Topics

The Atlas indexes 169 topics — genes and proteins, complexes, drugs, diseases, processes, outcomes. 116 have a page of their own; the rest are indexed and searchable but not written up, because a page with nothing on it but a name is worse than no page.

169 topics

Genes & proteins 69

mTOR 124 Serine/threonine kinase; central regulator of cell growth and metabolism; direct target of rapamycin.
Akt/PKB 44 Key kinase downstream of PI3K in growth signalling; activated by PDK1 at T308 and further phosphorylated by mTORC2 at S473, which shapes which substrates it hits.
TSC1/TSC2 44 Tuberin-hamartin tumor suppressor complex; acts as a GTPase-activating protein for Rheb; integrates growth-factor and energy signals to control mTORC1.
S6K1 40 Direct downstream effector of mTORC1 controlling protein synthesis, and the source of the pathway's main negative feedback: S6K1 phosphorylates and represses IRS-1, uncoupling the insulin receptor from PI3K (HAR2004, SHA2004). Its deletion extends lifespan in FEMALE mice (+19% median, not significant in males; SEL2009) and protects against diet-induced obesity.
AMPK 26 AMP-activated protein kinase; cellular energy sensor; inhibits mTORC1 under low-energy conditions.
Rag GTPases 25 Family of small GTPases that let mTORC1 sense amino acids by controlling its localization near its activator Rheb inside the cell.
PI3K 23 Phosphoinositide 3-kinase; produces signaling lipids downstream of growth-factor receptors; activates Akt and heads the growth-factor arm of the mTOR pathway. It is not upstream of everything: amino-acid sensing at the lysosome, AMPK-mediated energy stress and Ras-MAPK reach mTORC1 by routes that bypass it.
4E-BP1 22 Translational repressor; the master effector through which mTORC1 controls protein synthesis. mTORC1 phosphorylates 4E-BP1 to release eIF4E and switch translation ON.
Raptor 21 Defining subunit of mTORC1: its presence is what makes a complex 'mTORC1', and it is the scaffold that presents substrates (S6K1, 4E-BP1) to mTOR via their TOS motifs. It is also a direct AMPK substrate - AMPK phosphorylates Raptor on two conserved serines, inducing 14-3-3 binding, and that step is required for energy stress to inhibit mTORC1 independently of TSC2 (Gwinn 2008, PMID 18439900). So Raptor is both the substrate-presenting scaffold and one of the two arms by which energy stress reaches mTORC1.
TFEB 17 Master transcription factor for lysosome biogenesis and autophagy. mTORC1 phosphorylates TFEB to trap it in the cytosol; when mTORC1 is off, TFEB enters the nucleus and turns on the cell's recycling program.
Rheb 15 Small GTPase that directly activates mTORC1 when in its GTP-bound state; held inactive by TSC1/TSC2.
Rictor 12 Defining subunit of mTORC2 (Rapamycin-Insensitive Companion of mTOR); routes mTOR toward Akt and the cytoskeleton rather than S6K1/4E-BP1.
eIF4E 11 Cap-binding protein that recruits the ribosome to an mRNA. Held hostage by 4E-BP1 until mTORC1 phosphorylates the latter - the rate-limiting step of cap-dependent translation.
ULK1 11 Initiator of autophagy and a direct mTORC1 substrate: mTORC1 phosphorylates ULK1 at S757 to hold it back. The AMPK arm is contested rather than settled - the classic reading is that AMPK phosphorylates ULK1 at other sites to switch autophagy on directly, but under glucose starvation and mitochondrial energy stress AMPK has been reported to inhibit ULK1 activation while protecting the machinery from degradation. See the AMPK-ULK1 link for which effect dominates under which kind of energy stress.
Insulin 10 Pancreatic peptide hormone; the growth-factor input that reaches mTORC1 through the insulin receptor, IRS proteins, PI3K and Akt. Added 2026-10-10 after an audit found the Atlas modelled a single 'Growth hormone / IGF-1 axis' input whose edge text described insulin docking on its receptor, while insulin itself had no node and growth hormone does not use that receptor.
Sestrin2 9 Direct intracellular leucine sensor and a NEGATIVE regulator of mTORC1. When leucine is scarce, Sestrin2 binds and inhibits GATOR2, so GATOR1 stays active and keeps mTORC1 switched off. Leucine binding (~20 uM affinity) releases GATOR2 - the pathway is switched on by removing a brake, not by adding a signal. Sestrin2 does not act on the Rag GTPases directly; it works two steps upstream, through GATOR2 and GATOR1.
SLC38A9 8 Lysosomal amino-acid transporter and signaling component; acts as an arginine sensor on the lysosomal membrane. Works together with v-ATPase and Ragulator to relay luminal arginine availability to the Rag GTPases and thereby recruit mTORC1. Loss of SLC38A9 impairs arginine-dependent mTORC1 activation.
FLCN / FNIP1/2 7 Folliculin and its binding partners FNIP1/2; act as a GTPase-activating protein (GAP) for RagC/D, switching the Rag heterodimer into the configuration that recruits mTORC1 to the lysosome. FLCN-FNIP complements the GATOR1/GATOR2 arm by regulating the RagC/D half of the cycle. The immediate effect of FLCN loss is substrate-specific: TFEB and TFE3 escape phosphorylation and accumulate in the nucleus while canonical outputs (S6K1, 4E-BP1) are largely preserved in the short term (NAP2020). Over time this is not the whole picture: constitutively active TFEB/TFE3 feed back to raise overall mTORC1 activity, and in kidney and lung that mTORC1 hyperactivation is itself a key driver of cyst and tumour formation (Di Malta 2023, PMID 36987696; Ferniani 2026; Cao 2026, PMID 41697734). So BHD involves both a substrate-specific defect and, downstream, genuine mTORC1 hyperactivation - the balance is tissue- and time-dependent.
LKB1 (STK11) 7 A serine/threonine kinase that activates AMPK and acts upstream of mTOR to regulate cellular energy sensing, autophagy, and metabolism.
PTEN 7 Phosphatase that erases PIP3 and so shuts down the PI3K arm. One of the most frequently lost tumour suppressors in human cancer, and one of the most common ways this pathway is left switched on without its growth-factor brake.
SREBP1 / SREBP2 7 Sterol regulatory element-binding proteins 1 and 2; master transcription factors for de novo lipid and cholesterol biosynthesis. mTORC1 promotes SREBP nuclear entry (via Lipin-1 and S6K1), linking nutrient sensing to the lipogenic program. SREBP1/2 are thus a major downstream metabolic output of mTORC1 alongside protein synthesis and autophagy suppression.
CASTOR1 6 Direct cytosolic arginine sensor for the mTORC1 pathway; arginine binding releases its inhibition of GATOR2.
FoxO 6 Forkhead box O transcription factors (FOXO1/3/4) that act as key downstream targets of PI3K/Akt and mTOR signalling; they are excluded from the nucleus by Akt, with an mTORC2/SGK contribution, so catalytic or mTORC2-directed inhibition promotes nuclear entry and transcription of stress-response and longevity genes, whereas rapamycin can raise Akt activity through feedback relief and leave them cytoplasmic.
IRS-1 / IRS-2 5 Insulin receptor substrate proteins - the adaptors that carry the signal from the insulin/IGF-1 receptor to PI3K. S6K1 phosphorylates and represses them, which is one of the pathway's major negative feedback loops: sustained mTORC1 activity deafens the cell to insulin, and blocking mTOR restores insulin signalling and raises Akt activity.
mLST8 5 mLST8 (GbetaL) - a shared subunit of BOTH mTOR complexes. Especially required for mTORC2 to assemble and signal to Akt; largely dispensable for mTORC1.
p62/SQSTM1 5 Autophagy cargo receptor and mTORC1-activating scaffold on lysosomes. Its accumulation is NOT a reliable flux readout: in FLCN-null kidney cancer cells p62 accumulates in enlarged puncta while bulk autophagy flux and LC3 lipidation are unaffected, and the same pattern was recapitulated in patient tumour samples (Ullern 2026, PMID 42569319). p62 level is dissociable from bulk autophagic flux, so it needs a flux measurement beside it, exactly as LC3-II does.
SIN1 / MAPKAP1 5 Essential structural subunit of mTORC2 (stress-activated protein kinase-interacting protein 1). Required for mTORC2 assembly and integrity; controls the substrate specificity of mTORC2 toward Akt and other AGC kinases. Prolonged rapamycin treatment can disrupt SIN1-containing mTORC2 in some cell types but not others, which is one explanation for the impaired Akt signalling seen with chronic rapamycin.
v-ATPase 5 Vacuolar H+-ATPase. Necessary for amino acids to activate mTORC1, and it makes extensive amino-acid-sensitive contacts with Ragulator, but it is not itself the sensor: the Atlas assigns that role to SLC38A9, Sestrin2 and SAMTOR for their respective inputs. ATP hydrolysis by the pump is required for amino acids to regulate the v-ATPase-Ragulator interaction, which is the evidence the signal begins inside the lysosomal lumen (Zoncu 2011, PMID 22053050).
Beclin-1 (BECN1) 4 Core autophagy protein required for autophagosome nucleation; regulated by mTOR and inhibited by Bcl-2 family members.
ERK / RSK (MAPK) 4 The Ras-MAPK growth-signalling arm. ERK and its effector RSK phosphorylate TSC2 and inactivate the TSC complex, so MAPK signalling converges on the same brake that Akt releases (MA2005). This is the third major upstream input to mTORC1 alongside PI3K/Akt and AMPK, and it is a route to mTORC1 activation that PI3K inhibitors do not close. mTORC1 inhibition also feeds back to activate MAPK (CAR2008).
FKBP12 4 Rapamycin's docking protein. Rapamycin first binds FKBP12; only the FKBP12-rapamycin pair can grab mTOR. This is why rapamycin is an 'allosteric' (indirect) inhibitor - it works through a chaperone, not by blocking the active site.
HIF-1α 4 Hypoxia-inducible factor 1-alpha, the main transcription factor for metabolic and angiogenic responses to low oxygen. Its output is partly mTORC1-dependent: in an Akt-driven mouse prostate model, mTOR inhibition reversed the lesions partly through HIF-1-dependent programmes (MAJ2004).
LC3B (MAP1LC3B) 4 Key autophagosome membrane marker; LC3B lipidation (LC3-II) rises when mTORC1 is inhibited, but a single LC3-II level cannot separate more autophagosomes being built from fewer being cleared; flux has to be measured against a lysosomal block (bafilomycin or chloroquine) or a turnover readout.
PRAS40 4 Insulin-regulated inhibitor subunit of mTORC1. Insulin triggers Akt to phosphorylate PRAS40, which lifts one inhibitory subunit off the complex; that on its own is not the on-switch, as most of the insulin input runs through the TSC2/Rheb arm.
Vps34 (PIK3C3) 4 The class III phosphatidylinositol 3-kinase and the main source of PI(3)P (class II PI3Ks make local pools of it too). It has two jobs that meet in the Atlas: it is required to build the autophagosome, and it was reported as a nutrient-regulated input to mTORC1 that runs separately from the insulin/class I PI3K route (BYF2005, NOB2005). The relationship between that input and the later Rag/Ragulator account of amino acid sensing is unresolved.
Atg5 3 Core gene required for autophagosome formation; overexpressing it in mice is sufficient to extend lifespan on its own.
REDD1 (DDIT4) 3 Hypoxia- and glucocorticoid-induced protein that suppresses mTORC1. The route is tissue-dependent: the original cell-culture model runs through the TSC complex, but in mouse skeletal muscle in vivo REDD1-mediated inhibition is independent of TSC2/14-3-3 binding and runs through Akt and PRAS40 instead (Britto 2014, PMID 25315696). So low oxygen and weak growth-factor signals do not necessarily share a single brake.
SLC7A5 (LAT1) 3 Large neutral amino acid transporter 1. Not a one-way importer: it works only as a heterodimer with SLC3A2 (4F2hc) and is an obligatory antiporter, bringing leucine and other essential amino acids in only by simultaneously effluxing glutamine. Glutamine availability therefore gates leucine sensing, and glutamine uptake plus rapid efflux is the rate-limiting step for mTORC1 activation (Nicklin 2009, PMID 19203585).
DEPTOR 2 Endogenous inhibitor of both mTORC1 and mTORC2; paradoxically overexpressed in a subset of multiple myelomas, which depend on high DEPTOR: partial mTORC1 suppression relieves S6K1-IRS1 feedback and sustains PI3K/Akt survival signalling (Peterson 2009).
Grb10 2 mTORC1 substrate that, once phosphorylated, damps insulin/IGF-1 receptor signalling - one arm of the negative feedback that makes mTOR inhibitors paradoxically raise upstream Akt activity.
ITGA2 (Integrin alpha-2) 2 Integrin subunit alpha-2. Two separate findings in this Atlas: kynurenic acid from tumor microbiota induces ITGA2 upstream of an mTOR-dependent cascade that is inhibited, not activated, which sustains cathepsin V and suppresses CD8+ T cells (REN2026); and, in a different setting, collagen I signalling through alpha2beta1 integrin activates mTORC1/S6 and sustains amino-acid supply via LAT1-4F2hc (NAZ2026). The two point in opposite directions and must not be merged.
LARS (leucyl-tRNA synthetase) 2 Enzyme that charges tRNA with leucine, proposed as an alternative intracellular leucine sensor acting as a GAP for RagD. Competes with the Sestrin2 model - an unresolved question in the field.
PDCD4 2 Translation inhibitor that blocks the eIF4A helicase. S6K1 marks it for degradation, giving mTORC1 a second, 4E-BP-independent route to raising protein synthesis.
PFKFB3 2 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3, a rate-limiting glycolytic regulator controlled downstream of mTORC2.
PGC-1α / YY1 2 Transcriptional complex through which mTORC1 drives mitochondrial gene expression.
SAMTOR 2 Sensor of S-adenosylmethionine (SAM), linking methionine / one-carbon metabolism to mTORC1 via GATOR1.
SGK1 2 Serum- and glucocorticoid-regulated kinase 1; a second major AGC kinase phosphorylated and activated by mTORC2 at its hydrophobic motif. Controls ion transport, cell survival, and glucose metabolism. mTORC2→SGK1 signaling is a key output branch of mTORC2 parallel to the mTORC2→Akt axis.
ASCL1 1 Achaete-scute homolog 1, a bHLH transcription factor that acts upstream of a CCNB1/mTOR axis in renal injury.
eIF4A 1 ATP-dependent RNA helicase that unwinds 5' mRNA secondary structures; activated downstream of mTORC1 to promote selective cap-dependent translation initiation.
ErbB3 (HER3) 1 Receptor of the EGFR family with an impaired kinase domain; when paired with another family member it becomes a strong activator of PI3K/AKT/mTOR signalling.
FGF21 1 Fibroblast growth factor 21, a metabolic hormone regulating glucose metabolism. The one study in this Atlas does not show it activating mTOR: engineered FGF21-overexpressing exosomes activated AMPK and SUPPRESSED mTOR signalling while upregulating PFKFB3, reprogramming fibroblast glycolysis and accelerating wound closure in mice (Chen 2026, PMID 42551612). That is an engineered exosome preparation, not the endogenous hormone, and the direction of the mTOR effect should not be generalised from it.
GADD45alpha 1 Stress-inducible DNA repair protein regulated downstream of the mTOR-TFEB axis. Astragaloside IV reactivated TFEB by inhibiting mTOR, which restored GADD45alpha expression along with renal function, pathology, autophagic flux and DNA repair in a mouse model of tacrolimus nephrotoxicity; the effects were reversed by TFEB knockdown (GAO2026, PMID 42438242). Mouse in vivo plus cell work, not a human finding.
LYCHOS (GPR155) 1 A lysosomal transmembrane protein that reports cholesterol sufficiency to mTORC1. Cholesterol binds its amino-terminal permease-like region; at high cholesterol LYCHOS binds GATOR1 through a cytoplasm-facing loop, and sequestering GATOR1 removes the brake on the Rag GTPases, so mTORC1 is recruited to the lysosome (SHI2022). Structurally it is a fusion of a plant PIN-auxin-transporter-like domain with a class B2-like GPCR domain, with the cholesterol site between the two. Evidence is human cell lines and structures; no organismal or human endpoint. It is one of at least two cholesterol routes into this machinery, alongside the SLC38A9-NPC1 complex (CAS2017).
MRPS17 1 Mitochondrial ribosomal protein S17, upregulated in lung adenocarcinoma where it activates PI3K-AKT-mTOR signalling.
P-glycoprotein (ABCB1) 1 Multidrug resistance efflux transporter encoded by ABCB1; selectively upregulated at the translational level by mTOR-eIF4A signaling under oxidative stress.
PIK3CA 1 Phosphatidylinositol 3-kinase catalytic subunit alpha; its activating mutations (e.g. E545K, H1047R) frequently drive AKT/mTOR pathway hyperactivation in cancer.
PIP4K2A 1 Phosphatidylinositol-5-phosphate 4-kinase type II alpha; regulates autophagy and AKT/mTOR signaling and is neuroprotective in cerebral ischemia/reperfusion models.
PKM2 1 Pyruvate kinase M2, best known as a glycolytic enzyme. A single 2026 study (SANG2026, human cells, photoaffinity methionine probe and chemoproteomics) reports that PKM2 also binds free methionine through a pocket separate from its catalytic site and relays methionine availability to mTORC1 through the GATOR2 complex, independently of its enzyme activity. Not yet replicated, and its importance in whole animals is untested.
PXR (NR1I2) 1 Pregnane X receptor, a xenobiotic-sensing nuclear receptor. Its activation is associated with liver growth, and the AKT-mTOR pathway is the proposed route, but the evidence is male-mouse-only: no liver enlargement was seen in female mice, the 16-volunteer human arm carried no mTOR readout, and the authors' own wording is that PXR activation 'may also induce liver growth in humans' (LASSILA2026). Stated as a causal human mechanism this would be stronger than the source allows.
RUBCN (Rubicon) 1 Run domain Beclin-1-interacting and cysteine-rich domain-containing protein; a negative regulator of autophagy whose suppression activates autophagic flux.
SLC15A3 1 A lysosomal dipeptide transporter that imports dipeptides to sustain mTORC1 activation and can confer antimetabolite chemotherapy resistance in lymphoma.
Spalt-related (Salr) 1 Transcription factor in Drosophila identified as a novel inhibitor of mTORC1-mediated growth, activated by the integrated stress response to restrict anabolic processes during nutrient stress.
TAX1BP1 1 Tax1-binding protein 1, an autophagy adaptor. In ESP2026 it is the link between the v-ATPase and the kinases TBK1 and ULK1: lysosomal stress sensed through the v-ATPase recruits TBK1/ULK1 to lysosomes via TAX1BP1.
TBC1D7 1 Third constitutive subunit of the TSC complex; its loss weakens but does not abolish TSC1-TSC2 function.
TBK1 1 TANK-binding kinase 1, a kinase known from innate immunity and selective autophagy. In ESP2026 (human cell lines), lysosomal stress recruits TBK1 to lysosomes through the adaptor TAX1BP1, where it phosphorylates FNIP1 at S296, inhibits FLCN and lets TFEB enter the nucleus. ULK1 can do the same job, so the two act as alternative kinases on this route.
TET1 1 Ten-eleven translocation methylcytosine dioxygenase 1, an epigenetic eraser that drives DNA demethylation of target promoters.
TNKS2 (Tankyrase-2) 1 Tankyrase-2, a PARP family enzyme; its loss activates AMPK and suppresses mTORC1, impairing adipocyte differentiation.
USP7 1 Ubiquitin-specific protease 7, a deubiquitinase that modulates the TSC1/mTOR axis and promotes renal fibrosis via stabilization of KDM5B.
alpha-synuclein (SNCA) 0 Presynaptic protein whose misfolded aggregates form Lewy bodies in Parkinson's disease and related synucleinopathies. Cleared by autophagy and by chaperone-mediated autophagy. No study or pathway link in this Atlas supports a claim about mTOR and its clearance: the mTORC1-inhibition account rests on work outside this corpus, and chaperone-mediated autophagy is regulated by mTORC2/PHLPP1/Akt rather than by mTORC1 (ARI2015), so the two routes should not be merged.

Complexes & pathways 11

mTORC1 208 mTOR Complex 1; regulates protein synthesis, autophagy, and growth in response to nutrients and growth factors.
mTORC2 41 mTOR Complex 2; phosphorylates Akt/PKB, affects cell survival and glucose metabolism.
Ragulator 10 Lysosome-anchored scaffold that recruits the Rag GTPases and positions mTORC1 on the lysosomal surface for activation.
GATOR1 7 Negative regulator of the Rag GTPases (a GAP); switches mTORC1 OFF when amino acids are scarce. Tumor suppressor - mutated in some cancers.
GATOR2 6 Positive arm that inhibits GATOR1; the target through which amino acid sensors (Sestrin2, CASTOR1) relay their signal to mTORC1.
Growth hormone / IGF-1 axis 5 Upstream growth-signaling axis; reduced activity (as in Ames dwarf mice) is one of the most robust lifespan-extending interventions known in mammals, acting upstream of PI3K/Akt/mTOR.
Integrated stress response 4 Conserved response to unfolded protein, amino-acid and other stresses. Reaches mTORC1 by more than one route: ATF4-induced REDD1 acts through the TSC complex, while ATF4-induced Sestrin2 acts on GATOR2. It is not a single brake, and it is not the AMPK one.
NF-κB 3 Master pro-inflammatory transcription factor complex that cross-talks extensively with PI3K/AKT/mTOR signalling.
KICSTOR 2 A lysosomal scaffold complex (composed of KAPTIN, ITFG2, C12orf66, and SZT2) that recruits GATOR1 to the lysosomal surface. Required for amino-acid-deprivation-dependent suppression of mTORC1; without KICSTOR, GATOR1 cannot reach the Rag GTPases and mTORC1 remains inappropriately active during starvation.
cGAS-STING pathway 1 An innate immune sensing pathway triggered by cytosolic DNA; drives inflammatory senescence signaling. In aging mouse macrophages it is held in check by the Ragulator subunit Lamtor5, which binds cGAS directly and routes it for ESCRT-mediated degradation; whether mTORC1 or mTORC2 signalling contributes to this step is untested, because the one study behind it measured neither.
NLRP3 1 Inflammasome sensor driving IL-1β-mediated inflammation, regulated in part by mTOR-dependent immunometabolism.

Drugs 25

mTOR drugs in development → Stage, status and evidence for 8 programmes: selective mTORC1 inhibitors, rapalogs in ageing trials, and the ones that stopped.

Rapamycin 113 Sirolimus; mTORC1 inhibitor that acts as a complex with FKBP12. With chronic dosing it can also disrupt mTORC2 assembly in some cell types and tissues (SAR2006; mouse liver in LAM2012), a time- and cell-type-dependent effect. Immunosuppressant; extends lifespan in mice.
Everolimus 23 Rapamycin analog (RAD001); used in oncology and tested for immune function in older adults.
Metformin 9 Antidiabetic biguanide; activates AMPK (ZHO2001) and inhibits mTORC1. How much of its action actually runs through AMPK is disputed: metformin still suppresses hepatic gluconeogenesis in AMPK-null and LKB1-null mouse liver (FOR2010) and still inhibits mTORC1 in AMPK-null cells, via the Rag GTPases (KAL2010). Frequently discussed as a geroprotector alongside rapamycin.
ATP-competitive mTOR inhibitors 6 Torin1, AZD8055 and relatives occupy the mTOR active site directly, inhibiting both complexes.
Torin1 6 ATP-competitive ('active-site') mTOR inhibitor. Unlike rapamycin, it blocks the kinase active site directly and so fully inhibits BOTH complexes - the tool that revealed rapamycin-resistant functions of mTORC1.
Temsirolimus 4 Intravenous rapamycin ester (CCI-779); mTOR inhibitor approved for advanced renal cell carcinoma.
PP242 3 An ATP-competitive mTOR kinase inhibitor (a 'TORKinib'); like Torin1, inhibits both mTORC1 and mTORC2 and blocks outputs that rapamycin leaves intact.
Resveratrol 3 Plant polyphenol popularized as a sirtuin activator and 'calorie-restriction mimetic'; failed to extend lifespan in ITP mouse studies and showed no metabolic benefit in a human RCT.
Acarbose 2 Alpha-glucosidase inhibitor (diabetes drug) that slows carbohydrate absorption; found by the ITP to extend mouse lifespan, especially in males.
RTB101 2 An oral ATP-competitive inhibitor of both class I PI3K and mTOR (dactolisib, formerly BEZ235), used at low doses intended to hit TORC1; tested for immune function in older adults, where it raised antiviral gene expression but failed its phase 3 clinical endpoint.
Urolithin A 2 Gut microbiome-derived polyphenol metabolite that activates mitophagy via the AMPK-mTOR axis, with cardioprotective effects in heart failure models.
Astragaloside IV 1 Bioactive saponin from Astragalus membranaceus that inhibits mTOR to activate TFEB-mediated autophagy, protecting against tacrolimus-induced nephrotoxicity.
Bi-steric mTORC1-selective inhibitors 1 Bivalent compounds (e.g. RMC-5552) engaging both an FKBP12-dependent site and the active site, giving deeper mTORC1 inhibition with selectivity over mTORC2.
Cisplatin 1 Platinum-based chemotherapeutic whose tolerance is modulated by mTOR-dependent cytoprotective autophagy.
Corilagin 1 Natural ellagitannin with anti-inflammatory activity that inhibits PI3K/AKT/mTOR and NF-κB signalling and restores autophagy.
Curcumin 1 Turmeric-derived polyphenol widely marketed for anti-aging effects; showed no lifespan effect in ITP testing.
Dihydromyricetin 1 Flavonoid from Ampelopsis grossedentata reported to reduce fibrosis with accompanying suppression of PI3K/AKT/mTOR signalling.
Forsythoside A 1 Phenylethanoid glycoside from Forsythiae Fructus that binds ASCL1 and blocks a downstream CCNB1/mTOR axis.
Green tea extract 1 Polyphenol-rich supplement tested by the ITP for lifespan effects; no significant effect found overall.
MCT oil 1 Medium-chain triglyceride oil; tested by the ITP as a metabolic/longevity intervention with no significant lifespan effect.
Melittin 1 The main bioactive component of bee venom; suppresses PI3K/Akt/mTOR pathway and activates autophagy, showing anti-inflammatory effects in psoriasis models.
Oxaloacetic acid 1 Metabolic intermediate marketed as a longevity supplement; no lifespan effect found in ITP testing.
Pungenin 1 Phenolic glucoside from Picea wilsonii that promotes hair regrowth via transcriptional regulation of the PI3K/AKT/FoxO/mTOR axis.
Salvianolic acid B 1 Polyphenol from Salvia miltiorrhiza that engages AKT1 and the AKT/mTOR/HIF-1α axis to promote angiogenesis and repair.
Simvastatin 1 Cholesterol-lowering statin; tested as a candidate longevity drug in the same ITP cohort as rapamycin but showed no lifespan effect.

Diseases 15

Tuberous sclerosis complex 17 Genetic disorder from TSC1/TSC2 loss causing constitutive mTOR activation and benign tumors in brain, kidney, and elsewhere, as well as epilepsy, often the presenting problem, and TSC-associated neuropsychiatric disorders. Everolimus shrinks these tumors (EXIST trials) and is also approved for TSC-associated seizures - the clearest randomised human evidence that blocking mTOR helps a human disease driven by mTOR overactivation.
Breast cancer 8 Hormone-receptor-positive advanced breast cancer becomes resistant to endocrine therapy partly by activating mTOR; adding the rapalog everolimus to exemestane delays progression (BOLERO-2: progression-free survival roughly doubled, without a significant overall-survival benefit).
Alzheimer's disease 6 Neurodegenerative disease marked by amyloid-beta plaques and tau tangles. mTOR overactivation blocks the autophagy that would clear these toxic proteins, and rapamycin restores clearance in mouse models. Clinically unproven in people: the whole human programme is phase 1/2 at n=10-60, and the one completed trial found rapamycin undetectable in cerebrospinal fluid with CSF p-tau181, GFAP and neurofilament light all rising after treatment (NOR2026 and Gonzales 2025, PMID 40394335, outside this corpus). Mechanistically plausible, animal-supported, not shown to help patients. See question H8.
Renal cell carcinoma (RCC) 6 Cancer of the kidney; target indication for everolimus treatment in clinical practice.
Prostate cancer 3 Cancer in which oncogenic mTOR signaling reprograms the cell's translation to drive proliferation, invasion and metastasis.
Autoimmune cytopenia 2 Immune-mediated destruction of blood cell lineages (including Evans syndrome and pure red cell aplasia) in which sirolimus is used as a T-cell-directed therapy.
Huntington's disease 2 Neurodegenerative disease caused by a toxic polyglutamine-expanded protein; cleared via mTOR-inhibition-induced autophagy in animal models.
Lung cancer (NSCLC/LUAD) 2 Non-small cell lung cancer including lung adenocarcinoma, in which PI3K-AKT-mTOR and mTORC2 signalling are frequently dysregulated.
Lymphangioleiomyomatosis 2 LAM - a rare progressive cystic lung disease in women driven by inappropriate mTOR activation; sirolimus stabilizes lung function for as long as it is taken (MILES trial), with decline resuming after the drug is stopped.
Pancreatic neuroendocrine tumor 2 Pancreatic neuroendocrine tumor - a cancer where mTOR drives growth; everolimus more than doubled progression-free survival (RADIANT-3), an FDA-approved indication.
Renal angiomyolipoma 2 TSC-associated benign renal tumour; the measured endpoint of EXIST-2.
Atrial fibrillation 1 The most common age-related cardiac arrhythmia, driven by atrial electrical and structural remodelling.
Osteoarthritis 1 Age-related degenerative joint disease characterised by cartilage matrix loss, inflammation and impaired chondrocyte autophagy.
Parkinson's disease 1 Neurodegenerative disease marked by loss of dopaminergic neurons and accumulation of misfolded alpha-synuclein (Lewy bodies). The relationship to mTOR is not settled in one direction. The study held here reports the opposite of the autophagy-failure account: chronic integrated-stress-response/ATF4 signalling suppresses both mTORC1 and mTORC2, and that sustained mTOR inhibition drives dopaminergic neuron death via PUMA (DEMMINGS2026). The familiar reading - that mTORC1 hyperactivity blocks alpha-synuclein clearance and that rapamycin enhances it in animal models - rests on work outside this corpus and is not graded here.
Spinal cord injury 1 Traumatic CNS injury in which AKT/mTOR-driven angiogenesis and neuronal survival are targets for functional recovery.

Conditions 4

Energy & cellular stress 7 Falling ATP, glucose withdrawal and a range of other insults. They converge on mTORC1 chiefly through two routes: AMPK, which acts on both TSC2 and raptor, and physical relocation of the TSC complex to the lysosome.
Hypoxia 3 Low oxygen. Acts on mTORC1 transcriptionally, chiefly through REDD1 at the oxygen tensions used in these studies rather than through AMPK, so it is slower to engage and slower to release.
Lung transplant 1 Clinical setting in which mTOR inhibitors are used as antiproliferative, calcineurin-sparing immunosuppression. They are not used de novo: early sirolimus after lung transplantation caused fatal bronchial anastomotic dehiscence, so they are introduced only once the airway anastomosis has healed, and a benefit against chronic lung allograft dysfunction is not established.
Mitochondrial dysfunction 1 Loss of mitochondrial function, relayed to mTORC1 by AMPK and the HRI stress pathway.

Processes 20

Autophagy 51 Cellular recycling process suppressed by mTORC1 and activated upon its inhibition; linked to longevity.
Cellular senescence 19 State in which a cell permanently stops dividing but stays alive, secreting inflammatory signals (the SASP). Senescent cells accumulate with age and drive age-related disease. mTOR powers the inflammatory secretions of cells that are already senescent (LAB2015, the stronger evidence); that it also promotes entry into the senescent state rests on weaker cell-culture evidence (DEM2009).
Protein synthesis 19 Cap-dependent translation - the main output mTORC1 exists to control, and the step where a signalling decision becomes physical growth.
Tumor growth 15 The shared endpoint of the pathway's oncogenic lesions, and the outcome every mTOR inhibitor trial in this Atlas was actually measuring.
T cell differentiation 14 Process by which immune T cells commit to effector versus regulatory fates; directly controlled by mTOR complex activity.
Lipid synthesis 9 De novo synthesis of fatty acids and cholesterol via SREBP. A growing cell needs membrane as much as it needs protein; both mTOR complexes feed this.
5'TOP mRNA 6 Class of mRNAs with a 5' terminal oligopyrimidine tract encoding ribosomal proteins and translation factors; their translation is a canonical output of mTORC1 signaling.
Muscle growth 6 mTORC1-dependent process of skeletal muscle fiber enlargement (hypertrophy); driven by growth factors and exercise, blocked by rapamycin.
Nucleotide synthesis 6 De novo purine and pyrimidine production. mTORC1 matches supply to demand here, which is why proliferating cells are so dependent on it.
Oxidative phosphorylation 5 Mitochondrial respiratory capacity, supported by mTORC1.
Senescence-associated secretory phenotype (SASP) 5 Inflammatory secretory programme of senescent cells, supported translationally by mTORC1.
Actin cytoskeleton 4 Cell shape and motility machinery. The original TOR2 phenotype in yeast, and the mammalian mTORC2 function that showed the second complex is acutely rapamycin-insensitive (JAC2004, SAR2004); the two-complex model itself came from biochemistry (LOE2002).
Lysosomal biogenesis 4 TFEB-driven expansion of the lysosomal compartment.
Macrophage polarization 3 The M1/M2 phenotypic switch in macrophages, an immunometabolic decision governed substantially by PI3K/AKT/mTOR signalling.
Mitochondrial biogenesis 3 Production of new mitochondria and their oxidative machinery. mTORC1 drives it via a YY1-PGC-1alpha transcriptional program, linking growth signaling to energy production.
Mitophagy 3 Selective autophagic degradation of damaged or dysfunctional mitochondria; regulated by the AMPK-mTOR-ULK1 axis and implicated in cardiac protection, neurodegeneration, and aging.
Ribosome biogenesis 3 Making new ribosomes: rRNA transcription by RNA polymerase I, 5S and tRNA transcription by RNA polymerase III, and the translation of ribosomal-protein mRNAs. Distinct from how efficiently existing ribosomes work. Added 2026-10-10 after an audit found the Atlas had no node for it, although the 5'TOP mRNA entity already asserted that this output is canonical for mTORC1.
Chaperone-mediated autophagy 2 A selective form of autophagy in which a cytosolic chaperone delivers single proteins to the lysosomal surface, where they unfold and are pulled in through a LAMP2A translocation complex. No vesicle is formed, which is what distinguishes it from macroautophagy. Regulated at the lysosome by an mTORC2/PHLPP1/Akt axis (ARI2015), so mTOR's relationship to autophagy here runs through a different complex than the canonical mTORC1-ULK1 step.
Ferroptosis 1 Iron-dependent, lipid-peroxidation-driven regulated cell death that is modulated by mTOR signalling and autophagy.
Placental nutrient sensing 1 Placental mTORC1-dependent regulation of amino acid transport and mitochondrial respiration that sets fetal growth trajectory.

Outcomes 8

Longevity 60 Lifespan extension; the key outcome tracked across mTOR-targeting interventions.
Immune function 20 Function of the immune system, especially vaccine response. Low-dose everolimus improved the influenza-vaccine response of older adults (MAN2014), but the phase 3 trial of low-dose TORC1 inhibition with RTB101 did not reduce respiratory illness (MAN2021): the biomarker moved, the clinical outcome did not.
Cognition 8 Learning, memory and related brain function. mTOR inhibition can enhance cognition in young mice and blunt age-related cognitive decline.
Insulin resistance 6 Metabolic side effect of chronic mTOR inhibition. In mice, mTORC2 disruption is a major contributor (LAM2012). In humans the relative contributions are not resolved: mTORC2 loss, S6K1-IRS-1 feedback relief (HAR2004, SHA2004) and direct beta-cell effects are all plausible, and no study has apportioned them.
Age-related pathology 4 Tissue- and organ-level ageing phenotypes, graded separately from survival.
Cardiac aging 4 Age-related decline in heart function (hypertrophy, stiffening, reduced contractility). Late-life rapamycin partially reversed it in aged female mice (FLY2013); male mice were not tested.
Kidney transplant 1 The original clinical use of rapamycin (as sirolimus), preventing organ rejection by suppressing T cell activation. It is no longer standard first-line maintenance; today it is used in selected regimens, often to spare calcineurin inhibitors.
Skin aging 1 Visible and molecular aging of skin (photodamage, dermal thinning, senescence markers like p16). Topical rapamycin reduced these markers in a human trial.

Interventions 4

Caloric restriction 9 Reduced caloric intake without malnutrition; associated with lifespan extension across species.
Macronutrient ratio 3 Ratio of protein:carbohydrate:fat in the diet; affects mTOR activation independently of total caloric intake.
Leucine/BCAA restriction 2 Restriction of branched-chain amino acids (leucine, isoleucine, valine). Leucine reaches mTORC1 through Sestrin2 in the leading model, with LARS as a contested alternative. The effects are amino-acid- and sex-specific: in 3xTg mice, restricting isoleucine or valine improved metabolic health while restricting leucine did not (BAB2025).
Resistance exercise / mechanical load 2 Mechanical loading of skeletal muscle, the physiological stimulus for hypertrophy, acting through mTORC1.

Nutrients & metabolites 11

Leucine 13 Branched-chain essential amino acid and the best-characterised nutrient input to mTORC1. Free leucine binds Sestrin2, releasing the GATOR2 brake; a competing model has leucyl-tRNA synthetase as the sensor instead.
Arginine 7 Conditionally essential amino acid sensed by two separate routes: cytosolic arginine binds CASTOR1, and lysosomal arginine is read by the transporter-like protein SLC38A9.
Glutamine 4 Most abundant free amino acid; activates mTORC1 partly through glutaminolysis and, in some settings, through a Rag-independent Arf1 route - one of the clearest examples that 'amino acid sensing' is not a single mechanism.
Methionine 4 Essential sulfur-containing amino acid. The cell reads its supply in two ways: indirectly through its metabolite S-adenosylmethionine (SAM), which binds SAMTOR (GU2017), and, according to a 2026 chemoproteomic study in human cells (SANG2026), directly as free methionine bound by PKM2. Restricting methionine improves metabolic health and lifespan in animal models, as summarised in the review KNO2026, which is why these sensors matter for ageing research.
Reactive oxygen species 4 ROS generated by mitochondrial activity, both a consequence and a driver of mTOR signalling.
Cholesterol 3 A membrane sterol that mTORC1 treats as a nutrient input, read at the lysosome rather than at the cell surface. Two routes into the same machinery are described: cholesterol binds the permease-like region of LYCHOS, which then sequesters GATOR1 (SHI2022), and it acts through SLC38A9 independently of that transporter's arginine-sensing function, with NPC1 restraining the signal as it exports cholesterol from the lumen (CAS2017). Both rest on human cell lines and biochemistry. How the two routes divide the signal, and whether either matters at the level of an organism, is not measured in this corpus.
S-adenosylmethionine (SAM) 2 Universal methyl donor whose level reports methionine availability. SAM binds SAMTOR, which otherwise inhibits mTORC1 through the GATOR1-KICSTOR complex.
Spermidine 2 A natural polyamine present in food and in cells, whose concentration falls with age. It induces autophagy mainly by inhibiting histone acetyltransferases and raising transcription of autophagy genes, which is a route that does not require mTOR inhibition. Studied as a caloric-restriction mimetic (EIS2009, EIS2016).
Bisphenol A 1 Ubiquitous environmental plasticiser that disrupts intestinal barrier function and mitochondrial metabolism, perturbing AMPK-mTOR signalling.
Kynurenic acid 1 A tryptophan metabolite produced by tumor microbiota (e.g. Fusobacterium nucleatum); it induces ITGA2 and inhibits an mTOR-dependent cascade, which sustains cathepsin V expression and suppresses CD8+ T cell cytotoxic function, driving resistance to PD-1 blockade in gastric cancer.
Malonyl-CoA 1 Intermediate metabolite of fatty-acid biosynthesis (produced by acetyl-CoA carboxylase, consumed by fatty acid synthase). Binds the mTOR kinase catalytic pocket directly and acts as a conserved, ATP-competitive endogenous inhibitor of mTORC1, letting lipogenic capacity feed back onto mTORC1 activity.

Organelles 2

Lysosome 24 The organelle on whose surface mTORC1 is activated. Nutrient signals converge here: mTORC1 must be physically recruited to the lysosomal membrane before Rheb can switch it on.
MAM (ER–mitochondria contacts) 1 Mitochondria-associated ER membranes: a signalling platform distinct from the lysosome.

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