Grok comparison of Fisetin and D+Q

#1

Compare fisetin and D+Q efficacy:

Fisetin and dasatinib + quercetin (D+Q) are among the most studied senolytics, with D+Q being the first discovered and most clinically advanced combination, while fisetin (a natural flavonoid) has shown promising results in preclinical models and is gaining traction in trials. Efficacy comparisons are primarily from mouse studies, with limited direct head-to-head human data as of early 2026. Both reduce senescent cell burden, alleviate senescence-associated secretory phenotype (SASP)-driven inflammation, and improve age-related phenotypes, but they differ in potency, tissue specificity, safety profile, brain penetration, and functional outcomes.

Key Comparison Points

  • Mechanism and Discovery D+Q: Synergistic combo where dasatinib (tyrosine kinase inhibitor) targets senescent preadipocytes/fibroblasts, and quercetin targets endothelial cells; together they hit multiple anti-apoptotic pathways (e.g., BCL-2 family, PI3K/AKT). Fisetin: Single agent flavonoid that modulates multiple pathways (e.g., PI3K/AKT/mTOR, NF-ÎșB, BCL-xL inhibition); often described as more potent per molecule than quercetin alone.
  • Senolytic Potency and Clearance In many preclinical comparisons, fisetin shows superior or comparable clearance in certain tissues. For example:
    • Brain/hippocampus: Fisetin achieves ~65% senescent cell clearance vs. ~20% for D+Q (noted in some 2023–2025 analyses).
    • Overall tissues: Fisetin often clears 25–50%+ in adipose (~45–50%), kidney (~40%), liver (~30–35%), and brain (~25–65%), sometimes outperforming D+Q in neurodegeneration models (e.g., better cognitive rescue in Alzheimer’s-like models).
    • D+Q excels in adipose tissue (strong reduction in senescent adipocyte progenitors, macrophages, inflammation) and has demonstrated meaningful human clearance in fat and skin in pilot trials (e.g., diabetic kidney disease patients). Direct head-to-head mouse studies show context-dependent results: fisetin sometimes outperforms D+Q in bone preservation (e.g., progeria models), skeletal muscle function, and cognitive/metabolic outcomes, while D+Q may be stronger in certain metabolic or lung models.
  • Functional Outcomes and Healthspan Benefits Both extend healthspan in mice (e.g., reduced frailty, improved physical function). Recent 2025 studies show intermittent fisetin matches or equals genetic senescent cell clearance and synthetic senolytics (e.g., ABT-263/navitoclax analogs) in preserving grip strength, muscle function, and reducing skeletal muscle senescence—often comparable or superior to D+Q in frailty models. Fisetin frequently shows better brain benefits (e.g., reduced neuroinflammation, improved cognition in AD models) and mitigates some negative epigenetic effects seen with D+Q alone. D+Q has more evidence for broad systemic effects (e.g., improved pulmonary function in IPF models, physical performance in frailty trials) but can show sex-specific drawbacks (e.g., metabolic/cognitive dips in young female mice in some reports).
  • Clinical Translation and Human Data (as of 2026) D+Q: More advanced—multiple Phase 1/2 trials (e.g., diabetic kidney disease, IPF, Alzheimer’s, frailty) show safety, reduced senescence markers in human tissues (adipose, skin), and functional hints (e.g., improved physical function). It’s the “gold standard” first-generation senolytic. Fisetin: Emerging in trials (e.g., Phase 2 for sepsis in elderly, chronic kidney disease, childhood cancer survivors comparing fisetin alone vs. D+Q). Preclinical advantages (e.g., better safety, natural origin) position it well, but fewer completed human efficacy readouts. Some longitudinal studies (e.g., on DNA methylation clocks) suggest adding fisetin to D+Q (DQF) may blunt unwanted epigenetic age acceleration from D+Q alone.
  • Safety and Limitations Fisetin: Generally better profile (natural, lower reported off-target effects like thrombocytopenia; widely available as supplement). D+Q: Dasatinib is prescription (cancer drug) with potential side effects (e.g., cytopenias); intermittent dosing mitigates risks, but not universally effective across models/diseases. Both are intermittent (“hit-and-run”) to minimize side effects, but efficacy varies by sex, genotype, age, and disease context—no senolytic clears all senescent cells universally.

Summary Table of Relative Efficacy

Aspect Fisetin Advantage/Edge D+Q Advantage/Edge Notes/Context
Overall Potency Often superior in single-agent comparisons Strong synergy, first proven combo Fisetin > quercetin alone
Adipose Tissue Clearance Good (~45–50%) Excellent (primary target in humans) D+Q highlighted in human pilots
Brain Penetration/Clearance Superior (~65% in hippocampus) Lower (~20%) Fisetin better for neurodegeneration
Skeletal Muscle/Frailty Comparable to genetic/synthetic clearance Good, but fisetin matches/exceeds in recent data 2025 studies favor fisetin
Cognitive/Neuro Benefits Frequently outperforms in AD models Variable (some no brain effect) Fisetin stronger here
Human Clinical Progress Emerging (Phase 2 ongoing) More advanced (multiple Phase 1/2, human clearance proven) D+Q leads in translation
Safety Profile Better (natural, lower toxicity reports) Manageable but dasatinib risks Intermittent dosing for both

In short, D+Q remains the more clinically validated option with proven human senescent cell reduction, particularly in adipose and systemic inflammation. However, fisetin increasingly appears more efficacious in key areas like brain, muscle, bone, and frailty in recent preclinical data, with a potentially superior safety profile—making it a strong contender or complement (e.g., in DQF combos). Neither is definitively “better” across the board; efficacy is tissue-, model-, and context-specific. Ongoing trials (including direct comparisons) will clarify human relevance further.

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#2

What’s a recommended dose for Fisetin?

#3

Another run at the same question
 this time using Gemini Pro and a tweaked prompt I use for analyzing research papers and claims, Thinking mode. Human equivalent doses included:

Gemini Pro response.

A paradigm shift is underway in longevity science: the move from “maintenance” (antioxidants) to “demolition” (senolytics). For years, the gold standard for clearing senescent “zombie” cells—dysfunctional cells that refuse to die and poison their neighbors—has been the pharmaceutical cocktail of Dasatinib plus Quercetin (D+Q). While effective, Dasatinib is a toxic leukemia drug with significant baggage. Now, a natural flavonoid derived from strawberries, Fisetin, has emerged as a safer, “hit-and-run” alternative that may rival the heavyweight champion without the prescription-grade toxicity.

The “Big Idea” here is the rigorous validation of intermittent dosing. Unlike supplements taken daily, senolytics are designed to be taken in short, high-dose bursts (e.g., two days a month) to shock the system, clear the accumulated cellular debris, and then step back to allow tissue regeneration. This research confirms that Fisetin, when used in this specific “shock” protocol, selectively induces apoptosis (programmed cell death) in senescent cells while leaving healthy tissue unharmed.

However, recent comparative data suggests a nuance: while Fisetin is the “safest” broad-spectrum senolytic, it may lack the aggressive tissue-penetrating power of D+Q for specific deep-tissue pathologies like neurodegeneration or fibrosis. The race is no longer just about finding a senolytic, but about matching the weapon (Fisetin vs. D+Q) to the target (frailty vs. severe organ damage).

Part 2: The Biohacker Analysis (Style: Technical, Academic, Direct)

Study Design Specifications

  • Type: Pre-clinical (Murine) & Human Ex Vivo validation; Comparative analysis with Clinical Trial Protocols.
  • Subjects:
    • Murine: C57BL/6 wild-type mice (progeroid Ercc1-/Δ models and naturally aged 22-24 month old mice). Sex: Both Male and Female.
    • Human Validation: Adipose tissue explants from obese human subjects.
  • Protocol (Fisetin): Intermittent “Hit-and-Run.”
    • Mouse: 100 mg/kg oral gavage for 5 consecutive days, or intermittent weekly cycles.
    • Control: Vehicle-treated age-matched controls.

Lifespan Analysis

  • Extension: In the seminal EBioMedicine study, late-life intervention (starting at 85 weeks, approx. 20 months) extended median lifespan by ~10% and maximum lifespan by ~5-15% compared to controls.
  • Context: These gains are modest compared to Rapamycin (often 15-25%), but significant because the intervention began late in life—equivalent to a human starting treatment at age 60-70.
  • Control Validation: The control lifespans in these studies align with standard C57BL/6 historical data (~900 days median), validating that the treatment effect wasn’t due to weak controls.

Mechanistic Deep Dive

  • Target: SCAP Network (Senescent Cell Anti-Apoptotic Pathways). Senescent cells survive by upregulating pro-survival factors (BCL-2, BCL-xL, PI3K/AKT) to resist their own inflammatory signals.
  • Fisetin Action: Acts as a natural caloric restriction mimetic and PI3K/AKT/mTOR inhibitor. It lowers p16^Ink4a^ and p21^Cip1^ expression specifically in adipose and immune lineages.
  • D+Q Action: Dasatinib inhibits Src kinase (broad spectrum), while Quercetin targets BCL-2. Together, they cover a wider range of senescent cell types (SCAPs) than either alone, which explains D+Q’s superior potency in fibrotic tissue and bone.
  • Organ Specificity: Fisetin shines in visceral adipose tissue (reducing inflammation/frailty) and immune function. D+Q appears superior for vascular and neuronal clearance (e.g., clearing tau-associated senescence in Alzheimer’s models).

Novelty & Critical Limitations

  • Novelty: The demonstration that a single natural compound (Fisetin) could effectively reduce senescent burden in humans (adipose tissue) without the side-effect profile of tyrosine kinase inhibitors (Dasatinib).
  • Critical Limitations:
    • Translational Gap: The 100 mg/kg mouse dose is massive. Achieving similar tissue concentrations in humans requires liposomal formulations or extremely high oral doses (20 mg/kg), which leads to unknown long-term stress on the liver/kidneys.
    • Efficacy Ceiling: In direct head-to-head comparisons (e.g., Alzheimer’s models), Fisetin sometimes fails where D+Q succeeds Senolytic intervention improves cognition (2025). Fisetin may be too weak for severe, established pathology.
    • Bioavailability: Standard Fisetin has dismal oral bioavailability due to rapid Phase II metabolism (sulfation/glucuronidation).

Part 3: Claims & Verification

Claim 1: Fisetin selectively induces apoptosis in senescent cells (Senolysis) and extends lifespan.

Claim 2: The Dasatinib + Quercetin (D+Q) combination clears senescent cells in humans.

  • Verification: Confirmed in clinical trials for diabetic kidney disease and idiopathic pulmonary fibrosis.
  • Hierarchy: Level B (Open-label Clinical Trials).
  • Status: Senolytics decrease senescent cells in humans (2019)
  • Safety Note: Dasatinib has a boxed warning for pulmonary hypertension and fluid retention.

Claim 3: Fisetin reduces frailty and inflammation markers (IL-6, hsCRP).

Part 4: Actionable Intelligence (The Protocol)

Warning: The following contains analysis of research chemicals and off-label protocols. This is for informational analysis only, not medical advice. Safety data is largely absent for long-term intermittent use in humans.

1. The Translational Protocol (Rigorous Extrapolation)

A. Fisetin Protocol (The “Mayo” Approach)

  • Target: General frailty, adipose inflammation, “health maintenance.”
  • Mouse Dose: 100 mg/kg.
  • HED Calculation (Conservative BSA):

    • 100 mg/kg×(3/37)≈8.1 mg/kg

    • For a 75kg Male: ≈600 mg.

  • The Clinical Reality (Aggressive): The Mayo Clinic trials use 20 mg/kg, which is ~2.5x the BSA-calculated dose.
    • Protocol: ~1,400–1,600 mg (for 75kg human) taken orally for 2 consecutive days.
    • Frequency: Repeated once every 30 days.
    • Bioavailability Hack: Consumption with fats (yogurt/olive oil) or use of Liposomal formulations is widely recommended by biohackers to bridge the bioavailability gap, though clinical trials use standard oral powder.

B. Q+D Protocol (The “Heavy Hitter”)

  • Target: Fibrosis, severe metabolic dysfunction, potential neurodegeneration.
  • Standard Trial Dose:
    • Dasatinib: 100 mg (Prescription Only - Oncology).
    • Quercetin: 1,000 mg (Phytosome/Liposomal preferred for absorption).
  • Frequency: Dosed for 3 consecutive days, repeat every 2 weeks or monthly (protocols vary).
  • Cost-Benefit: Dasatinib is expensive and risky. The ROI is only justified for significant pathology, not general “anti-aging.”

2. Safety & Toxicity Check

  • Fisetin:
    • Safety Profile: Excellent. No dose-limiting toxicity observed in mice even at high doses.
    • Data Gap: Long-term effects of “mega-dosing” (1.5g+) on the human liver are unverified.
  • Dasatinib (D+Q):
    • Known Risks: Fluid retention (pleural effusion), QT prolongation, myelosuppression.
    • Monitoring: Requires CBC and metabolic panel monitoring if used repeatedly. NOT a casual supplement.

3. Biomarker Verification Panel

  • Don’t fly blind. If attempting these protocols, monitor:
    • SASP Factors: IL-6, TNF-alpha, hs-CRP (Should decrease post-cycle).
    • Toxicity: ALT/AST (Liver), Cystatin C (Kidney), CBC (for Dasatinib myelosuppression).

Part 5: The Strategic FAQ

1. Q: Can I just take Fisetin every day like a multivitamin? A: No. The science supports “hit-and-run.” Continuous suppression of senescent cells/SCAP networks may interfere with wound healing and immune signaling. The goal is a pulse to induce apoptosis, then a pause to regenerate. Daily low doses likely fail to reach the threshold to kill senescent cells and may just act as a weak antioxidant.

2. Q: Can I stack Rapamycin with Fisetin? A: Theoretically, yes. Rapamycin inhibits mTOR (slowing geroconversion), while Fisetin clears cells that have already become senescent. Many biohackers cycle them: Rapamycin weekly, Fisetin monthly. However, no clinical trial has validated this “stack” for safety yet.

3. Q: Is Liposomal Fisetin actually better? A: Likely. Fisetin is hydrophobic and rapidly metabolized. Liposomal delivery bypasses first-pass metabolism. If using standard powder, the Mayo dose (20 mg/kg) is necessary to force enough into the blood. If using true Liposomal, a lower dose might suffice, but we lack conversion data.

4. Q: Why not just use Quercetin alone? A: It’s too weak. Research shows Quercetin targets some SCAP pathways (BCL-2) but misses others. It works synergistically with Dasatinib but is a poor senolytic on its own compared to Fisetin.

5. Q: How do I know if it’s working? A: Subjective: Reduced joint pain, “lighter” feeling, improved endurance. Objective: Lower hs-CRP and reduced “biological age” on methylation clocks (though clock data is noisy/mixed).

6. Q: Does Fisetin cross the blood-brain barrier? A: Yes. It is neuroprotective and has shown efficacy in reducing cognitive deficits in mice, though recent data suggests D+Q might be stronger for specific Alzheimer’s pathologies (tau clearance).

7. Q: Should I fast while taking senolytics? A: Plausible. Fasting inhibits mTOR and induces autophagy, potentially sensitizing senescent cells to apoptosis. Many protocols recommend taking the senolytics in a fasted state or with a pure fat source (for absorption) without protein/carbs.

8. Q: Are there contraindications? A: Blood Thinners. Fisetin and Quercetin have mild anti-coagulant properties. High doses could increase bleeding risk if combined with Warfarin/Aspirin.

9. Q: What is the biggest “known unknown”? A: Long-term tissue depletion. We don’t know if clearing senescent cells repeatedly over 10 years eventually depletes the stem cell pool (exhaustion) or if the “space” is filled by fibrosis instead of healthy tissue in older humans.

#4

And, for those who are seriously considering either of these approaches, I would recommend reading this Google Gemini Deep Search report on the topic:

Senolytic Interventions in Geroscience (2021–2026): A Comprehensive Review of Fisetin and Dasatinib Plus Quercetin

Executive Summary

The pursuit of interventions to delay aging and extend healthspan has coalesced around the “senolytic hypothesis”—the premise that the selective elimination of senescent cells (SnCs) can ameliorate age-related tissue dysfunction. Over the reporting period of 2021 to 2026, the field has transitioned from broad preclinical optimism to a phase of rigorous scrutiny, characterized by divergent outcomes in high-fidelity animal models and the initiation of pivotal human clinical trials. This report provides an exhaustive analysis of the scientific and clinical landscape regarding the two primary senolytic candidates: the flavonoid Fisetin and the combination therapy of the tyrosine kinase inhibitor Dasatinib plus the flavonoid Quercetin (D+Q).

The past five years have yielded a complex dichotomy in results. While the senolytic combination D+Q remains the most potent intervention for clearing senescent burden in specific pathological contexts—such as idiopathic pulmonary fibrosis (IPF) and Alzheimer’s disease—it faces intensifying safety scrutiny following 2025 reports of exacerbated renal damage in acute injury models. Conversely, Fisetin has emerged as a safer, albeit dose-sensitive, alternative. A landmark 2024 study by the National Institute on Aging’s Interventions Testing Program (ITP) demonstrated that chronic dietary administration of Fisetin failed to extend lifespan in genetically heterogeneous mice, contradicting earlier gavage-based studies. This failure has catalyzed a paradigm shift toward “hit-and-run” pulsed dosing protocols, which are now the standard in ongoing human trials like AFFIRM-LITE.

Crucially, this period saw the validation of Fisetin in preventing atrial fibrillation in aged lagomorph models (2026), providing some of the strongest organ-specific efficacy data to date. Concurrently, the definition of success in human trials has evolved from vague “anti-aging” metrics to precise biomarkers, specifically the quantification of p16 {Ink4a} variant 5 in T-cells and the modulation of the Senescence-Associated Secretory Phenotype (SASP).

This document synthesizes data from molecular mechanisms to clinical outcomes, offering a granular comparison of efficacy, safety profiles, and translational dosing protocols. It serves as a definitive reference for interpreting the disparate findings of the last half-decade and guiding future therapeutic strategies.

Google Deep Search Full report: https://gemini.google.com/share/e22c29aaf37a

#5

Lara, I was loosely following the Mayo fisetin protocol (a 20 mg dose per kg body weight, three days in a row, each month for five months). RapAdmin’s Gemini response is a little different, but ballpark is probably the best we can do at this point.

#6

Grok doesn’t think it’s worth considering: “No, there is no evidence from current research that repeatedly clearing senescent cells over 10 years using the described Mayo fisetin protocol (approximately 20 mg/kg body weight for three consecutive days each month for five months, though protocols vary slightly in trials) would deplete the stem cell pool or cause stem cell exhaustion in older humans. In fact, the available data point in the opposite direction: senolytic interventions like fisetin tend to preserve or restore stem cell function by removing the harmful effects of senescent cells and their senescence-associated secretory phenotype (SASP), which otherwise impair stem cell niches through chronic inflammation, disrupted tissue homeostasis, and inhibited regeneration.”

Dueling AIs. It’s like robot boxers. I’ll stop now.

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#7

Just to chime in, I looked at this same comparison with ChatGPT about 2 months ago and got very similar results/conclusions. I started Fisetin using the Mayo Protocol based on my analysis.

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