Using the senolytic fisetin to suppress mortality in aged mice acutely exposed to murine beta-coronavirus

Aging and the chronic diseases associated with aging place a tremendous burden on our healthcare system andreduce quality of life for the elderly. As our world population ages dramatically over the next three decades, theburden will only increase. Hence, there is a great need to discover fundamental mechanisms of aging to developrationale strategies for minimizing the impact of aging on our health and economy. This fostered the Gerosciencehypothesis, which posits that therapeutically targeting fundamental mechanisms of aging will yield a largerdividend in terms of improving the health of an aging population than would treating individual age-relateddiseases. The fundamental mechanism of aging where this has borne out most successfully to date is throughelimination of senescent cells. Senolytic drugs were first described by us and others in 2015 and have alreadyfostered multiple clinical trials beginning in 2018. In mice, senolytics improve physical function, tissue health andsuppress all cause mortality. COVID-19 has emerged as an urgent threat to our aged population. The goal of the parent project is to fully define the mechanism by which an aged / senescent immune systemdrives morbidity and mortality using mice as a model organism. The goal of this revision is to use the knowledgeand resources we have to study the role of cellular senescence in driving adverse outcomes in aged organismsacutely exposed to novel viral pathogens. Preliminary data indicate that mice with a substantial senescent cellburden respond much worse to inflammatory challenges than mice without senescent cells. Furthermore,exposure to normal pathogens carried by wild or pet store mice is sufficient to kill old experimental mice housedin specified pathogen-free conditions, but it does not kill young mice. Here, we propose to use this experimentalparadigm to determine if senolytics, drugs that specifically kill senescent cells, suppress mortality in aged, obese,diabetic or diseased mice. The immediate goal of this revision is to generate sufficient preclinical data to supportclinical trials using nutraceuticals with senolytic activity to prevent adverse outcomes in those at high risk ofCOVID-19 infection or grave illness after infection. The long term goal of this project is to enable rigorouslytesting the Geroscience hypothesis.