Fisetin
A naturally-occurring flavonol found in strawberries (highest concentration), apples, persimmons, grapes, onions, and cucumbers. Studied as a senolytic — a compound that selectively kills senescent cells of certain types. Currently in human Phase 2 trials. Average dietary intake in Japan reported as ~0.4 mg/day 1, orders of magnitude below experimental doses.
Identity
- PubChem CID: 5281614
- InChIKey: XHEFDIBZLJXQHF-UHFFFAOYSA-N
- CAS: 528-48-3
- Class: flavonol (flavonoid subclass)
- Molecular weight: 286.24 g/mol
- Solubility: poorly water-soluble; soluble in DMSO and ethanol
Mechanism of action
Primary supported mechanism: senolytic via disruption of PI3K/AKT/mTOR signaling — one of the SCAPs (Senescent-Cell Anti-Apoptotic Pathways) that protect senescent cells from their own pro-apoptotic SASP 1. Yousefzadeh et al. screened 10 flavonoids in vitro and identified fisetin as the most potent senolytic.
Cell-type-dependent mode of action 1:
- In HUVECs, fisetin induces apoptosis (caspase 3/7 activation) — classical senolytic
- In MEFs, fisetin reduces senescence markers without cell killing — senomorphic
- In vivo: significant clearance of p16+ c-Kit+ stem/progenitor cells, CD4+/CD8+ T cells, NK cells, and endothelial cells; no effect on p16+ macrophages or dendritic cells. Fisetin is not a pan-senolytic.
Other documented activities that may or may not contribute to senolysis:
- Direct ROS scavenger and antioxidant
- Increases hSIRT1 catalytic activity in vitro
- Topoisomerase inhibitor
- Inhibits TNFα, IL-6, and NF-κB activity
no-mechanism — Despite the in vivo phenotype, no single direct molecular target of fisetin’s senolytic activity has been identified. Polypharmacology (the combined effect of many weak interactions) is plausible. Fisetin is not a Bcl-xL/Bcl-2 inhibitor (that mechanism applies to the navitoclax/a1331852 class, not to fisetin per Yousefzadeh 2018).
Effects on aging hallmarks
| Hallmark | Effect | Evidence |
|---|---|---|
| cellular-senescence | Reduces p16+ senescent cells in fat, spleen, liver, kidney, blood T cells (mouse) and adipose explants (human ex vivo) | 1 |
| chronic-inflammation | Indirect — reduces SASP factor expression in tissues; reduces serum MCP-1 | 1 |
Pharmacokinetics
Bioavailability is the dominant uncertainty for human translation.
- Half-lives (per Yousefzadeh 2018 Discussion citing earlier work): 0.09 h rapid, 3.1 h terminal. Extremely short — far shorter than typical drug half-lives for a chronic supplement.
- Reported oral bioavailability in rodents: <5% for free fisetin; rapidly conjugated (glucuronidated, sulfated). Most circulating fisetin is in conjugate form.
- Lipophilic; tissue accumulation favors adipose.
The very short half-life argues for a “hit-and-run” senolytic mechanism — one-time elimination of vulnerable senescent cells per dose, rather than continuous receptor occupancy. This rationalizes the intermittent dosing schedules used in clinical trials (e.g., 2 days/month).
dose-response-unclear — The mouse experimental dose (100 mg/kg gavage; ~60 mg/kg/day chow) does not translate cleanly to human supplement doses (typical 100–500 mg total). Allometric body-surface scaling suggests ~600 mg/day human-equivalent for a 70 kg adult — but factoring in bioavailability and rapid clearance, effective tissue exposure at supplement doses is likely well below the experimental range. The Mayo Phase 2 trial uses 20 mg/kg/day × 2 days, which is closer to mouse-equivalent exposure when adjusted for short dosing window and “hit-and-run” assumption.
Formulation & bioavailability enhancement
Free fisetin’s <5% oral bioavailability has driven extensive nano- and lipid-based reformulation. A 2023 review catalogues the landscape 2; representative preclinical gains vs free fisetin:
| Formulation | Species | Reported gain vs free fisetin |
|---|---|---|
| Nanocochleates (DMPC/cholesterol/Ca²⁺) | mouse | ~141-fold bioavailability |
| Nanoemulsion (Miglyol/Labrasol/Tween) | mouse | 11.92-fold AUC (i.p.) |
| Polymeric micelles (Pluronic F127 + folate) | rat | 6.3-fold AUC; 1.8-fold Cmax |
| Liposomes (DOPC/DODA-PEG2000) | mouse | 4.43-fold AUC (i.p.); 1.64-fold (i.v.) |
| SNEDDS | rat | 3.7-fold Cmax; 1.52-fold AUC |
The only human PK data is for a micelle-in-fenugreek-galactomannan hydrogel (FF-20, “Hybrid-FENUMAT”) — not a liposome. In a randomized double-blind single-dose crossover (n=15 healthy volunteers; 1000 mg FF-20 delivering 192 mg fisetin vs 1000 mg unformulated, 10-day washout), FF-20 raised AUC₀₋₁₂ₕ 26.9-fold (341.4 vs 12.67 ng·h/mL) and Cmax 23.9-fold (238.2 vs 9.97 ng/mL) 3.
Critical caveat — formulation gains do not yet bridge the senolytic concentration gap. The best-in-human Cmax of 238.2 ng/mL ≈ 0.83 µM — roughly 24-fold below the 20 µM threshold at which fisetin cleared senescent cells in human adipose explants ex vivo 1, and reached only transiently at peak. No fisetin formulation study has measured a senolytic or clinical efficacy endpoint — all are PK-only. Consumer “liposomal fisetin” products are not the validated FF-20 system and carry no published human senolytic PK. Whether any oral formulation achieves senolytic tissue concentrations in humans remains open dose-response-unclear.
Dose-response evidence
| Study | Organism | Subjects | Dose | Route | Schedule | Effect |
|---|---|---|---|---|---|---|
| Yousefzadeh 2018 — acute 1 | 22–24 month WT C57BL/6 | n=6–7/group | 100 mg/kg | Oral gavage | 5 consecutive days | Significant p16+ cell reduction in fat (Fig 4A, p<0.01); cell-type-specific clearance in WAT |
| Yousefzadeh 2018 — chronic 1 | 85-week f1 C57BL/6;FVB/n WT | n=8–9/group | 500 ppm chow (~60 mg/kg/day) | Oral diet | Continuous from 85 wks | Extended median + max lifespan (Log rank p<0.05); reduced multi-organ pathology |
| Yousefzadeh 2018 — human ex vivo 1 | Human adipose explants | n=3 (1 lean, 1 obese, F, 55–66 yr) | 20 μM | In media | 48 h | Reduced SA-β-gal+ cells; reduced IL-6, IL-8, MCP-1 in conditioned media |
| Mayo Phase 2 (NCT03675724) | Older women | n=~40 (planned) | 20 mg/kg/day | Oral | 2 consecutive days/month | (In progress; not yet reported) |
Human evidence
Active fisetin trial roster (ClinicalTrials.gov, 2026-05-08; 17 RECRUITING / ACTIVE_NOT_RECRUITING / ENROLLING_BY_INVITATION):
| Trial | NCT | Phase | Status | Endpoint |
|---|---|---|---|---|
| Alleviation by Fisetin of Frailty, Inflammation in Older Women | NCT03675724 | Phase 2 | Enrolling by invitation (status updated; estimated completion 2027-04) | Frailty, inflammation markers |
| Alleviation by Fisetin in Older Adults (parallel) | NCT03430037 | Phase 2 | Enrolling by invitation | Frailty, inflammation markers |
| Diabetic Kidney Disease | NCT03325322 | Phase 2 | Suspended (no reason posted; estimated completion 2027-01) | Renal markers |
| TROFFi — physical function in BCa survivors 4 | NCT05595499 | Phase 2 | Recruiting | Δ6MWD baseline-to-end (primary); planned n=88 postmenopausal early-stage breast cancer survivors with 6MWD <400 m post-chemotherapy; fisetin 20 mg/kg/day d1–3 of 14-day cycle × 4 cycles vs placebo. First placebo-controlled fisetin senolytic RCT with hard physical-function primary endpoint. |
| Vascular function in older adults | NCT06133634 | Phase 1/2 | Active, not recruiting | Vascular function |
| Multimorbidity pilot | NCT06431932 | Phase 1/2 | Recruiting | Senescence biomarkers |
| Mobility impairment in PAD | NCT06399809 | Phase 2 | Recruiting | Walking distance |
| Frailty + exercise in BCa survivors | NCT06113016 | Phase 2 | Recruiting | Frailty |
| Cancer-survivor fatigue | NCT06819254 | Phase 4 | Recruiting | Fatigue |
| Mild Alzheimer’s disease | NCT07279714 | Phase 2 | Recruiting | Cognitive endpoints |
| Healthy aging | NCT07195318 | NA | Recruiting | Aging biomarkers |
| ILD in CVID | NCT05593588 | Phase 2 | Enrolling by invitation | Pulmonary function |
| Childhood-cancer-survivor frailty (D+Q+F) | NCT04733534 | Phase 2 | Active, not recruiting | Frailty |
| Sleep + aging biomarkers (urolithin A + fisetin) | NCT06990256 | NA | Recruiting | Sleep + biomarkers |
| Fisetin PK in young vs old | NCT06796374 | NA | Recruiting | PK comparison |
| STOP-Sepsis (D+Q+F + senolytics) | NCT05758246 | Phase 2 | Recruiting | Sepsis progression |
| D+Q+F+temozolomide for prostate cancer | NCT07025226 | Early Phase 1 | Recruiting | Safety |
Completed: NCT05416515 (carpal tunnel syndrome, Phase 2, completed); NCT04313634 (skeletal health older humans, Phase 2, completed); NCT04771611 (COVFIS-HOME, Phase 2, completed) — primary results not yet integrated into this page needs-replication.
Ex vivo human evidence exists (Yousefzadeh 2018, n=3 adipose explants) — fisetin reduces senescent-cell burden and SASP cytokine secretion in human tissue at 20 μM. This is mechanistically supportive but not equivalent to in vivo human efficacy.
needs-human-replication — As of 2026-05-08 no large completed placebo-controlled fisetin senolytic RCT has reported on a hard endpoint. The trial pipeline has expanded substantially since 2024; TROFFi (NCT05595499) is the first multicenter RCT design with a placebo arm and hard physical-function primary endpoint to enter recruitment.
Recent mechanistic findings (2024–2026)
Mahoney 2026 — fisetin reverses age-related endothelial dysfunction via CXCL12 SASP 5: Aging Cell 2026, single-cell aortic transcriptomics in young (6 mo) and old (27 mo) C57BL/6 mice ± in vivo fisetin (100 mg/kg/day intermittent gavage). Senescent endothelial cells exhibit elevated CXCL12 expression; fisetin treatment reduces tissue and circulating CXCL12, restoring endothelial function. Plasma-transfer experiments (old plasma onto young arteries) show CXCL12 is mechanistically required: it impairs endothelial NO bioavailability, increases mitochondrial oxidative stress, and drives endothelial-to-mesenchymal transition. First identification of a specific SASP factor (CXCL12) as a mediator of fisetin’s vascular phenotype and a candidate biomarker for senolytic trials with vascular endpoints.
Numani 2026 — topical fisetin improves diabetic wound healing 6: Adv Wound Care 2026; topical fisetin reduces senescent-cell burden in skin and accelerates wound closure dynamics in diabetic mice — extends fisetin’s senolytic context to dermal/topical delivery, relevant to translational design where systemic exposure is unwanted.
Class context: Fisetin remains the most-trialed senolytic in aging-relevant indications as of 2026 (17 active/enrolling vs 0 active senolytic-aging trials for navitoclax). Mechanistically positioned as a polypharmacological flavonol senolytic distinct from the BCL-xL-axis BH3-mimetic class (navitoclax, a1331852, foselutoclax).
Classification
- SENS strategy: ApoptoSENS — senolytic
- Hallmark target: cellular-senescence
- Clinical category: dietary supplement / investigational drug
Limitations and concerns
- Cell-type specificity: fisetin clears some p16+ populations (T cells, NK cells, MSCs, endothelial cells) but not others (macrophages, dendritic cells per Yousefzadeh 2018). Whole-tissue p16+ clearance is incomplete.
- Polypharmacology: fisetin engages many targets at low affinity — senolytic effect may be one of several in vivo activities.
- CYP3A4 inhibitor in vitro — possible drug-drug interactions for co-administered drugs.
- Yousefzadeh 2018 lifespan study used F1 C57BL/6;FVB/n hybrid mice and small n (8–9/group). Replication in larger cohorts and other backgrounds would strengthen confidence.
- Long-term safety in humans unknown. Authors note “no adverse effects of fisetin have been reported, even when given at high doses,” but no dedicated long-term safety study has been conducted. long-term-unknown
- Disclosed financial conflicts: Mayo Clinic holds patents on senolytic drugs; several Yousefzadeh authors are inventors.
Footnotes
Footnotes
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yousefzadeh-2018-fisetin-senolytic · n=8–9/group (lifespan) · in-vivo (mouse) + ex vivo (human) · Log rank p<0.05 (lifespan) · model: f1 C57BL/6;FVB/n WT mice fed 500 ppm fisetin chow from 85 weeks ↩ ↩2 ↩3 ↩4 ↩5 ↩6 ↩7 ↩8 ↩9
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doi:10.3390/ijms241814158 · Szymczak J, Cielecka-Piontek J · Int J Mol Sci 2023;24(18):14158 · review · compilation of fisetin nano/lipid formulation PK (animal data: nanocochleates ~141-fold per §4.5.4 body text citing Bothiraja 2014 [review ref 97], nanoemulsion 11.92-fold AUC i.p., Pluronic-F127 micelles 6.3-fold AUC + 1.8-fold Cmax i.p. rat, DOPC/DODA-PEG2000 liposomes 4.43-fold AUC i.p. + 1.64-fold i.v. mouse, SNEDDS 3.7-fold Cmax + 1.52-fold AUC oral rat) · full PDF end-to-end verified 2026-05-31 · ⚠️ Internal inconsistency in this review: nanocochleate body text (§4.5.4) reports 141-fold; review’s own Table 4 reports 13-fold for the same reference (Bothiraja 2014). Wiki uses the body-text figure (141-fold); cannot adjudicate without the primary source (doi:10.1517/17425247.2014.848184). needs-replication ↩
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doi:10.1017/jns.2022.72 · Krishnakumar IM, Jaja-Chimedza A, Joseph A, Balakrishnan A, Maliakel B, Swick A · J Nutr Sci 2022;11:e74 · randomized double-blind comparative crossover · n=15 healthy volunteers (12 male, 3 female; age 22–55 yr; BMI 18–25) · single dose 1000 mg FF-20 hybrid micelle-in-fenugreek-galactomannan hydrogel (delivering 192 mg fisetin; 19.2% fisetin content by HPLC) vs 1000 mg unformulated fisetin (98.2% purity), 10-day washout · AUC₀₋₁₂ₕ 341.4 ± 130.05 (FF-20) vs 12.67 ± 4.86 (UF) ng·h/mL = 26.9-fold (p<0.0001); Cmax 238.2 ± 87.26 vs 9.97 ± 3.97 ng/mL = 23.9-fold (abstract: “more than twenty-three times”; Discussion: “23.9-fold”) · t₁/₂ 1.51 h (FF-20) vs 1.14 h (UF) · PK-only, no senolytic/efficacy endpoint · funder: Akay Natural Ingredients (FF-20 manufacturer); Life Extension co-author (sells FF-20 as “Bio-Fisetin”) — CoI present · PMID 36304817 / PMC9574875 · full PDF end-to-end verified 2026-05-31 — all PK figures confirmed against Table 1 and body text ↩
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doi:10.1177/17588359261424668 · Ji J, Crespi CM, Yee L, Zekster YA, Al-Saleem A, Petersen L, Lee C, Son N, Smith C, Evans T, Tchkonia T, Kirkland JL, Kuchel GA, Cohen HJ, Sedrak MS · Ther Adv Med Oncol 2026 Mar 11;18:17588359261424668 · TROFFi study rationale and trial design publication (not yet results) · Phase 2 multicenter randomized double-blind placebo-controlled · planned n=88 postmenopausal early-stage breast cancer survivors with 6MWD <400 m, completed neo/adjuvant chemotherapy within 12 mo · 1:1 randomization to fisetin 20 mg/kg/day d1–3 of 14-day cycle × 4 cycles vs placebo · primary endpoint Δ6MWD baseline-to-end-of-treatment · NCT05595499 · status: recruiting as of 2026-05. ↩
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doi:10.1111/acel.70500 · Mahoney SA, Mazan-Mamczarz K, Tsitsipatis D, VanDongen NS, Henry-Smith C, Okereke AN, Munk R, Darvish S, Murray KO, De S, Gorospe M, Seals DR, Rossman MJ, Herman AB, Clayton ZS · Aging Cell 2026 May;25(5):e70500 · in-vivo + plasma-exposure ex vivo · model: young (6 mo) and old (27 mo) male+female C57BL/6 mice ± in vivo fisetin 100 mg/kg/day intermittent + cultured human aortic ECs · single-cell transcriptomics on aortas; fisetin reduces senescent-EC CXCL12 expression and circulating CXCL12; old-plasma exposure impairs vascular function and induces endothelial senescence partially driven by CXCL12 · NIH/NIA Intramural; preprint update from bioRxiv 2025 Aug · abstract-only verification 2026-05-08 — full PDF not end-to-end verified. ↩
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doi:10.1177/21621918261426580 · Numani A, Carrasco-Jeldres M, Hernandez-Rovi… (full author list TBD) · Adv Wound Care (New Rochelle) 2026 Feb 23 (online ahead of print) · in-vivo · model: diabetic mice; topical fisetin · reports improved wound healing dynamics with reduced cutaneous senescent-cell burden · abstract-only verification 2026-05-08 — full PDF not end-to-end verified. ↩