#09 - David Sabatini, M.D., Ph.D.: rapamycin and the discovery of mTOR — the nexus of aging and longevity?
This episode features David Sabatini, Professor of Biology at MIT, discussing his discovery of mTOR and its central role in nutrient sensing and longevity. He explains how rapamycin, an mTOR inhibitor, extends lifespan across species and its implications for fasting and anti-aging strategies.
Deep Dive Analysis
14 Topic Outline
Introduction to David Sabatini and his mTOR/Rapamycin work
Sabatini's MD-PhD journey and the genesis of mTOR research
The discovery and initial naming of mTOR (RAFT1)
Independent discovery of mTOR and the FKBP co-receptor
Challenges and breakthroughs in identifying mTOR complexes (mTORC1, mTORC2)
The central role of mTORC1 in growth, metabolism, and longevity
mTOR as the cell's general contractor for rejuvenation
The dual nature of mTOR inhibition and rapamycin's partial effects
Nutrient sensing by mTORC1: glucose, insulin, and amino acids
The significance of methionine sensing and restriction
Intermittent dosing strategies for rapamycin and longevity
Rapamycin's effects on cancer, cardiovascular disease, and neurodegeneration
Gedankenexperiment: Rapamycin vs. lifestyle interventions for longevity
Dream experiments for understanding mTOR across tissues and states
7 Key Concepts
mTOR (Mechanistic Target of Rapamycin)
A protein kinase discovered by David Sabatini, central to nutrient sensing and cell growth. It acts as a 'general contractor' for the cell, coordinating many processes like protein synthesis, metabolism, and autophagy.
Rapamycin
A small molecule drug that acts as an immunosuppressant and has been shown to extend lifespan in various organisms by inhibiting mTOR. It first binds to a co-receptor (FKBP) to then interact with and inhibit mTOR.
mTORC1 (mTOR Complex 1)
One of two major protein complexes containing mTOR, primarily responsible for regulating cell growth, metabolism, translation, and autophagy. It is sensitive to rapamycin and its inhibition is linked to longevity.
mTORC2 (mTOR Complex 2)
The second major protein complex containing mTOR, involved in the PI3 kinase pathway and regulating AKT. It is less sensitive to rapamycin and its functions were mysterious for a longer period compared to mTORC1.
Autophagy
A cellular process of 'self-eating' where cells break down and recycle their own components. It is regulated by mTORC1, and its induction is thought to contribute to the longevity effects observed with mTOR inhibition.
S-adenosylmethionine (SAM)
A metabolite made from methionine, which acts as a sensor for methionine levels. SAM is a crucial cofactor for hundreds of methylation reactions in the cell, and its levels influence mTORC1 activity.
FKBP (FK506-binding protein)
A co-receptor protein that rapamycin first binds to. The rapamycin-FKBP complex then interacts with and inhibits mTOR, making rapamycin a unique type of drug that doesn't directly bind its primary target.
9 Questions Answered
David Sabatini, as a graduate student, methodically investigated how the immunosuppressant rapamycin worked, eventually purifying and identifying the protein now known as mTOR (originally RAFT1) in mammalian cells in the early 1990s.
Unlike most drugs that directly bind to a protein target, rapamycin first binds to a co-receptor protein called FKBP. This rapamycin-FKBP complex then interacts with and inhibits mTOR.
mTORC1 regulates cell growth, metabolism, translation, and autophagy, and is sensitive to rapamycin. mTORC2 is involved in the PI3 kinase pathway and regulates AKT, and is less sensitive to rapamycin.
While not fully understood, one theory is that mTORC1 acts as a 'general contractor' for the cell, influencing numerous processes. Inhibiting it with rapamycin may rejuvenate cells by promoting autophagy and coordinating beneficial changes across many cellular subsystems.
Both glucose and insulin activate mTORC1 through independent pathways. Insulin signals the organism's overall fed state, while glucose provides a local signal of nutrient availability to individual cells.
Methionine levels, particularly through its metabolite S-adenosylmethionine (SAM), act as a sensor that can inhibit mTORC1 when levels are low. Methionine restriction has been shown to have beneficial effects, including lifespan extension, potentially mediated by this pathway.
Intermittent dosing allows for periods of mTORC1 inhibition (inducing autophagy and other catabolic processes) followed by periods of rebuilding, which is thought to be crucial for cellular rejuvenation and avoiding the negative effects of chronic inhibition.
While immunosuppression generally increases cancer rates, rapamycin-treated transplant patients do not show this increase. This suggests that rapamycin has direct anti-cancer effects on cells, mitigating the increased risk from immune suppression.
The brain prioritizes nutrient supply, maintaining constant levels even during fasting, making nutrient sensing for mTOR less straightforward. Neuronal activity is known to regulate mTORC1 in the brain, but specific brain-specific regulatory factors are still largely unknown.
13 Actionable Insights
1. Prioritize Anabolism-Catabolism Cycling
Recognize that cycling between anabolic and catabolic states is potentially the single most important factor for cellular health and longevity, as both too little and too much mTOR activity or autophagy can be toxic.
2. Intermittent Rapamycin Dosing
If considering rapamycin for longevity, an intermittent dosing approach is recommended to induce a relatively weak autophagy and allow the system to rebuild, aligning with the crucial principle of anabolism-catabolism cycling.
3. Consider Methionine Restriction
Explore methionine restriction as a dietary intervention for beneficial effects on glucose homeostasis and lifespan extension, as it significantly drops during fasting and its metabolite, SAM, directly inhibits the mTOR pathway when reduced.
4. Modulate mTOR for Systemic Rejuvenation
To broadly impact cellular state, rejuvenate cells, and slow aging, target mTOR because it acts as a ‘general contractor’ for the cell, influencing numerous processes simultaneously, which is more effective than targeting individual pathways.
5. Avoid Complete mTORC1 Inhibition
Do not completely inhibit mTORC1 as it is essential for the growth of normal cells; full inhibition would mimic a crude chemotherapeutic agent, leading to atrophy and cell death.
6. Leucine & Arginine Activate mTORC1
Understand that leucine (and to a lesser extent isoleucine, but not valine in their findings) and arginine directly activate mTORC1 by binding to intracellular receptors, signaling nutrient availability and driving anabolism.
7. mTOR Modulation Differs from Fasting
Be aware that while mTOR modulation can mimic some effects of fasting, systemic nutrient levels remain high, potentially leading to nutrient accumulation in cells, unlike actual fasting where nutrient levels are lower.
8. SAM May Counter Methionine Restriction
Be aware that the beneficial effects of methionine restriction, which work by reducing SAM and inhibiting mTOR, could potentially be bypassed or counteracted by supplementing with SAM (S-adenosylmethionine).
9. Glucose and Insulin Activate mTORC1
Recognize that both glucose and insulin activate mTORC1 through independent pathways, which aligns with its role as a nutrient sensor, signaling a fed state.
10. mTORC1 Senses Diverse Cellular States
Understand that mTORC1 activity is regulated by a wide array of cellular conditions, including nutrients, oxygen levels, pH, growth factors, and osmotic pressure, making it a central hub for cellular state sensing.
11. Integrate Local & Global Nutrient Signals
When assessing the body’s anabolic/catabolic state, consider both global signals (like insulin reflecting overall organismal fed state) and local signals (like specific nutrient availability within cells) as mTOR integrates both.
12. Rapamycin May Mitigate Cancer Growth
While rapamycin is an immunosuppressant, it appears to have direct anti-cancer effects that can mitigate the increased cancer risk from immune suppression, potentially by affecting the growth and immune evasion of existing cancer cells rather than preventing initial mutations.
13. Foster Independent Project Ownership
Allow individuals, especially students, complete freedom to pursue their own projects, as this can be a foundational experience for developing into an independent scientist or professional.
5 Key Quotes
I don't think there's anybody on the planet who knows more about rapamycin and mTOR than David Sabatini.
Peter Attia
I've kind of stuck with this mTOR protein. And in many ways, I was very lucky because we were there at the beginning, and it turned out to be such an exciting thing to work on.
David Sabatini
To some extent, mTOR is like the general contractor for the cell. I don't know of any other pathway that does as many things.
David Sabatini
Cycling, anabolism, catabolism might be the single most important thing to do.
David Sabatini
Your brain, your body... Yeah, your brain prioritizes nutrients in the brain over it. It basically protects your body.
David Sabatini