Longevity Ingredient Spotlight: Fisetin Benefits

Cellular senescence is one of the twelve Hallmarks of Aging [1]; it is a characteristic of getting older in most organisms (including humans). Fisetin is one of a small group of compounds called senolytics that researchers are studying for countering cellular senescence.

Senescence is a cellular stress response characterized by a permanent state of growth arrest (i.e., cells stop dividing but don’t die) and the production of chemical mediators that influence tissue health. With aging, senescent cells can linger in tissues and gradually accumulate, promoting tissue dysfunction, unhealthy aging, and age-related health decline [2,3].

Senescent cells can be selectively eliminated with senolytics. Senolytics are substances that have an affinity for finding senescent cells, counteracting their pro-survival and anti-apoptotic mechanisms, and driving them into cell death by apoptosis [4]. 

Fisetin supports healthy aging and longevity by promoting the clearance of lingering senescent cells that can drive tissue dysfunction and unhealthy aging.

Fisetin is a senolytic compound. The main benefit of fisetin is to help our body mitigate age-related cellular and tissue dysfunction associated with senescence. Fisetin supports healthy aging and longevity by promoting the clearance of lingering senescent cells that can drive tissue dysfunction and unhealthy aging [5]. These promising scientific findings resulted in the anti-aging and research communities becoming much more interested in fisetin.

What Is Fisetin?

Fisetin is a flavonol, a type of molecule made by some plants that is part of the flavonoid polyphenol group. Like many polyphenols, fisetin plays an important role in protecting plants from environmental stress. Fisetin is found in many plants, including some that are part of the human diet, albeit in low amounts.

The best food sources of fisetin include: 

• Strawberries
• Apples
• Persimmon
• Lotus root
• Onions
• Grapes
• Kiwi
• Peach
• Cucumber

Figure 1: Best fisetin food sources. Source: Rahmani et al (2022). Molecules; 27(24), 9009; Licence: CC BY 4.0.

While these foods supply relatively high amounts of fisetin compared to other foods in the diet, they don’t supply anywhere near the amount of fisetin researchers are using to support a senolytic benefit.    

What Are The Fisetin Benefits?

Similarly to its role in dealing with stress in plants, fisetin also has a role in helping cells that are under stress in our body. The benefits of fisetin are primarily the consequence of two properties that are associated with cellular stress: its antioxidant and senolytic actions. These properties endow fisetin with the ability to promote healthy cellular and tissue function, contribute to healthy aging, and support healthy brain function and cognition with aging [5–7]. 

As an antioxidant, fisetin has the ability to scavenge free radicals and reactive oxygen species (ROS) that contribute to oxidative stress. These molecules can damage other molecules in cells, such as proteins, DNA, and membrane lipids, affecting cellular structures and their functions. Additionally, fisetin promotes the production of natural cellular antioxidant defenses, further contributing to the protection from oxidative damage [6]. 

As a senolytic compound, fisetin has an affinity for normalizing a senescent cell’s pro-survival and anti-apoptotic mechanisms—the lingering senescent cells that accumulate as we get older use these mechanisms to resist apoptosis. The end result is that fisetin supports senescent cells in finally going  through apoptosis, the cellular process used to eliminate cells that are no longer repairable [8]. By promoting the elimination of lingering senescent cells that can drive tissue dysfunction and aging, fisetin supports healthy aging [5,7].

Fisetin also activates a number of signaling pathways that are associated with healthy aging and longevity, such as those involving mTOR, AMPK, and SIRT1, for example [9–13]. Through these pathways, fisetin supports cell quality control processes by helping to balance autophagy [9,10,12–15], which removes dysfunctional or unnecessary cellular components, and mitophagy [16,17], which removes dysfunctional mitochondria. By doing so, fisetin may help to restore tissue homeostasis and to extend healthspan, as supported by studies in aged mice [5]. 

The antioxidant and senolytic actions of fisetin also contribute to healthy brain aging. Studies have shown that fisetin affects multiple pathways involved in the maintenance of neuronal function during aging. Fisetin not only has direct antioxidant activity but it can also increase intracellular levels of glutathione, the major intracellular antioxidant, and maintain mitochondrial function in the presence of oxidative stress [18].  In the brain of aged rats, fisetin enhanced antioxidant defenses that helped to reduce aging-induced oxidative stress, apoptosis, and neurodegeneration, and supported mitochondrial function and autophagy mechanisms [15].

Studies have shown that fisetin affects multiple pathways involved in the maintenance of neuronal function during aging.

In senescence-accelerated prone mice, an animal model in which mice age more quickly than normal, fisetin reduced the cognitive deficits associated with aging and restored markers associated with impaired synaptic function and cellular stress [19]. In normally aged rats, fisetin also supported cognitive and behavioral performance [20]. 

In addition, fisetin can influence the activity of microglia, the primary immune cells of the central nervous system, as well as the production of immune mediators that have a detrimental effect on neuronal function, thereby helping to balance immune responses and signaling in the brain [18]. 

Accumulation of senescent cells is also one of the main drivers of skin aging. Preclinical studies using skin grafts from aged individuals showed that fisetin selectively eliminated senescent dermal fibroblasts, reduced the production of senescence-associated secretory phenotypes (SASP) mediator, and promoted an increase in collagen density [21]. In animal studies, fisetin also promoted hair growth by inducing the proliferation of hair follicle bulge stem cells [22].

Does Fisetin Really Work?

The most robust type of evidence that an intervention works comes from high-quality scientific studies in humans in which the effect of a given compound is compared to that of a placebo control. These are known as randomized placebo-controlled clinical trials. There are several ongoing clinical trials of this type for fisetin as a senolytic, but they haven’t been completed yet. 

Another type of evidence comes from preclinical studies which are carried out in research animals or in vitro (i.e., using cells or fragments of tissues in which pathways and mechanisms can be studied). Although these do not provide the robust evidence of working in humans that a placebo-controlled trial would, they may provide proof of mechanism and proof of principle, i.e., they may show that a given compound targets a certain process or pathway of interest in such a way that qualifies them as a senolytic. That’s the case with fisetin. Despite the lack of completed clinical trials, preclinical and in vitro studies such as the ones described above have provided proof of mechanism and proof of principle that fisetin works as a senolytic to support healthier aging [5–7,18].

Which Is Better: Fisetin or Quercetin?

Quercetin and fisetin are two of the most studied senolytic compounds. Quercetin, like fisetin, is flavonoid polyphenol. Fisetin and quercetin are closely related molecules with very similar chemical structures and color—they are both yellow in color. Therefore, it is highly likely that they have many similar properties and actions. Both fisetin and quercetin are thought to have both senolytic and senomorphic potential [note: senomorphics are compounds that neutralize the senescence-associated secretory profile (SASP) of senescent cells] [23]. 

In a study that screened a panel of flavonoid polyphenols for senolytic activity using senescent murine and human fibroblasts, it was found that, of the 10 flavonoids tested, which included quercetin, fisetin was the most potent senolytic [5]. In this study, fisetin was senolytic when used on its own, while quercetin has, in most studies, been combined with another compound in order to produce a senolytic outcome. And, fisetin may be active as a senolytic in tissues where quercetin is less active or inactive, such as adipose tissue. This combination of reasons gives some advantage to fisetin, but both have shown great potential in preclinical studies. And as with fisetin, clinical trials using quercetin (usually combined with another senolytic compound) are still ongoing. So it’s early to tell with confidence which is better, but since fisetin appears to be the more versatile senolytic compound when used on its own, the edge currently goes to it. 

In a study that screened a panel of flavonoid polyphenols for senolytic activity using senescent murine and human fibroblasts, it was found that, of the 10 flavonoids tested, which included quercetin, fisetin was the most potent senolytic.

For now, based on the available evidence, it seems they’re both good in ways that may complement each other. Because they are both promising senolytic compounds and because we believe their actions may be complementary, we included both fisetin and quercetin in Qualia Senolytic.

Fisetin in Qualia Senolytic

Fisetin supplements differ in their source, extraction processes, and purity levels, all of which can influence their quality. We use fisetin obtained from the stems of Rhus succedanea (Japanese fruit wax tree), the primary source of fisetin for dietary supplements. We use a high-purity standardized extract containing not less than 98% fisetin. 

We chose the recommended serving of fisetin based on the fisetin dosage most commonly being used in clinical research to support senolytic functions. As an example, in several ongoing studies sponsored by the Mayo Clinic, fisetin is being dosed at 20 mg per kg body weight daily, orally for two consecutive days (ClinicalTrials.gov identifier NCT03675724, NCT03430037, NCT04476953, NCT04771611, NCT03325322). The 1400 mg fisetin serving in Qualia Senolytic would correspond to the daily amount being used in these studies for a person weighing approximately 155 pounds (70 kg). Our recommended serving selection also took into account that Qualia Senolytic contains several other ingredients that would be expected to be complementary with fisetin. For example, luteolin, which is also included in Qualia Senolytic, has been shown to complement fisetin in supporting healthy immune signaling [24,25]*

Fisetin Bioavailability 

Most polyphenols—fisetin included—are relatively poorly absorbed through the gut barrier. But science has been showing more and more that they can also act locally inside the gut and may exert effects on gut microbiota and through the gut-brain axis as well. What if some of the functional health benefits of a polyphenol occur because of the poor bioavailability and the interaction with our gut microbiomes? If the polyphenol is made too bioavailable, these benefits may be lessened or missed entirely. Because of this consideration, our science team puts much more weight on scientific studies evaluating body and brain responses over bioavailability alone. And, big picture, despite evidence suggesting poor bioavailability there are a lot of studies suggesting beneficial support for the brain and body even from poorly absorbed polyphenols. 

The data on the bioavailability of fisetin is a main reason that the Mayo Clinic chose to use a high dose of fisetin in their senolytic studies, and why we are recommending the 1400 mg/day serving of fisetin (which for a person of average weight matches the Mayo serving size). In published animal studies of fisetin, oral fisetin in this human-equivalent range has supported the management of senescence cells, which is the main outcome we care about (not bioavailability). We think the recommended serving included in Qualia Senolytic is sufficient taking into account the data on fisetin’s low bioavailability, but we would not be as confident that the amount we've seen in other supplements claiming a senescent cell benefit (often 100 mg of fisetin and sometimes a bit more) would be enough to provide the intended support.*

Is It OK to Take Fisetin Every Day?

In a study in which fisetin was administered to 10 participants, after a month of placebo, at a dose of 200 mg/day (2 x 100 mg/day) for a month, followed by another month of 800 mg/day (2 x 400 mg/day) fisetin, no serious adverse effects were reported [26]. A few mild to moderate side effects occurred in the fisetin group, including upset stomach, nausea, fatigue, and headaches, but these were also observed in the placebo group. So there was no evidence of significant side effects that could be attributed to fisetin taken daily for two months. Still, this was a study with a very small number of participants, so conclusions must be cautious. 

But one of the features of Qualia Senolytic is that it is not something that needs to be taken every day; it is a 2-day a month supplement. The approach to intake recommended (i.e., take for two consecutive days followed by 28 days before the next intake cycle) is consistent with the intermittent intake approaches being used in some ongoing studies, and more broadly with the approach to supplementing with fisetin for senolytic purposes being recommended by experts in the healthy aging community the Neurohacker science team has been in communication with.* 

*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.

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