Summary

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

Introduction

• 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.

Rapamycin

• 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.

Sources

• The Drive with Peter Attia — David Sabatini
• Wikipedia