Coronavirus-19 (CoV) can cause physical dysfunction, morbidity, and death from hyper-inflammation, acute respiratory distress syndrome (ARDS), and multi-organ failure, particularly in older or chronically-ill individuals. Across the US, >50% of CoV deaths are in nursing homes and 25-50% of nursing home residents who test positive for CoV die from these complications. Senescent cells accumulate with age and drive frailty and chronic diseases. These cells can acquire a senescence-associated secretory phenotype (SASP) entailing release of many of the same factors as in CoV-induced cytokine storm. We found CoV antigens exacerbate the SASP, SASP factors increase CoV viral entry proteins, and SASP factors impair viral defense mechanisms in non-senescent cells. A coronavirus related to human CoV rapidly kills old but not young mice. We discovered drugs that selectively eliminate senescent cells, senolytics. They alleviate age-related phenotypes and chronic disorders in mice and are now in clinical trials, in which they have been found to reduce senescent cell burden, inflammation, and frailty. We found that Fisetin, a natural product flavonoid, has a favorable safety profile in old mice, monkeys, and elderly humans with multi-morbidity in a trial now underway in which 53 patients have been treated. Fisetin decreased cytokine storm and mortality in mice infected with ?-coronavirus. An FDA- approved clinical trial of ours has now begun in older hospitalized CoV patients to prevent progression to respiratory failure. Our hypothesis is that targeting senescent cells with Fisetin will delay or prevent complications of CoV infection in those at great risk: elderly nursing home residents.
Aim 1 is to test if Fisetin prevents progression of morbidity in nursing home residents with rt-PCR-proven CoV infection but no, mild, or moderate symptoms (WHO/NIH Classification) in a double-blind, placebo-controlled, multicenter clinical trial across nursing homes associated with the NIA-supported Translational Geroscience Network. The primary outcome in men and women age >65 (75 Fisetin-treated, 75 placebo) will be prevention of progression, based on the WHO Ordinal Scale for Clinical Improvement of CoV. Other outcomes will be safety, need for supplemental oxygen, escalation of care, and death. TGN-based nurses/study coordinators with their own PPE will minimize impact on thinly-stretched nursing home staff. Fisetin can be provided to the study subjects in foods and drinks.
Aim 2 is to test if Fisetin delays, prevents, or alleviates hyper-inflammation and ARDS/multi- organ failure in CoV-infected elderly nursing home residents. When feasible, we will ascertain if Fisetin decreases SASP factors, senescent cell abundance, and viral entry proteins and reduces: progression to severe or critical CoV, delirium, and hypo-oxygenation.
Aim 3 is to test if Fisetin promotes recovery of CoV- infected nursing home residents followed up to 6 months, including antibody response, physical function, and lung fibrosis. This trial will pave the way for more nursing home trials of interventions not only for CoV, but other conditions in the frail elderly. The impact of this clinical trial will extend beyond the current CoV epidemic.

Public Health Relevance

Most deaths from -coronavirus-19 in the US are in elderly, chronically-ill nursing home residents from hyper- inflammation, cytokine storm, thrombosis (strokes, heart attacks), and multi-organ failure. Senescent cells that accumulate with aging and chronic disease produce factors that cause inflammation, thrombosis, fibrosis, and impaired resistance to viruses and that promote entry of -coronavirus-19 into normal cells. We discovered drugs that ablate senescent cells, senolytics, including the natural product, Fisetin, and found: 1) Fisetin decreases death of old mice infected with -coronavirus, 2) Fisetin causes few or no side-effects in frail elderly humans, and 3) senolytics decrease senescent cells and inflammation in humans, so we propose a double- blind, placebo-controlled clinical trial of Fisetin to decrease progression and complications in older nursing home residents who have -coronavirus-19 across the multi-center Translational Geroscience Network.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZAG1)
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Sazonova, Irina Y
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Mayo Clinic, Rochester
United States
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