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


What is remarkable the first senolytic candidates were discovered very quickly by analyzing they pathways and drug libraries. What is really strange that we don't see dozens of promising candidates. If it is a small molecule 99% of the articles will be about D+Q.

Posted by: Cuberat at October 15th, 2021 7:05 AM

@Cube Rat
You don't look hard enough if you don't see dozens of promising candidates.


But in a field that is still figuring out how to properly identify senescent cells... how will they measure efficacy of their candidate and avoid collateral damage?

'Oh sorry, we killed a bit of your brain and diminished your eyesight. But your liver is now free of SCs.' Kinda doesn't cut it for me.

Posted by: Jones at October 15th, 2021 8:44 AM

I am guessing the mechanism of action here is that senescent cell destruction will stimulate an immune response.

Posted by: JohnD at October 15th, 2021 12:54 PM

Senolytics have a log way to go

The oncology world has been struggling to selectively kill cancer cells for >100 years and still struggling with both means and method

These are the early days of senolytics with a few decades to go before any real breakthoughs

Posted by: Tim Willis at October 15th, 2021 3:13 PM

"" the only senolytic therapy demonstrated to clear senescent cells in old humans is dasatinib and quercetin combination."

This means that Fisetin did not demonstrate to clear scenescent cell in old humans.
Fisetin was tested and found to clear senescent cells in animals (but not in humans).

Senescent cells in animals can be different than senescent cells in humans. What works in animals may not work in humans.

So, this is a flawed (scientifically incorrect) trial-experiment.
The method and procedure must be correct to establish the TRUTH. [true science, not pseudoscience].
1. First there must be a clinical trial to establish that Fisetin clears scenescent cells in humans
( repeated by independent researchers and published)
2. Second, a clinical trial to show that clearance of scenescent cells improves health in patients ( such as reduces symptoms of a disease, or reduces and eliminates signs and symptoms of AGEing.
3. Third , a trial to show that a safe and effective dose of Fisetin clears scenescent cells and improves health.
Why didn't anyone complete these 3 ( trials)? Fisetin had been known for many years

Fisetin is a natural substance and not patentable, clinical trials cost a lot of money .So, the scientists, investors, venture capitalists will not have a huge return on their investment.
Supplement sellers make some money, but they don't bear the costs of clinical trials.

Posted by: Nicholas D. at October 15th, 2021 5:00 PM

@Nicholas It seems to me your point is that Human Trials have not been done on Fisetin because it is not patentable, and thus not cost effective. Of course that is Correct in large part, pretty much everyone that follows this forum on the regular understands that. Curiously Dasatinib, a patented molecule, only works as a senolytic when mixed with ten times as much Quercetin, another unpatentable Flavonol.

Posted by: JohnD at October 15th, 2021 11:21 PM

In the spring of 2013, I was very seriously ill with bilateral pneumonia (according to my assumptions due to MERS-CoV). The recovery began only after I began to eat large quantities of strawberries (source of fisetin). This may be a coincidence, but it is in favor of the hypothesis of fisetin.

Posted by: Dmitry Dzhagarov at October 16th, 2021 12:42 AM

So, drug companies aren't going to test natural anti aging therapies. Supplement companies mostly won't either - so where do we go with this quest?

I wish I was a billionaire who could fund a Foundation For Unprofitable Therapies - to deliberately move science forward.

Posted by: Christopher R. Zell at October 16th, 2021 7:27 AM

I would say fisetin can be tested as an additional control group

Posted by: Cuberat at October 16th, 2021 10:34 AM

@Tim Willis "The oncology world has been struggling to selectively kill cancer cells for >100 years and still struggling with both means and method"

The oncology world didn't have the instruments, tools and methods that have been recently developed and are continuing to be developed at an accelerating pace.

Posted by: Carl White at October 17th, 2021 9:57 AM

These are lots of human clinical trials currently going on, or going to begin shortly, primarily being done at the Mayo Clinic. Look at clinical studies.gov and search "Fisetin"

Posted by: Terri Remedio at October 21st, 2021 7:53 AM
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