mTOR
Also called: mTORC1, Mechanistic target of rapamycin
Written by Aaron CuhaReviewed Sep 2026
The switch that decides whether a cell should build or save. It is the reason protein, and not calories in general, is what ends the fasted state.
What it is
mTOR is a large enzyme that works inside two different protein teams. This page is about the team called mTORC1, which is held together by a frame protein called raptor. mTORC1 is the one that senses food. The other team, mTORC2, has different partners and different jobs, and is not covered here.
mTORC1 makes one choice for the cell: build, or save. When it is on, the cell makes protein, fat and DNA building blocks, and it keeps recycling in check. When it is off, protein making slows, autophagy is let loose, and the cell builds up more of its digestion sacs.
It listens to at least four separate kinds of signal: protein building blocks (amino acids), the cell's energy level, insulin and growth signals, and stress. It needs several of them to be good at the same time. That is why insulin alone does not fully switch it on when amino acids are missing. It is also why a fast turns it down in more than one way at once.
How it works
The key fact is that switching on mTORC1 is about where it sits, not just about its chemistry. With no amino acids around, mTORC1 floats loose in the cell. With amino acids present, it gets pulled onto the surface of the lysosome, the cell's digestion sac. Its direct on-switch, a small protein called Rheb, lives on that surface. If mTORC1 never reaches the lysosome, Rheb cannot switch it on, no matter what else is true.
The pulling is done by a family of four proteins called the Rag proteins. They work in pairs, grab raptor when amino acids are around, and are needed for amino acids to switch on mTORC1 at all. Lab versions of the Rags that are stuck in the "on" position hold onto mTORC1 tightly, and the switch stays on even when amino acids are taken away. Versions stuck in the "off" position stop amino acids from working at all. The Rags do not make mTOR work better. They move it to where Rheb is.
Three sensors for specific amino acids feed into this, and all three work the same back-to-front way. Sestrin2 holds back the switch when leucine is scarce. Leucine fits into a single pocket on Sestrin2, and that breaks its hold. CASTOR1 does the same job for arginine. SAMTOR senses methionine in a roundabout way, through a molecule called SAM whose level follows methionine.
Follow that backwards, and it is clear why protein gets special treatment. Every known, well-mapped chemical sensor in this pathway is a sensor for leucine, arginine or SAM. A meal of pure fat gives none of them anything to sense. A meal with protein delivers leucine and arginine within minutes of digestion.
Insulin works through a separate route. It sets off a chain of signals that disables a brake called the TSC complex. TSC normally keeps Rheb switched off. So when insulin disables TSC, Rheb turns on, and mTORC1 turns on at the lysosome. A fast shuts both routes at once. The energy sensor AMPK adds a third brake by acting on TSC2 and raptor directly.
Downstream, mTORC1 switches on two proteins, S6K1 and 4E-BP1, that together start the cell's protein making. It tags ULK1 to hold autophagy back. And it tags a protein called TFEB to keep it out of the cell's control centre. That is how it holds down the cell's whole digestion capacity, not just the start of autophagy.
What switches it on
Falling leucine, arginine and methionine, falling insulin, and rising AMPK. Any one of those turns mTORC1 down, and a fast supplies all three. Eating less protein without eating fewer calories reaches this switch through the amino acid sensors alone.
On the timing
Nobody has tracked mTORC1 hour by hour through a multi-day fast in people, in more than one tissue. Measuring it means taking a muscle sample with a needle and running a lab test on it. What exists is a few sample points. At 72 hours, mTOR activity in human muscle is down by about half. In the first 8 hours of a fast, the mTORC1 readings do not move much. Between those two points, nobody has looked.
What has been measured
In people
In a living person, mTORC1 is measured by testing a needle sample of muscle for chemical tags on the enzyme and its targets. There is no scan and no blood test for it. Within that limit, the 72 hour result is clear and consistent. There is also a separate line of evidence in people from drugs that turn the pathway down on purpose.
- The biggest study: 264 older adults took a low-dose mix of two drugs that turn down mTORC1, or a dummy pill, for 6 weeks. This was an early-stage study. The drug group reported fewer infections over the following year. Their antiviral genes were more active, and they responded better to the flu vaccine (Science Translational Medicine, 2018).
- An earlier drug study, in 2014. Older volunteers were given RAD001, a drug in the same family as rapamycin, at doses people handled fairly well. Their response to the flu vaccine was about 20% stronger. Fewer of their CD4 and CD8 immune T cells carried a marker called PD-1 (Science Translational Medicine, 2014).
- The first 8 hours: 10 healthy men gave muscle samples at 4 and 8 hours of fasting, with and without about 400 calories of extra arm-cycling exercise. The mTORC1 readings did not move much. Adding the exercise did not change that (Pflugers Archiv, 2021).
- A 72 hour fast in 8 healthy men, with muscle samples and tracer tests. mTOR activity fell by about half, and so did the activity of its targets 4EBP1, rpS6 and ULK1. In the same samples, LC3B-II rose about 30% and p62 rose about 10%. That mix is truly hard to read, and it is reported here just as it was measured (PLoS One, 2014).
- A 72 hour fast in people with obesity and lean people. The same mTOR and ULK1 signals in muscle were measured before and after the fast in both groups (American Journal of Physiology: Endocrinology and Metabolism, 2016).
- The warning that undercuts the whole reading, and it belongs here, not in a footnote. Six young men did weight training and then ate 0, 5, 10, 20 or 40 g of whole egg protein. Muscle protein building rose with the dose, up to a top at 20 g. But the standard mTORC1 tag markers did not change with protein at all. So in the very tissue and time where protein building clearly moved, the usual mTORC1 markers stayed flat (American Journal of Clinical Nutrition, 2009).
In animals and in cells in a dish
The whole sensing system was worked out with lab chemistry, protein structure work and cells in a dish. Most of that used long-lived lines of human cells and purified proteins. The lifespan evidence for turning this pathway down comes from mice, and it is unusually well controlled work in mice.
- In a dish, with human proteins in human cells: the Rag proteins grab raptor and carry the amino acid signal to mTORC1 (Science, 2008). Sestrin2 is the leucine sensor, and leucine sits in a single pocket on it (Science, 2016, two papers). CASTOR1 is the arginine sensor, and its structure shows how it senses arginine (Cell, 2016; Nature, 2016). SAMTOR is the SAM sensor (Science, 2017). This is human biology at the molecule level. It is not a measurement in a living person.
- In a dish: mTORC1 tags ULK1 to hold the start of autophagy back, and AMPK tags other spots to switch it on (Nature Cell Biology, 2011).
- In mice, at three separate labs, using mice of mixed genetic background. Rapamycin in the food from 600 days of age, which is late in a mouse's life, extended both typical and maximum lifespan in males and females. Measured by the age when 90% had died, lifespan rose 14% in females and 9% in males. The effect showed up at all three labs. Treated mice got the same diseases as untreated mice. The authors say the effect could be delayed cancer death, slower ageing, or both (Nature, 2009).
- In mice, at higher doses. At three times the dose, rapamycin raised typical lifespan by 23% in males and 26% in females, and raised maximum lifespan in both. The effect was bigger in females at every dose. The same paper reports that several hormone and metabolism changes seen in mice on a restricted diet do not show up in mice on rapamycin. The genes the liver uses to clear foreign chemicals also differed sharply between the two. The authors conclude the two are different treatments (Aging Cell, 2014).
Why it matters
mTORC1 is where the claim that fasting is about more than calories can be made exact, not vague. The sensors are for leucine, arginine and methionine. Nothing in the pathway grabs a fat or a sugar. That is why a meal with protein ends the fasted signal more firmly than the same calories as carbs or fat. It is also why eating less protein and eating less food overall are not the same thing at this switch.
It is also the switch with the strongest drug evidence for longer life in a mammal. Rapamycin extended lifespan in mice of mixed genetic background at three separate labs. That is one of the most solid results in the science of ageing. But it is a result in mice. No study of rapamycin, or any drug like it, has measured lifespan in people. What has been measured in people is immune function and infections over one year in older adults. That is a real and useful result, and it is a different one.
A claim you will see repeated
Rapamycin is often called a fasting copycat, and fasting is often called natural rapamycin. Neither is right. Rapamycin turns down one route into one switch, over and over, without any of the fuel changes, hormone changes or recycling context of a fast. And the higher-dose paper found that mice on rapamycin had a clearly different metabolic pattern from mice on a restricted diet. The second thing to hold onto is the measurement warning above. A study saying a fast lowered mTORC1 markers in human muscle has shown that the markers fell. In the one experiment in people where protein building and the markers were measured side by side, protein building moved and the markers did not.
Sources
- Study in people2014Fasting increases human skeletal muscle net phenylalanine release and this is associated with decreased mTOR signaling
PLoS One
8 healthy men gave muscle samples after an overnight fast and after a 72 hour fast. The growth switch mTOR was about 50% less active after 72 hours. The proteins it controls were less active too, including the brake mark it puts on ULK1, the recycling starter. Two recycling markers rose, LC3B-II by about 30% and p62 by about 10%.
8 healthy men studied postabsorptive and after a 72 hour fast, with forearm amino acid tracer kinetics and vastus lateralis biopsies. mTOR phosphorylation at serine 2448 fell approximately 50%, with reduced phosphorylation of 4EBP1 threonine 46, rpS6 serine 235/236 and ULK1 serine 757. LC3B-II rose approximately 30% and p62 rose approximately 10%.
- Study in people2016Differential regulation of lipid and protein metabolism in obese vs. lean subjects before and after a 72-h fast
American Journal of Physiology: Endocrinology and Metabolism
Researchers measured the growth switch mTOR and a recycling brake signal in the muscle of obese and lean people, before and after a 72 hour fast. They also tracked how fat and protein were used. This entry does not give the results.
Skeletal muscle mTOR and ULK1 serine 757 signalling measured in obese and lean subjects before and after a 72 hour fast, alongside lipid and protein metabolism.
- Study in people2021Increasing whole-body energetic stress does not augment fasting-induced changes in human skeletal muscle
Pflugers Archiv, European Journal of Physiology
10 healthy men did two supervised fasts, one with 2 hours of arm cycling that burned roughly 400 extra calories. Thigh muscle samples were taken at the start, 4 hours and 8 hours. The extra exercise made no clear difference to muscle signals, genes, proteins or fuel stores in the first hours of fasting.
10 healthy males, two supervised fasts with and without 2 hours of arm ergometer exercise adding roughly 400 kcal, vastus lateralis biopsies before, at 4 hours and at 8 hours. Signalling, mRNA and protein expression and substrate storage appeared unaffected by whole body energetic stress during the initial hours of fasting.
- Study in people2014mTOR inhibition improves immune function in the elderly
Science Translational Medicine
Older volunteers took RAD001, a drug in the rapamycin family that blocks mTOR. Their flu shot response was about 20% better, at doses they handled fairly well. Fewer of their immune T cells carried a marker called PD-1.
Elderly volunteers given the rapalog RAD001. The vaccine response to influenza was enhanced by about 20% at doses that were relatively well tolerated, and the percentage of CD4 and CD8 T lymphocytes expressing PD-1 fell.
- Study in people2018TORC1 inhibition enhances immune function and reduces infections in the elderly
Science Translational Medicine
264 older adults took a low dose of two mTOR-blocking drugs together, or a dummy pill, for 6 weeks. Over the next year, the drug group reported fewer infections. Their antiviral genes were more active and their flu shot response was better.
Phase 2a randomised placebo controlled trial in 264 elderly subjects, low dose combination of a catalytic and an allosteric TORC1 selective inhibitor for 6 weeks. Significant decrease in the rate of infections reported over the following year (P = 0.001), upregulation of antiviral gene expression, and improved influenza vaccine response.
- Study in people2009Ingested protein dose response of muscle and albumin protein synthesis after resistance exercise in young men
American Journal of Clinical Nutrition
6 healthy young men did leg weights, then ate 0, 5, 10, 20 or 40 g of egg protein, one amount per visit. Muscle building peaked at 20 g. At 20 and 40 g, the body burned more leucine for fuel. Several growth signal markers did not change with protein.
6 healthy young men, five trials, leg resistance exercise then 0, 5, 10, 20 or 40 g whole egg protein, synthesis measured over 4 hours by primed constant leucine infusion. Muscle protein synthesis was maximally stimulated at 20 g and leucine oxidation rose significantly at 20 and 40 g. Phosphorylation of S6K1 threonine 389, rpS6 serine 240/244 and eIF2B epsilon serine 539 was unaffected by protein ingestion.
- Lab (cells in a dish)2008The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1
Science
In a dish. Proteins called Rag GTPases grab the mTORC1 growth switch when protein building blocks are around. They do not switch it on directly. They move it to the surface of the cell's digestion sac, where its activator Rheb sits.
Cultured cells. The Rag GTPases bind raptor in an amino acid sensitive manner and are required for amino acid activation of mTORC1. They do not stimulate mTOR kinase activity directly; they relocalise mTORC1 to the lysosomal surface where its activator Rheb resides.
- Lab (cells in a dish)2016Sestrin2 is a leucine sensor for the mTORC1 pathway
Science
In a dish. When leucine is scarce, a protein called Sestrin2 grabs a partner called GATOR2 and holds back the mTORC1 growth switch. Leucine sticks to Sestrin2 at levels normal in the body. That makes Sestrin2 let go, so mTORC1 can switch on.
Cultured cells and purified proteins. Sestrin2 binds and inhibits GATOR2 when leucine is scarce; leucine binds Sestrin2 directly with a dissociation constant in the physiologically relevant range and releases GATOR2, permitting mTORC1 activation.
- Lab (cells in a dish)2016Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway
Science
In a dish. A structure study showed leucine fits into a single pocket in Sestrin2. That fit is what breaks Sestrin2's hold on GATOR2.
Structural work showing leucine bound in a single pocket in Sestrin2, and that this binding is what breaks the Sestrin2 to GATOR2 interaction.
- Lab (cells in a dish)2016The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway
Cell
In a dish. A protein called CASTOR1 holds back GATOR2. Arginine sticks to CASTOR1 and breaks that hold. So CASTOR1 is how cells sense arginine for the mTORC1 growth switch.
Cultured cells and purified proteins. CASTOR1 binds and inhibits GATOR2; arginine binds CASTOR1 directly and disrupts the CASTOR1 to GATOR2 interaction.
- Lab (cells in a dish)2016Mechanism of arginine sensing by CASTOR1 upstream of mTORC1
Nature
In a dish. Scientists mapped the shape of CASTOR1 with arginine stuck to it. That showed the chemistry of how cells sense arginine on the way to the mTORC1 growth switch.
Structure of arginine bound CASTOR1, establishing the chemical basis of arginine sensing upstream of mTORC1.
- Lab (cells in a dish)2017SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway
Science
In a dish. Cells sense methionine through a molecule made from it, called SAM. A protein called SAMTOR sticks to GATOR1 and holds back mTORC1. SAM sticks to SAMTOR and breaks that hold.
Cultured cells and purified proteins. Methionine is sensed indirectly through S-adenosylmethionine. SAMTOR binds GATOR1 and inhibits mTORC1; SAM binds SAMTOR and disrupts that interaction.
- Lab (cells in a dish)2011AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1
Nature Cell Biology
In a dish. When food is plentiful, mTORC1 tags ULK1 at one spot to keep recycling off. When energy is short, AMPK tags other spots on the same protein to switch recycling on.
Cultured cells. mTORC1 phosphorylates ULK1 at serine 757 to hold autophagy initiation off when nutrients are plentiful, and AMPK phosphorylates other sites on the same kinase to switch it on when energy is short.
- Animal study2009Rapamycin fed late in life extends lifespan in genetically heterogeneous mice
Nature
In mice. Mice from a mixed genetic background, at three separate labs, got rapamycin starting at 600 days old, which is late in life. Both sexes lived longer, on average and at the top end. Measured at the age when 90% had died, females gained 14% and males 9%. Treated mice got the same diseases as untreated ones. A second group started at 270 days also lived longer at an early check.
Genetically heterogeneous UM-HET3 mice at three independent sites, rapamycin started at 600 days of age. Median and maximal lifespan increased in both sexes; on the basis of age at 90% mortality the increase was 14% for females and 9% for males. Disease patterns in treated mice did not differ from controls. A separate cohort started at 270 days also showed increased survival at interim analysis.
- Animal study2014Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction
Aging Cell
In mice. At three times the dose of the first studies, rapamycin raised typical lifespan 23% in males and 26% in females. Top lifespan rose in both sexes, and females gained more at every dose. Many body changes seen in mice on a strict diet did not show up with rapamycin, so the two work differently.
At a threefold higher dose than the original studies, rapamycin increased median lifespan 23% in males and 26% in females, with maximal longevity increased in both sexes and larger effects in females at every dose. Several endocrine and metabolic changes seen in diet restricted mice were not seen in rapamycin treated mice, and hepatic xenobiotic metabolism gene expression was quite distinct between the two.