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

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

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3023-3033
Number of pages11
JournalJournal of the American Geriatrics Society
Volume69
Issue number11
Early online dateAug 10 2021
DOIs
StatePublished - Nov 2021

Bibliographical note

Funding Information:
National Institutes of Health, Grant/Award Numbers: P01 AG62413, R01 AG063543‐S1, R01 AG72301, R33 AG61456, R37 AG13925, U19 AG056278; Noaber Foundation; Robert J. and Theresa W. Ryan; The Connor Fund Funding information

Funding Information:
The authors would like to acknowledge the support received from NIH grants R01 AG72301 (PI: James L. Kirkland); R33 AG61456 (Translational Geroscience Network; PI: James L. Kirkland, Stephen B. Kritchevsky, George A. Kuchel, Tamara Tchkonia); R37 AG13925 (PI: James L. Kirkland); P01 AG62413 (Co‐PIs: Sundeep Khosla and James L. Kirkland), U19 AG056278 (PI: Paul D. Robbins), R01 AG063543‐S1 (PI: Laura J. Niedernhofer), the Connor Fund (James L. Kirkland, Tamara Tchkonia), Robert J. and Theresa W. Ryan (James L. Kirkland, Tamara Tchkonia), and the Noaber Foundation (James L. Kirkland, Tamara Tchkonia).

Publisher Copyright:
© 2021 The Authors. Journal of the American Geriatrics Society published by Wiley Periodicals LLC on behalf of The American Geriatrics Society.

Keywords

  • SARS-CoV-2
  • Translational Geroscience Network
  • cellular senescence
  • facility for geroscience analysis
  • senolytics

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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