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Fisetin
Plant flavonol from strawberries (~160 mg/kg fresh weight — the richest natural source), apples, persimmons, and onions, repositioned as the first "scientifically validated senolytic" after Yousefz…
Aliases (5)
Overview
What is Fisetin?
Plant flavonol from strawberries (~160 mg/kg fresh weight — the richest natural source), apples, persimmons, and onions, repositioned as the first "scientifically validated senolytic" after Yousefzadeh et al. 2018 (Mayo, EBioMedicine, PMID 30279143) — selectively clearing senescent ("zombie") cells in aged mice and extending median + maximum lifespan. The Mayo "hit-and-run" protocol — 20 mg/kg × 2 consecutive days, repeated every 1-2 months — is the mechanistically-coherent dosing strategy and the one tested in active trials (AFFIRM-LITE, COVFIS, ALLEGRO-class). Bioavailability is awful (under 5% oral, rapid glucuronidation), partially rescued by liposomal/Novusol/Indena formulations (~3-40× PK improvement in animal data). First published human RCT (Murray-adjacent, knee OA, OARSI 2025) was NEGATIVE for pain/function/cartilage at the Mayo protocol, although safety was confirmed. Subjective experience in users is minimal-to-none, consistent with low bioavailability and a cellular (not neurochemical) mechanism. For a 20-year-old MMA athlete with effectively no senescent-cell load, daily fisetin is not justified. Verdict: OPTIONAL-ADD, MEDIUM — reserved for 1-2 hit-and-run pulses per year post-fight-camp on anti-inflammatory grounds, not as a longevity stack pillar.
Pharmacokinetics
Research Protocols
Disclaimer: These are commonly discussed research protocols and not medical advice.
Peptide Interactions
most-combined-with fisetin (n=67 in community data). Both flavonols, both senolytic-leaning. Dasatinib + quercetin (D+Q) is the other major senolytic protoco…
both modulate mTOR. Common in longevity-focused stacks. Theoretical concern: both suppress mTOR signaling → additive immune/metabolic effects. Communities ru…
orthogonal mechanism. Bryan-Johnson-style stacks combine routinely.
overlapping SIRT1 activation; redundant on that mechanism but additive on antioxidant. Mostly stacked for branding-of-longevity rather than synergy.
autophagy-stimulating; complementary to senolytic. Found together in many longevity protocols.
antioxidant overlap; helpful for glutathione support during high-pulse polyphenol load.
anti-inflammatory overlap; co-administering with fisetin pulse may improve absorption (lipid carrier) and broaden inflammation knockdown.
CYP2C9 inhibition by fisetin theoretically raises warfarin levels. Monitor INR more frequently around pulses.
theoretical additive bleeding risk; fisetin's antiplatelet signal is mild but real.
OATP inhibition by fisetin reduces statin uptake; statin efficacy could fall. Timing-separation by 4-6 h during pulse days.
fisetin's CYP1B1 inhibition + estrogenic-pathway modulation creates an uncharacterized interaction. Defer to oncology.
senescent cells play roles in some chemo responses (treatment-induced senescence is part of mechanism). Senolytic interference during chemo is contraindicate…
What to Expect
- Day 1-2(dosing days): Most users report nothing acutely. A subset report mild GI upset (nausea, loose stools) — likely a high-polyphenol-load effect, not specific. …
- Day 3-7(post-pulse window): A subset of users report a "settling" or "anti-inflammatory wash" — joints feel less stiff, gum or skin inflammation eases, fatigue lift…
Side Effects & Safety 6
Side Effects
- 1GI upset — nausea, loose stools, mild abdominal discomfort during the 2-day pulse (likely from high polyphenol load + carrier-fat combo). Typically self-limited within 12-24 h of last dose.
- 2Mild headache — ~10-15% of users during/after pulse; usually mild, resolves within hours.
- 3Fatigue / transient tiredness during pulse — community survey reports n=6 of 207 (3%); plausible as part of senolytic-cell-clearance response (the SASP cleanup itself may release transient cytokines).
- 4Joint discomfort — paradoxical; reported in the knee-OA RCT as an AE in both placebo and fisetin arms with no group difference.
- 5Dry mouth — mild, transient.
- 6Sleep disturbance — both directions reported (improved sleep in n=6, insomnia in n=2 in community data); not a strong signal either way.
When to Stop
- Pro-oxidant chemistry at very high doses. In vitro, fisetin + Cu2+ catalyzes DNA cleavage. Not demonstrated in vivo at human doses but a caveat for users contemplating mega-dosing (>4-5 g/day).
- Drug-interaction-mediated adverse events. Most plausible: warfarin INR rise (CYP2C9 inhibition — see Drug interactions), statin pharmacokinetic change (OATP inhibition), increased benzodiazepine effect (CYP3A4 inhibition). No published case reports but theoretical.
- Bleeding risk if combined with antiplatelet/anticoagulant. Theoretical, low-confidence; flagged in the supplement-drug AI-seeded interaction matrix.
- Allergic reaction. Standard supplement-allergy possibility; no specific fisetin syndrome documented.
- Theoretical wound-healing impairment. Senescent cells participate in acute wound healing; clearing them during active repair could (in theory) slow healing. No human evidence; mechanism-driven concern only.
- Pulse day 1-2: GI tolerance check. If significant nausea/diarrhea, reduce next pulse to 1,000 mg or skip.
- Post-injury / post-surgery (30-90 day window): Defer pulse — let acute repair complete before clearing senescent cells from healing tissue.
- First time using bioavailability-enhanced form (liposomal/Novusol): Effective exposure is higher; start with single 1,000 mg dose to check tolerance before going to full 1,500-2,000 mg × 2 days.
- Unknown. No human data beyond 12 months. The Mayo knee-OA trial reported 12+ months follow-up with no safety concerns at 3 cycles. The theoretical concern is whether routinely clearing senescent cells across decades has unintended consequences (immune-surveillance changes, wound-healing changes, age-paradox tumor-microenvironment effects).
- For young users (<35): This is the bigger concern because pulse-clearance would be applied to a population that isn't gaining a benefit — no upside to offset theoretical downside.
References
Yousefzadeh MJ et al. 2018, "Fisetin is a senotherapeutic that extends health and lifespan" (EBioMedicine, PMID 30279143)
landmark senolytic paper
View StudyKhan N et al. 2013, "Fisetin: a dietary antioxidant for health promotion" (Antioxid Redox Signal, PMID 23121441)
foundational mechanism review
View StudyVerdoorn BP et al. 2021, COVFIS trial design (J Am Geriatr Soc, PMID 34375437)
Phase 2 fisetin × COVID-19 in older SNF residents
View StudyMurray KO et al. 2025, intermittent fisetin in aged mice (Aging Cell, PMID 40437670)
muscle-specific senolytic effect; physical function gain
View StudyKrivak D et al. 2024, fisetin as senotherapeutic blueprint (PMID 39688310)
molecular modeling of senolytic targets
View StudyAhmad A et al. 2017, fisetin × amyloid-β cognitive dysfunction (Mol Neurobiol, PMID 26944285) — RETRACTED
TrkB/BDNF mechanism, treat with caution
View StudyChiruta C et al. 2012, chemical modification of fisetin for drug-like properties (J Med Chem, PMID 22356471)
neuroprotection SAR
View StudyBothiraja C et al. 2013, liposomal fisetin (Int J Pharm, PMID 23380621)
47× PK improvement in mice
View StudyHickson LJ et al. 2019, D+Q senolytic in diabetic kidney disease (EBioMedicine, PMID 31542391)
first human senolytic biomarker proof-of-principle
View StudyFirst human knee-OA RCT of fisetin (Osteoarthritis & Cartilage, OARSI 2025)
00692-2/abstract) — Phase I/II Mayo-protocol fisetin; safety confirmed, efficacy NEGATIVE
View StudyClinicalTrials.gov NCT03675724 — AFFIRM-LITE (fisetin in frail older women, Mayo)
ClinicalTrials.gov NCT06133634 — Fisetin to improve vascular function in older adults (Mayo)
ClinicalTrials.gov NCT06431932 — Pilot trial of fisetin in healthy volunteers
ClinicalTrials.gov NCT07195318 — Fisetin supplementation for healthy aging
Frontiers in Pharmacology 2022 — fisetin neuroprotection in neurodegenerative disease (review)
Fisetin: In Search of Better Bioavailability (Int J Mol Sci 2023, review)
formulation strategies overview
View StudySalk Institute Maher lab fisetin program overview
multi-target neuroprotection background
View StudyHow was your experience with this compound?
Anonymous · one vote per session · results below at 5+ votes.
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