytics, the older mice were able to withstand the stress of infection. This suggests that reducing the burden of senescent cells in ill or elderly individuals could improve their resilience and reduce their risk of dying from COVID-19.”
These results in mice supported the initiation of two clinical trials to reduce mortality in elderly COVID-19 patients. The team also plans to study if senescent cells contribute to the long-hauler effect in many COVID-19 survivors.