🧬 Aging Wiki

deregulated-nutrient-sensing

Properties1
aliasesinsulin signaling deregulation, IIS hyperactivation, growth-signaling hyperactivity, nutrient sensing deregulation, IIS dysregulation

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Deregulated Nutrient Sensing

One of the three Antagonistic hallmarks in the López-Otín 2013 / 2023 framework. Nutrient-sensing pathways evolved to allocate resources between growth, reproduction, and stress resistance. With age, these pathways shift toward chronic anabolic signaling — even without true nutrient excess — accelerating cellular dysfunction downstream. The somatotropic (GH/IGF-1) and mTOR axes are the most empirically supported pro-aging growth-signaling systems in biology: reducing their activity extends lifespan in every major model organism tested, with human genetic evidence converging on the same conclusion. Together with hyperfunction-theory, this hallmark represents the wiki’s strongest empirically-supported aging mechanism cluster.

Definition (López-Otín 2013)

Age-associated dysregulation of the four canonical nutrient-sensing pathways — IIS, mTOR, AMPK, and sirtuins — resulting in loss of metabolic homeostasis and downstream activation of multiple other hallmarks. Crucially, the dysregulation is one-directional: IIS and mTOR become overactive relative to what is optimal for post-reproductive animals, while AMPK and sirtuin activity declines. The net effect is a chronic pro-anabolic, anti-autophagic, pro-inflammatory state that the cell cannot escape.

The four canonical pathways at a glance

PathwayAging directionPrimary aging effectCanonical interventionEvidence page
IIS (INSR/IGF1R → PI3K → AKT/SGK1 → FOXO/mTOR)Overactive with ageSuppresses FOXO; activates mTORC1; promotes growth over repairGenetic reduction (GHR-/-, Igf1r+/-), CRinsulin-igf1 (verified-partial)
mTOR (mTORC1 → S6K1/4E-BP1; mTORC2 → AKT)Overactive with ageSuppresses autophagy (via ULK1); promotes protein synthesis; SASP amplificationrapamycin (NIA ITP-validated)mtor (verified-partial)
AMPK (LKB1/CaMKK2 → AMPKαβγ → TSC2/Raptor/ULK1)Declines with ageFalls silent → mTOR brakes released; autophagy suppressedmetformin, exercise, CRampk (verified, FULL)
Sirtuins (NAD⁺-dependent deacetylases, SIRT1–7)Declines with age (NAD⁺ depletion)Reduced deacetylation of FOXO, PGC-1α, NF-κB; less metabolic flexibilityNMN (nmn), NR (nr), caloric-restrictionsirtuin (verified-partial)

IIS axis: the founding longevity pathway

The daf-2 paradigm

The insulin/IGF-1 receptor in C. elegans, DAF-2, is the founding longevity gene of modern molecular gerontology. Loss-of-function daf-2(e1370) approximately doubles adult worm lifespan 1 — an effect completely suppressed by daf-16 loss-of-function, establishing the epistasis that defines the pathway’s longevity output. See daf-2 (verified) and daf-16 (verified-partial).

The mammalian somatotropic axis

The GH → IGF-1 → IGF1R → IIS axis is the principal mammalian longevity-regulating signaling cascade, with convergent evidence across the longest-lived engineered mouse models:

  • GHR-/- (Laron) mice are the longest-lived laboratory mouse model (~40–55% median lifespan extension; exact figure unconfirmed from closed-access source) 2 — see growth-hormone (verified). The mechanism is complete ablation of GH-stimulated IGF-1 production → near-zero circulating IGF-1 → IIS silencing.
  • Igf1r+/- mice (129/Sv background) live ~26% longer combined sexes (+33% females, p<0.001; +15.9% males, NS) 3 — see igf1r (verified-partial). Receptor haploinsufficiency — a mild manipulation — produces striking lifespan extension, consistent with tonic IIS as a causal aging driver.
  • Laron syndrome in humans (GHR loss-of-function; Ecuador cohort, n=99): zero cancer deaths in Laron subjects vs 17% cancer mortality in unaffected relatives; dramatically reduced diabetes 4 — see growth-hormone (verified). no-fulltext-access (Guevara-Aguirre 2011 download failed in archive)
  • Klotho transgenic mice (EF-1alpha OE): ~+20-30% median lifespan extension; mechanism is secreted Klotho (sKlotho) inhibition of IGF-1R/INSR at cell surface → FOXO nuclear retention → oxidative stress resistance. KL-VS heterozygous humans show survival advantage (Arking 2002: 1.43-fold OR for survival to age 75 in Czech cohort, 95% CI 1.02–2.01, P=0.036; the widely-cited “+3 yr life expectancy” figure is NOT in the Arking 2002 paper and was a downstream synthesis error) plus higher HDL, lower blood pressure. Klotho is a natural circulating IIS brake that declines with age — see klotho (verified 2026-05-05).
DimensionStatus
Pathway conserved in humans?yes — IIS pathway is deeply conserved from worms to humans
Phenotype (IIS reduction → lifespan extension) in humans?partial — Laron cohort, IGF1R centenarian variants, FOXO3 GWAS; no RCT lifespan endpoint
Replicated in humans?in-progress — GWAS replicated across cohorts; Laron syndrome is observational; no RCT

The Suh 2008 paradox — a critical nuance

Female Ashkenazi Jewish centenarians (n=384) with IGF1R loss-of-function alleles carry paradoxically elevated circulating IGF-1, not reduced 5 — see igf-1 (verified) and igf1r (verified-partial). The interpretation: partial receptor LoF reduces receptor signaling → compensatory upregulation of IGF-1 ligand secretion. Cellular-level IIS is reduced even as serum IGF-1 rises. This dissolves the paradox mechanistically but underscores that serum IGF-1 is not a reliable proxy for cellular IIS signaling. needs-human-replication (direct intracellular IIS readout in centenarians not yet done)

Pathway hierarchy and the SGK-1 correction

The core IIS intracellular cascade:

INSR / IGF1R
    ↓
IRS-1 / IRS-2   (adapter tier — see [[irs-1]], [[irs2]])
    ↓
PI3K (p110/p85) → PIP3   (see [[pi3k]])
    ↓
PDK1 → phospho-Thr308 AKT   (see [[pdk1]])
mTORC2 → phospho-Ser473 AKT  (see [[rictor]])
    ↓ AKT (see [[akt]])
    ├→ FOXO (phospho → cytoplasmic export → silenced)
    ├→ TSC2 (phospho-Thr1462 → Rheb activated → mTORC1 on)
    └→ MDM2 (p53 suppression)
    ↓ SGK1 (parallel to AKT — see [[sgk1]])
    └→ FOXO / DAF-16

Critical narrative correction: In C. elegans, SGK-1, not AKT-1 or AKT-2, is the dominant longevity kinase downstream of DAF-2. Hertweck 2004 showed sgk-1 LoF extends mean adult lifespan +63% (14.7→24.0 days; p<0.0001; n=147), while akt-1 LoF alone was NS (p=0.1642) and akt-2 LoF alone was NS (p=0.3717) 6 — see sgk1 (verified) and akt (verified-partial). This reframes the pathway: SGK-1 is the functionally dominant arm for longevity output in the model organism with the cleanest genetics. Mammalian equivalence is assumed but not directly verified. needs-human-replication

The mTOR axis: from nutrient signal to aging effector

mTORC1 is the convergent output node where IIS, amino acid sensing, AMPK, and growth factor inputs integrate. Its chronic over-activation drives the two most directly downstream hallmarks — disabled-macroautophagy (ULK1 inhibition) and loss-of-proteostasis (excess protein synthesis, suppressed clearance). See mtor (verified-partial) for full pathway biology.

S6K1-IRS1 negative feedback — the insulin-resistance amplification loop

mTORC1 → S6K1 → phospho-IRS-1 (Ser-307/Ser-632 mouse; Ser-312/Ser-636/Ser-639 human per Um 2004 corrigendum) → IRS-1 degradation → attenuated insulin signaling. This negative-feedback loop is the molecular basis of mTOR-driven insulin resistance: chronic mTOR/S6K1 activation (as occurs with nutrient excess or age-related IIS hyperactivation) progressively impairs upstream insulin sensitivity. See s6k1 (verified-partial) and irs-1 (verified-partial).

DimensionStatus
mTOR pathway conserved in humans?yes — essentially identical from yeast to humans
S6K1 negative feedback on IRS-1 in humans?yes — Ser-636/Ser-639 confirmed in human adipose; basis of metformin’s mechanism
Rapamycin lifespan extension in humans?not yet — PEARL 2025 null on VAT endpoint; ongoing trials

Rapamycin: the most-validated longevity intervention

Harrison 2009 (NIA ITP): late-life rapamycin (14 mg/kg food, initiated at ~600 days = ~60 human-equivalent years) extended mean lifespan +13% females / +9% males and 90th-percentile lifespan +14%/+9% in genetically heterogeneous UM-HET3 mice 7 — see rapamycin (verified-partial). This is the single most informative result for the hyperfunction-deregulated-nutrient-sensing axis: the prediction that reducing growth signaling late in life should extend lifespan was confirmed. See hyperfunction-theory (verified) for the mechanistic interpretation.

AMPK: the counter-regulator

AMPK is the cell’s primary energy-stress sensor and the functional opponent of mTORC1. When ATP drops and AMP rises, the γ-subunit’s allosteric site 1 activates the heterotrimer up to ~10-fold (combined allosteric + dephosphorylation-protection effect) 8 — see ampk (verified, FULL). AMPK then directly phosphorylates Raptor (Ser722/Ser792) to inhibit mTORC1 and phosphorylates ULK1 (Ser317/Ser777) to activate autophagy — the dual brake-release mechanism that makes AMPK activation longevity-relevant.

With age, AMPK activity declines in most tissues. This means the mTOR brakes weaken even without true nutrient excess. metformin (complex I inhibitor → AMP rise → AMPK activation → mTOR suppression) extended mean lifespan +5.83% in male C57BL/6 mice at 0.1% diet 9 — see metformin (verified-partial).

FOXO transcription factors: the central longevity effector

When IIS/AKT/SGK-1 signaling is reduced, FOXO transcription factors translocate to the nucleus and drive transcriptional programs for stress resistance, proteostasis, autophagy, DNA repair, and longevity. They are the molecular bridge between reduced nutrient sensing and cellular protection.

FOXO3 human longevity association

rs2802292 GG genotype in FOXO3: OR=2.75 (95% CI 1.51–5.02; p=0.0007) for living to 95+ in Japanese-American men (HHP/HAAS cohort; Honolulu, Oahu; nested case-control, n=615; male-only cohort) 10 — see foxo3 (verified) and foxo-transcription-factors (verified). This is the most robustly replicated human longevity GWAS signal across populations.

Phosphosite precision (verified against Brunet 1999): AKT phosphorylates FOXO3 at Thr32 and Ser253, which creates 14-3-3 binding sites → cytoplasmic sequestration. Ser315 phosphorylation (also by AKT) drives CRM1-dependent nuclear export — a mechanistically distinct step — and does not create 14-3-3 binding sites. This is a common misattribution in secondary literature. See foxo3 (verified) and pi3k-akt-pathway (verified-partial).

DAF-16 / FOXO4 / FOXO1

  • daf-16 (verified-partial): single ancestral C. elegans FOXO ortholog; required for all daf-2 longevity effects; daf-16 LoF completely suppresses daf-2 longevity.
  • foxo4 (verified-partial): target of the FOXO4-DRI senolytic peptide (Baar 2017), which disrupts FOXO4–p53 interaction → apoptosis of senescent cells → see senolytics for clinical relevance.
  • foxo1 (verified-partial): dominant FOXO in liver/adipose; Taguchi 2007 brain-Irs2 KO paradox — female lifespan +~18% despite obesity and peripheral hyperinsulinemia — implicates tissue-specific FOXO/IIS as more important than systemic IIS for longevity 11. no-fulltext-access (Taguchi 2007 closed-access)

Sirtuins: the NAD⁺-dependent arm

SIRT1 (nuclear) is the primary longevity-associated sirtuin in mammals. It deacetylates FOXO1/3 (potentiating transcriptional activity), PGC-1α (mitochondrial biogenesis), and NF-κB (anti-inflammatory). SIRT1 activity declines with age as cellular NAD⁺ falls. NAD⁺ precursors (NMN, NR) aim to restore SIRT1 function — see nmn, nr. For full sirtuin pathway biology, see sirtuin (verified-partial) and sirt1 (verified-partial).

Note: Sirtuins are discussed here as part of the deregulated-nutrient-sensing hallmark per López-Otín 2013. Their mechanistic overlap with mitochondrial-dysfunction (SIRT3/SIRT5 mitochondrial deacetylases) and epigenetic-alterations (SIRT1/SIRT6 histone deacetylation) means they appear as contributing factors in multiple hallmarks. The canonical home for sirtuin pathway biology is sirtuin.

Hypotheses that this hallmark grounds

hyperfunction-theory (verified — active, most empirically supported)

Hyperfunction theory is the direct mechanistic reading of this hallmark taken to a causal claim: aging is caused by the continued activity of developmental and growth programs (mTOR/IIS) past their useful window, not primarily by accumulation of molecular damage. This hallmark provides the empirical substrate for that claim. Every finding listed above under IIS and mTOR — daf-2 LoF worm longevity, Igf1r+/- mouse longevity, GHR-/- Laron longevity, S6K1 KO, PTEN GOF, rapamycin ITP — is also the primary evidence for hyperfunction theory. See hyperfunction-theory (verified) for the prediction table, evidence-against section, and what would update the hypothesis.

disposable-soma-theory (verified — active-frame)

The disposable-soma theory provides the evolutionary frame for why IIS/mTOR hyperfunction persists: natural selection optimized growth and reproduction in early life, leaving insufficient power to silence those programs post-reproductively. Reducing IIS classically comes with fertility trade-offs (daf-2 LoF worms are constitutive dauer-formers; GHR-/- mice are infertile/sub-fertile), consistent with the soma-vs-germline investment logic. See disposable-soma-theory (verified) for the trade-off framing.

Downstream hallmark cascade

This hallmark sits upstream of several integrative and primary hallmarks that it drives:

Downstream hallmarkMechanism of linkage
disabled-macroautophagymTORC1 phosphorylates ULK1 Ser757 → autophagy suppression; chronic mTOR hyperactivity → chronically suppressed autophagy
loss-of-proteostasisSuppressed autophagy + enhanced protein synthesis → proteotoxic burden
cellular-senescencemTOR in senescent cells drives SASP translation; rapamycin reduces SASP output
chronic-inflammationSASP → inflammaging; S6K1/mTOR-driven pro-inflammatory translation
mitochondrial-dysfunctionIIS/mTOR suppresses mitophagy and mitochondrial quality control

Translational interventions targeting this hallmark

InterventionMechanismStrongest evidenceEvidence pageGap
rapamycinmTORC1 inhibitor (FKBP12-rapamycin-FRB complex)Harrison 2009 NIA ITP: +9–13% mouse lifespan; PEARL 2025 null on VAT primary endpointrapamycin (verified-partial)No human lifespan RCT; mTORC2 side effects at chronic doses
caloric-restrictionmTOR suppression + AMPK activation + IGF-1 reductionMattison 2017 (rhesus); Redman 2018 CALERIE (humans: biomarker improvements, no lifespan)caloric-restriction (verified)Human lifespan endpoint infeasible; adherence limits
metforminComplex I → AMP rise → AMPK → mTOR suppression+5.83% mean lifespan C57BL/6 male mice (Martin-Montalvo 2013); TAME trial in progressmetformin (verified-partial)B12 depletion; TAME primary results pending
GLP-1 receptor agonists (semaglutide, tirzepatide)GLP-1RA → insulin sensitization; weight/metabolic normalizationParadigm-shifting for T2D + obesity; aging trial pipeline openingtype-2-diabetes (stub)Aging-specific RCTs nascent; longevity endpoint absent unsourced
SGLT2 inhibitors (empagliflozin, dapagliflozin)Glucosuria → caloric loss (~280 kcal/day) → CR-like signaling; AMPK activation; ketogenesis (BHB rise) → mTORC1 suppression + HDAC inhibitionEMPA-REG OUTCOME (CV mortality HR 0.62), EMPEROR-Preserved/-Reduced, EMPA-KIDNEY (kidney disease progression HR 0.72) — none with aging endpointsempagliflozin (verified)No aging-endpoint human RCT in non-diabetic older adults needs-human-replication

Phenotypic outputs

  • type-2-diabetes (stub): the prototypical clinical consequence of chronic IIS hyperactivation → insulin resistance via S6K1-IRS1 negative feedback → pancreatic beta-cell exhaustion → frank hyperglycemia. Aging-associated rise in T2D incidence is mechanistically continuous with the IIS deregulation described here.
  • sarcopenia (stub): anabolic resistance — the paradox of high systemic IIS/mTOR signaling but impaired muscle protein synthesis response to feeding or exercise. Chronic mTOR activation contributes to satellite cell dysfunction and impaired regeneration.
  • Metabolic syndrome / visceral adiposity — not separately paged; cross-references caloric-restriction and metformin.

Sex-specific effects

Sex dimorphism is a consistent feature of IIS/mTOR longevity manipulations and is underexplained by the basic hyperfunction model:

  • Igf1r+/- lifespan extension: +33% females, +15.9% males (NS) — see igf1r (verified-partial). Female-specific effect.
  • Rapamycin NIA ITP: larger effect in females (+13% mean) than males (+9% mean) — see rapamycin (verified-partial).
  • S6K1 KO: female-specific lifespan extension — see s6k1 (verified-partial).

no-mechanism (sex-differential rapamycin/IGF1R longevity effects unexplained; possible mTORC2 sensitivity difference or estrogen-IIS interaction)

Targeted interventions

TABLE WITHOUT ID file.link AS Compound, mechanisms AS Mechanism, clinical-stage AS Stage, human-evidence-level AS "Evidence", translation-gap AS "Gap"
FROM "molecules/compounds" OR "interventions"
WHERE contains(hallmarks, [[deregulated-nutrient-sensing]])
  OR contains(target-hallmarks, [[deregulated-nutrient-sensing]])
SORT clinical-stage DESC

See interventions-by-hallmark for the full matrix, class-level synthesis, and gaps. This hallmark has the densest intervention cluster in the wiki.

Limitations and gaps

  • #gap/needs-human-replication — all direct lifespan evidence is from model organisms; human evidence is genetic association (FOXO3 GWAS, IGF1R centenarian variants) or observational (Laron syndrome cohort). No human RCT has a lifespan primary endpoint, and none is feasible.
  • #gap/contradictory-evidence — the Suh 2008 paradox (centenarians with elevated serum IGF-1 despite IGF1R LoF alleles) complicates the simplest IIS-reduction model. Cellular vs serum IGF-1 disconnect requires direct measurement in humans.
  • #gap/no-fulltext-access — Coschigano 2003 (GHR-/- lifespan %; closed-access); Taguchi 2007 (brain-Irs2 KO; closed-access); Selman 2009 (S6K1 KO lifespan %; closed-access); Kenyon 1993 (daf-2 founding paper; closed-access).
  • #gap/long-term-unknown — Chronic rapamycin in humans: immunosuppression, dyslipidemia, and mTORC2 inhibition risks over multi-year use are not characterized in healthy aging adults.
  • #gap/dose-response-unclear — Optimal rapamycin dosing for human longevity (intermittent vs continuous; rapalogs) and metformin dosing for aging-specific endpoints are not established.
  • #gap/needs-replication — GLP-1 RA and SGLT2 inhibitor aging benefits: large T2D/CV RCTs exist, but these were not designed to test aging hallmarks or longevity.
  • #gap/unsourced — Sirtuin NAD⁺ decline with age: widely cited; specific human tissue/age-quantified data not cited on this page — see sirtuin for sourcing.
  • [[mtor-kinase]] — planned protein page for the mTOR kinase itself (distinguished from the pathway page mtor); not yet seeded.
  • [[type-2-diabetes]] — phenotype page is a stub; full expansion planned.
  • [[sarcopenia]] — phenotype page is a stub.
  • [[jak-stat-pathway]] — GH signals via JAK2/STAT5B; this pathway is not yet seeded; GH biology deferred to growth-hormone.
  • [[antagonistic-pleiotropy]] — evolutionary frame overlapping with disposable-soma-theory; not yet seeded as a dedicated hypothesis page.

Cross-references

Pathways (verified):

  • insulin-igf1 (verified-partial) — canonical home for IIS pathway architecture
  • pi3k-akt-pathway (verified-partial) — PI3K/AKT/PTEN/FOXO intracellular cascade
  • mtor (verified-partial) — mTOR complex biology and rapamycin mechanism
  • ampk (verified, FULL) — energy sensing; mTOR antagonism; longevity via FOXO/ULK1

Key proteins:

Compounds / interventions:

Hypotheses:

Other hallmarks:

Framework MOC:

Model-organism natural experiments:

  • canis-lupus-familiaris — breed-size lifespan paradox; single IGF1 haplotype (Sutter 2007) underlies giant-vs-small-breed lifespan difference (~2–3×); within-species replication of IIS/GH axis longevity tradeoff

Position in causal hierarchy

This hallmark is classified as Intermediate response/damage tier (mechanistic-tier: intermediate / intervention-tractability: high). See hallmark-causality-graph for the full hierarchy and intervention-sequencing argument.

Direct upstream nodes per caused-by: frontmatter: none (intrinsic age-related deregulation; evolutionary hyperfunction driver). Direct downstream nodes per causes: frontmatter: disabled-macroautophagy, cellular-senescence, mitochondrial-dysfunction, stem-cell-exhaustion, epigenetic-alterations (via NAD+/SIRT1 axis). Edge evidence is in causal-graph-data.

Footnotes

  1. doi:10.1038/366461a0 · in-vivo · genetic · model: C. elegans daf-2(e1370) · ~2× adult lifespan extension; completely suppressed by daf-16 LoF · closed-access (not_oa) — founding result; see daf-2 (verified) ↩

  2. doi:10.1210/en.2003-0247 · in-vivo · genetic · model: GHR-/- Laron mice · substantial lifespan extension (~40–55% range widely cited; exact % unconfirmed from closed-access source) · closed-access (not_oa) no-fulltext-access; see growth-hormone (verified) ↩

  3. doi:10.1038/nature01298 · in-vivo · genetic · model: Igf1r+/- 129/Sv mice · +26% combined (Cox p<0.02); +33% females (p<0.001); +15.9% males (NS) · local PDF available; see igf1r (verified-partial) ↩

  4. doi:10.1126/scitranslmed.3001845 · observational · n=99 Laron, ~1,600 controls (Ecuador) · zero cancer deaths in Laron subjects; dramatically reduced diabetes · download failed no-fulltext-access; see growth-hormone (verified) ↩

  5. doi:10.1073/pnas.0705467105 · observational · n=384 Ashkenazi Jewish centenarians · IGF1R LoF alleles 2.3% vs 0.3% controls (p=0.02); paradoxically elevated circulating IGF-1 · local PDF available; see igf-1 (verified) ↩

  6. doi:10.1016/s1534-5807(04)00095-4 · in-vivo · genetic · model: C. elegans sgk-1 LoF · +63% mean adult lifespan (14.7→24.0 d; p<0.0001; n=147); akt-1 alone p=0.1642 NS; akt-2 alone p=0.3717 NS · local PDF available; see sgk1 (verified) ↩

  7. doi:10.1038/nature08221 · in-vivo · randomized · model: UM-HET3 mice, late-life rapamycin (14 mg/kg food) initiated at ~600 d · mean lifespan +13% females / +9% males; 90th-percentile +14%/+9% · local PDF available; see rapamycin (verified-partial) ↩

  8. doi:10.1038/nrm3311 · review · γ-subunit AMP allosteric activation ~10-fold (combined allosteric + dephosphorylation protection); site 1/3/4 nucleotide-binding model · see ampk (verified, FULL) ↩

  9. doi:10.1038/ncomms3192 · in-vivo · model: C57BL/6 male mice, 0.1% metformin diet · +5.83% mean lifespan (p=0.02); AMPK activation; mTOR suppression · local PDF available; see metformin (verified-partial) ↩

  10. doi:10.1073/pnas.0801030105 · observational · n=615 men (nested case-control, HHP/HAAS cohort, Honolulu; 213 cases ≥95y vs 402 controls died <81y) · rs2802292 GG OR=2.75 (CI 1.51–5.02; p=0.0007) for living to 95+ · local PDF available; male-only cohort; see foxo3 (verified) ↩

  11. doi:10.1016/j.cell.2007.02.005 · in-vivo · genetic · model: brain-specific Irs2 KO (Nestin-Cre) female mice · +~18% lifespan despite obesity + hyperinsulinemia · closed-access (not_oa) no-fulltext-access; see irs2 (verified-partial) ↩

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