Fisetin is a special kind of polyphenol known to deliver various longevity benefits in cell and animal-based studies. Specifically, fisetin is a flavonoid, a unique class of polyphenols that is believed to prevent disease and encourage healthy aging through potent antioxidant and anti-inflammatory effects.

Perhaps most exciting is fisetin’s ability to function as a senolytic, a compound that may extend lifespan and prevent age-related disease by promoting natural cellular senescence.

There are a variety of foods that naturally contain fisetin. Strawberries, apples, and kiwis are a few of the most common. Though delicious, these foods do not contain enough fisetin to mirror the dosages used in studies.

Supplementation is likely the best way to increase intake of fisetin, although it comes with caveats (see below: Fisetin Dosages and Supplementation)

Compared to other well-known sources of polyphenols and flavonoids like green tea extract and red wine, fisetin has only just recently caught the attention of the scientific community.

Animal and cell culture studies already indicate fisetin is a powerful anti-inflammatory, anti-cancer, and immune supporting compound.

Few human studies have been conducted to date. However, researchers are actively pursuing several studies to better understand fisetin’s role in promoting longevity and extending lifespan.

For example, researchers at the Mayo Clinic in Rochester, Minnesota, are launching several studies at the time of this writing. Most exciting, the clinic plans to investigate the use of fisetin to prevent or reduce symptoms of COVID-19 (see Looking Ahead: Current Clinic Trials to Watch).

The primary mechanisms of action for fisetin include reducing oxidative damage within cells, enhancing existing antioxidants, blocking the NF-KB pathway to reduce inflammation, and blocking the mTOR pathway to promote longevity.

Most surprising, fisetin outperformed resveratrol, quercetin, and curcumin– three well known compounds made popular by vast amounts of research and cultural adoration. The results catapulted fisetin into the limelight, triggering many more cell-based and animal studies. At the time of this writing, over a dozen human studies are being pursued.

Overview of health benefits observed in animal and cell-based research of Fisetin:

• Enhanced Longevity
• Stabilized Blood Sugar Levels
• Reduced Inflammation
• Prevention of Certain Cancers
• Improved Cognition and Neuroprotection
• Prevention of Alzheimer’s and Huntington’s Disease
• Improved Cardiovascular System
• Preservation of Bone Density

Potential risks of Fisetin:

• Few human trials
• Poorly absorbed (although taking fisetin with fish oil or another form of healthy fat may help)
• Little known about side effects and drug interactions in humans
• Not currently “Generally Recognized As Safe” (GRAS) by FDA

Disclaimer: Always consult your health care professional prior to making changes in your diet or exercise regimen, including whether to use supplements like fisetin. Pregnant women, women who are nursing, and children especially must always consult a physician prior to taking supplements or medications.

When it comes to flavonoids, fisetin shows exceptional promise. This plant compound has already demonstrated great potential to ward off disease and promote healthy aging in cell-based and animal studies. These studies have identified at least three core mechanisms of action, including:

• Enhancing antioxidant activity
• Suppressing inflammation
• Inducing senolytic effects

Under prolonged periods of oxidative stress, free radicals have been shown to damage lipids, protein structures, and even DNA itself. Increasing the presence of antioxidants can prevent such damage, as they neutralize free radicals and prevent their adverse effects.

As an antioxidant, fisetin shines. Not only does it neutralize free radicals, but it also promotes the production of other naturally occurring antioxidants within the cell itself.

In one cell-based study, fisetin was found to increase levels of glutathione, a powerful antioxidant that helps cells defend against free radicals and other harmful reactive oxygen species.

In another study, fisetin was found to inhibit tumour growth in rodent liver cells examined in vitro. Commenting on the study, researchers suggest fisetin may have inhibited tumour growth in at least two ways: As an antioxidant, and as an anti-inflammatory.

The NF-κB pathway is one of the most important networks affecting inflammation in the human body. This protein complex responds to environmental stressors, including viruses, UV rays, and even the free radicals mentioned above.

Once triggered, the NF-κB pathway induces a pro-inflammatory response. When overstimulated by excessive stress, research suggests NF-κB overactivity plays a causal role in the development of autoimmune and inflammatory conditions, including rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, multiple sclerosis, and cancerous tumors.

Fisetin may prevent this chain reaction by suppressing NF-κB pathway activation. This was observed in a cell-based study as early as 2009, when researchers found fisetin to inhibit the activity of NF-κB in human mast cell line, or HMC-1.

Elaborating on the study, authors note that fisetin may protect against inflammatory diseases by suppressing NF-κB and “limiting the interactions between mast cells and activated T-cells”.

Enhancing antioxidant activity and suppressing inflammation do not make fisetin unique. Many plant compounds deliver similar health benefits, though not necessarily to the same degree. What makes fisetin different– and what has researchers so excited–is the compound’s added senolytic effects.

According to the Journal of Internal Medicine, senolytic drugs are characterized by the following:

Senolytic compounds (called “senolytics”) can include both synthetic drugs and plant-derived compounds, like the flavonoid fisetin.

Senolytics help organisms clear-out senescent cells, which are cells that have naturally reached end of life.

By proactively removing senescent cells, early trials suggest senolytics like fisetin may delay, prevent, and/or alleviate a wide range of age-related diseases, including cancer, frailty, and diseases associated with the heart, liver, lungs, kidneys, skin, and metabolism.

It is important to note that authors of this report have a financial interest that is related to the research. The authors are affiliated with Mayo Clinic, which owns patents on senolytic drugs. Mayo Clinic is also conducting human trials on the compound (see below, Looking Ahead: Current Human Trials to Watch)

According to a 2013 study published by the peer-reviewed medical journal, Antioxidants and Redox Signaling, the highest concentrations of fisetin can be found in the foods below*:

• Strawberries: 160μg fisetin per gram
• Apples: 26.9μg fisetin per gram**
• Persimmons: 10.6μg fisetin per gram
• Lotus Root: 5.8μg fisetin per gram
• Onion: 4.8μg fisetin per gram
• Grapes: 3.9μg fisetin per gram
• Kiwis: 2.0μg fisetin per gram
• Peaches: 0.6μg fisetin per gram
• Cucumbers: 0.1μg fisetin per gram

*Authors note that concentrations were measured from freeze-dried food samples. Actual concentrations of fisetin may vary depending on where produce is grown, and how it is harvested, transported, prepared, and consumed.

**Authors do not note exactly what kind of apples were measured. This is problematic, given the study was conducted in Iwate, Japan. Iwate is the country’s 3rd largest producer of apples, growing at least 5 different varieties.

Due to unique pigmentation and nutrient content, fisetin concentrations are likely to vary across each: Fuji, Shinano Gold, Jonagold, Fuyukoi, and Orin.

Referring back to the findings published by Antioxidants and Redox Signaling, the region of Iwate, Japan represents a good proxy when considering how feasible it is to consume enough fisetin to receive the antioxidant, anti-inflammatory, and senolytic benefits observed in recent studies.

In Iwate, researchers found average daily intake of flavonoids to be 0.4mg per capita. That differs drastically from what has been studied in two important ways:

• First, it is very low. In current human trials, dosage is ~20mg per kilogram of bodyweight. For a 150lb person, that equals about 1,300mg– well over 3,000x more than residents of Iwate consume naturally.
• Second, and more interestingly, human trials are using a “hit and run” protocol where a high dose of fisetin is administered for two consecutive days, followed by a long break period (typically 30 days).

This intermittent exposure model is very different from the kind of exposure documented in Iwate, where food-based fisetin intake was likely to be relatively consistent over time.

Although a plant-based helps to fortify the body with major vitamins and minerals, certain phytonutrients are difficult to consume in therapeutic quantities. This is especially true for individuals who do not have access to fresh produce, herbs, and spices– to say nothing of exotic varieties of Japanese apples.

In short, a fisetin supplement that delivers around 20mg/kg of bodyweight– along with some fat to enhance absorption– is likely the best way to benefit from the flavonoid’s therapeutic effects. However, more research and human trials are needed.

Enhanced Longevity

When it comes to longevity, leading research suggests the key to living longer and healthier lies in managing a very special cellular pathway named mammalian target of rapamycin, or mTOR. This nutrient-sensitive pathway helps to regulate everything from metabolism to disease prevention and healthy aging in mammals.

Astonishingly, interventions that block the mTOR pathway have been shown to extend lifespan across a variety of organisms, ranging from fruit flies to nematodes and mice.

One explanation: Blocking the mTOR pathway increases cellular autophagy, a critical process in which cells rid themselves of unnecessary or dysfunctional components. In doing so, cells can function healthier, longer, and without complications that lead to DNA damage and cancer.

In one cell-based study, researchers found fisetin to suppress the mTOR pathway and induce autophagy. In doing so, results suggest fisetin supplementation may extend lifespan by promoting cellular senescence, increasing genome stability, and preventing cellular necrosis.

Blood sugar instability can be devastating to health and longevity. Whether a product of genetics or lifestyle choices, frequent blood sugar spikes place a heavy burden on the pancreas. Over time, the pancreas may become unable to produce enough insulin to dispose of blood sugar, leading to a condition known as insulin resistance.

Insulin resistance is often a progressive condition, leading to a variety of costly and fatal health conditions like metabolic syndrome, nonalcoholic fatty liver disease, and type 2 diabetes. Studies now indicate a strong correlation between insulin resistance and cardiovascular disease, the world’s leading cause of death.

Later, a 2013 rodent study found oral administration of fisetin to protect liver cells from damage associated with diabetes. Although fisetin did not directly prevent blood sugar spikes in the study, the findings indicate the plant compound’s potential to mitigate the downstream effects of insulin resistance and associated diseases.

Finally, a 2014 study demonstrated fisetin’s ability to reduce blood lipids, another adverse health condition that may be caused by insulin resistance and diabetes.

According to an epidemiological study published in 2014, eating an anti-inflammatory diet can also reduce inflammation via NF-κB suppression, thereby reducing the risk of age-related diseases like cancer.

This is noteworthy because anti-inflammatory diets are typically plant-based. It is likely that such diets have much higher concentrations of polyphenols and flavonoids, although the aforementioned study did not mention this mechanism of action specifically.

Reducing inflammation is known to not only soothe symptoms, but also to reduce the proliferation of cancerous cells.

Fisetin may help. In one study, key markers of inflammation were notably reduced after administering fisetin to male patients with colon cancer. The study consisted of 37 patients. And with a dose of just 100mg fisetin per day, researchers noted a drop in both IL-8 and hs-CRP, two known markers of systemic inflammation.

It is important to note, however, that researchers did not comment on fisetin’s ability to arrest the proliferation of cancer. Further studies are needed to determine the full extent to which fisetin may serve as an anti-tumor agent.

Improved Cognition and Neuroprotection

Fisetin also appears to promote cognition. However, these studies involve rodents and require a significant caveat: Fisetin can easily cross the blood-brain barrier in mice. Currently, it is unknown if the same holds true for humans.

Nevertheless, research findings are promising and include one study in which fisetin prevented memory loss in mice exposed to toxic levels of scopolamine, a common motion sickness medicine.

In another study, fisetin demonstrated an ability to enhance object recognition and long-term memory in mice. Commenting on the study, researchers suggest fisetin may someday be useful for treating patients with memory disorders.

Fisetin has been shown to intervene in two exciting ways. First, by preventing the release of inflammatory compounds in the brain. Second, by flushing amyloid plaques via promotion of cellular autophagy.

Fisetin has also been shown to prevent Huntington’s Disease, though the mechanism of action may be different. Huntington’s is characterized by a progressive breakdown of neuronal tissue, causing motor impairment, dementia, and death. In a 2011 study, fisetin was found to preserve motor function and extend the life of mice.

Branching out from the heart, arteries and blow flow also play a crucial role in both cardiovascular health and longevity. Blood is the means through which oxygen and nutrients are delivered to each cell in the body. Good arterial health and blood pressure are therefore critical in preventing age-related disease.

At the time of this writing (April 2022), there are 17 human trials listed on ClinicalTrials.gov involving use of fisetin. Some are active, while others are recruiting and have not yet begun.

Major studies have been detailed below to illustrate the dosages and frequency protocols being implemented. Readers interested in benefits, risks, side effects, and potential drug interactions are encouraged to follow each to learn more as results are published.

What we know: Most planned/future human trials are examining effects of fisetin based on 20mg per day per kilogram of bodyweight. For a specific range based on bodyweight in pounds, please see Fisetin Dosages and Supplementation section above.

Mayo Clinic in Rochester, Minnesota USA

Pilot in SARS-CoV-2 of Fisetin to Alleviate Dysfunction and Inflammation

• Aim: To see if fisetin treatment can prevent deterioration of oxygen status and progression from mild to moderate and severe SARS-CoV-2 infection.
• Dosage: ~20 mg/kg/day

COVID-19 Pilot Study of Fisetin to Alleviate Dysfunction and Decrease Complications

• Aim: To see if the senolytic properties of fisetin can reduce complications in patients with COVID-19
• Dosage: ~20mg/kg/day

Alleviation by Fisetin of Frailty, Inflammation, and Related Measures in Older Adults

• Aim: Test the ability of fisetin to reduce inflammation and markers of frailty in elderly adults.
• Dosage: 20mg/kg/day, orally for 2 consecutive days

Pilot in COVID-19 (SARS-CoV-2) of Fisetin in Older Adults in Nursing Homes

• Aim: To test if fisetin can prevent escalation of symptoms and alleviate complications of coronavirus due to inflammatory reaction.
• Dosage: ~20 mg/kg/day

Alleviation by Fisetin of Frailty, Inflammation, and Related Measures in Older Women

• Aim: Test if fisetin will help reduce markers of insulin resistance, inflammation, bone resorption and physical dysfunction in elderly women with gait disturbance.
• Dosage: 20/mg/kg/day

The Steadman Clinic in Vail, Colorado USA

Senolytic Agent Improve the Benefit of Platelet-Rich Plasma and Losartan

• Aim: Determine if fisetin will improve the potency of platelet-rich plasma (PRP) administered during and after surgery on the hip labrum
• Dosage: 20mg/kg per day for the first two days prior to surgery, and days 33, 34, 63, 64, 93, and 94 afterwards.

Use of Senolytic and Anti-Fibrotic Agents to Improve the Beneficial Effect of Bone Marrow Stem Cells for Osteoarthritis

• Aim: Randomized, double-blind, active control clinical trial to evaluate the safety and efficacy of fisetin when used to help treat osteoarthritis in the knee.
• Dosage: 20mg/kg for 4 total days prior to surgery and 6 days afterwards. Specifically, on the 32nd, 31st, 3rd, and 2nd day PRIOR to surgery. Then, on days 32, 33, 61, 62, 90, and 91 after surgery.

St. Jude Children’s Research Hospital in Memphis, Tennessee USA

Trial to Reduce Senescence and Improve Frailty in Adult Survivors of Childhood Cancer

• Aim: To test the impact of two senolytic regimens on walking speed and senescent cells in the blood (comparing a combination of Dasatinib and Quercetin vs. Fisetin alone)
• Dosage: 20mg/kg on days 1, 2, 30 and 31