Side-by-side comparison of mechanisms, dosing, interactions, and stacking potential.
| Rapamycin (Sirolimus) | Semaglutide | |
|---|---|---|
| Category | Pharmaceuticals | Pharmaceuticals |
| Standard Dose | 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. | Research indicates 0.25 mg weekly SC for 4 weeks, escalating to 0.5 mg, then 1.0 mg, then 1.7 mg, then 2.4 mg weekly (FDA weight management protocol). Oral: 3 mg daily for 30 days, then 7 mg, then 14 mg daily. |
| 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. | SC injection any time of day, with or without food, on the same day each week. Oral: take on empty stomach with no more than 4 oz water, 30+ minutes before first food/drink/medications. |
| Cycle Duration | Long-term (years) for longevity applications. The PEARL trial assessed up to 12 months of treatment in healthy older adults. | Long-term/continuous use. Weight regain occurs upon discontinuation (67% regain within 1 year in trials). |
| Evidence Level | Strong (preclinical), Emerging (human longevity) | Strong (FDA-approved) |
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.
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.
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.
Long-term (years) for longevity applications. The PEARL trial assessed up to 12 months of treatment in healthy older adults.
Semaglutide is a GLP-1 receptor agonist with 94% structural homology to native GLP-1, modified with amino acid substitutions and a C-18 fatty acid chain that enables albumin binding, extending half-life to approximately 7 days. Centrally, it activates anorexigenic POMC/CART neurons and inhibits orexigenic NPY/AgRP neurons in the arcuate nucleus of the hypothalamus, reducing hunger and increasing satiety. Peripherally, it slows gastric emptying, enhances glucose-dependent insulin secretion from pancreatic beta-cells, and reduces glucagon secretion, providing comprehensive metabolic regulation.
Research indicates 0.25 mg weekly SC for 4 weeks, escalating to 0.5 mg, then 1.0 mg, then 1.7 mg, then 2.4 mg weekly (FDA weight management protocol). Oral: 3 mg daily for 30 days, then 7 mg, then 14 mg daily.
SC injection any time of day, with or without food, on the same day each week. Oral: take on empty stomach with no more than 4 oz water, 30+ minutes before first food/drink/medications.
Long-term/continuous use. Weight regain occurs upon discontinuation (67% regain within 1 year in trials).
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