A Look at Fisetin: Is Intermittent Supplementation Best?

Fisetin is a flavonoid polyphenol found in many fruits and vegetables, including strawberries, apples, persimmons, cucumbers, and onions—and increasing evidence for its use against cellular senescence is emerging.

Senescence is a hallmark of aging, characterized by irreversible growth arrest of cells. Cellular senescence occurs with increasing age or in response to various stressors, including a buildup of reactive oxygen species or ROS—unstable compounds that cause oxidative stress and can damage cells and DNA.  

This cellular growth arrest is accompanied by SASP—senescence-associated secretory phenotype—which is a complex mechanism that triggers the secretion of damaging compounds, including proteins, cytokines, and growth factors. SASP-associated molecules can then induce the senescence of surrounding cells, leading to a cascade of destruction.  

Researchers have identified several compounds or drugs that act as senolytics, meaning they kill senescent cells. However, senolytics tend not to have specific targets, leading to unwanted clearance of non-senescent cells and an increased risk of toxic side effects.  

Rather, compounds called senotherapeutics can eliminate senescent cells safely and suppress SASP and its damaging features without inducing non-senescent cell death—and fisetin is one of these selective compounds.

In a preclinical study with aged mice, fisetin exhibits senotherapeutic effects, including reducing markers of senescence and SASP in multiple tissues, in addition to extending their median and maximum lifespans.  

But unlike many other supplements in the longevity world, it’s thought that senolytics and senotherapeutics may work best when taken intermittently or in a cyclical fashion—meaning, not daily. This is for two reasons—one, because senescent cells can take several weeks to form and develop a SASP, and two, because daily clearance of senescent cells could interfere with the beneficial aspects of senescence (like wound healing).  

This “hit-and-run” approach was studied in a recent preclinical study with older mice. In this research, aged mice receiving intermittent fisetin supplementation (one week of 100mg of fisetin per kilogram of body weight per day, followed by two weeks off, then one more week on) had reductions in vascular cell senescence. This translated to increased vascular endothelial function—an essential component of blood flow regulation and the ability to deliver oxygen and nutrients throughout the body.  

Mice receiving intermittent fisetin also had elevated nitric oxide bioavailability—a gaseous signaling molecule that acts as a vasodilator, relaxing and widening blood vessels to increase blood flow and circulation. Fisetin also was found to reduce cellular and mitochondrial ROS, a key feature of senescent cells. However, this study did not also test non-intermittent (daily) supplementation to compare the differences between the two methods.

Although fisetin is safe for daily use and no significant adverse effects have been reported, the results from this research showing how intermittent dosing selectively clears senescent cells could be an interesting new approach to fisetin supplementation.

-

* These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.