- mTOR Activation and Inhibition.
- 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.
- 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.
- Intermittent dosing important, allowing for cycle of cell death and rebuild.