Fisetin vs Metformin

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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Mechanism

Metformin activates AMP-activated protein kinase (AMPK) via inhibition of mitochondrial Complex I, increasing the AMP/ATP ratio. AMPK activation triggers a cascade of metabolic effects: inhibition of hepatic gluconeogenesis, enhanced glucose uptake in skeletal muscle via GLUT4 translocation, and suppression of mTORC1 signaling. In the longevity context, metformin's mTOR inhibition mimics caloric restriction signaling, activating autophagy, reducing inflammatory cytokines (IL-6, TNF-a), decreasing insulin and IGF-1 signaling, and modulating the gut microbiome (increasing Akkermansia muciniphila). It also reduces AGE formation and mitochondrial ROS production.

Standard Dosing

Research indicates 500-1000 mg daily for longevity/anti-aging protocols. Standard diabetes dosing: 500-2550 mg daily.

Timing

Take with food (dinner) to minimize GI side effects. Extended-release formulation once daily with dinner. Immediate-release split into 2-3 doses with meals.

Cycle Duration

Ongoing for longevity applications. The TAME (Targeting Aging with Metformin) trial is designed to assess long-term geroprotective effects.

Side Effects

• GI distress: nausea, diarrhea, bloating, metallic taste (common initially, improves with XR formulation)
• Vitamin B12 deficiency (with chronic use — monitor annually)
• Lactic acidosis (rare but serious — primarily in renal impairment)
• Potential blunting of exercise-induced mitochondrial adaptations (debated)
• Weight loss (often considered a benefit)

Contraindications

• eGFR <30 mL/min/1.73m2 (contraindicated) or <45 (use with caution)
• Acute or chronic metabolic acidosis including lactic acidosis
• Heavy alcohol consumption
• Acute decompensated heart failure
• Hepatic failure
• Planned procedures with iodinated contrast dye

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