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

gap/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). Skeletal muscle not among the tissues where clearance was measured	1
cellular-senescence (skeletal muscle)	Transcriptomic only — see § Skeletal muscle below; lowers muscle senescence-gene expression but no senescent-cell counting, and does not lower p16/Cdkn2a	2
chronic-inflammation	Indirect — reduces SASP factor expression in tissues; reduces serum MCP-1	1

Skeletal muscle and physical function

Whether fisetin clears senescent cells in skeletal muscle is not established — the muscle evidence is functional and transcriptomic, not a demonstrated reduction in senescent-cell number.

• Murray et al. 2025 (Aging Cell) gave old C57BL/6N mice intermittent oral fisetin (100 mg/kg/day, 1 week on / 2 off / 1 on). It improved grip strength (+14% vs vehicle, p=0.0038; attenuating the aging change by ~40%) and frailty (−15%, p=0.0264) in old mice, with no effect in young mice ². See murray-2025-fisetin-muscle-function.
• In quadriceps the senescence readout was bulk RNA-seq + RT-PCR only — Cellular Senescence / p53 KEGG pathways de-enriched; Ddit4 lower (p<0.01); Cdkn1a/p21 directionally lower (~46% of the age increase, but RT-PCR p≈0.18, not significant). No SA-β-gal, p16/p21 immunohistochemistry, or any senescent-cell count was done in muscle in any arm — the authors explicitly call for histological confirmation before claiming a senolytic (vs senomorphic) effect in muscle. No effect on muscle mass.
• Notable mechanistic gap: fisetin did not lower Cdkn2a/p16, whereas the comparator arms — genetic p16+ clearance (p16-3MR) and the synthetic senolytic ABT-263 — lowered both p21 and p16. The authors note this may indicate weaker p16+ senescent-cell clearance by fisetin in muscle. The “comparable to ABT-263 / genetic clearance” claim is an absence-of-difference null test (not non-inferiority), and ABT-263’s effects were numerically larger. gap/needs-replication
• For contrast, the muscle-hypertrophy senolytic experiment with direct senescent-cell clearance (Dungan 2022) used dasatinib + quercetin, not fisetin — so fisetin is untested in the resistance-exercise / overload-hypertrophy context.

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).

gap/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 ³; 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) ⁴.

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 gap/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
Murray 2025 — skeletal muscle 2	27–29 month C57BL/6N (both sexes)	Old Veh n=31, Old Fis n=39	100 mg/kg/day	Oral gavage	1 wk on / 2 off / 1 on	Grip strength +14% (p=0.0038), frailty −15% (p=0.0264); muscle senescence genes lower (Ddit4 p<0.01; Cdkn1a directional); no senescent-cell counting; no Cdkn2a/p16 reduction; no muscle-mass effect; no effect in young mice
Harrison 2024 — NIA ITP lifespan 5	UM-HET3 heterogeneous (3 sites), both sexes	large multi-site cohort	600 ppm chow (~60–80 mg/kg/day)	Oral diet	Continuous or cyclic 3d-on/11d-off, from 20 mo	No lifespan extension — either sex, either schedule (♂ p=0.85/0.54; ♀ p=0.37/0.75)
Harrison 2024 — NIA ITP p16 biomarker 5	UM-HET3, 22–24 mo	sub-cohort	600 ppm	Oral diet	2–4 mo	No reduction in p16^Ink4a^ mRNA (qPCR) in kidney, brain, or liver — antibody-independent readout
Mayo Phase 2 (NCT03675724)	Older women	n=~40 (planned)	20 mg/kg/day	Oral	2 consecutive days/month	(In progress; not yet reported)

The most rigorous mouse test of fisetin is negative. The NIA Interventions Testing Program — three independent sites, genetically heterogeneous UM-HET3 mice, both sexes — found no lifespan extension under either continuous or intermittent dosing at the most faithfully-achieved dose of its cohort (600 ppm, 99% of target), and an antibody-independent Cdkn2a/p16 qPCR sub-cohort found no senescent-cell clearance ⁵. This directly stress-tests the Yousefzadeh 2018 lifespan + p16-clearance result ¹, which came from small n (8–9/group), a single inbred-hybrid background, and one lab. The discordance (strain, dietary-vs-gavage bioavailability, regimen) is unresolved gap/contradictory-evidence — but the ITP is the design built to break false positives. See harrison-2024-itp-astaxanthin-meclizine.

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 6	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

First reported fisetin efficacy RCT is negative. A completed Phase 1/2 randomized double-blind placebo-controlled trial in knee osteoarthritis (NCT04210986, n=74) found no significant benefit of intermittent fisetin (~20 mg/kg/day × 2 consecutive days, repeated) over placebo on pain (NRS), function (WOMAC), cartilage quality (MRI T2), or serum biomarkers (CRP, COMP); safety was comparable ⁷. This is the first completed senolytic RCT in osteoarthritis to report efficacy data, and it is null — paralleling the UBX0101/UNITY OA failure. Caveats: Phase 1/2 (primary endpoint was safety), single-site, only ~4 days’ total fisetin exposure, no pharmacodynamic confirmation of senescent-cell clearance in joint tissue. Abstract-level evidence (OARSI 2025); full paper unpublished as of mid-2026. See tashman-2025-fisetin-knee-oa-rct.

Completed (results not yet integrated): NCT05416515 (carpal tunnel syndrome, Phase 2); NCT04771611 (COVFIS-HOME, Phase 2) gap/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.

gap/needs-human-replication — The first completed placebo-controlled fisetin efficacy RCT (NCT04210986, knee OA, n=74) was null ⁷, but was Phase 1/2 (safety-powered), single-site, and gave only ~4 days’ total exposure — not a definitive efficacy test. No adequately-powered placebo-controlled fisetin RCT on a hard endpoint has yet reported a positive result; TROFFi (NCT05595499) is the first multicenter placebo-controlled design with a hard physical-function primary endpoint.

Recent mechanistic findings (2024–2026)

Mahoney 2026 — fisetin reverses age-related endothelial dysfunction via CXCL12 SASP ⁸: 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 ⁹: 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, UBX1325/foselutoclax).

Classification

• SENS strategy: ApoptoSENS — senolytic
• Hallmark target: cellular-senescence
• Clinical category: dietary supplement / investigational drug

Limitations and concerns

• p16-readout reliability: the senolytic field’s tissue p16INK4a immunohistochemistry — a primary efficacy readout — is broadly confounded by the 2026 p16/p16-ARC (ARPC5) antibody mis-selection finding (see p16-immunodetection). Fisetin’s strongest antibody-independent senescence tests were both null — ITP Cdkn2a qPCR ⁵ and Murray 2025 muscle Cdkn2a ² — which makes the IHC-based clearance claims ¹ harder to weight upward, not easier.
• 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. gap/long-term-unknown
• Disclosed financial conflicts: Mayo Clinic holds patents on senolytic drugs; several Yousefzadeh authors are inventors.

Footnotes

Footnotes

1. 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 ↩¹⁰ ↩¹¹

2. murray-2025-fisetin-muscle-function · doi:10.1111/acel.70114 · PMID 40437670 · PMC12341784 (gold OA) · Murray KO et al. · Aging Cell 2025;24(8):e70114 · in-vivo · old (27 mo M / 29 mo F) vs young (6–8 mo) C57BL/6N, both sexes; fisetin 100 mg/kg/day oral gavage, 1 wk on / 2 off / 1 on; comparator arms p16-3MR genetic clearance (GCV 25 mg/kg i.p. ×5) and ABT-263 50 mg/kg/day same schedule · old-mouse grip strength +14% (p=0.0038), frailty −15% (p=0.0264); no effect in young; quadriceps bulk RNA-seq + RT-PCR: Cellular Senescence/p53 pathways de-enriched, Ddit4 lower (p<0.01), Cdkn1a directional (RT-PCR p≈0.18, NS) · NO senescent-cell quantification in muscle (no SA-β-gal / p16 / p21 IHC) in any arm; fisetin did NOT lower Cdkn2a/p16 (GCV + ABT-263 did) → possibly weaker p16+ clearance; no muscle-mass effect; “comparable to comparators” = absence-of-difference null test, ABT-263 numerically larger · authors call for histological confirmation of senolytic vs senomorphic muscle effect · full PDF end-to-end verified 2026-06-26 ↩ ↩² ↩³ ↩⁴

3. 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). gap/needs-replication ↩

4. 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 ↩

5. harrison-2024-itp-astaxanthin-meclizine · doi:10.1007/s11357-023-01011-0 · PMID 38041783 · PMC10828146 (gold OA) · Harrison DE, Strong R, Reifsnyder P, … Miller RA · GeroScience 2024;46(1):795–816 · in-vivo, NIA Interventions Testing Program · model: UM-HET3 genetically heterogeneous mice, 3 sites, both sexes · fisetin 600 ppm chow (~60–80 mg/kg/day) from 20 mo, continuous or cyclic 3d-on/11d-off → no lifespan extension either sex (♂ p=0.85 / 0.54; ♀ p=0.37 / 0.75); separate 22–24-mo sub-cohort (2–4 mo dosing): no reduction in p16^Ink4a^ mRNA by qPCR in kidney, brain, or liver (antibody-independent). Same paper: astaxanthin +12% ♂ median (p=0.003), meclizine +8% ♂ (p=0.03), both male-only; SG1002 / DMF / mycophenolic acid / 4-PBA also null. Note: the “263 mg/kg/day” fisetin figure circulating in secondary summaries is not in the paper — the achieved dose was 600 ppm. abstract+PMC-text seeded; full-text verifier pass pending (verified: false). ↩ ↩² ↩³ ↩⁴

6. 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. ↩

7. tashman-2025-fisetin-knee-oa-rct · doi:10.1016/j.joca.2025.02.667 · Tashman S, Philippon M, Dornan G, Huard J · Osteoarthritis and Cartilage 2025;33(Suppl):S456 · conference abstract (brief-communication) · randomized double-blind placebo-controlled Phase 1/2 · n=74 (fisetin 34 / placebo 40), knee OA (Kellgren-Lawrence II–IV), Steadman Philippon Research Institute · fisetin 100 mg ~20 mg/kg/day × 2 consecutive days, 28 off, second course d31–32 · NCT04210986 · null on all efficacy endpoints (NRS pain, WOMAC function, MRI T2 cartilage, CRP, COMP, performance tests); safety comparable (efficacy data sourced from ClinicalTrials.gov posted results; abstract body Cloudflare-blocked) · full paper unpublished as of mid-2026 · verified: false gap/needs-full-paper-publication ↩ ↩²

8. 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. ↩

9. 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. ↩