• Introduction.
  • mTOR Activation and Inhibition.
  • Rapamycin.
  • Sources.


  • Mammalian target of rapamycin (mTOR).
  • Involved in cell metabolism, survival, and growth
    • Central regulator of metabolism and physiology.
    • Regulates many cellular processes.
    • Ccell growth, proliferation, protein synthesis, autophagy.
  • Within the cell, mTOR is found in 2 distinct protein complexes.
    • mTORC1 and mTORC2.
    • Differ with regards to their upstream activators, downstream effectors.
  • mTOR signaling pathway is complex.
    • Integrating different signals coming from insulin, cytokines (immune system), nutrients, oxygen and mitogens (cell division).
  • mTOR particularly useful and efficient target to modulate.
    • Involved in many different cell pathways (one stop shop).

mTOR Activation and Inhibition

  • Activated by many substrates.
    • Including glucose, insulin, amino acids.
  • Amino acids are particularly potent activators.
    • Leucine, arginine, methionine.
  • Once activated, mTOR inhibits autophagy:
    • TOR is involved in the inhibition of autophagy.
    • Inhibition of autophagy may lead to protein accumulation / aggregates.
    • Protein accumulation is associated with neurodegenerative diseases.
  • Inhibiting mTOR may be positive for life extension.
    • Increases lifespan across all animal models.
    • mTOR inhibitors are currently the only known pharmacological intervention that increases lifespan in all experimental animal models tested.
  • The mechanisms of lifespan regulation remain incompletely understood.
    • Involves the two complexes, mTORC1 vs mTORC2.
    • mTORC1 and mTORC2 complexes perform different functions.
    • Different functions may differentially affect longevity.
  • Pathways to mTOR inhibition:
    • caloric restriction.
    • methionine restriction.
    • rapamycin.
  • Speculation on why mTOR inhibition may be helpful:
    • Perhaps mTOR signaling gets higher / too high with age.
    • Perhaps mTOR signaling is high early in life, which is good, but fails to decrease with age.


  • Stops the activation of mTOR.
    • Thereby stopping the TOR inhibition of autophagy.
  • High doses:
    • Immunosuppressant (organ transplants).
  • Lower doses:
    • Potential extension of life span, reduction of neurodegenerative diseases.
    • These effects are likely related to (activating) autophagy.
  • Rapamycin may have unwanted, mainly metabolic, effects.
    • Including insulin resistance, hyperlipidemia, glucose intolerance and hypophosphatemia.
    • Most of these side effects are dosage-dependent and may regress with lower dosage.
  • mTORC1 vs. mTORC2:
    • Short-term rapamycin exposure: blocks mTORC1 but not mTORC2.
    • Long-term exposure: inhibits both complexes.
  • Dosage:
    • Intermittent dosing important, allowing for cycle of cell death and rebuild.


Leave a Reply