Intermittent Fisetin Supplementation Improves Vascular Function in Old Mice

Given that the Interventions Testing Program found that fisetin supplementation did not extend life in mice, it is interesting to see that other researchers are still demonstrating that this intervention clears senescent cells and, as a direct consequence, improves function in older mice. Fisetin is something of a puzzle in this respect, and the Mayo Clinic needs to hurry up and publish useful data from their ongoing phase 2 human trials of fisetin supplementation.

Cellular senescence and the senescence-associated secretory phenotype (SASP) contribute to age-related arterial dysfunction, in part, by promoting oxidative stress and inflammation, which reduce the bioavailability of the vasodilatory molecule nitric oxide (NO). In the present study, we assessed the efficacy of fisetin, a natural compound, as a senolytic to reduce vascular cell senescence and SASP factors and improve arterial function in old mice. We found that fisetin decreased cellular senescence in human endothelial cell culture.

In old mice, vascular cell senescence and SASP-related inflammation were lower 1 week after the final dose of oral intermittent (1 week on-2 weeks off-1 weeks on dosing) fisetin supplementation. Old fisetin-supplemented mice had higher endothelial function. Leveraging old p16-3MR mice, a transgenic model allowing genetic clearance of p16INK4A-positive senescent cells, we found that ex vivo removal of senescent cells from arteries isolated from controls but not fisetin-treated mice increased endothelium-dependent dilation, demonstrating that fisetin improved endothelial function through senolysis. Enhanced endothelial function with fisetin was mediated by increased NO bioavailability and reduced cellular- and mitochondrial-related oxidative stress.

Arterial stiffness was lower in fisetin-treated mice. Ex vivo genetic senolysis in aorta rings from p16-3MR mice did not further reduce mechanical wall stiffness in fisetin-treated mice, demonstrating lower arterial stiffness after fisetin was due to senolysis. Lower arterial stiffness with fisetin was accompanied by favorable arterial wall remodeling. The findings from this study identify fisetin as promising therapy for clinical translation to target excess cell senescence to treat age-related arterial dysfunction.



I wonder if the Mayo Clinic isn't releasing what they have found yet because they had some decent results. Big Pharma is as crooked as they come. Just a one person anecdotal but blasting very high dose liposomal fisetin and quercetin for a few days definitely cleared out a lot of trash with me. My guess is high dose liposomal fisetin is on about the same level as that cancer drug and quercetin combo when it comes to clearing senescent cells.

Posted by: Mike Best at December 18th, 2023 7:30 AM

The findings of a 20% reduction in aortic wall stiffness and a 36% reduction in AGEs in the aortic wall are huge IMO. Eta Reductions were relative to the control group.

Posted by: JohnD at December 18th, 2023 8:26 AM

It is interesting to note that the mice fisetin supplementation study confirmed that the supplementation was done via addition to food. Fisetin, as all all flavonoids, has a very bad bioavailability, so like Resveratrol, Ptersostilbene and others it is no surprise that the effect was hardly detectable. Most oft the Fisetin never reached the blood stream after all.

Posted by: Jan at December 18th, 2023 10:35 AM
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