Canagliflozin vs Fisetin

Mechanism

SGLT2 inhibitor originally developed for type 2 diabetes. Blocks glucose reabsorption in kidneys, creating a mild glucose deficit that activates AMPK and mimics caloric restriction. Extended lifespan in male mice in the ITP.

Contraindications

• Type 1 diabetes (DKA risk)
• Severe renal impairment (eGFR <30)
• History of recurrent UTIs

Mechanism

Fisetin is a naturally occurring flavonol (3,7,3',4'-tetrahydroxyflavone) found in strawberries, apples, and persimmons that acts as a senolytic by inhibiting the PI3K/Akt/mTOR survival pathway and BCL-2 family anti-apoptotic proteins in senescent cells. It also activates sirtuin-mediated pathways (SIRT1), reduces NF-kB-driven inflammation, and scavenges free radicals as a direct antioxidant. Fisetin demonstrated the most potent senolytic activity among 10 flavonoids screened in a 2018 study, reducing senescent cell burden in aged mice and extending both healthspan and lifespan markers.

Standard Dosing

Research indicates 20 mg/kg/day for 2 consecutive days as an intermittent senolytic protocol (approximately 1400-2000 mg for a 70-100 kg individual).

Timing

Take with fat-containing meal for improved bioavailability (fisetin is lipophilic with poor water solubility). Liposomal or lipophilic formulations preferred.

Cycle Duration

Intermittent senolytic courses ongoing. Daily low-dose use for antioxidant/anti-inflammatory effects can be continuous.

Side Effects

• GI discomfort at high senolytic doses
• Diarrhea
• Headache
• Generally well-tolerated — no serious adverse events reported in clinical trials to date

Contraindications

• Known hypersensitivity to fisetin or flavonoids
• Pregnancy and breastfeeding (insufficient safety data)
• Active chemotherapy without oncologist coordination

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