Fisetin for COVID‐19 in skilled nursing facilities: Senolytic trials in the COVID era

Verdoorn, Brandon P.; Evans, Tamara K.; Hanson, Gregory J.; Zhu, Yi; Langhi Prata, Larissa G. P.; Pignolo, Robert J.; Atkinson, Elizabeth J.; Wissler‐Gerdes, Erin O.; Kuchel, George A.; Mannick, Joan B.; Kritchevsky, Stephen B.; Khosla, Sundeep; Rizza, Stacey A.; Walston, Jeremy D.; Musi, Nicolas; Lipsitz, Lewis A.; Kiel, Douglas P.; Yung, Raymond; LeBrasseur, Nathan K.; Singh, Ravinder J.; McCarthy, Teresa; Puskarich, Michael A.; Niedernhofer, Laura J.; Robbins, Paul D.; Sorenson, Matthew; Tchkonia, Tamara; Kirkland, James L.

The burden of senescent cells (SnCs), which do not divide but are metabolically active and resistant to death by apoptosis, is increased in older adults and those with chronic diseases. These individuals are also at the greatest risk for morbidity and mortality from SARS‐CoV‐2 infection. SARS‐CoV‐2 complications include cytokine storm and multiorgan failure mediated by the same factors as often produced by SnCs through their senescence‐associated secretory phenotype (SASP). The SASP can be amplified by infection‐related pathogen‐associated molecular profile factors. Senolytic agents, such as Fisetin, selectively eliminate SnCs and delay, prevent, or alleviate multiple disorders in aged experimental animals and animal models of human chronic diseases, including obesity, diabetes, and respiratory diseases. Senolytics are now in clinical trials for multiple conditions linked to SnCs, including frailty; obesity/diabetes; osteoporosis; and cardiovascular, kidney, and lung diseases, which are also risk factors for SARS‐CoV‐2 morbidity and mortality. A clinical trial is underway to test if senolytics decrease SARS‐CoV‐2 progression and morbidity in hospitalized older adults. We describe here a National Institutes of Health‐funded, multicenter, placebo‐controlled clinical trial of Fisetin for older adult skilled nursing facility (SNF) residents who have been, or become, SARS‐CoV‐2 rtPCR‐positive, including the rationale for targeting fundamental aging mechanisms in such patients. We consider logistic challenges of conducting trials in long‐term care settings in the SARS‐CoV‐2 era, including restricted access, consent procedures, methods for obtaining biospecimens and clinical data, staffing, investigational product administration issues, and potential solutions for these challenges. We propose developing a national network of SNFs engaged in interventional clinical trials.