Senolytics (Fisetin + Quercetin)

Senolytics are compounds that selectively induce apoptosis in senescent cells by targeting their anti-apoptotic survival networks. Senescent cells accumulate with age, resist normal clearance, and secrete the senescence-associated secretory phenotype (SASP): a pro-inflammatory cocktail of cytokines (IL-6, IL-8, TNF-alpha) and matrix-degrading enzymes that drives chronic inflammation and tissue dysfunction. Normal cells depend on BCL-2/BCL-xL and PI3K/AKT signaling for survival, but senescent cells become especially dependent on these pathways. Zhu 2015 (Kirkland lab) demonstrated this vulnerability; senolytics exploit it by blocking these survival signals, triggering apoptosis selectively in senescent cells while sparing healthy cells. The 'hit-and-run' dosing model (2 consecutive days every 1-3 months) reflects that once senescent cells are killed, they take weeks to months to reaccumulate.

Different evidence tiers, different risk profiles. D+Q (dasatinib 100 mg + quercetin 1,250 mg for 3 consecutive days monthly) has the strongest human pilot data: Hickson 2019 showed reduced senescent cell markers in diabetic kidney disease at 11 days post-dose; Justice 2019 showed improved physical function in idiopathic pulmonary fibrosis. Dasatinib is a prescription tyrosine kinase inhibitor with real risks: pulmonary arterial hypertension, QT prolongation, cytopenias, black box warnings. F+Q (fisetin 20 mg/kg + quercetin 1,000-1,250 mg for 2 consecutive days quarterly) trades evidence strength for dramatically better safety. Both fisetin and quercetin are OTC polyphenols with decades of safe consumption data. Zero published F+Q human senolytic RCTs; fisetin extends mouse lifespan ~10% (Yousefzadeh 2018). F+Q is the right entry point for most biohackers; D+Q for those with clinical supervision and specific indication.

Not yet proven in humans. Yousefzadeh 2018 showed fisetin extended median mouse lifespan by approximately 10 percent when administered late in life, reduced senescent cell markers across multiple tissues, and improved physical function. Human senolytic RCTs are ongoing: AFFIRM-LITE at Mayo Clinic studying fisetin in frail elderly adults, COVID-FISETIN for post-acute COVID sequelae, and FISIOS for skeletal frailty. Results remain unpublished as of April 2026. Hickson 2019 D+Q pilot (n=14) showed reduced senescent cell markers at 11 days, but that is D+Q not F+Q. Quercetin's senolytic contribution has been demonstrated only in combination with dasatinib in human pilots, so its independent contribution is unclear. The mechanistic rationale for F+Q is sound (complementary BCL-2/BCL-xL targeting across different senescent cell populations), but the translational gap between mouse lifespan extension and human clinical benefit remains entirely unbridged for this specific combination.

Community-standard F+Q protocol: fisetin 1,000 to 2,000 mg (roughly 20 mg/kg body weight) + quercetin 1,000 to 1,250 mg, taken together for 2 consecutive days, repeated quarterly (every 3 months). Take with a fat-containing meal (both are fat-soluble, absorption increases substantially with dietary fat). Some community members extend to 3 consecutive days modeled after D+Q protocols. Hold any CYP3A4-metabolized medications during and for 1 to 2 days after the dosing window (quercetin is a CYP3A4 inhibitor). Pause fish oil, vitamin E, garlic, ginkgo, and anticoagulants 48 hours before and during dosing (additive bleeding risk from fisetin's anti-platelet activity). The hit-and-run pattern exploits the fact that senescent cells take weeks to months to reaccumulate; daily dosing is unnecessary and potentially counterproductive (senescence has tumor-suppressive functions in healthy young cells).

F+Q is generally well-tolerated. Quercetin holds GRAS status (GRN 341). Fisetin has limited human safety data but no serious adverse events in any published trial or study. Removing dasatinib eliminates pharmaceutical-grade risks: no pulmonary arterial hypertension, no QT prolongation, no cytopenias. Primary concerns: CYP3A4 inhibition by quercetin (relevant for drug interactions during the 2-day dosing window and roughly 24 hours after), anticoagulant potentiation by both compounds (fisetin has inherent anti-platelet activity; quercetin potentiates warfarin), and mild GI discomfort at high doses. D+Q carries substantially different risk profile: dasatinib black box warnings and specific monitoring requirements; should only be used under clinical supervision with cardiology and pulmonology screening. The theoretical concern for all senolytics: senescence has tumor-suppressive functions in healthy young cells, so using senolytics prematurely (under age 40-50) may have unintended consequences the community cannot yet quantify.

Most experts suggest age 50+ as the likely threshold where senescent cell burden becomes high enough to justify senolytic intervention. Senescent cells accumulate progressively with age but remain modest in young adults. Yousefzadeh 2018 mouse data showed strongest lifespan extension when treatment began late in life, consistent with the higher senescent burden that makes senolytics effective. Chronic disease states that accelerate senescence (obesity, diabetes, fibrosis, post-chemotherapy) may lower the meaningful intervention age. Young healthy adults using senolytics quarterly likely see minimal benefit (few senescent cells to kill) and may incur theoretical downside from removing cells performing tumor-suppressive functions. Nick's position: has F+Q on hand, uses infrequently because young, and considers senolytics increasingly important post-50. Emerging biomarkers including senescent cell plasma markers (from Mayo Clinic research) may eventually enable personalized timing rather than age-based rules.

Five populations. Active cancer or recent cancer history: senescence has tumor-suppressive functions; clearing senescent cells could theoretically remove a protective barrier, though the net effect is debated and still under investigation. Concurrent anticoagulant use (warfarin, DOAC, high-dose aspirin): quercetin potentiates warfarin, fisetin has inherent anti-platelet activity; hold both 48 hours before and during dosing. Medications strongly dependent on CYP3A4 metabolism (statins, calcium channel blockers, certain immunosuppressants, some antidepressants): quercetin CYP3A4 inhibition during dosing window could increase drug levels; consult prescriber. Pregnancy or breastfeeding (safety data insufficient). Severe renal or hepatic impairment (clearance uncertain). Young adults under 40 without accelerated aging signs (risk-benefit uncertain; likely minimal benefit, small theoretical downside from affecting tumor-suppressive senescent cell populations).