Fisetin is a flavonol, a type of organic compound that falls under the broader category of flavonoids, which are polyphenols. It is found in various plants, including fruits and vegetables such as strawberries, onions, apples, and grapes, contributing to their yellowish tint. Fisetin offers numerous health benefits, primarily due to its potent antioxidant activity that helps scavenge free radicals and combat oxidative stress in the body.

One of the most significant properties of fisetin is its role as a senolytic agent. Senolytics are substances that target and eliminate senescent cells – cells that have stopped dividing and lost their function yet remain in the body, causing inflammatory damage. This damage contributes to tissue and organ dysfunction and various age-related diseases. In a landmark 2018 study, fisetin was the most effective among ten potential senolytics tested on aged mice. This study demonstrated that fisetin cleared senescent cells and extended these mice’s lifespan by over 10% ¹. This property makes fisetin a promising tool for anti-aging interventions.

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Fisetin Benefits in Anti-Aging:

Senolytic Effects: Fisetin acts as a senolytic agent, selectively eliminating senescent cells, which are dysfunctional cells that accumulate with age and contribute to various age-related diseases and tissue dysfunction. ²

Lifespan Extension: In animal studies, fisetin has been shown to extend lifespan by reducing the number of senescent cells in tissues and potentially restoring tissue homeostasis. ³

Neuroprotection: Fisetin has neuroprotective effects in animal models of aging-associated neurological disorders, potentially preventing cognitive and memory impairments.

Anti-inflammatory and Antioxidant Properties: By reducing oxidative stress and inflammation, fisetin can mitigate conditions that often worsen with age, such as neuroinflammation and brain health issues.

Potential Reduction of Age-Related Diseases: Given its various properties, fisetin might help reduce the risk of several common age-related diseases, including cancer, diabetes, cardiovascular diseases, and dementia

Other Health Benefits of Fisetin:

Cancer Prevention and Treatment: Fisetin exhibits anticarcinogenic properties, particularly against pancreatic and colon cancer cells. It has shown antiproliferative properties against various cancers, including inhibiting cancer cells and tumor cells, potentially reducing angiogenesis, and suppressing cancer progression and tumor growth. ⁴

Neuroprotective Effects: Beneficial for brain health, fisetin protects neural cells from degeneration and inflammation, supports the growth of new brain cells, and offers protection against brain-related diseases and cognitive decline.

Potential in Mental Health: Some studies suggest fisetin may improve symptoms of depression and offer protective effects against neurological conditions like stroke and Alzheimer’s disease.

Diabetes Management: Fisetin can help regulate blood sugar levels, making it a potential treatment option for diabetes. It increases insulin levels, enhances the conversion of sugar to energy, and assists in removing sugars from the blood, storing them as glycogen in the liver.

Antibacterial Activity: Initial studies pointed out fisetin’s antibacterial activity. ⁵

These findings predominantly come from animal studies and preclinical research. While the results are promising, it’s important to note that more research, especially human clinical trials, is needed to fully understand the extent and mechanisms of fisetin’s anti-aging benefits. 

Fisetin, a flavonoid polyphenol found in various fruits and vegetables, offers several health benefits beyond its anti-aging properties:

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How Fisetin Works in Anti-Aging:

Targeting Senescent Cells: Fisetin selectively targets and kills senescent cells, which have stopped dividing and contribute to aging and related diseases. By clearing these cells, fisetin helps reduce inflammation and cellular dysfunction associated with aging.

Inhibiting mTOR Pathway: The mechanism for lifespan extension likely involves inhibition of the mTOR pathway, a key regulator of cell growth and metabolism, which, when dysregulated, can lead to aging and age-related diseases. Specifically, Fisetin inhibits the mTOR pathway both indirectly and directly by binding to mTOR and its downstream target, p70S6K, thereby inhibiting their functions.

Neuroprotective Actions: Fisetin is believed to exert neuroprotective effects by decreasing markers of oxidative stress and neuroinflammation in the brain, thus potentially preventing neurodegeneration.

Antioxidant Activity: As an antioxidant, fisetin neutralizes free radicals, reducing oxidative stress, a significant factor in aging and cellular damage.

Anti-Inflammatory Effects: Fisetin’s anti-inflammatory properties are evident in its ability to inhibit inflammatory pathways and its effect on mast cells, which are central to the body’s inflammatory and allergic responses

Dosage

Fisetin, a flavonoid found in many fruits and vegetables, has been studied for its potential benefits in anti-aging and overall health. The protocols and dosages for taking fisetin vary depending on the specific use and form of fisetin:

The recommended dosage for fisetin varies based on the context of its use and the source of information:

1. General Supplements: Most fisetin supplements range from 100-500mg daily. A clinical trial with cancer patients used 100mg per day⁶. For higher doses, such as 1000mg or more, it’s recommended not to take fisetin daily. Instead, supplementing only for a couple of days per month is advised.
2. Clinical Trial for Older Adults: An ongoing clinical trial investigating the effects of fisetin on older adults uses a higher dose of 20mg per kg of body weight for two consecutive days, which amounts to approximately 1,400mg per day for an average-sized person weighing 155 pounds. However, such high doses are not recommended for daily use.⁷
3. Dietary Sources: The amount of fisetin found in common fruits and vegetables varies. For example, strawberries contain 160µg/g, apples 26.9µg/g, onions 4.8µg/g, and grapes 3.9µg/g. Fisetin supplements are significantly higher in concentration than these dietary sources, generally falling in the 100-mg range.
4. Recommended Daily Dosage as a Dietary Supplement: The daily recommended dosage for fisetin as a dietary supplement is suggested to be 100 mg per day. This recommendation is based on human studies that used a daily dosage of 100 mg, calculated from extensive animal data demonstrating efficacy and safety, under United States Food and Drug Administration guidelines.⁸

The varied dosages and protocols reflect the ongoing nature of this research. Individuals interested in fisetin supplementation should consult healthcare professionals to discuss the most appropriate dosage and regimen for their specific health needs and to understand the potential risks and benefits.

Side Effects of Fisetin

Some of the potential side effects include:

Gastrointestinal Distress: Commonly reported with many dietary supplements, fisetin can cause gastrointestinal discomfort. This may manifest as stomach upset, nausea, bloating, or diarrhea. These effects can occur due to the concentrated form of fisetin in supplements, which might be more intense than the natural amounts found in fruits and vegetables.

Allergic Reactions: Allergic responses to fisetin are another potential side effect. These reactions can range from skin issues like itching, hives, or rashes to respiratory symptoms such as sneezing, runny nose, coughing, or shortness of breath, and even digestive problems like nausea, vomiting, abdominal pain, or diarrhea.

Drug Interactions: Fisetin can interact with certain medications, potentially causing complications. For instance, its anti-platelet effects might enhance the blood-thinning action of certain medications, raising the risk of bleeding. Combining fisetin with certain anti-inflammatory drugs could amplify their effects, potentially leading to an excessive immune response. Additionally, mixing fisetin with other antioxidant-rich medications could lead to an overdose.

Hormonal Effects: Fisetin may influence hormonal balance. Its interactions with hormones are complex and can vary depending on individual factors. Fisetin’s estrogenic activity might be beneficial for some but concerning for others. It could also influence testosterone levels and affect thyroid function, potentially affecting metabolism and energy regulation.

Liver Function: Fisetin may impact liver enzymes, critical for various metabolic reactions. Elevated liver enzymes can indicate liver stress or damage, necessitating careful consideration when supplementing with fisetin.

Given the limited scope of research on fisetin, especially in humans, it’s essential to approach its use cautiously. Consulting a healthcare professional before starting fisetin supplements is advisable to assess individual health conditions and potential risks. As with any supplement, personal reactions can vary; what works for one person may not be suitable for another.

Precautions

Specific Groups: Pregnant women, children, and nursing mothers are advised to avoid fisetin supplements due to the lack of safety data for these groups.

Drug Interactions: Fisetin may interact with certain medications, which can be dangerous or even life-threatening in some cases. For example, the liver processes fisetin using the same pathway for the blood-thinning warfarin (Coumadin) medication. This interaction could increase the effects of warfarin. Additionally, fisetin significantly lowers blood sugar in diabetic animals, so combining it with blood-sugar-lowering drugs might lead to an excessive reduction in blood sugar levels.

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Brief History

The history of fisetin dates back to the early 19th century and has involved several significant developments:

Initial Discovery (1833): In 1833, fisetin was first isolated, with varying sources indicating its extraction from either the Venetian sumach plant or the smoke bush. This marked the compound’s first identification.

Chemical Characterization (1886): J. Schmidt, in 1886, described the fundamental chemical attributes of fisetin, a vital step in comprehending its nature and potential applications, including its analysis in cell culture studies.

Defining Chemical Structure (1890s): The 1890s saw S. Kostanecki defining fisetin’s chemical structure. His work expanded scientific knowledge about fisetin, classifying it as a flavonoid and polyphenol in various vegetables, plants, and fruits. It also contributed to the understanding of multiple pathways in which fisetin operates.

Recognition as a Senolytic (2018): Despite being known for almost two centuries, fisetin’s role in targeting aging senescent cells and its contribution to anti-aging and longevity were not recognized until 2018. This recognition established fisetin as a senolytic agent known for its ability to selectively destroy senescent cells linked to accelerated aging and age-related diseases based on extensive research, including clinical trial data.

Fisetin has been studied extensively in food, and chemical toxicology has been identified as a metabolic byproduct in many plants, present in green parts, fruits, bark, and hardwood. The evolution of our understanding of fisetin—from its initial Discovery to its recent recognition in longevity and anti-aging—underscores the continuous development in the scientific exploration of natural compounds and their health benefits.

Conclusion

Fisetin, a flavonoid discovered in 1833 and found in various fruits and vegetables, has gained interest for its potential health benefits, particularly in anti-aging. Its recognition as a senolytic agent in 2018 marked a significant development in understanding its role in longevity. Fisetin is known for its antioxidant, anti-inflammatory, and neuroprotective properties and its ability to remove senescent cells, contributing to longevity and improved quality of life in aging models. However, the safety profile of fisetin, especially in supplemental forms and at higher dosages, still needs to be fully established.

Precautions are necessary, particularly for pregnant women, children, and individuals on certain medications like blood thinners and diabetes drugs. While current research, mainly from animal studies, shows promising results, comprehensive human clinical trials are essential to validate its efficacy, determine optimal dosages, and establish long-term safety. Thus, Fisetin presents a good yet under-explored avenue in natural health and anti-aging research.

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FAQ’s

How does fisetin interact with senescent and normal cells?

Fisetin specifically targets aging senescent cells, facilitating their removal through mechanisms like cell death while maintaining normal cells’ health.

Can fisetin delay aging in senescent cells?

Fisetin’s role in inhibiting cell invasion is crucial, especially in its ability to modify the extracellular matrix, a critical factor in the progression of cancers and the formation of blood vessels.

How does fisetin induce apoptosis in senescent cells?

Fisetin induces apoptosis by disrupting pro-survival pathways within senescent cells. This action overcomes the natural resistance of these cells to apoptosis, leading to their elimination.

What is the significance of reducing senescent cell burden?

Reducing senescent cell burden can prevent age-related diseases and improve overall health and longevity.

Does fisetin impact cellular metabolism?

Fisetin can influence cellular metabolism, protecting against metabolic disorders and supporting cellular health.

Can fisetin affect cell invasion and the extracellular matrix?

Fisetin inhibits cell invasion and may alter the extracellular matrix, a crucial factor in cancer progression and metastasis.

What is the role of fisetin in cancer cells?

Fisetin demonstrates anti-cancer properties, particularly its effectiveness against pancreatic cancer cells, where it inhibits growth and promotes cell death.

What are the anti-cancer properties of fisetin?

Fisetin’s anti-cancer properties include inducing apoptosis in cancer cells and reducing the inflammatory response.

How does fisetin influence the cell cycle in cancer cells?

Fisetin can induce cell cycle arrest in cancer cells, hindering their growth and proliferation, an essential aspect of its anti-cancer effects.

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Citations

1. Fisetin—a new analytic ↩︎
2. Fisetin: A Dietary Antioxidant for Health Promotion ↩︎
3. Fisetin is a senotherapeutic that extends health and lifespan ↩︎
4. Biological effects and mechanisms of fisetin in cancer: a promising anti-cancer agent ↩︎
5. Antibacterial Effect of Fisetin and Fisetinidin ↩︎
6. Phytomedicine-Based Potent Antioxidant, Fisetin Protects CNS-Insult LPS-Induced Oxidative Stress-Mediated Neurodegeneration and Memory Impairment ↩︎
7. Attenuation of reserpine‑induced fibromyalgia via ROS and serotonergic pathway modulation by fisetin, a plant flavonoid polyphenol ↩︎
8. Effect of fisetin supplementation on inflammatory factors and matrix metalloproteinase enzymes in colorectal cancer patients ↩︎