Rapamycin (Sirolimus) vs Tesofensine

Mechanism

Rapamycin binds the intracellular protein FKBP12, and the rapamycin-FKBP12 complex inhibits mechanistic target of rapamycin complex 1 (mTORC1), a serine/threonine kinase that integrates nutrient sensing, growth factor signaling, and cellular energy status. mTORC1 inhibition suppresses S6K1-mediated ribosomal protein synthesis, activates ULK1-mediated autophagy and mitophagy, enhances lysosomal biogenesis via TFEB nuclear translocation, reduces senescent cell accumulation, and suppresses the SASP (senescence-associated secretory phenotype). At higher chronic doses, rapamycin also inhibits mTORC2, which regulates Akt-mediated insulin signaling — this is believed to drive the metabolic side effects.

Standard Dosing

Research indicates 5-6 mg once weekly (intermittent/pulsed dosing) for longevity protocols. This weekly pulsed approach preferentially inhibits mTORC1 while allowing mTORC2 to remain functional.

Timing

Once weekly, consistent day each week. Take with or without food (food increases bioavailability by ~35% — be consistent either way). Grapefruit juice significantly increases rapamycin bioavailability via CYP3A4 inhibition — some practitioners use this intentionally to reduce pill burden.

Cycle Duration

Long-term (years) for longevity applications. The PEARL trial assessed up to 12 months of treatment in healthy older adults.

Side Effects

• Mouth ulcers/canker sores (most common, dose-dependent)
• Elevated lipids (triglycerides and LDL — typically manageable with weekly dosing)
• Impaired wound healing
• Mild immunosuppression (increased susceptibility to infections)
• Insulin resistance (primarily from mTORC2 inhibition at higher/daily doses)
• Acne-like skin eruptions
• Thrombocytopenia and leukopenia (rare at longevity doses)

Contraindications

• Active infections (immunosuppression risk)
• Poorly healing wounds or planned surgery (delays wound healing)
• Severe hepatic impairment
• Uncontrolled hyperlipidemia
• Pregnancy and breastfeeding
• Organ transplant patients on calcineurin inhibitors (specialized dosing required)
• Active infection
• Immunocompromised states
• Poorly controlled diabetes
• Wound healing (pause 2 weeks pre-surgery)

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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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