Fisetin is a flavonoid found in strawberries and other fruits that functions as a senolytic agent, selectively removing senescent (aging) cells from the body. Research in animal models shows it may extend lifespan, reduce inflammation, provide neuroprotection, and support cognitive function. Human clinical trials are ongoing to evaluate its effects on frailty and inflammation in older adults. Due to poor natural bioavailability, enhanced delivery systems like liposomal formulations are often preferred.
Alternative Names: 3,3′,4′,7-Tetrahydroxyflavone, 3,7,3′,4′-Tetrahydroxyflavone
Categories: Flavonoid, Polyphenol, Senolytic, Antioxidant
Primary Longevity Benefits
- Senolytic activity
- Cellular senescence reduction
- Anti-inflammatory effects
Secondary Benefits
- Neuroprotection
- Cognitive support
- Antioxidant protection
- Blood glucose regulation
Mechanism of Action
Fisetin functions as a senolytic agent that selectively induces apoptosis in senescent cells while sparing healthy cells. This selective elimination of senescent cells helps reduce the senescent cell burden that accumulates with age and contributes to age-related dysfunction and chronic inflammation. At the molecular level, fisetin inhibits the PI3K/AKT/mTOR pathway, which is involved in cellular senescence and aging processes. It also activates SIRT1, a longevity-associated gene that regulates various cellular processes including stress responses, metabolism, and DNA repair.
As an antioxidant, fisetin helps neutralize free radicals and reduce oxidative stress, which is a key contributor to cellular damage and aging. It has been shown to increase glutathione levels and enhance the activity of antioxidant enzymes such as superoxide dismutase and catalase. Fisetin modulates various inflammatory pathways by inhibiting NF-κB signaling and reducing pro-inflammatory cytokine production, including TNF-α, IL-6, and IL-1β. This anti-inflammatory action contributes to its potential benefits for age-related conditions characterized by chronic inflammation.
In the brain, fisetin crosses the blood-brain barrier and exerts neuroprotective effects by reducing oxidative stress, inflammation, and protein aggregation. It has been shown to enhance long-term potentiation and synaptic plasticity, which are important for learning and memory. Fisetin also influences glucose metabolism by enhancing insulin sensitivity and promoting glucose uptake in tissues. It activates AMPK (AMP-activated protein kinase), a key regulator of cellular energy homeostasis that influences metabolism and mitochondrial function.
Additionally, fisetin has been shown to inhibit mTOR (mammalian target of rapamycin) signaling, which plays a role in cellular growth, proliferation, and protein synthesis. Inhibition of mTOR is associated with extended lifespan in various model organisms and may contribute to fisetin’s potential longevity benefits.
Optimal Dosage
Disclaimer: The following dosage information is for educational purposes only. Always consult with a healthcare provider before starting any supplement regimen, especially if you have pre-existing health conditions, are pregnant or nursing, or are taking medications.
The typical dosage range for fisetin supplementation is 100-500 mg daily. However, for senolytic purposes, higher doses are often used in a cyclical pattern rather than continuous daily supplementation.
Detailed Information
Dosing strategies for fisetin vary based on the intended purpose. For senolytic effects, which involve the selective elimination of senescent cells, higher doses of 500-1000 mg daily for 2-3 consecutive days, repeated monthly or quarterly, are commonly used in research and clinical settings. This pulse-dosing approach is based on the understanding that senolytic compounds need only be present intermittently to eliminate senescent cells, and continuous exposure is not necessary or potentially beneficial. For general health maintenance and antioxidant support, lower doses of 100-200 mg daily may be sufficient.
When used for cognitive support and neuroprotection, doses typically range from 100-200 mg daily, which may be taken on a more regular basis. It’s important to note that optimal dosing for humans is still being established through ongoing clinical trials. Much of the current dosing recommendations are extrapolated from animal studies and preliminary human research. The Mayo Clinic’s clinical trials on fisetin for senolytic effects in older adults have used doses of 20 mg/kg/day for 3 consecutive days (approximately 1400-1800 mg for a 70-90 kg person), which is higher than typical supplement recommendations.
Due to fisetin’s relatively poor bioavailability in standard form (less than 10%), enhanced delivery systems such as liposomal formulations may allow for effective results at lower doses. When using such formulations, dosage may need to be adjusted downward. As with many supplements, it’s advisable to start with lower doses and gradually increase as needed and tolerated. Individual responses to fisetin may vary based on factors such as age, health status, and concurrent supplements or medications.
By Condition
| Condition | Dosage | Frequency | Notes |
|---|---|---|---|
| Senolytic protocol | 500-1000 mg daily for 2-3 consecutive days | Repeated monthly or quarterly | Higher doses used specifically for senolytic effects, often in pulse dosing patterns rather than continuous use |
| Cognitive support | 100-200 mg daily | Daily or several times per week | Lower doses may be effective for general neuroprotection and cognitive benefits |
| General antioxidant support | 100-200 mg daily | Daily or several times per week | For general health maintenance and antioxidant protection |
| Anti-inflammatory support | 200-500 mg daily | Daily or several times per week | Moderate doses may help manage chronic inflammation |
By Age Group
| Age Group | Dosage | Notes |
|---|---|---|
| Adults (18-50) | 100-200 mg daily | Lower doses typically sufficient for preventative benefits in younger adults |
| Older adults (50+) | 200-500 mg daily or senolytic protocol | Higher doses or senolytic protocols may be more beneficial for older adults with greater senescent cell burden |
Special Populations
| Population | Recommendation | Notes |
|---|---|---|
| Pregnant or nursing women | Not recommended due to insufficient safety data | Should be avoided during pregnancy and lactation |
| Individuals with bleeding disorders | Use with caution and medical supervision | May have mild anticoagulant effects |
| Individuals on multiple medications | Consult healthcare provider before use | Potential for drug interactions, particularly with blood thinners and medications metabolized by cytochrome P450 enzymes |
Bioavailability
Absorption Rate
Fisetin has poor natural bioavailability, with estimates suggesting less than 10% absorption in its standard form.
This low bioavailability is primarily due to its limited water solubility, extensive first-pass metabolism in the intestine and liver, and rapid elimination from the body. After oral administration, fisetin undergoes significant metabolism, primarily through glucuronidation and sulfation, resulting in metabolites that may have different biological activities compared to the parent compound.
Pharmacokinetics
Absorption: Absorption occurs primarily in the small intestine. As a flavonoid, fisetin is subject to the same absorption limitations as many other polyphenols, including poor water solubility and extensive metabolism before reaching systemic circulation.
Distribution: Once absorbed, fisetin can distribute to various tissues, including crossing the blood-brain barrier, which is significant for its neuroprotective effects. However, due to its poor bioavailability, tissue concentrations may be relatively low with standard formulations.
Metabolism: Fisetin undergoes extensive Phase II metabolism, primarily through glucuronidation and sulfation in the intestine and liver. The primary metabolites include fisetin glucuronides and sulfates, which may have altered biological activity compared to the parent compound.
Elimination: Fisetin and its metabolites are primarily eliminated through renal excretion, with a relatively short half-life of approximately 3-4 hours for the parent compound.
Enhancement Methods
| Method / Effectiveness Rating | Description |
|---|---|
| Liposomal formulations | Encapsulating fisetin in phospholipid bilayers can significantly enhance its bioavailability by protecting it from degradation in the digestive tract and facilitating cellular uptake. Liposomal delivery systems have been shown to increase fisetin bioavailability by 5-10 times compared to standard formulations. |
| Phytosome complexes | Complexing fisetin with phospholipids creates a phytosome structure that enhances absorption through the intestinal epithelium. This technology can improve both the absorption rate and the amount of fisetin reaching systemic circulation. |
| Nanoparticle delivery | Formulating fisetin as nanoparticles increases its surface area and can improve dissolution rate and bioavailability. Various nanoparticle formulations, including solid lipid nanoparticles and polymeric nanoparticles, have shown promise for enhancing fisetin delivery. |
| Taking with fat-containing meals | As a lipophilic compound, fisetin absorption can be enhanced when taken with dietary fats, which stimulate bile release and may facilitate absorption through mixed micelle formation. |
| Combining with quercetin | Co-administration with quercetin, another flavonoid, may enhance fisetin bioavailability through competitive inhibition of metabolizing enzymes, potentially reducing first-pass metabolism. |
| Micronization | Reducing particle size through micronization can increase the dissolution rate of fisetin, potentially improving its absorption in the gastrointestinal tract. |
| Cyclodextrin complexation | Forming inclusion complexes with cyclodextrins can enhance fisetin’s aqueous solubility and stability, potentially improving its bioavailability. |
| Piperine co-administration | Black pepper extract containing piperine may enhance fisetin absorption by inhibiting certain drug-metabolizing enzymes and P-glycoprotein efflux pumps. |
Timing Recommendations
Fisetin is best taken with meals containing fat to improve absorption, as its lipophilic nature makes it more readily absorbed in the presence of dietary fats. For standard formulations, taking fisetin with breakfast or lunch that contains healthy fats may optimize absorption. When using fisetin as part of a senolytic protocol (higher doses for 2-3 consecutive days), maintaining consistent timing across the dosing period may help maintain more stable blood levels. For enhanced bioavailability formulations such as liposomal fisetin, the timing may be less critical, but following manufacturer recommendations is advisable.
If taking multiple doses throughout the day, spacing them evenly with meals may help maintain more consistent blood levels.
Food Interactions
Enhancing Foods
- Fatty foods (avocados, nuts, olive oil)
- Medium-chain triglycerides (MCT oil)
- Full-fat yogurt or milk
Inhibiting Foods
- No specific inhibiting foods have been well-documented, though high-fiber meals might theoretically reduce absorption rate
Safety Profile
Safety Rating
Safety Overview
Fisetin appears to have a favorable safety profile based on available research, though long-term human studies are limited. It has been consumed as part of the human diet for centuries in fruits and vegetables, particularly strawberries. Preclinical studies in animals have shown minimal toxicity even at relatively high doses. The limited human clinical trials conducted thus far have not reported serious adverse effects.
However, as a bioactive compound with multiple mechanisms of action, fisetin may have potential interactions with certain medications and may not be appropriate for all individuals.
Side Effects
| Effect | Frequency | Severity | Notes |
|---|---|---|---|
| Mild gastrointestinal discomfort | Uncommon | Mild | May include nausea, stomach upset, or loose stools, particularly at higher doses |
| Headache | Rare | Mild | Typically transient and resolves without intervention |
| Dizziness | Rare | Mild | More commonly reported with higher doses |
| Fatigue | Rare | Mild | Typically transient |
| Mild allergic reactions | Very rare | Mild to moderate | May include skin rash or itching in sensitive individuals |
Contraindications
| Condition | Severity | Notes |
|---|---|---|
| Pregnancy and lactation | Absolute | Insufficient safety data exists for use during pregnancy or breastfeeding |
| Bleeding disorders | Relative | Fisetin may have mild anticoagulant effects and could potentially increase bleeding risk in susceptible individuals |
| Upcoming surgery | Temporary | Should be discontinued at least 2 weeks before scheduled surgery due to potential mild anticoagulant effects |
| Known hypersensitivity to fisetin or related flavonoids | Absolute | Individuals with known allergies to fisetin or similar compounds should avoid use |
Drug Interactions
| Drug Class | Examples | Interaction Severity | Mechanism | Recommendation |
|---|---|---|---|---|
| Blood thinners/anticoagulants | Warfarin, aspirin, clopidogrel, heparin | Moderate | Fisetin may have mild anticoagulant effects that could potentially enhance the action of these medications | Use with caution and medical supervision; monitoring of coagulation parameters may be advisable |
| Immunosuppressants | Cyclosporine, tacrolimus, sirolimus | Theoretical | Fisetin has immunomodulatory effects that could potentially interact with immunosuppressive medications | Use with caution and medical supervision |
| Medications metabolized by cytochrome P450 enzymes | Many prescription medications | Theoretical | Fisetin may inhibit certain cytochrome P450 enzymes, potentially affecting the metabolism of drugs that rely on these pathways | Use with caution, particularly with medications with narrow therapeutic windows |
| Anti-diabetic medications | Insulin, metformin, sulfonylureas | Low | Fisetin may enhance glucose uptake and insulin sensitivity, potentially enhancing the effects of anti-diabetic medications | Monitor blood glucose levels if used concurrently |
Upper Limit
No established upper limit has been determined for fisetin. In preclinical studies, doses equivalent to several grams in humans have been used without significant toxicity. In human clinical trials, doses up to 1000-1800 mg daily for short periods (2-3 days) appear to be well-tolerated. However, long-term safety data for high-dose fisetin supplementation is limited.
For general use, staying within the 100-500 mg daily range is recommended unless higher doses are being used under a specific protocol with appropriate monitoring. For senolytic protocols using higher doses (500-1000 mg daily), limiting use to 2-3 consecutive days and using such protocols intermittently (monthly or quarterly) rather than continuously may help minimize potential adverse effects.
Special Populations
| Population | Recommendation | Notes |
|---|---|---|
| Children | Not recommended | Safety and appropriate dosing have not been established |
| Elderly | Generally considered safe, but start with lower doses | May be more sensitive to effects and potential interactions due to age-related changes in metabolism and higher likelihood of medication use |
| Liver or kidney impairment | Use with caution and at reduced doses | Clearance may be affected, potentially leading to higher blood levels |
Toxicity
Acute Toxicity: Low based on animal studies. LD50 in mice is >2000 mg/kg body weight.
Chronic Toxicity: Limited data available, but no significant concerns have been identified in available research.
Genotoxicity: No evidence of genotoxicity in standard assays.
Carcinogenicity: No evidence of carcinogenic potential; may have anti-cancer properties.
Regulatory Status
Fda Status
Classification: Dietary Supplement
Details: In the United States, fisetin is regulated as a dietary supplement under the Dietary Supplement Health and Education Act (DSHEA) of 1994. As such, it is not approved for the prevention, treatment, or cure of any disease. The FDA does not evaluate or approve dietary supplements for safety or efficacy before they reach the market. Manufacturers are responsible for ensuring their products are safe before marketing them and that any claims made about the products are not false or misleading. Fisetin has not been the subject of any significant FDA enforcement actions or safety alerts as of the last update.
Labeling Restrictions: Supplement manufacturers cannot make specific disease claims for fisetin (e.g., ‘treats Alzheimer’s disease’ or ‘prevents cancer’). They are limited to structure/function claims (e.g., ‘supports cellular health’ or ‘promotes healthy aging’) or general well-being claims. All such claims must be accompanied by the FDA disclaimer: ‘This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.’
International Status
Eu
- Food Supplement
- In the European Union, fisetin is regulated as a food supplement. It is not approved as a Novel Food under Regulation (EU) 2015/2283, as it has been consumed as part of the normal diet (in strawberries and other foods) prior to May 15, 1997. However, specific high-dose fisetin supplements may potentially fall under novel food regulations in some cases. Health claims for fisetin are strictly regulated under Regulation (EC) No 1924/2006 and must be authorized by the European Food Safety Authority (EFSA). Currently, there are no authorized health claims specific to fisetin in the EU.
- Some individual EU member states may have specific national regulations affecting fisetin supplements.
Canada
- Natural Health Product
- In Canada, fisetin falls under the Natural Health Products Regulations. Products containing fisetin must have a Natural Product Number (NPN) issued by Health Canada before they can be legally sold. Health Canada evaluates these products for safety, efficacy, and quality before they can be marketed. Permitted claims are more flexible than in the US but must be supported by evidence and pre-approved by Health Canada.
Australia
- Complementary Medicine
- In Australia, fisetin is regulated as a complementary medicine by the Therapeutic Goods Administration (TGA). Products containing fisetin must be listed or registered on the Australian Register of Therapeutic Goods (ARTG) before they can be legally marketed. Listed medicines (the most common category for supplements) are not evaluated for efficacy before marketing, but manufacturers must hold evidence to support any claims made.
Japan
- Food with Health Claims
- In Japan, fisetin-containing products would likely be regulated either as a regular food supplement or potentially as a ‘Food with Functional Claims’ if specific health claims are made. The latter requires notification to the Consumer Affairs Agency and scientific evidence to support the claims.
China
- Health Food
- In China, fisetin supplements would be regulated as ‘Health Foods’ by the National Medical Products Administration (NMPA). These products require pre-market approval and must be registered or filed with the NMPA before they can be legally sold. The approval process is rigorous and includes requirements for safety and efficacy data.
Prescription Status
Global Overview: Fisetin is not approved as a prescription medication in any country. It is exclusively available as a dietary supplement or food ingredient. Some clinical trials are investigating its potential therapeutic applications, particularly for age-related conditions, but these have not yet led to approved pharmaceutical products.
Research Status: While not available as a prescription medication, fisetin is being studied in clinical trials for potential therapeutic applications. The Mayo Clinic and other research institutions are conducting trials investigating its effects on frailty, inflammation, and other age-related conditions in older adults. If these trials demonstrate significant benefits, they could potentially lead to pharmaceutical development in the future, though this would likely be many years away.
Regulatory Trends
Recent Developments: There have been no significant recent regulatory developments specifically targeting fisetin. However, there is increasing regulatory attention to anti-aging supplements and senolytics as a category, which may affect fisetin in the future.
Potential Future Changes: As research on fisetin’s senolytic effects continues to develop, there may be increased regulatory scrutiny of high-dose fisetin products, particularly those making explicit or implied anti-aging claims. If clinical trials demonstrate significant therapeutic benefits, there may eventually be interest in developing pharmaceutical-grade fisetin products, which would require formal drug approval processes. Additionally, as the field of senolytics advances, regulatory frameworks may evolve to better address this emerging category of compounds.
Compliance Considerations
For Manufacturers: Manufacturers of fisetin supplements must comply with Good Manufacturing Practices (GMPs) as specified by regulatory authorities in their respective markets. They must ensure product safety, accurate labeling, and avoid making disease claims. In the US, manufacturers must report serious adverse events associated with their products to the FDA. Substantiation for any structure/function claims should be maintained and available upon request.
For Consumers: Consumers should be aware that fisetin supplements, like other dietary supplements, are not evaluated by regulatory authorities for efficacy before marketing. The quality, purity, and potency of supplements can vary significantly between manufacturers. Third-party testing certifications (USP, NSF, ConsumerLab, etc.) can provide additional assurance of product quality.
Synergistic Compounds
Antagonistic Compounds
Cost Efficiency
Relative Cost
Rating: Medium to high
Comparison: Fisetin is generally more expensive than common supplements like vitamin C or D, comparable to mid-tier specialty supplements like CoQ10 or resveratrol, but less expensive than premium longevity compounds like NMN or certain peptides. Enhanced bioavailability formulations such as liposomal fisetin command significantly higher prices than standard forms.
Price Ranges
Standard Formulations
- $0.30-$0.50 per 100mg
- $0.50-$0.80 per 100mg
- $0.80-$1.20 per 100mg
- Price variations typically reflect differences in purity, manufacturing quality, and third-party testing.
Enhanced Bioavailability Formulations
- $1.00-$1.50 per 100mg
- $1.50-$2.50 per 100mg
- $2.50-$4.00 per 100mg
- Liposomal, phytosomal, and nanoparticle formulations typically cost 2-4 times more than standard forms but may offer 3-10 times greater bioavailability.
Cost Per Effective Dose
Standard Formulations
- $0.30-$1.20 per day (100-200mg)
- $1.50-$6.00 per day (500-1000mg for 2-3 days)
- When used cyclically (e.g., 3 days monthly), the annualized cost of senolytic protocols is substantially lower than daily use.
Enhanced Bioavailability Formulations
- $1.00-$5.00 per day (100-200mg)
- $5.00-$20.00 per day (500-1000mg for 2-3 days)
- Higher upfront cost but potentially better value due to increased absorption and efficacy.
Value Analysis
Standard Vs Enhanced: While enhanced bioavailability formulations are significantly more expensive, they may offer better overall value due to fisetin’s naturally poor bioavailability (less than 10%). A standard 100mg dose with 10% bioavailability delivers approximately 10mg of active compound to the bloodstream, while a liposomal formulation might deliver 50-100mg from the same dose. For senolytic effects in particular, achieving adequate tissue concentrations is likely critical for efficacy, making enhanced formulations potentially worth the premium price.
Dosage Considerations: Higher doses used in senolytic protocols (500-1000mg) substantially increase costs, particularly with enhanced formulations. However, the cyclical nature of these protocols (typically 2-3 days per month or quarter) makes the annualized cost more reasonable. For general health support, lower daily doses (100-200mg) are more cost-effective and may be sufficient.
Quality Considerations: Higher-priced products often reflect better manufacturing practices, higher purity, and third-party testing. Given the variability in supplement quality and the importance of purity for compounds like fisetin, paying a moderate premium for verified quality from reputable manufacturers is generally worthwhile.
Cost Benefit Ratio: For older adults or those with significant inflammatory conditions who may benefit most from fisetin’s senolytic effects, the cost-benefit ratio may be favorable even at higher price points, particularly when compared to other interventions. For younger, healthy individuals seeking preventative benefits, standard formulations at moderate doses may offer a more appropriate cost-benefit balance.
Cost Saving Strategies
| Strategy | Details | Potential Savings |
|---|---|---|
| Bulk purchasing | Buying larger quantities typically reduces the per-dose cost. Many manufacturers offer significant discounts for multi-bottle purchases. | 15-30% |
| Subscription services | Many supplement companies offer subscription options with regular automatic shipments at reduced prices. | 10-20% |
| Cyclical protocols | Using fisetin cyclically (e.g., 2-3 days monthly or quarterly) rather than daily significantly reduces the annual cost while potentially maintaining senolytic benefits. | 70-90% compared to daily use |
| Combination products | Some products combine fisetin with complementary compounds like quercetin or resveratrol, which may offer better value than purchasing multiple separate supplements. | Varies, but typically 10-30% compared to separate purchases |
| Sales and promotions | Many supplement companies run regular sales events, particularly around holidays. | 10-40% during promotional periods |
Market Trends
Historical Pricing: Fisetin prices have remained relatively stable over the past few years, despite increasing popularity. The introduction of enhanced bioavailability formulations has expanded the price range upward rather than affecting standard formulation pricing.
Future Projections: As research on fisetin continues to develop and manufacturing scales up, prices may gradually decrease, particularly for standard formulations. However, enhanced bioavailability formulations will likely maintain premium pricing due to more complex manufacturing processes and intellectual property considerations.
Comparative Value
Vs Other Senolytics: Compared to other senolytic compounds like dasatinib (a prescription medication used off-label as a senolytic), fisetin is substantially less expensive and more accessible. Compared to quercetin, another natural senolytic, fisetin is moderately more expensive but may offer greater potency based on preclinical research.
Vs Other Antioxidants: Fisetin is more expensive than common antioxidants like vitamin C or E but offers different and potentially complementary mechanisms of action, particularly its senolytic effects, which most basic antioxidants lack.
Stability Information
Shelf Life
Fisetin is generally stable for 2-3 years when properly stored in its dry form. However, this can vary significantly based on the specific formulation, packaging, and storage conditions. Enhanced delivery systems such as liposomal formulations may have shorter shelf lives of 1-2 years due to the potential for oxidation of the phospholipid components.
Storage Recommendations
Store in a cool, dry place away from direct light, heat, and moisture. Ideally, fisetin supplements should be kept at temperatures below 25°C (77°F). Refrigeration is not typically required for dry formulations but may extend shelf life, particularly for enhanced delivery systems like liposomal formulations. Always keep containers tightly closed when not in use to prevent moisture exposure.
If the product changes color significantly (becoming much darker), develops an unusual odor, or shows other signs of degradation, it should be discarded.
Degradation Factors
| Factor | Impact | Details |
|---|---|---|
| Heat | High | Elevated temperatures accelerate the degradation of fisetin. Prolonged exposure to temperatures above 40°C (104°F) can significantly reduce potency. |
| Light | High | Fisetin is photosensitive and can degrade when exposed to direct light, particularly UV light. This is why most supplements are packaged in opaque or amber containers. |
| Moisture | High | Exposure to moisture can accelerate hydrolysis reactions and promote microbial growth, leading to degradation of fisetin. |
| Oxidation | High | As an antioxidant, fisetin is susceptible to oxidation when exposed to air. Oxidized fisetin may have reduced biological activity. |
| pH extremes | Moderate | Fisetin is most stable at slightly acidic to neutral pH (pH 5-7). Strongly acidic or alkaline environments can accelerate degradation. |
Stability In Different Formulations
| Formulation | Stability | Special Considerations |
|---|---|---|
| Powder | Generally stable when kept dry and protected from light and heat. Most susceptible to degradation from moisture exposure. | Should be stored with desiccants and in airtight containers. |
| Capsules | Good stability when properly manufactured and stored. Gelatin capsules may be affected by extreme humidity or dryness. | Vegetable capsules may offer better protection against moisture compared to gelatin. |
| Tablets | Generally stable due to compression and binding agents that limit exposure to environmental factors. | Coating can provide additional protection against moisture and light. |
| Liposomal | More susceptible to degradation due to potential oxidation of phospholipids. Typically has shorter shelf life than dry formulations. | May benefit from refrigeration and addition of antioxidants as stabilizers. |
| Liquid solutions | Least stable form, particularly in water-based solutions. Alcoholic or oil-based solutions may offer better stability. | Should include preservatives and antioxidants; amber glass bottles recommended. |
Stabilization Techniques
| Technique | Description | Effectiveness |
|---|---|---|
| Antioxidant addition | Including complementary antioxidants such as vitamin E, ascorbic acid, or rosemary extract can help protect fisetin from oxidation. | Moderate to high |
| Microencapsulation | Enclosing fisetin particles in a protective matrix to shield from environmental factors. | High |
| Nitrogen flushing | Replacing oxygen in packaging with nitrogen to prevent oxidation during storage. | High |
| Desiccant inclusion | Adding desiccant packets to packaging to absorb moisture. | Moderate for moisture protection |
| pH adjustment | Formulating at optimal pH (slightly acidic to neutral) to minimize degradation. | Moderate |
Stability Testing Methods
Accelerated stability testing under elevated temperature and humidity conditions, Real-time stability testing under recommended storage conditions, HPLC analysis to monitor fisetin content over time, Spectrophotometric analysis for preliminary degradation assessment, Physical observation for color changes, odor, or appearance alterations
Sourcing
Synthesis Methods
| Method | Description | Advantages | Disadvantages |
|---|---|---|---|
| Extraction from plant sources | Fisetin is typically extracted from strawberries or other plant sources using solvents such as ethanol, methanol, or acetone. The extract is then purified through various chromatographic techniques to isolate fisetin from other flavonoids and plant compounds. | Can be more natural if done with food-grade solvents; may retain natural co-factors | Variable yield and purity; potential for solvent residues if not properly processed |
| Chemical synthesis | Fisetin can be synthesized through various chemical routes, typically starting from resorcinol or other phenolic compounds. Common methods include the Allan-Robinson reaction or chalcone route followed by cyclization and selective demethylation steps. | Consistent purity and yield; scalable production; no dependence on agricultural sources | May use harsh chemicals; potentially higher environmental impact; synthetic product may lack natural co-factors |
| Semi-synthesis | Starting with naturally occurring flavonoids or related compounds that are more abundant, then chemically modifying them to produce fisetin. | May be more cost-effective than total synthesis; potentially fewer synthetic steps | Still requires chemical modification steps; intermediate purity concerns |
| Biotechnological production | Using engineered microorganisms or plant cell cultures to produce fisetin through fermentation or biocatalysis processes. | Environmentally friendly; potential for high purity; scalable | Emerging technology; currently higher cost; limited commercial availability |
Natural Sources
| Source | Concentration | Notes |
|---|---|---|
| Strawberries | 160 μg/g | Highest natural food source of fisetin |
| Apples | 26.9 μg/g | Concentration varies by variety; skin contains higher amounts than flesh |
| Persimmons | 10.6 μg/g | Japanese persimmons (Diospyros kaki) are a good source |
| Kiwi | 2.0 μg/g | Moderate source |
| Grapes | 3.9 μg/g | Concentration varies by variety |
| Onions | 4.8 μg/g | Yellow onions contain more than white varieties |
| Cucumbers | 6.5 μg/g | Primarily in the skin |
| Lotus root | 5.8 μg/g | Used in traditional Asian cuisine |
| Acacia trees | Varies | Found in the wood of various Acacia species |
| Rhus verniciflua (Toxicodendron vernicifluum) | Varies | Traditional medicinal plant in East Asia |
Quality Considerations
High-quality fisetin supplements should contain at least 95-98% pure fisetin, verified by HPLC or other analytical methods. Some premium products may offer >99% purity.
- High-Performance Liquid Chromatography (HPLC) for purity determination
- Mass spectrometry for identity confirmation
- Nuclear Magnetic Resonance (NMR) spectroscopy for structural verification
- Testing for heavy metals, microbial contamination, and solvent residues
- cGMP (Current Good Manufacturing Practice) certification
- Third-party testing verification (USP, NSF, ConsumerLab, etc.)
- Organic certification for plant-derived extracts (when applicable)
- Non-GMO verification (when applicable)
- Products not specifying fisetin content or purity percentage
- Unusually low prices compared to market standards (may indicate low purity)
- Lack of third-party testing or quality certifications
- Unclear sourcing information
- Excessive claims not supported by scientific evidence
Supplier Evaluation
- Transparency about sourcing and manufacturing processes
- Provision of certificates of analysis (CoA) for each batch
- Implementation of quality control measures throughout production
- Adherence to cGMP standards
- Investment in research and development
- Sustainability practices
- What is the purity percentage of the fisetin?
- What analytical methods are used to verify purity and identity?
- Is the product tested for heavy metals, microbial contamination, and solvent residues?
- Is the fisetin derived from natural sources or synthesized?
- What measures are taken to ensure batch-to-batch consistency?
- Are certificates of analysis available upon request?
Form Considerations
| Form | Advantages | Disadvantages |
|---|---|---|
| Powder | Versatility in dosing; typically lower cost; can be used in custom formulations | Poor taste; requires measuring; lower bioavailability unless specially formulated |
| Capsules | Convenient; precise dosing; masks taste; widely available | Limited dosage flexibility; may contain additional excipients |
| Tablets | Stable; convenient; often cost-effective | May have lower dissolution rate; typically contains more binders and excipients |
Liposomal fisetin
Phytosome complexes
Nanoparticle formulations
Micronized fisetin
Historical Usage
Traditional Use
Fisetin itself was not specifically identified or isolated for use in traditional medicine systems. However, many plants containing fisetin have been used in various traditional medicine practices around the world. For example, strawberries, which are the richest natural source of fisetin, have been used in European folk medicine for various ailments including digestive issues, gout, and as a general tonic. In traditional Chinese medicine, persimmons (another source of fisetin) have been used to treat digestive disorders, hiccups, and bleeding.
Rhus verniciflua (also known as Toxicodendron vernicifluum), which contains fisetin, has been used in East Asian traditional medicine for centuries to treat digestive disorders, inflammatory conditions, and as a cancer remedy after the allergenic components were removed.
Modern Discovery
Fisetin was first isolated and identified as a plant flavonoid in the late 19th century. Its chemical structure was elucidated in the early 20th century as part of broader research into plant pigments and flavonoids. However, it remained relatively obscure and was primarily of interest to phytochemists rather than medical researchers for many decades. In the late 20th century, as research into flavonoids and their potential health benefits expanded, fisetin began to receive more scientific attention.
Initial studies focused on its antioxidant and anti-inflammatory properties, similar to other flavonoids.
Research Evolution
Pre 2000: Limited research primarily focused on basic biochemical properties and antioxidant activity of fisetin as part of broader flavonoid research. Some early studies examined its potential anti-inflammatory and anti-cancer properties in basic cell models.
2000 2010: Increased research interest in fisetin’s potential neuroprotective effects and mechanisms of action. Studies began to explore its effects on specific cellular signaling pathways and its potential benefits for conditions like diabetes and cancer. The number of published papers on fisetin began to grow significantly during this period.
2010 2018: Research expanded to include more diverse potential applications, including skin protection, anti-allergic effects, and cardiovascular benefits. More sophisticated in vitro and animal studies were conducted to elucidate mechanisms of action. Interest in fisetin’s effects on longevity pathways began to emerge.
2018 Present: Breakthrough research from the Mayo Clinic identified fisetin as a potent senolytic agent capable of selectively eliminating senescent cells, which are implicated in aging and age-related diseases. This discovery dramatically increased interest in fisetin as a potential anti-aging compound. The first human clinical trials specifically investigating fisetin’s senolytic effects in older adults were initiated during this period. Research continues to expand into various aspects of fisetin’s potential health benefits, with particular focus on its senolytic properties and implications for age-related conditions.
Commercial Development
Supplement History: Fisetin has been available as a dietary supplement since the early 2000s, initially marketed primarily for its antioxidant and anti-inflammatory properties. Following the 2018 publication identifying fisetin as a potent senolytic, there was a significant increase in commercial interest and product development. Numerous supplement companies began offering fisetin products specifically marketed for their potential anti-aging and senolytic effects. Enhanced bioavailability formulations, such as liposomal fisetin, began to appear on the market around 2019-2020 in response to concerns about fisetin’s poor natural bioavailability.
Market Evolution: The market for fisetin supplements has grown substantially since 2018, with increasing consumer awareness of its potential benefits for healthy aging. Initially available primarily from specialty supplement companies, fisetin products have become more mainstream and are now offered by numerous supplement manufacturers. Dosages have generally increased over time, particularly for products marketed for senolytic effects, which often recommend higher doses taken cyclically rather than daily. Enhanced bioavailability formulations command premium prices in the market, reflecting both increased production costs and consumer demand for more effective delivery systems.
Notable Milestones
| Year | Event |
|---|---|
| Late 19th century | First isolation and identification of fisetin as a plant flavonoid |
| Early 20th century | Elucidation of fisetin’s chemical structure |
| 1990s | Early research on fisetin’s antioxidant and anti-inflammatory properties |
| 2006 | Publication of research suggesting neuroprotective effects of fisetin |
| 2011 | Studies showing fisetin’s potential to extend lifespan in simple organisms |
| 2018 | Landmark Mayo Clinic study identifying fisetin as a potent senolytic agent capable of extending health and lifespan in mice |
| 2019 | Initiation of first human clinical trials investigating fisetin’s senolytic effects in older adults |
| 2020-present | Expansion of clinical research into fisetin’s potential benefits for various age-related conditions |
Cultural Significance
Fisetin has not had significant cultural or historical significance as an isolated compound, as its specific identification and use is relatively recent.
However , strawberries and other fisetin-containing foods have been valued in various cultures for their health benefits and have featured in traditional diets and folk medicine practices. In recent years, fisetin has gained attention in the longevity and biohacking communities as a potential anti-aging compound, particularly following the 2018 Mayo Clinic research identifying
it as a senolytic agent.
It is frequently discussed in longevity-focused media, conferences, and online communities alongside other compounds being investigated for their potential to extend healthspan and lifespan.
Scientific Evidence
Evidence Rating
Evidence Summary
Fisetin has shown promising results in preclinical studies, particularly in animal models of aging and age-related diseases. Research indicates potential benefits for senolytic activity, neuroprotection, and metabolic health. However, human clinical evidence remains limited, with most studies being small-scale or preliminary. Several clinical trials are currently underway to better establish fisetin’s effects in humans, particularly for senolytic applications in older adults.
Key Studies
Meta Analyses
Ongoing Trials
Research Gaps
Long-term human clinical trials evaluating safety and efficacy, Optimal dosing protocols for different health conditions and age groups, Comparative studies of different bioavailability-enhanced formulations, Effects on specific biomarkers of aging and cellular senescence in humans, Potential interactions with common medications used by older adults, Comparative effectiveness against other proposed senolytic compounds
Expert Opinions
| Expert | Affiliation | Opinion | Source |
|---|---|---|---|
| Dr. James Kirkland | Mayo Clinic | Fisetin shows promise as a senolytic agent based on preclinical studies. Clinical trials are needed to determine its effectiveness in humans. | Various scientific publications and presentations |
| Dr. Paul Robbins | University of Minnesota | Fisetin appears to be one of the most potent natural senolytics identified thus far, with a favorable safety profile compared to some pharmaceutical senolytics. | Co-author on key fisetin studies |
Future Research Directions
Completion of ongoing clinical trials to establish efficacy in humans, Development of more bioavailable formulations, Investigation of potential synergies with other senolytic or geroprotective compounds, Exploration of tissue-specific effects and optimal timing of intervention, Identification of biomarkers to monitor senolytic efficacy in humans
Disclaimer: The information provided is for educational purposes only and is not intended as medical advice. Always consult with a healthcare professional before starting any supplement regimen, especially if you have pre-existing health conditions or are taking medications.