This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "deregulated_nutrient_sensing#mTORC1 Hyperactivation"). Conforming nodes in disorder files should include the corresponding biological processes and causal edges, specialized to their disease context. The module is intentionally kept lean: it captures the conserved anabolic-vs-catabolic nutrient-sensing imbalance, its convergence on autophagy suppression, and the geroprotector drug-target pattern (rapamycin and metformin both restrain the anabolic mTORC1 node via target_mechanisms; dietary protein/amino-acid restriction is the non-pharmacological arm of the same pattern), but deliberately does NOT embed disease-specific or contested downstream theories (e.g. tissue-specific mTOR-driven pathologies, or the antagonistic-pleiotropy debate on whether mTOR inhibition trades growth for longevity). Such specific or context-dependent claims belong on the relevant disorder or comorbidity/trajectory entry, which may conforms_to or reference this module. Complements the cellular_senescence module (another antagonistic hallmark of aging): deregulated nutrient sensing is one of several senescence-inducing stresses, and both converge on age-related tissue dysfunction. Key conformance target: "deregulated_nutrient_sensing#mTORC1 Hyperactivation". The module models TWO catabolic sensing arms that nutrient surplus leaves attenuated, and they are not interchangeable: AMPK/sirtuins sense energy (low ATP/high AMP, NAD+), while GCN2 senses amino-acid scarcity via uncharged tRNAs. The distinction matters because dietary protein and amino-acid restriction acts through the GCN2 arm - and its FGF21 endocrine output - rather than through energy restriction, which is why protein restriction extends lifespan without reducing calorie intake. A disorder conforming only to the mTORC1 node should not be assumed to engage the GCN2/FGF21 arm. Two cautions on the amino-acid arm, both carried as open discussions rather than settled model content. First, individual amino acids are NOT interchangeable: isoleucine or valine restriction each extends mouse lifespan on its own, while leucine restriction - the strongest mTORC1 activator of the three branched-chain amino acids - does not improve metabolic health, so a conforming entry should name the amino acid it means. Second, the evidence is split across the chain: the proximal FGF21/energy-expenditure response is now shown directly in humans, but the lifespan benefit is rodent-only and repeatedly male-biased, and no long-term human data exist in the older adults for whom higher protein intake is clinically recommended.
Pharmacokinetic (Drug-Exposure) Model of Sex-Dimorphic Geroprotector Response
sex_dimorphic_geroprotector_exposure
EMERGING
Evidence: 8
Evidence balance
3 support
5 refute
The most reproducible single finding of the NIA Interventions Testing Program across two decades is that most lifespan-extending compounds work preferentially in one sex, usually males. This hypothesis holds that the dimorphism is pharmacokinetic - that males and females achieve different effective drug exposures, so the aging substrate itself responds equally and the apparent sex difference is a dosing artifact. The competing reading, which this module does not currently model as a separate group, is pharmacodynamic: that the nutrient-sensing network is differently wired or differently rate-limiting for lifespan in the two sexes, so matched exposure would still produce divergent outcomes. The two make an experimentally separable prediction - under the pharmacokinetic model, dose-matching to equal blood levels should abolish the sex difference.
Scope caveat a curator must carry forward: this module is an imperfect home for the hypothesis. The ITP male bias spans compounds that act well outside nutrient sensing (17-alpha-estradiol, nordihydroguaiaretic acid), so the phenomenon is broader than the mechanism modeled here; the hypothesis is filed on this module because rapamycin, acarbose, canagliflozin and metformin are the compounds it can be tested against structurally. Note also that the SUPPORT and REFUTE evidence come from the same program and are genuinely in tension - the pharmacokinetic model may hold for some compounds (canagliflozin, rapamycin) and fail for others (NDGA), in which case the single-model framing is itself wrong and should be split. Assessed against the openscientist run under kb/hypotheses/deregulated_nutrient_sensing/sex_dimorphic_geroprotector_exposure/. That assessment's verdict - refuted as a general model, surviving as a compound-specific contributor - stays in its sidecar and is deliberately not written here, for the reason recorded on the sibling hypothesis: MechanisticHypothesisStatusEnum records where a hypothesis sits among competing accounts of a mechanism, not how one provider run read the evidence on one date, so the status remains EMERGING. What the added evidence changes is the balance. The model has one prediction that can be manipulated rather than observed, and it has now failed every time it was manipulated: dose-matched blood levels for NDGA, threefold dose escalation for NDGA and 17-alpha-estradiol, and dose reduction alongside measured over-accumulation for canagliflozin. Against that, the disposition differences themselves are real and are now evidenced at class level for rapalogs, and rapamycin remains the one compound whose numbers stay internally consistent with the model, since its sex gap narrows at the higher dose instead of persisting. Three limits on the counter-evidence, all of which keep this short of a settled refutation. The canagliflozin item is an unreviewed preprint measuring cognition and neuroinflammation, so its lifespan conclusion is reached by extension. The castration results are positive evidence for the competing pharmacodynamic account rather than a second exposure-matching test, because drug levels were not measured in the gonadectomized animals. And every study on both sides is UM-HET3 mice from one program, so none of this has been replicated in another model or in any human cohort. The split this note has called for since seeding - a pharmacokinetic-modulatory group for rapamycin and a gonadal-hormone-gated pharmacodynamic group for NDGA, 17-alpha-estradiol, acarbose and canagliflozin - is now the reading the evidence favours, but it is left as an open curation decision rather than made here on the strength of one provider run. The untested half of it is recorded as discussions#knowledge_gap_exposure_matched_lifespan_test_by_compound.
Rapamycin Extends Lifespan by a Route Distinct from Dietary Restriction
rapamycin_distinct_from_dietary_restriction
EMERGING
Evidence: 9
Evidence balance
7 support
2 refute
Rapamycin is routinely described as a dietary-restriction mimetic, on the reasoning that both down-shift anabolic nutrient signaling and both extend lifespan. This hypothesis holds that the shared endpoint conceals distinct routes - that pharmacologic mTORC1 inhibition and dietary restriction produce materially different endocrine, metabolic, proteostatic and hepatic transcriptional states, and therefore converge on longevity without being the same intervention. The claim as curated is "distinct but partially overlapping", not "fully distinct", because the same body of evidence that shows the divergence also locates genuine convergence: both interventions enter at mTORC1, both suppress translation and relieve the block on autophagy, and both leave overlapping hepatic gene-body hypermethylation. Where they part is downstream and endocrine - most sharply on insulin sensitivity, which dietary restriction improves and rapamycin degrades, and on protein turnover, where the two move canonical pathways in opposite directions. That insulin-sensitivity divergence is not by itself proof that the longevity routes differ: the improvement dietary restriction produces is dispensable for its own lifespan benefit, so the most-cited divergence sits on an axis at least partly off the longevity path. The distinction matters for this module because it determines whether mTORC1 hyperactivation is the single hub through which the whole hallmark acts, or one of several partly independent routes to the same consequence node.
Assessed against the openscientist run under kb/hypotheses/deregulated_nutrient_sensing/rapamycin_distinct_from_dietary_restriction/. That assessment's verdict (PARTIALLY_SUPPORTED) stays in its sidecar and is deliberately not written here: MechanisticHypothesisStatusEnum records where a hypothesis sits among competing accounts of a mechanism, not how one provider run read the evidence on one date, so the status remains EMERGING. What the added evidence changes is the shape of the claim rather than its standing. The divergence now rests on four modalities - endocrine and metabolic, hepatic xenobiotic-metabolism expression, liver proteome turnover and polysome loading, and cross-model lifespan responses - instead of on the single study the hypothesis was seeded with; but the same corpus establishes convergence at the mTORC1 entry point and in part of the hepatic methylome, which is why the shared-signature result is carried as REFUTE rather than left out. Three limits to carry forward. The additivity result that most directly discriminates the two models is in Drosophila, not mice. The insulin-sensitivity divergence, which is the one most often cited and the only one with human grounding, is weaker support than it looks: dietary restriction extends lifespan just as far in mice that cannot sensitize to insulin, so that axis is at least partly off the longevity path, and the REFUTE item recording this is a check on the hypothesis's own best-known argument rather than on its conclusion. And the decisive experiment - one lifespan-matched cohort comparing dietary restriction, rapamycin and the combination on a common readout - was not located, which is recorded as discussions#knowledge_gap_head_to_head_rapamycin_versus_dietary_restriction rather than resolved here. The module's own framing tension noted at seeding is unchanged: the mTORC1 node describes rapamycin as targeting the anabolic hub without asserting equivalence to dietary restriction, while the AMPK node cites a review that groups caloric restriction, sirtuin activation and rapamycin together as one longevity-promoting arm.
Which dietary amino acid restriction actually drives the benefit, and by what sensor - is the GCN2/FGF21 arm modelled here the route for all of them, or does each amino acid act through a partly distinct mechanism?
KNOWLEDGE GAP
OPEN
knowledge_gap_which_amino_acid_is_the_signal
Attached to:
GCN2 Amino-Acid-Scarcity Sensing Attenuation
Attenuated FGF21 Endocrine Starvation Response
This module's treatment node names "dietary protein and amino-acid restriction" as one intervention acting on one sensing arm, and that framing is now known to be under-specified. Restriction of isoleucine alone, or of valine alone, is each sufficient to extend mouse lifespan, yet restricting leucine - the strongest mTORC1 activator of the three branched-chain amino acids, and therefore the one the anabolic-signalling model predicts should matter most - did not improve metabolic health. Methionine restriction is a third, chemically unrelated route. If a single upstream sensor explained all of these, the amino acids should be broadly substitutable, and they are not. The unresolved question is whether GCN2/FGF21 is the common trunk with amino-acid-specific branches downstream, or whether isoleucine, valine and methionine each engage largely separate mechanisms that this module currently collapses into one node. Until that is settled, a conforming entry should name the specific amino acid it means rather than asserting generic amino-acid restriction.
Proposed experiments:
GCN2-dependence of single-amino-acid restriction benefits
FGF21-dependence of single-amino-acid restriction benefits
Human evidence now supports the proximal FGF21 and energy-expenditure response to protein restriction, but does the mouse lifespan benefit - which is largely male-specific - translate to humans at all?
HUMAN MODEL MISMATCH
OPEN
human_model_mismatch_amino_acid_restriction_lifespan
Attached to:
Attenuated FGF21 Endocrine Starvation Response
Accelerated Cellular Aging and Age-Related Tissue Decline
The two ends of this chain are not equally evidenced in humans, and the gap between them is where over-claiming happens. The proximal end now has direct human support: a controlled eucaloric intervention in healthy lean men raised fasting FGF21 and the energy intake needed to hold weight steady, and improved insulin sensitivity. The distal end - that this delays ageing - rests entirely on rodents, and there the benefit is repeatedly sex-dimorphic: isoleucine restriction extends lifespan more in males, and valine restriction raises median male lifespan by 23% without a female lifespan benefit. Three things therefore do not follow from the human data and must not be curated as if they did: that protein restriction extends human lifespan; that a benefit shown in young lean men generalises to older adults, women, or people with metabolic disease; or that a 5-week study speaks to lifelong exposure. The countervailing clinical concern - that reduced protein intake accelerates sarcopenia and frailty in the elderly, which is why higher intakes are recommended above age 65 - is exactly the population in which no long-term human data exist. Note the human study preserved lean body mass over 5 weeks, but only in young men, and only when energy intake was raised to hold weight constant.
Proposed experiments:
Protein restriction in older adults with body-composition endpoints
Sex-stratified single-amino-acid restriction in humans
Has anyone run the decisive comparison - dietary restriction, rapamycin, and the two combined, in one lifespan-matched mouse cohort on a common multi-omic readout - or is the "distinct routes" reading still assembled from separately designed studies?
KNOWLEDGE GAP
OPEN
knowledge_gap_head_to_head_rapamycin_versus_dietary_restriction
Attached to:
rapamycin_distinct_from_dietary_restriction
mTORC1 Hyperactivation
Rapamycin (mTOR Inhibition)
The evidence that rapamycin and dietary restriction reach longevity by partly separate routes is real but it is assembled, not designed. Each study behind it compares the two interventions on one modality in one tissue - hepatic xenobiotic-metabolism expression in one, liver proteome turnover and polysome loading in another, hepatic methylation in a third - at doses and durations chosen for that study rather than matched for equivalent lifespan effect. Differences read off such a set are confounded with dose and with exposure duration, and the confound runs both ways: a divergence may be a dose artifact, and a convergence may be the coincidence of two interventions happening to sit at comparable points on different curves. The experiment that would settle it is a single cohort in which dietary restriction and rapamycin are titrated to comparable lifespan extension and profiled on one platform, with a combination arm. The combination arm is what makes the question tractable rather than merely tidier: full additivity would be strong evidence for separate routes, and no additivity for a shared one, and the review that concludes rapamycin is not a true dietary-restriction mimetic predicts additivity explicitly. No such study was located by the provider run assessed for this hypothesis, which is a claim about that search and not about the literature; a curator who finds one should retire this gap rather than treat the absence as established.
Proposed experiments:
Lifespan-matched dietary restriction versus rapamycin, one cohort, one platform
Combination arm testing additivity of dietary restriction and rapamycin
Outside nordihydroguaiaretic acid, has any geroprotector been dose-matched to equal blood exposure in both sexes and then followed to a lifespan endpoint - and does rapamycin's female-favouring dimorphism, the one case still consistent with a dosing explanation, survive that test?
KNOWLEDGE GAP
OPEN
knowledge_gap_exposure_matched_lifespan_test_by_compound
Attached to:
sex_dimorphic_geroprotector_exposure
Rapamycin (mTOR Inhibition)
The pharmacokinetic account of sex-dimorphic geroprotector response makes one prediction that can be manipulated rather than merely observed - equalize exposure and the sex difference should go - and that prediction has been put to two compounds. It failed both times. For nordihydroguaiaretic acid the test was done properly, on survival: females dosed to male blood levels still got no benefit, and escalating the dose threefold did not change that. For canagliflozin the exposure was manipulated in both directions and the benefit tracked neither, but the endpoints were cognition and neuroinflammation rather than lifespan and the report is an unreviewed preprint. What is missing is the clean version of the experiment for the drugs this module actually owns: rapamycin, acarbose and canagliflozin have all been fed at a fixed dietary concentration to both sexes and followed to death, never at matched measured exposure. The gap matters most for rapamycin, because rapamycin is the one compound whose data still fit the model - its sex gap narrows at the higher dose rather than persisting - so it is where the model has most to lose and has never been made to risk anything. Two further limits belong here rather than on the hypothesis. The castration experiments that carry the competing pharmacodynamic account did not measure drug concentrations, so they infer equal exposure from equal dosing. And the whole evidence base on both sides is UM-HET3 mice from a single program, so nothing here has been replicated in another model, another laboratory, or any human cohort.
Proposed experiments:
Sex-equalized blood-exposure survival trial, one compound at a time
Gonadectomy by drug factorial with drug levels measured in every arm
APRT heterozygous turquoise killifish (Nothobranchius furzeri)
Naturally short-lived vertebrate aging model
Direct genetic manipulation of the AMPK complex has produced detrimental phenotypes in mice, so Astre and colleagues went upstream instead and perturbed the nucleotide pool that AMPK senses, mutating APRT in killifish. Heterozygous males lived longer, old mutants showed rejuvenated metabolic function and a fasting-like profile, and mutant cells showed reduced ATP with AMPK activation. A lifelong intermittent fasting arm abolished the benefit, which is the epistasis result that places the manipulation inside the nutrient-sensing pathway rather than beside it.
Species
Turquoise killifish (Nothobranchius furzeri)
Genotype
APRT heterozygous loss-of-function mutant (adenine phosphoribosyltransferase, AMP salvage biosynthesis)
Background
CRISPR-generated APRT mutant line; the lifespan effect is reported in heterozygous males, with integrated omics on old mutants, a high-fat-diet challenge arm, and a lifelong intermittent fasting arm.
Pathograph links
AMPK and Sirtuin Catabolic-Sensing Attenuation
perturbs
fidelity: moderate
The module holds that catabolic sensing through AMPK is attenuated with age. This model perturbs the node in the opposite direction by genetic means: reducing AMP biosynthesis capacity lowers cellular ATP and activates AMPK, producing enhanced nutrient sensitivity in heterozygous cells.
Limitations: The manipulation is on the upstream nucleotide pool rather than on AMPK itself, so AMPK activation is a downstream consequence and other effects of altered purine metabolism are not excluded. The cellular measurements are in heterozygous cells, and the lifespan benefit is confined to heterozygous males, so sex- and dose-dependence are unresolved. APRT deficiency in humans causes a kidney stone disorder, not a longevity phenotype, so this is a pathway-probing manipulation and not a model of a human condition.
Readouts
Cellular ATP level in heterozygous cells
ATP levels measured in cells from APRT heterozygous fish against wild-type cells.
Direction: DECREASED
Interpretation: Reduced ATP is the energetic change the AMP-pool manipulation produces, and is the input the AMPK sensor responds to.
Evidence: 1
AMPK activation and nutrient sensitivity in heterozygous cells
AMPK activation status and nutrient sensitivity measured in cells from APRT heterozygous fish against wild-type cells.
Direction: INCREASED
Interpretation: AMPK activation is the direct evidence that the manipulation lands on this node; the direction is opposite to the age-associated attenuation the module describes, which is what makes it a probe of the node rather than a model of it.
Evidence: 1
Lifespan of APRT heterozygous males
Survival of APRT heterozygous fish compared against wild-type siblings.
Direction: INCREASED
Interpretation: A lifespan extension from the manipulation is what makes this node's perturbation consequential rather than merely biochemical.
Evidence: 1
Longevity benefit under lifelong intermittent fasting
Lifespan of APRT heterozygous fish maintained on lifelong intermittent fasting, as an epistasis test against a dietary intervention acting on the same sensing pathway.
Direction: ABOLISHED
Interpretation: The benefit disappearing under fasting places the mutation and the dietary intervention on a shared pathway; a non-epistatic result would have argued the mutation acts elsewhere.
Evidence: 1
Evidence: 1
Accelerated Cellular Aging and Age-Related Tissue Decline
rescues
fidelity: moderate
Old APRT heterozygous fish show rejuvenated metabolic function, a fasting-like metabolic profile, and resistance to a high-fat diet challenge, so the perturbation reaches the module's terminal node with both a molecular and a challenge-based readout.
Limitations: Rejuvenation is established at the level of integrated omics profiles and a dietary challenge rather than by tissue-level histopathology or an organ function panel, so the tissue-decline half of the node is supported indirectly. As with the lifespan effect, the finding is in heterozygotes and its sex-dependence limits generality.
Readouts
Metabolic profile of old heterozygous mutants
Integrated omics profiling of old APRT heterozygous fish against age-matched wild type, plus a high-fat diet challenge.
Direction: RESTORED
Interpretation: A fasting-like profile with high-fat-diet resistance in old animals is the rejuvenation signal on which the rescue claim rests.
Evidence: 1
Evidence: 1
Curated as part of a tranche adding turquoise killifish models across the hallmarks-of-aging modules. This is the only killifish entry in the tranche built on a directed genetic manipulation rather than on natural aging, and it exists because the equivalent manipulation in mice has been detrimental, which is the authors' stated reason for taking the upstream nucleotide-pool route.
Sonntag2012 IRS-Dependent Regulation of AMPK by Insulin
SBML
KINETIC
Combined modelling and experimental study of the insulin-AMPK-mTOR network showing that insulin regulates AMPK through insulin receptor substrate (IRS), establishing a direct link between the anabolic insulin arm and the catabolic energy-sensing arm rather than treating them as independent inputs to mTORC1.
Pathograph links
AMPK and Sirtuin Catabolic-Sensing Attenuation
partially recapitulates
fidelity: moderate
Shows AMPK activity being suppressed by insulin via IRS, a mechanistic route by which chronic nutrient surplus attenuates catabolic sensing.
Limitations: Covers the AMPK arm only; the sirtuin arm of this node is not represented.
DallePezze2016 Concurrent AMPK and mTOR Activation by Amino Acids
SBML
KINETIC
Systems study, with an accompanying kinetic model, showing that amino acids activate AMPK and mTOR concurrently rather than reciprocally. This complicates the standard picture in which AMPK and mTORC1 are simple antagonists, and matters for interpreting dietary and pharmacological interventions that act through amino-acid availability.
Pathograph links
mTORC1 Hyperactivation
recapitulates
fidelity: moderate
Models amino-acid-driven mTORC1 activation, the input most directly manipulated by dietary protein restriction.
AMPK and Sirtuin Catabolic-Sensing Attenuation
partially recapitulates
fidelity: moderate
Demonstrates concurrent rather than reciprocal AMPK activation, qualifying the assumption that mTORC1 hyperactivation implies AMPK suppression.
Limitations: Derived in cultured cells under controlled amino-acid stimulation; it does not establish that the same concurrency holds under chronic in vivo nutrient surplus.
Relevant to this module's own framing: the antagonism the node assumes between mTORC1 and AMPK is condition-dependent, not absolute.
Smith2010 FOXO Post-Translational Modification Model
SBML
KINETIC
Model of how FOXO transcription factors integrate multiple post-translational modifications made by ageing-related signalling pathways, so that competing inputs - insulin/PI3K-AKT, stress, and nutrient-sensing signals - are resolved into a single transcriptional output.
Pathograph links
Nutrient Surplus and Anabolic Signaling
recapitulates
fidelity: moderate
Models FOXO as the integration point at which insulin/IGF-1 signalling suppresses the stress-resistance and longevity transcriptional program.
Accelerated Cellular Aging and Age-Related Tissue Decline
partially recapitulates
fidelity: low
Connects the modification state of FOXO to the downstream transcriptional program associated with cellular ageing.
Limitations: Stops at transcription-factor activity; it does not model the tissue-level decline this node asserts.
FOXO is the node through which this module connects to the insulin/IGF-1 longevity axis conserved from C. elegans daf-16 upward.
Nutrient Surplus and Anabolic Signaling
trigger
A sustained state of nutrient and growth-factor abundance keeps the anabolic arm of the nutrient-sensing network engaged: the somatotroph GH/IGF-1 axis and amino-acid/nutrient sensing upstream of mTORC1. Because reducing the activity of these nutrient-sensing pathways (by dietary restriction, mutation, or chemical inhibitors) extends lifespan and lowers age-related disease, their chronic engagement is the initiating driver of the deregulated-nutrient-sensing hallmark.
Downstream
-
mTORC1 Hyperactivation
-
AMPK and Sirtuin Catabolic-Sensing Attenuation
-
GCN2 Amino-Acid-Scarcity Sensing Attenuation
Show evidence (2 references)
"When the food intake of organisms such as yeast and rodents is reduced (dietary restriction), they live longer than organisms fed a normal diet. A similar effect is seen when the activity of nutrient-sensing pathways is reduced by mutations or chemical inhibitors."
Establishes that the activity of nutrient-sensing pathways is the lever on lifespan - reducing it extends life - so their chronic engagement in nutrient surplus is the initiating driver modeled here. Evidence source is OTHER because this is a review.
"These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication."
Enumerates deregulated nutrient sensing as one of the conserved hallmarks of aging, framing this module. Evidence source is OTHER because this is a review.
mTORC1 Hyperactivation
central effector
Persistent nutrient and growth-factor input drives chronic activation of mTOR complex 1 (mTORC1), the master anabolic sensor that couples nutrient availability to cell growth, protein translation, and biosynthesis. Because inhibition of the mTOR pathway extends lifespan across model organisms and protects against a growing list of age-related pathologies, its age-associated hyperactivation is the central effector of this hallmark and the node targeted by rapamycin and (indirectly, via AMPK) metformin. This is the conserved central node that disease-specific mTOR-activating lesions converge upon.
Downstream
-
Autophagy Suppression and Anabolic Bias
-
Accelerated Cellular Aging and Age-Related Tissue Decline
Show evidence (3 references)
"A leading target for such interventions is the nutrient response pathway defined by the mechanistic target of rapamycin (mTOR). Inhibition of this pathway extends lifespan in model organisms and confers protection against a growing list of age-related pathologies."
Establishes the mTOR nutrient-response pathway as the leading modifiable aging target and its inhibition as protective, supporting mTORC1 hyperactivation as the central effector node. Evidence source is OTHER because this is a review.
"it is now clear that mTOR functions as a central coordinator of organismal metabolism in response to both environmental and hormonal signals"
Characterizes mTOR as the central coordinator of metabolism in response to nutrient and hormonal cues, supporting its role as the hub of the nutrient-sensing hallmark. Evidence source is OTHER because this is a review.
"A pilot screen identified compounds that preferentially increased the expression of mRNAs with short 5'-UTRs relative to those with long 5'-UTRs, and these hits were enriched for known lifespan-extending agents, such as curcumin and rapamycin."
Identifies the translational output of this node - 4E-BP/eIF4E-dependent, 5'-UTR-length-selective translation - as a shared signature of lifespan-extending compounds, recovered by an unbiased cell-based screen rather than assumed. Supports translational control as the functional readout of mTORC1 activity that geroprotectors act through. Evidence source is IN_VITRO because the screen is a cell-based reporter assay; the paper's accompanying lifespan work in Drosophila and C. elegans is separate.
AMPK and Sirtuin Catabolic-Sensing Attenuation
effector
In parallel with anabolic hyperactivation, the catabolic low-energy sensors that oppose mTORC1 - AMP-activated protein kinase (AMPK, which senses a low energy/high-AMP state) and the NAD+-dependent sirtuins - are relatively attenuated in the nutrient-replete aging state. These sensors normally drive the protective, pro-longevity response to nutrient scarcity (the mechanism engaged by dietary restriction, Sirtuin 1 activation, and metformin), so their reduced activity reinforces the anabolic bias and its downstream consequences.
Downstream
-
Autophagy Suppression and Anabolic Bias
-
Accelerated Cellular Aging and Age-Related Tissue Decline
Show evidence (3 references)
"its inhibition compromises the longevity-promoting effects of caloric restriction, Sirtuin 1 activation, inhibition of insulin/insulin growth factor signaling, or the administration of rapamycin, resveratrol, or spermidine"
Groups caloric restriction, Sirtuin 1 activation, and reduced insulin/IGF signaling as the conserved longevity-promoting arm opposed to anabolic nutrient signaling, supporting the catabolic-sensing node whose attenuation is modeled here. Evidence source is OTHER because this is a review.
"In rodents, both dietary restriction and decreased nutrient-sensing pathway activity can lower the incidence of age-related loss of function and disease, including tumors and neurodegeneration."
Shows that engaging the catabolic/low-nutrient response (dietary restriction) lowers age-related disease, so its attenuation in the nutrient-replete state is pathogenic. Evidence source is OTHER because this is a review.
"In contrast to FOXO/DAF-16, the Akt-phosphorylation targeted Nrf2 homolog SKN-1 and heat shock transcription factor 1 homolog HSF-1, along with the conserved catalytic subunit of the energy sensor AMPK AAK-2, are required for atRA-induced lifespan extension."
Genetic epistasis establishing that the AMPK catalytic subunit is required for a pharmacological longevity effect, not merely correlated with it - loss of function at aak-2 abolishes the lifespan extension. This is the strongest available evidence class for the causal role of catabolic nutrient sensing modeled in this node, since it tests necessity rather than association. Note the same paper finds aak-2 accounts for only about a quarter of the compound's transcriptional response, so the requirement is not purely transcriptional. Evidence source is MODEL_ORGANISM (Caenorhabditis mutant strains).
GCN2 Amino-Acid-Scarcity Sensing Attenuation
effector
The second catabolic sensing arm, sensing amino-acid rather than energy scarcity. GCN2 (general control nonderepressible 2) is the conserved stress-responsive kinase activated by the uncharged tRNAs that accumulate when amino acids are limiting; activated GCN2 phosphorylates eIF2-alpha, repressing global translation while selectively increasing translation of ATF4, and it additionally restrains TORC1 directly. Because this sensor is engaged only by amino-acid scarcity, a protein- and amino-acid-replete state leaves the GCN2-eIF2-alpha-ATF4 integrated stress response unmobilized: translation is not restrained, ATF4 target genes are not induced, and the GCN2-mediated brake on TORC1 is absent. Engaging this arm is what dietary protein and amino-acid restriction does, and GCN2 is required for the lifespan extension those diets produce - so its quiescence in nutrient surplus is the amino-acid-sensing counterpart of AMPK/sirtuin attenuation.
Downstream
-
mTORC1 Hyperactivation
-
Attenuated FGF21 Endocrine Starvation Response
-
Autophagy Suppression and Anabolic Bias
Show evidence (5 references)
"Cells containing a defective aminoacyl-tRNA synthetase also stimulated GCN2 phosphorylation of eIF-2 in the absence of amino acid starvation, indicating that uncharged tRNA levels are the most direct regulator of GCN2 kinase."
Identifies uncharged tRNA as the direct activating ligand of GCN2, establishing GCN2 as the amino-acid-scarcity sensor that stays quiescent when amino acids are abundant. Evidence source is IN_VITRO (biochemical and genetic analysis in cultured budding yeast).
"When activated by their cognate upstream stress signals, the mammalian eIF2 kinases PERK and GCN2 repress translation of most mRNAs but selectively increase translation of Activating Transcription Factor 4 (ATF4)"
Establishes the mammalian GCN2-eIF2-alpha-ATF4 output - global translational repression with selective ATF4 induction - that is the protective response not mobilized in the amino-acid-replete state modeled here. Evidence source is IN_VITRO (targeted mutations in cultured murine cells).
"Here, we show that GCN2 and its downstream transcription factor, ATF4, mediate 4E-BP induction, and GCN2 is required for lifespan extension in response to dietary restriction of amino acids."
Shows GCN2 is required for the lifespan extension produced by amino-acid restriction, establishing that engagement of this sensing arm - and hence its attenuation in nutrient surplus - is causally tied to longevity. Evidence source is MODEL_ORGANISM (Drosophila melanogaster).
+ 2 more references
Attenuated FGF21 Endocrine Starvation Response
effector
The organism-level endocrine output of the amino-acid-sensing arm. FGF21 is a hepatokine induced by amino-acid scarcity downstream of GCN2/ATF4 acting on amino-acid response elements in the FGF21 promoter; once secreted it drives the systemic adaptive starvation response (increased energy expenditure, improved insulin sensitivity, restrained somatic growth via the GH/IGF-1 axis). In a protein-replete state this signal stays low. The node is included because FGF21 is not merely correlative: it is required for dietary protein restriction to extend lifespan, and raising it alone is sufficient to extend lifespan - making the attenuated FGF21 signal an independent endocrine route from deregulated amino-acid sensing to age-related decline, parallel to the cell-autonomous mTORC1/autophagy route. The dependence on GCN2 is partial and time-limited rather than absolute: Gcn2-null mice recover low-protein-induced FGF21 after roughly two weeks on diet, so GCN2-independent routes to FGF21 induction operate on longer timescales and this node should not be curated as strictly GCN2-gated.
Downstream
-
Accelerated Cellular Aging and Age-Related Tissue Decline
Show evidence (5 references)
"These data indicate that FGF21 is essential for the metabolic response to protein restriction but that GCN2 is only transiently required for LP-induced FGF21."
Supports the FGF21 endocrine arm as essential, but only partially supports the upstream GCN2 -> FGF21 edge: Gcn2 KO mice initially phenocopy Fgf21 KO yet recover LP-induced hepatic Fgf21 expression and circulating FGF21 after roughly 14 days on diet, so GCN2 is transiently rather than permanently required and GCN2-independent routes to FGF21 induction operate on longer timescales. Evidence source is MODEL_ORGANISM (Fgf21 and Gcn2 knockout mice).
"These data demonstrate that protein restriction in aging male mice exerts marked beneficial effects on lifespan and metabolic health and that a single metabolic hormone, FGF21, is essential for the anti-aging effect of this dietary intervention."
Shows FGF21 is necessary for protein restriction to extend lifespan, so failure to induce it in a protein-replete state is a mechanistically required step toward age-related decline. Evidence source is MODEL_ORGANISM (Fgf21 knockout vs wildtype male mice).
"Here we show that transgenic overexpression of FGF21 markedly extends lifespan in mice without reducing food intake or affecting markers of NAD+ metabolism or AMP kinase and mTOR signaling."
Elevated FGF21 alone is sufficient to extend lifespan, and does so without engaging AMPK or mTOR - establishing this endocrine arm as an independent route rather than a readout of the mTORC1 node. Evidence source is MODEL_ORGANISM (FGF21-transgenic mice).
+ 2 more references
Autophagy Suppression and Anabolic Bias
amplifier
Active mTORC1 suppresses macroautophagy, while attenuated AMPK/sirtuin signaling fails to induce it. Autophagy is the cytoplasmic recycling process that clears damaged organelles and proteins; its induction by starvation or genetic inactivation of nutrient signaling counteracts the age-associated accumulation of cellular damage. When nutrient signaling holds autophagy suppressed, this quality-control capacity is lost and damaged components accumulate - the amplifying step that links deregulated nutrient sensing to tissue decline.
Downstream
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Accelerated Cellular Aging and Age-Related Tissue Decline
Show evidence (2 references)
"Both starvation and the genetic inactivation of nutrient signaling converge on the induction of autophagy, a cytoplasmic recycling process that counteracts the age-associated accumulation of damaged organelles and proteins as it improves the metabolic fitness of cells."
Establishes that inactivating nutrient signaling induces autophagy, which clears age-associated damage; conversely, active nutrient signaling suppresses autophagy, the mechanism modeled in this node. Evidence source is OTHER because this is a review.
"normal and pathological aging are often associated with a reduced autophagic potential"
Documents reduced autophagic potential as a feature of aging, supporting autophagy suppression as an amplifying step. Evidence source is OTHER because this is a review.
Rapamycin (mTOR Inhibition)
Platform:
Small molecule
Rapamycin (sirolimus) is a small-molecule inhibitor of mTORC1 that, by binding FKBP12, decreases mTOR complex 1 activity. It is the prototypical geroprotector: pharmacologic inhibition of the anabolic nutrient-sensing hub extends lifespan in model organisms including mice, even when started late in life. Represents the anabolic-node inhibition drug-target design pattern for conforming disorders.
Evidence: 3
Metformin (AMPK-Mediated Nutrient-Signaling Restraint)
Platform:
Small molecule
Metformin is a biguanide that activates AMPK and acts as a caloric-restriction mimetic, indirectly restraining anabolic mTORC1 signaling and re-engaging the catabolic, autophagy-permissive state. It has demonstrated protective effects against several age-related diseases in humans and is the agent of the TAME (Targeting Aging with Metformin) trial, the flagship test of a geroprotector for healthy aging.
Evidence: 1
Dietary Protein and Amino-Acid Restriction
Platform:
Behavioral / lifestyle
Lowering total dietary protein - or restricting specific essential amino acids (methionine, isoleucine, valine) - while still meeting nutritional needs. This is the non-pharmacological arm of the same design pattern: instead of inhibiting the anabolic node with a drug, it removes the amino-acid input that drives it and simultaneously engages the GCN2 amino-acid-scarcity sensor that a protein-replete state leaves quiescent. It is distinct from calorie restriction - the benefit tracks the macronutrient ratio rather than energy intake, and calorie restriction achieved with high-protein diets does not extend lifespan.
Evidence: 5