Metformin vs Tesofensine

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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Mechanism

Tesofensine (NS2330) is a triple monoamine reuptake inhibitor with affinity for dopamine (DAT), serotonin (SERT), and norepinephrine (NET) transporters. It suppresses appetite through indirect stimulation of alpha-1 adrenoceptor and dopamine D1 receptor pathways, reflecting additive effects of increased NE and DA activity. Tesofensine is a dual-action drug with both anorexigenic properties (appetite suppression) and metabolic properties (increased energy expenditure), silencing GABAergic hypothalamic neurons in the lateral hypothalamus.

Standard Dosing

Research indicates 0.25-0.5 mg daily via oral administration.

Timing

Morning dosing only. Avoid afternoon/evening dosing due to stimulant properties and potential insomnia.

Cycle Duration

12-24 week cycles. Monitor cardiovascular parameters throughout.

Side Effects

• Increased heart rate
• Elevated blood pressure
• Dry mouth
• Insomnia
• Constipation
• Nausea
• Headache
• Anxiety/restlessness

Contraindications

• Uncontrolled hypertension
• History of cardiovascular disease
• Concurrent MAOI use
• Glaucoma
• Hyperthyroidism
• Pregnancy and breastfeeding
• History of seizures
• Anorexia nervosa
• Cardiovascular disease
• Uncontrolled anxiety

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