COVID-19 positive patients with elevated age, diabetes, or other metabolic diseases have two to ten-fold risk of hospitalization from severe morbidity and an elevated mortality rate. Old age, itself, is a key risk factor for metabolic disease. The underlying increase in senescent cells, chronic inflammation, and the accompanying immune dysfunction, are likely drivers of a cytokine storm, severe tissue pathology, including acute respiratory distress syndrome (ARDS) following viral infection. The precise mechanisms behind SARs-CoV2-related mortality in individuals with chronic disease are unknown. Senescent cells and their senescence-associated secretory phenotype (SASP) are established as a driver of aging and most chronic diseases. Genetic or pharmacologic clearance of senescent cells in aged or obese mice, or mice transplanted with senescent cells, improves tissue homeostasis and physical and metabolic function and blunts all-cause mortality. Fisetin is one senolytic that is currently in phase II clinical trials at the Mayo Clinic for multiple diseases, with no evidence of adverse reactions. The Geroscience hypothesis, which proposes to target fundamental aging processes, including senescent cells, as a means for therapeutically reducing age-related causal factors to improve health and resilience in the elderly, is also relevant to obese persons.
β-coronavirus (mouse hepatitis virus; MHV) is one of the first pathogens transferred during the exposure of SPF mice to normal microbial exposure via exposure to pet store mice or their fomite bedding. Preliminary data show that aged mice, with increased senescent cells, a systemic cytokine storm and 85-100% mortality following exposure to fomite bedding as compared to 90% survival in young mice. Strikingly, pretreatment or therapeutic administration of the senolytic fisetin to aged mice suppressed mortality by ~50% and led to the development of MHV-specific antibodies. Senolytic therapy has potential to prevent mortality in COVID-19 positive patients with chronic disease, and it is possible that senolytics in combination with anti-virals or anti-inflammatory drugs may boost survival further. To delineate potential candidates, it is important to define whether infection is altered and which immune pathways are impacted by senolytic treatment.
The central hypothesis for this project states that obesity or age-induced senescent cell burden and immune dysfunction increases susceptibility to β-coronavirus. The immediate goal is to identify how chronic disease-induced mortality to β-coronavirus can be prevented by senolytic therapy. To address this hypothesis, these researchers evaluate the viral infection and the immune cell responses in aged and obese mice, left untreated or given senolytic therapy to reduce the cytokine storm and improve antibody production. This would define immune pathways impacted by senolytic treatment and those left unaltered. The successful completion of the project should lead to clinically relevant approaches to treat the most vulnerable population to COVID-19: the elderly and those with pre-exising conditions like obesity.