Fisetin
Fisetin
Fisetin is a naturally occurring flavonoid polyphenol found in fruits and vegetables such as strawberries, apples, persimmons, and onions. It is primarily researched for its senolytic properties—the ability to selectively clear senescent cells—as well as its potent antioxidant, anti-inflammatory, and neuroprotective effects. Fisetin has gained significant attention in longevity research for its potential to extend healthspan and support cognitive function.
Mechanism of Action
Fisetin exerts senolytic activity by inhibiting pro-survival pathways in senescent cells, including PI3K/AKT/mTOR and BCL-2 family anti-apoptotic proteins, leading to selective apoptosis of these dysfunctional cells. It also activates SIRT1 and AMPK pathways, promotes autophagy, and inhibits NF-κB-mediated inflammatory signaling, reducing the senescence-associated secretory phenotype (SASP). Additionally, fisetin crosses the blood-brain barrier and modulates ERK and CREB pathways, supporting synaptic plasticity, memory formation, and neuroprotection against oxidative stress.
Evidence by Health Goal(18 goals)
Dosing Protocols
With a high-fat meal to maximize absorption due to poor aqueous solubility
Cycle: Senolytic: 2 consecutive days on, ~28 days off. Maintenance: daily use with no strict cycling needed
Absorption is significantly enhanced when taken with dietary fat or phospholipid-based formulations. The high-dose senolytic protocol (500-1500mg over 2 days) is modeled after Mayo Clinic research protocols. Lower daily doses of 100-200mg are used for ongoing antioxidant and cognitive support.
Safety & Side Effects
Fisetin has a favorable safety profile at typical supplemental doses, with most adverse effects being mild and transient, particularly at lower daily doses; however, the high-dose senolytic protocols (≥500mg/day) have limited long-term human safety data and are based primarily on preclinical and early-phase clinical studies. It is not a controlled substance and is widely available over the counter, but individuals on anticoagulants, immunosuppressants, or chemotherapy should consult a physician before use.
Possible Side Effects
- !Gastrointestinal discomfort, nausea, or loose stools at higher doses (≥500mg)
- !Headache, particularly during higher-dose senolytic protocols
- !Fatigue or transient flu-like symptoms during senolytic clearance phase
- !Mild skin flushing at elevated doses
- !Potential pro-oxidant effects at very high doses in certain contexts
- !Theoretical risk of hypoglycemia in sensitive individuals due to insulin-sensitizing properties
Interactions
- -May potentiate anticoagulant effects of warfarin and other blood thinners due to platelet aggregation inhibition—monitor INR closely
- -May enhance the effects of chemotherapy agents (e.g., cisplatin) by sensitizing cancer cells, but could also interfere with treatment timing—consult oncologist
- -Additive hypoglycemic effects possible when combined with metformin, insulin, or other glucose-lowering agents
- -May inhibit CYP3A4 and CYP2C9 drug-metabolizing enzymes at high doses, potentially increasing plasma levels of statins, cyclosporine, or other CYP substrates
- -Synergistic senolytic effects reported in combination with quercetin or dasatinib, which may amplify both benefits and adverse effects
Cost & Where to Buy
Low-dose daily supplementation (100-200mg) is very affordable at $15-25/month. High-dose senolytic protocols using 500-1500mg over 2 days/month cost more per session but remain affordable monthly. Price varies significantly by formulation—standard powder capsules are cheapest, while enhanced-bioavailability liposomal or phospholipid-complexed products command premium pricing.
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