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#09 – David Sabatini, M.D., Ph.D.: rapamycin and the discovery of mTOR — Whalespan

Content›Video›#09 – David Sabatini, M.D., …

#09 – David Sabatini, M.D., Ph.D.: rapamycin and the discovery of mTOR

Peter Attia1h 11m · 2019-12-23

Claims Made

140

Claims Supported

103

Support Rate

74%

Support rate

103 of 140 claims supported

103 supported37 partial / not

Claims from this content

90

✓Well SupportedRapamycin was discovered in the mid-1960s from Streptomyces hygroscopicus found on Easter Island and was initially identified as a potent antifungal.✓Well SupportedRapamycin acts by first binding to FKBP, forming a complex that then interacts with mTOR.◐Partially SupportedPrior to recent research, rapamycin's only known human application was for immune suppression in organ transplant patients.✓Well SupportedRapamycin is one of the most effective known cancer-preventive agents in mice, and lifespan extension in mice may largely reflect a delay of multiple forms of cancer.Well Supported

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The discovery of mTORC1 and its associated proteins enabled the measurement of its enzymatic activity and phosphorylation of known substrates like S6 kinase.

✓Well SupportedRapamycin may offer longevity benefits when administered pulsatilely, unlike its less consistent use in cancer therapy.

✓Well SupportedGenetics related to Raptor protein and mTORC1 have been linked to lifespan and aging.

✓Well SupportedRapamycin was approved by the FDA in 1999 as a frontline treatment for organ transplant patients.

✓Well SupportedRapamycin, by inhibiting mTOR, is believed to slow biological aging and can be an effective anti-cancer drug.

✓Well SupportedCycling between anabolism and catabolism may be crucial for health as both mTOR and autophagy are toxic in extreme quantities.

✓Well SupportedMethionine is the amino acid that drops the most when an animal is fasted.

◐Partially SupportedRapamycin may penetrate the blood-brain barrier better in aged animals and humans due to age-related decline in barrier function.

✓Well SupportedmTOR is driven by amino acid intake, with leucine being the primary driver.

✓Well SupportedAutophagy is critical in the brain for preventing neurodegeneration.

◐Partially SupportedIntermittent rapamycin dosing is proposed as a method to chemically induce autophagy without fasting.

◐Partially SupportedRapamycin's life-extending properties may be due to delaying disease onset rather than directly killing cancer cells.

◐Partially SupportedDavid Sabatini is considered an expert on rapamycin and mTOR.

◐Partially SupportedThe brain is likely a modulator, not the primary appetite center, which is hypothesized to be located in the periphery, such as the liver.

◐Partially SupportedAchieving cellular rejuvenation and slowing aging likely requires a comprehensive approach targeting pathways like mTOR.

✓Well SupportedGenetic inhibition of mTOR in model systems recapitulates the longevity and healthspan benefits seen with rapamycin.

✓Well SupportedSAMe administration can rescue the effects of methionine restriction on the TOR pathway.

✓Well SupportedMethionine restriction shows beneficial effects on glucose homeostasis and lifespan extension comparable to caloric restriction.

◐Partially SupportedRapamycin does not increase the risk of certain cancers, unlike other immunosuppressants used for transplant patients.

◐Partially SupportedIn C. elegans, autophagy activation accounts for most or all benefits of inhibiting mTOR.

◐Partially SupportedmTOR inhibition's aging effects differ across contexts, tissues, and pathologies.

◐Partially SupportedRapamycin may affect the incidence of atherosclerotic plaque formation in cardiovascular disease.

◐Partially SupportedRapamycin does not fully inhibit mTORC1, as it only effectively inhibits some of its substrates, with autophagy being only weakly modulated.

◐Partially SupportedImpacting the aging process requires acting on multiple cellular processes regulated by mTOR.

◐Partially SupportedmTORC2 is less critical for survival than mTORC1, as individuals can tolerate more modulation of mTORC2 and still survive.

◐Partially SupportedThe speaker purified mTOR from rat brains, requiring the sacrifice of hundreds of rats.

◐Partially SupportedFasting mimics caloric restriction and differs from mTOR modulation by maintaining high nutrient levels during modulation.

◐Partially SupportedRapamycin is an allosteric inhibitor of mTOR that binds near the kinase domain, sterically blocking substrates.

◐Partially SupportedModulating mTORC1 activity is required for autophagy, which is essential for maintaining overall system health.

◐Partially SupportedThe detergent commonly used in labs to lyse mammalian cells breaks apart protein complexes, hindering purification.

✓Well SupportedmTORC in muscle has a higher affinity for leucine than mTORC1 in fat or hepatocytes, potentially signaling muscle growth during nutrient deprivation.

◐Partially SupportedBranched-chain amino acids, particularly leucine, are important for muscle building due to leucine's role in activating TOR (mTORC1).

◐Partially SupportedThe ideal molecule to modulate mTORC1 activity would not touch mTORC2, act constitutively, or cause 100% inhibition.

◐Partially SupportedNutrients are unlikely to be the primary modulators of mTORC1 in the brain due to their constant availability.

◐Partially SupportedTargeting upstream regulators of mTORC1, rather than mTORC1 itself, may allow for modulation of all mTORC1 substrates and achieve tissue specificity.

◐Partially SupportedThe first silver stain showing a glimpse of mTOR provided confirmation that the purification was achievable.

◐Partially SupportedmTOR modulation alone may not confer all the benefits of lifestyle interventions like dietary manipulation or exercise.

◐Partially SupportedThe protein identified as mTOR bound to FKBP, and this binding could be competed by FK506.

◐Partially SupportedFK-506 has antifungal, immunosuppressive, and anti-cancer effects.

◐Partially SupportedCalcineurin is highly expressed in the brain.

?Limited ResearchIt is unknown if other signaling effects of nutrients, beyond mTOR, are significant for lifespan manipulation.

?Limited ResearchThe precise mechanism by which mTORC1 inhibition extends lifespan is not fully understood.

◐Partially SupportedmTORC1 is regulated by nutrients, oxygen, pH, growth factors, and osmotic pressure.

◐Partially SupportedSmall molecules in pharmacology are generally defined as compounds around 1,000 Daltons or less, and are non-peptide.

◐Partially SupportedmTORC1 regulates translation, autophagy, metabolic pathways, and influences cell size.

◐Partially SupportedIf nutrients signal through mTOR, inhibiting downstream processes may lead to similar outcomes whether nutrient levels are high or low.

◐Partially SupportedNeuronal activity regulates mTORC1 in the brain.

◐Partially SupportedThe discovery of mTOR involved identifying a full-length cDNA of approximately 9,000 base pairs.

✕Not SupportedRapamycin's inhibition of mTORC2 may be detrimental to glucose homeostasis.

◐Partially SupportedMaintaining healthy synapses during brain growth requires mTORC1 activity, but modulating mTORC1 is also necessary for autophagy.

◐Partially SupportedA pan-mTORC1 inhibitor with no mTORC2 activity is a desirable therapeutic molecule.

◐Partially SupportedAutophagy may rejuvenate cells by removing old components and creating new ones.

◐Partially SupportedmTORC2 is part of the PI3 kinase pathway and regulates AKT.

◐Partially SupportedSAM is the second most common cofactor in enzymes after ATP and is used in hundreds of methylation reactions.

◐Partially SupportedThe appetite center requires regulation by something that senses rapid external changes.

◐Partially SupportedmTORC1 activity remains high in the brain during fasting, suggesting an external inhibitor is needed to modulate it for autophagy.

◐Partially SupportedAmino acids like leucine and arginine, and glucose act as local signals for mTORC1, while larger peptides like insulin act as central signals.

◐Partially SupportedThe affinities of valine and isoleucine for the leucine receptor are unlikely to be relevant for mTORC1 activation.

◐Partially SupportedGlucose and insulin activate mTORC1 through independent pathways.

✕Not SupportedMalfunctioning of a single regulatory switch like mTOR can have significant negative consequences.

◐Partially SupportedA protein that senses SAM (S-adenosylmethionine), a metabolite derived from methionine, has been identified.

✕Not SupportedCurrent understanding of tissue physiology is limited by a lack of deep kinetic understanding and integral measurements over time.

◐Partially SupportedFlies' mTOR pathway senses leucine and other amino acids, but not arginine, unlike humans.

?Limited ResearchIt is uncertain whether longevity interventions need to impact all tissues, or if targeting specific tissues like muscle, liver, or brain is sufficient.

◐Partially SupportedRapamycin provided significant knowledge about mTORC1 function before genetic tools were readily available.

◐Partially SupportedMuscle cells require both central and local signals to determine anabolic or catabolic state.

◐Partially SupportedThe discovery of mTOR as a signaling pathway was appreciated by the scientific community.

◐Partially SupportedMutations in the C. elegans raptor gene (DAF15) are connected to mTORC1 signaling.

◐Partially SupportedIf a sensor mediates methionine restriction's health benefits, knocking it out prevents those benefits.

◐Partially SupportedThe brain prioritizes nutrient availability and protects itself from nutrient deprivation, as evidenced by the brain not shrinking during a two-day fast in mice, unlike other tissues.

◐Partially SupportedRapalogs produce the same mechanistic effect as rapamycin on mTORC1.

◐Partially SupportedThe SAM sensor integrates multiple signals because it binds to SAMe, a metabolite that can be influenced by various inputs.

✕Not SupportedComplete inhibition of mTORC1 is likely not tolerated by the body and would cause atrophy, cell death, and hair loss.

◐Partially SupportedAn ideal longevity experiment in humans would involve groups receiving rapamycin (intermittently dosed with biomarker monitoring) and groups manipulating lifestyle behaviors like diet and exercise.

◐Partially SupportedCombining methionine restriction with rapamycin may reveal synergistic effects.

◐Partially SupportedmTORC1, identified via Raptor, is responsible for functions previously ascribed to rapamycin.

◐Partially SupportedRapalogs are mechanistically similar to rapamycin, with differences primarily in pharmacokinetic and pharmacodynamic properties.

◐Partially SupportedLeucine and arginine are transported into cells via high-capacity transporters and bind to cytosolic receptors that activate mTORC1.

◐Partially SupportedFasting regimens and rapamycin may be similar in their ability to manipulate lifespan within the range achievable by current interventions.

◐Partially SupportedThe mTOR pathway plays a central role in nutrient sensing and longevity.

◐Partially SupportedThe brain has the highest concentration of mTOR compared to other tissues.

◐Partially SupportedFK-506 and rapamycin share the same molecular target, calcineurin, despite structural differences.

◐Partially SupportedSAMe has convincing clinical data supporting its antidepressive effects.

◐Partially SupportedGenetic inhibition or activation of the mTOR pathway can lead to negative outcomes like muscular dystrophy.

◐Partially SupportedNutrient sensors for mtorc1 are targets for drug development.

◐Partially SupportedEarly purification experiments for mTOR consistently showed two bands on gels, indicating the presence of mTOR and a smaller, unidentified associated protein.