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Fisetin for COVID-19 in skilled nursing facilities: Senolytic trials in the COVID era |
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| Authors: | Brandon P Verdoorn MD Tamara K Evans BS Gregory J Hanson MD Yi Zhu PhD Larissa G P Langhi Prata PhD Robert J Pignolo MD PhD Elizabeth J Atkinson MS Erin O Wissler-Gerdes MA George A Kuchel MD Joan B Mannick MD Stephen B Kritchevsky PhD Sundeep Khosla MD Stacey A Rizza MD Jeremy D Walston MD Nicolas Musi MD Lewis A Lipsitz MD Douglas P Kiel MD Raymond Yung MB ChB Nathan K LeBrasseur PhD Ravinder J Singh PhD Teresa McCarthy MD MS Michael A Puskarich MD Laura J Niedernhofer MD PhD Paul D Robbins PhD Matthew Sorenson JD MA Tamara Tchkonia PhD James L Kirkland MD PhD |
| Institution: | 1. Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota, USA;2. Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota, USA
Division of Geriatrics and Gerontology, Mayo Clinic, Rochester, Minnesota, USA;3. Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA;4. University of Connecticut Center on Aging, UConn Health, Farmington, Connecticut, USA;5. Life Biosciences, Boston, Massachusetts, USA;6. Sticht Center for Healthy Aging and Alzheimer's Prevention, Winston-Salem, North Carolina, USA;7. Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota, USA Division of Endocrinology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA;8. Division of Infectious Diseases, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA;9. Department of Medicine, Division of Geriatric Medicine and Gerontology, Johns Hopkins University, Baltimore, Maryland, USA;10. Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA;11. Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts, USA Division of Gerontology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA Harvard Medical School, Boston, Massachusetts, USA;12. Geriatrics Center and Institute of Gerontology, University of Michigan, Ann Arbor, Michigan, USA VA Ann Arbor Geriatrics Research, Education and Clinical Center, Ann Arbor, Michigan, USA Department of Internal Medicine Division of Geriatric and Palliative Medicine, University of Michigan, Ann Arbor, Michigan, USA;13. Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota, USA Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, Minnesota, USA;14. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA;15. Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA;16. Legal Contract Administration, Mayo Clinic, Rochester, Minnesota, USA |
| 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. |
| Keywords: | cellular senescence facility for geroscience analysis SARS-CoV-2 senolytics Translational Geroscience Network |