Fisetin
SupplementMedical evidence for fisetin in humans is very limited (score 28), as few clinical RCTs exist [s1, s7]. The community shows moderate interest and mixed experiences; many users report no measurable effect [c1, c3], which lowers the community score to 55. The gap of -27 reflects the discrepancy between promising animal model data and the absence of confirmed human evidence.
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TL;DR
Fisetin is a flavonoid with compelling senolytic data in animal models, but human evidence remains sparse — and a significant share of users report zero noticeable effect. The popular 'Mayo Protocol' of intermittent high-dosing is extrapolated from rodent studies, not validated in humans. Bioavailability is poor without specialized formulations (liposomal, hydrogel). Anyone on CYP2C19- or CYP1A2-sensitive medications should exercise caution due to potent in vitro enzyme inhibition.
Description
Fisetin is a natural flavonoid with senolytic, antioxidant, and neuroprotective properties; clinical human studies remain limited [s1, s3].
Fisetin (3,3',4',7-tetrahydroxyflavone) is a yellow flavonol occurring naturally in strawberries, apples, persimmons, onions, and cucumbers [s2]. In a Mayo Clinic screening study, fisetin proved to be the most potent senolytic flavonoid among ten tested compounds: it selectively induced apoptosis in senescent cells without significantly damaging healthy cells [s1]. In animal models, intermittent fisetin reduced senescence markers in multiple tissues and extended both the median and maximum lifespan of aged mice [s1]. These findings have generated considerable interest in the longevity community, although translatability to humans has not yet been established [s3]. In humans, only a few Phase I/II pilot studies and ongoing clinical trials exist to date (including NCT06431932, NCT06399809, NCT07195318) [s4, s5, s6]. An initial bioequivalence study demonstrated that an improved formulation (hybrid hydrogel FF-20) significantly increases bioavailability compared to unformulated fisetin [s7]. Liposomal forms also promise improved absorption but are still considered experimental due to the lack of large human studies [s8]. In addition to its senolytic activity, fisetin exhibits neuroprotective properties in preclinical models, anti-inflammatory effects via NF-κB inhibition, and antioxidant activity through stimulation of the Nrf2 signaling pathway [s9, s10]. Clinical human evidence for these additional effects is largely absent. In the oncology field, in vitro and animal models show antiproliferative effects via multiple signaling pathways; clinical human studies are not available [s11].
Legal Status (DE)
In Germany and the DACH region, fisetin is freely available as a dietary supplement (NEM) provided it is classified as a food or food ingredient. No specific EFSA or BfR authorization as a novel food exists; the legal status may change if a novel food classification is applied [s12, s13].
Mechanism of Action
{'CYP450_note_de': 'CYP450 inhibition by pure fisetin: In vitro (recombinant human enzyme assay), isolated fisetin shows potent inhibition of CYP2C19 (IC₅₀ < 0.001 µg/mL), CYP1A2, and CYP2C9; moderate inhibition of CYP2D6; weak inhibition of CYP3A4. These data originate from a study in which fisetin was isolated from Rhus verniciflua extract and tested separately (not as a crude extract). ', 'source_ids_CYP450': ['s18']}
Dosing
Senolytisch (Mayo-Protokoll, intermittierend)
- Dose
- 100–500 mg per day
- Frequency
- 2-3 aufeinanderfolgende Tage pro Monat
- Route
- oral
- Duration
- fortlaufend monatlich
- Timing
- With a high-fat meal for better absorption
- With food
- empfohlen
Tägliche Einnahme (niedrig dosiert, Antioxidans)
- Dose
- 100–200 mg per day
- Frequency
- 1× täglich
- Route
- oral
- Duration
- fortlaufend
- Timing
- With breakfast or a fat-containing meal
- With food
- empfohlen
No official regulatory upper limit exists. In biohacking circles, up to 500 mg daily is discussed [c2]. Long-term safety data for doses exceeding 100 mg daily in humans are lacking; intake >500 mg daily is not advisable without medical supervision [s2, s16].
Unformulated fisetin has poor oral bioavailability. Improved formulations (hybrid hydrogel, liposomal) can significantly enhance absorption [s7, s8]. Intake with fat improves uptake. The intermittent "Mayo Protocol" is based on animal data and has not yet been validated in humans [s1].
Side Effects
| Side Effect | Frequency | Severity |
|---|---|---|
| Cyp450 | selten | leicht |
Contraindications
Fisetin potently inhibits CYP2C9, CYP1A2, and CYP2C19 in vitro. Caution with concomitant use of substrates of these enzymes (e.g., warfarin/CYP2C9, theophylline/CYP1A2, omeprazole/CYP2C19).
Interactions
Synergistic
Quercetin and fisetin are frequently combined in stacks, as both exhibit senolytic activity and may complement each other in mechanisms of action. Clinical RCT evidence for the combination is lacking [s3, c4].
Piperine may improve the bioavailability of fisetin as a CYP3A4 and P-gp inhibitor. Evidence is based on mechanistic considerations and has not been confirmed by clinical studies [s17].
Fisetin and curcumin are frequently used together in anti-inflammatory and senolytic protocols. In cell studies, fisetin was able to eliminate curcumin-induced senescent cancer cells via apoptosis, suggesting a meaningful complementary effect.
Fisetin may support NAD+ longevity pathways as a SIRT1 activator. A combination with NMN could synergistically promote SIRT1 activation and NAD+ metabolism. Evidence is currently based on mechanistic considerations.
Similar to NMN, fisetin as a SIRT1 activator may act synergistically with NR, which also elevates NAD+ levels. The combination targets cellular senescence and NAD+ metabolism.
Spermidine and fisetin are combined in commercial longevity products and share anti-senescent properties. Both compounds address cellular aging via distinct mechanisms.
Apigenin and fisetin are both flavonoids with senolytic and anti-senescent properties and are used together in combination products (e.g., Senolytic Activator). The combination targets the reduction of senescent cells.
Fisetin and berberine both activate AMPK and inhibit mTOR, which could potentiate anti-aging and metabolic benefits. The combination is common in longevity protocols; however, clinical studies are lacking.
Quercetin and fisetin may improve the absorption of epicatechins from green tea or other sources as COMT inhibitors by inhibiting their methylation and excretion. This has been demonstrated in in vitro and animal models.
Resveratrol and fisetin are frequently used together in longevity stacks. Both activate SIRT1, with resveratrol additionally stimulating NMNAT1 and elevating NAD+ levels. The combination targets complementary aspects of the sirtuin pathway.
Caution
CYP2C9 inhibition by fisetin may increase plasma concentrations of warfarin and elevate bleeding risk [s15].
CYP1A2 inhibition by fisetin may increase levels of these substances. Close monitoring when combining is recommended [s15].
Combining multiple antioxidants may theoretically attenuate training adaptations. Individual user reports describe increased fatigue [c3].
Studies
Tier A — High Evidence
Effect Size: Significantly increased AUC and Cmax for FF-20 vs. unformulated fisetin (single dose, double-blind, crossover; n=40); exact values: see full text doi:10.1017/jns.2022.72.
Community Evidence
Top reported benefits
- No perceptible short-term side effects
- Subjective well-being with intermittent high-dose administration (Mayo protocol)
- Combination with quercetin as a popular longevity stack
- Positive reports of increased general vitality (subjective, not objectively measurable)
Top reported issues
- No measurable subjective effect in many users
- Mild gastrointestinal discomfort at higher doses
- Possible fatigue and reduced training motivation with daily use
- Uncertainty regarding optimal dosing protocol and formulation
Several prominent Reddit threads in r/longevity explicitly report no measurable effect from fisetin as a senolytic [c1]. The lack of human evidence is regularly raised by critical users. Popularity is largely driven by animal model data and the influence of longevity influencers (e.g., David Sinclair) [c4]. Users caution against inflated expectations in the absence of clinical confirmation.
Scientific Sources
- Fisetin is a senotherapeutic that extends health and lifespan
Yousefzadeh MJ, Zhu Y, McGowan SJ, et al. (2018). EBioMedicineCPMID:30279143DOI - The neuroprotective effects of fisetin, a natural flavonoid in neurodegenerative diseases: Focus on the role of oxidative stress
Maher P, Dargusch R, Bodai L, et al. (2022). PMC / Frontiers in PharmacologyBLink - The Natural Flavonoid Fisetin Inhibits Cellular Proliferation of Hepatic, Colorectal, and Pancreatic Cancer Cells through Modulation of Multiple Signaling Pathways
Lall RK, Adhami VM, Mukhtar H, et al. (2016). PLOS ONECDOI - Novel Food - Neuartige Lebensmittel
Bundesamt für Verbraucherschutz und Lebensmittelsicherheit (BVL) (2023). BVL Bundesamt für Verbraucherschutz und LebensmittelsicherheitALink - Health assessment of food supplements - BfR
Bundesinstitut für Risikobewertung (BfR) (2023). BfR Bundesinstitut für RisikobewertungALink - Fisetin Reduces the Impact of Aging on Behavior and Physiology in the Rapidly Aging SAMP8 Mouse
Currais A, Prior M, Dargusch R, et al. (2018). PMC / eLifeCLink - Inhibition of Human Cytochrome P450 Enzymes by Allergen Removed Rhus verniciflua Stoke Standardized Extract and Constituents
Kim H, Yoon YJ, Shon JH, et al. (2014). PMC / Evidence-Based Complementary and Alternative MedicineCLink - Ist es sicher, täglich Fisetin einzunehmen? Einblicke in die Vorteile und Dosierung
MASI Longevity Science (2024). masi.euDLink - Fisetin: Benefits, Dosage, Side Effects, Drug Interactions, and Other Important Information
Nootropics Planet Editorial Team (2023). nootropicsplanet.comDLink - Fisetin – Pflanzenstoff: zellverjüngend, antioxidativ & entzündungshemmend
artgerecht Redaktion (2024). artgerecht.comDLink - New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463
Zhu Y, Doornebal EJ, Pirtskhalava T, et al. (2017). AgingCPMID:28273655DOI - Pilot Trial of Fisetin in Healthy Volunteers and Older Adults
Unbekannt (2024). ClinicalTrials.govBLink - Fisetin to Reduce Senescence and Inflammation
Unbekannt (2024). ClinicalTrials.govBLink - Fisetin Supplementation for Healthy Aging
Unbekannt (2025). ClinicalTrials.govBLink - Enhanced bioavailability and pharmacokinetics of a novel hybrid-hydrogel formulation of fisetin orally administered in healthy individuals: a randomised double-blinded comparative crossover study
Gopi S, Amalraj A, Kuttikkadan R, et al. (2022). PMC / Journal not specified in search resultsALink - Liposomal encapsulation of the natural flavonoid fisetin improves bioavailability and antitumor efficacy
Muqbil I, Masood A, Sarkar FH, et al. (2013). International Journal of PharmaceuticsCDOI - The Potential Role of Fisetin, a Flavonoid in Cancer Prevention and Treatment
Elshaer M, Wang L, Shaheen S, et al. (2022). PMC / MoleculesBLink
Community Sources
Storage
Unopened
Store dry, cool, and protected from light at room temperature (15–25 °C).
Opened
Seal container tightly after each use; avoid moisture.
Notes
Fisetin is light-sensitive; store in a dark location. Store liposomal preparations according to manufacturer instructions; refrigeration may be required.