Longevity Briefs: Targeting 'Zombie Cells' To Protect Against COVID-19

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Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

Why is this research important: One of the main ways in which COVID-19 kills is by causing a cytokine storm, a powerful inflammatory reaction that causes potentially fatal hypotension (low blood pressure) and organ damage. The elderly are more at risk of a cytokine storm because ageing is accompanied by an increase in the levels of inflammatory molecules that circulate in the blood, even in the absence of infection, while the immune system as a whole gravitates towards a more inflammatory state. This is called inflammageing.

One of the drivers of inflammageing is the accumulation of senescent cells with age. These are ‘zombie cells’ that have stopped dividing and release various harmful signalling molecules, including inflammatory mediators. Drugs that can can clear senescent cells, called senolytics, might therefore help reduce the risk of cytokine storm.

What did the researchers do: In this study, researchers investigated how human senescent cells responded to the presence of pathogen-associated molecules including SARS-CoV-2 spike protein. They then exposed old mice to unencountered pathogens including a SARS-CoV-2-related mouse coronavirus, and studied whether targeting senescent cells using senolytic drugs (Fisetin and Dasatinib+Quercetin) could improve the mice’s chance of survival.

Key takeaway(s) from this research: Human senescent cells became hyperinflammatory in response to the SARS-CoV-2 spike protein, and also released signals that reduced the expression of antiviral genes in neighbouring cells. In old mice, both senolytic treatments reduced mortality at 30 days from 100% to roughly 50%, reduced cellular senescence and inflammatory markers, and increased anti-viral antibody levels.

30 day survival in young control mice, old control mice, old mice treated with Fisetin and old mice treated with Dasatinib+Quercetin
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This study hints at the possibility of protecting at risk groups against a range of pathogens simply by treating the underlying biology of ageing. It’s worth noting that Fisetin was able to protect mice against adverse effects even when administered after infection, which would increase its usefulness should it also prove successful in treating human disease. Several clinical trials are currently investigating whether Fisetin can reduce COVID-19 mortality in hospitalised elderly patients (NCT04476953) and in nursing homes (NCT04537299).