A Trial of the Senolytic Fisetin as a Treatment for Older SARS-CoV-2 Patients

Senolytic treatments are those that selectively destroy senescent cells, a form of intervention that has produced rejuvenation in older animals. A high dose of the flavonol fisetin is not yet proven to be usefully senolytic in humans, but has shown a surprising degree of efficacy in mice. The only senolytic therapy demonstrated to clear senescent cells in old humans is the dasatinib and quercetin combination. Quercetin itself, though similar to fisetin, does not appear to be usefully senolytic on its own. The paper here notes a clinical trial of fisetin for older COVID-19 patients. It is thought that the larger number of senescent cells present in older individuals contribute meaningfully to a greater susceptibility to the severe inflammatory events that are the cause of death in COVID-19. This is one of a number of trials of fisetin as a senolytic; we might hope that at least one of these studies reports on whether or not senescent cell burden is actually reduced in these patients, as was done in one of the dasatinib and quercetin trials.

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 residents who have been, or become, SARS-CoV-2 rtPCR-positive, including the rationale for targeting fundamental aging mechanisms in such patients.

Link: https://doi.org/10.1111/jgs.17416