Tier 4 — mechanistic

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. Singh, Teresa McCarthy, Michael A. Puskarich, Laura J. Niedernhofer, Paul D. Robbins, Matthew Sorenson, Tamara Tchkonia, James L. Kirkland

Journal of the American Geriatrics Society 2021 69:3023-3033

Bibliography

DOI: 10.1111/jgs.17416
PubMed: PMID 34375437
PubMed Central: PMC8447437
Funding: 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
Competing interests: Patents on senolytic drugs and their uses are held by Mayo Clinic and the University of Minnesota. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and was conducted in compliance with Mayo Clinic conflict of interest policies.

Study snapshot

Design	Randomized, placebo-controlled, double-blind secondary prevention pilot study
Model	Human subjects (skilled nursing facility residents aged 65+)
Sample	150 randomized subjects (target)
Intervention	Fisetin (~20 mg/kg/day orally or by feeding tube) for 2 consecutive days, repeated one week later (Days 0, 1, 8, and 9)
Duration	6 months total participation (screening, 4 days treatment, follow-up visits)
Endpoints	Prevention of SARS-CoV-2 disease complications by a 7-point ordinal severity scale; Evaluation of safety and tolerability of Fisetin; Reduction of progression of severity of SARS-CoV-2 infections; Decrease in senescent cells, inflammation, and physical dysfunction (frailty)

What the study showed, in plain terms

Older adults residing in skilled nursing facilities face disproportionate risks from COVID-19, potentially exacerbated by a higher burden of senescent cells. These are aging, metabolically active cells that resist death and secrete inflammatory factors, contributing to age-related chronic diseases and overall immune dysfunction.

This paper outlines the scientific rationale and operational design for the COVID-FIS trial, a Phase II placebo-controlled clinical study. The researchers hypothesize that administering the senolytic compound Fisetin could selectively clear senescent cells, thereby reducing the hyper-inflammatory response (often referred to as a cytokine storm) and the physical dysfunction associated with COVID-19 infection in highly vulnerable older adults.

Key findings

Trial Design: Initiated a Phase II, randomized, double-blind, placebo-controlled trial to test Fisetin in skilled nursing facility residents.
Target Population: Adults aged 65 and older who reside in a skilled nursing facility and have a test-proven SARS-CoV-2 infection with an oxygen saturation of ≥85% at enrollment.
Dosing Protocol: Oral or feeding-tube administration of Fisetin at approximately 20 mg/kg/day for two consecutive days, repeated a week later (Days 0, 1, 8, and 9).
Primary Endpoint: Measuring the prevention of SARS-CoV-2 disease complications using a 7-point ordinal severity scale adapted from the World Health Organization.

What this study can and cannot tell us

Lack of Outcome Data: This is a protocol and scientific rationale paper; it does not contain active clinical results demonstrating the safety or efficacy of Fisetin for COVID-19 in humans.
Translational Uncertainty: While senolytics like Fisetin have shown promise in reducing coronavirus-related mortality in aged mouse models, these physiological benefits may not directly translate to frail older adults with complex comorbidities.
Dosing Efficacy: It remains unknown if the specific Fisetin dosage utilized in the COVID-FIS trial is optimal for effectively targeting senescent cells in a human clinical population.

Tier 2

Fisetin as a senotherapeutic agent — evidence and perspectives for age-related diseases

Tavenier J et al. · Mechanisms of Ageing and Development · 2024

Tier 3

Fisetin is a senotherapeutic that extends health and lifespan

Yousefzadeh MJ et al. · EBioMedicine · 2018