IGF1R (Insulin-like Growth Factor 1 Receptor)

IGF1R is the canonical longevity-determining receptor of the insulin/IGF-1 signaling (IIS) pathway. Heterozygous loss-of-function extends mammalian lifespan — +33% in female 129/Sv mice ¹ — and loss-of-function alleles are enriched in human centenarians from at least two independent cohorts ²³. It is a receptor tyrosine kinase (RTK) that transduces extracellular IGF-1 and IGF-2 signals into the intracellular PI3K–AKT and MAPK/ERK cascades, ultimately controlling cell survival, growth, and the FOXO longevity program.

Identity

Field	Value
UniProt	P08069 (IGF1R_HUMAN)
NCBI Gene	3480
HGNC	5465
Ensembl	ENSG00000140443
GenAge ID	HAGRID 15
Mouse ortholog	Igf1r (one-to-one)
Chromosomal location	15q26.3
Precursor length	1,367 amino acids

Structure and domain organization

IGF1R is synthesized as a single-chain 1,367 aa precursor that is co-translationally glycosylated and then cleaved by a furin-like protease in the Golgi ⁴. The mature receptor is an α₂β₂ disulfide-linked heterotetramer displayed at the plasma membrane.

Chain processing (UniProt numbering, precursor)

Fragment	Residues	Notes
Signal peptide	1–30	Cleaved co-translationally
Alpha chain	31–736	Extracellular; ligand-binding
Furin-linker	737–740	4-residue connector; removed
Beta chain	741–1,367	Contains transmembrane + kinase

Two alpha and two beta chains assemble into the α₂β₂ disulfide-bonded tetramer via inter-subunit disulfide bonds (Cys-rich region of alpha chain).

Domain architecture

Signal peptide (1–30): Directs ER co-translational insertion.
L1 / CR / L2 extracellular domain (alpha chain, 31–736): L-domain repeats flanking a cysteine-rich region constitute the high-affinity ligand-binding site for IGF-1.
Fibronectin type III repeats (three; located in alpha chain and the extracellular segment of the beta chain): Structural scaffold.
Transmembrane helix (beta chain, ~936–959): Single-pass type I topology.
Juxtamembrane region (beta chain, ~960–1000): Contains Tyr980, whose phosphorylation is required for IRS-1 and SHC1 recruitment.
Kinase domain (beta chain, ~1,003–1,259): The catalytic core. Activation requires phosphorylation of three tyrosines in the activation loop. Ullrich 1986 identifies tyrosine kinase features between proreceptor residues 973–1,229 (= precursor residues ~1,003–1,259); the ATP-binding Lys is at proreceptor position 1,003 (precursor Lys1,033).
C-terminal tail (1,275–1,367): Contains regulatory ubiquitination sites (Lys1168, Lys1171) controlling receptor internalization.

Activation-loop phosphorylation

Sequential autophosphorylation of Tyr1165, Tyr1161, and Tyr1166 (precursor numbering; equivalent to Tyr1135, Tyr1131, Tyr1136 in the conventional mature-beta-chain offset used in much of the biochemical literature) is required for full kinase activation. Tyr1165 is phosphorylated first; Tyr1161 and Tyr1166 follow. These three tyrosines in the activation loop are the most-used pharmacological readout of receptor activation status in cell-based assays.

Note on sourcing: Ullrich 1986 ⁴ defines the primary structure of IGF1R and identifies the kinase domain region (proreceptor residues 973–1229, equivalent to precursor residues ~1003–1259) and ATP-binding motif (Lys1003 in proreceptor = Lys1033 in precursor), but does not enumerate the individual activation-loop phosphotyrosines by position. The Tyr1161/1165/1166 assignments are the standard UniProt/biochemical literature consensus; the sequential phosphorylation order is from subsequent kinetic studies. needs-replication (activation-loop phosphorylation order in intact cells vs. isolated kinase)

Ligand specificity and INSR comparison

Receptor	Primary ligand	Affinity for insulin	Kinase-domain identity to IGF1R
IGF1R	IGF-1 (high), IGF-2 (moderate)	Very low (~100-fold lower than INSR)	—
INSR	Insulin (high), IGF-2 (moderate)	—	~84% (in kinase domain)

Because of the very high kinase-domain similarity (~84%), INSR and IGF1R can form hybrid receptors (one INSR alpha/beta hemireceptor linked to one IGF1R alpha/beta hemireceptor) in tissues co-expressing both receptors (notably skeletal muscle, fat, and heart). Hybrid receptors bind IGF-1 with higher affinity than INSR homodimers, complicating pharmacological targeting of either receptor in isolation. needs-replication (hybrid receptor biology in vivo)

Downstream signaling

Ligand binding induces trans-autophosphorylation, activating the kinase toward exogenous substrates:

IRS-1/-2 docking (via Tyr980 phosphorylation in juxtamembrane region) → IRS acts as scaffold for PI3K p85 SH2-domain binding → PI3K activation → PIP3 generation → AKT recruitment and activation → downstream FOXO inhibition and mTORC1 activation. See pi3k-akt-pathway and insulin-igf1 for full cascade.
SHC1 and GRB2–SOS docking → RAS → RAF → MEK → ERK (MAPK pathway) → proliferation, differentiation. This arm is less directly longevity-relevant than the PI3K–AKT–FOXO arm, but contributes to anti-apoptotic signaling.
Negative feedback: mTORC1-activated S6K1 phosphorylates IRS-1 on serine residues (Ser307/Ser312 in humans), blocking IRS-1/PI3K coupling — the molecular basis for IGF-1 resistance under chronically anabolic conditions. See s6k1.

Role in development: null lethality

Homozygous Igf1r-null mice die at birth from respiratory failure due to severe growth retardation (~45% of normal birth weight) ⁵. This establishes that the receptor is essential for normal prenatal growth but is dispensable for early embryogenesis per se (unlike Igf1-null mice, which also die at birth but are larger than Igf1r-null). The lethality has precluded pharmacological complete-inhibition strategies for longevity in vivo.

Role in aging: the haploinsufficiency longevity result

The pivotal mammalian IIS-longevity paper is Holzenberger et al. 2003 (Nature) ¹. Heterozygous Igf1r+/- mice on a 129/Sv background survived significantly longer than wild-type littermates:

Group	Lifespan extension	Significance
Females (Igf1r+/-)	+33% (756±46 vs 568±49 days)	P<0.001 (t-test); P<0.001 (Cox)
Males (Igf1r+/-)	+15.9% (679±80 vs 585±69 days)	NS
Both sexes combined	+26%	P<0.02 (Cox)

Key features of the result:

Haploinsufficiency only — a 50% reduction in receptor levels is sufficient. This is notable because it suggests signaling flux, not complete pathway silencing, is the key variable.
Sex dimorphism — females extend lifespan significantly; males do not reach significance. The mechanism is unexplained. no-mechanism — sex-specific IIS longevity biology may involve interaction with sex steroids or sex-specific IGF-1 axis set-points.
Metabolic phenotype — Igf1r+/- mice show improved resistance to oxidative stress, not reduced body weight or altered glucose tolerance, suggesting the longevity effect is not mediated by caloric restriction or systemic metabolic re-programming.
Strain caveat — 129/Sv background. A subsequent study on a C57BL/6 congenic background found a smaller effect (~11% in females; males NS). See GenAge HAGRID 15. The magnitude is strain-dependent. needs-replication

Extrapolation assessment:

Dimension	Status
Pathway conserved in humans?	yes — IGF1R, IRS1/2, PI3K, AKT, FOXO all human-orthologous
Phenotype (longevity via IGF1R reduction) conserved?	partial — centenarian cohort associations in humans, but no prospective evidence
Replicated in humans?	no (intervention) / yes (centenarian association, two independent cohorts)

Human centenarian evidence

Willcox 2008 — FOXO3A / IIS in Japanese-American men

Willcox et al. 2008 (PNAS) ² performed a nested case-control study within the Honolulu Heart Program / HAAS cohort — a male-only cohort of Japanese-American men (n=615 total: 213 men who survived to age ≥95 y vs 402 controls who died up to age 81 y, mean death age ~78.5 y). The primary finding was association of FOXO3A rs2802292 with longevity in men only (GG vs TT: OR=2.75, 95% CI 1.51–5.02, P=0.0007). As the FOXO3 locus reports pathway-output status rather than IGF1R per se, this study does not directly implicate IGF1R variants. However, the result is mechanistically interpreted as reflecting reduced IIS–AKT–FOXO3 flux in long-lived individuals, of which IGF1R is the receptor-tier node.

Note on cross-reference: This study is fully cited on pi3k-akt-pathway and insulin-igf1; the canonical home of the Willcox 2008 data is pi3k-akt-pathway (verified-partial). Quoted here for IIS-receptor-tier context only.

Suh 2008 — functional IGF1R variants in Ashkenazi female centenarians

Suh et al. 2008 (PNAS) ³ comprehensively screened the IGF1R coding sequence in the entire cohort of 384 centenarians (286 female + 98 male; mean age 97.7 y) and 312 age-matched controls, all Ashkenazi Jewish. The key variant screen was first performed on 79 female centenarians (selected for heights below the population mean, as a proxy for potential IGF-axis alteration) and 161 female controls. The full-cohort results for the two functionally significant nonsynonymous variants were:

Variant	Full-cohort centenarians (n=384)	Full-cohort controls (n=312)	Notes
Ala-37-Thr (244G>A)	2 het carriers (0.52%)	0	Alpha-chain L1 domain
Arg-407-His (1355G>A)	7 het carriers (1.82%)	1 het carrier (0.32%)	Alpha-chain L2 domain
Combined rare functional variants	9 carriers (2.3%)	1 carrier (0.3%)	P=0.02

Note: The per-variant frequencies in the pilot screen of n=79 female centenarians were 1/79 (~1.3%) for each variant, with 0/161 controls carrying either. The full-cohort numbers above are the primary reported results.

Functional follow-up in immortalized lymphocytes from variant carriers (n=6 female centenarian carriers) showed reduced IGFR levels and reduced IGF-I-stimulated AKT phosphorylation compared to 10 noncarrier centenarian lymphocyte controls, confirming partial loss-of-function. Crucially, despite reduced receptor activity, centenarian mutation carriers showed elevated circulating IGF-1 levels (165±21 vs 121±6 ng/mL in noncarriers, P=0.04) — a pattern consistent with compensatory IGF-1 up-regulation in response to reduced receptor signaling. This inverted IGF-1 level is an important caveat when using circulating IGF-1 as a biomarker: elevated IGF-1 in centenarians does not imply high signaling flux when the receptor is partially inactive.

needs-replication — Only 9 centenarian carriers identified in the full cohort of 384; replication in a larger Ashkenazi or European centenarian cohort has not been reported as of 2026-05-04. Combined result P=0.02 with a small number of carriers warrants independent replication.

IGF1R vs INSR in aging context

Both receptors are IIS entry points, but their aging-relevant biology differs:

Feature	IGF1R	INSR
Primary longevity relevance	Yes — haploinsufficiency extends lifespan in mice; LOF alleles in centenarians	Indirect — insulin sensitivity/metabolic disease; FIRKO mice modestly long-lived
Tissue distribution	Ubiquitous; high in muscle, brain, liver, bone	High in insulin-sensitive tissues (liver, fat, muscle)
Cancer relevance	Pro-tumorigenic; IGF1R overexpressed in many cancers	Less directly oncogenic
Hybrid receptor formation	Yes (with INSR); complicates in-vivo pharmacology	Yes (with IGF1R)
Longevity via complete KO	Perinatal lethal ⁵	Embryonic lethal
Longevity via heterozygous KO	+26% (129/Sv combined); +33% females ¹	FIRKO: ~18% (fat-restricted KO) — different model

Laron syndrome: a natural experiment in human IGF1R pathway reduction

Laron syndrome results from loss-of-function mutations in the growth hormone receptor (GHR), not IGF1R itself. However, because GHR signaling is required for hepatic IGF-1 production, GHR-null individuals have very low circulating IGF-1 — phenocopying IGF1R haploinsufficiency in terms of pathway output.

Laron syndrome patients (>300 individuals studied in Ecuador and elsewhere) show:

Short stature and obesity
Apparent resistance to cancer and diabetes compared to unaffected relatives
No reduction in cardiovascular disease

This is a natural human experiment supporting the hypothesis that low IGF-1 signaling protects against specific age-related diseases, though it does not demonstrate longevity per se. needs-replication — lifespan data in Laron syndrome cohorts is limited by cohort size and access to mortality records.

Note: Laron syndrome is a GHR-mutation phenotype, not an IGF1R phenotype. The canonical page for Laron syndrome biology would be growth-hormone-receptor (implicit stub).

Pharmacological targeting

Anti-cancer IGF1R inhibitors (failed in oncology)

Several monoclonal antibodies (figitumumab/CP-751,871, ganitumab/AMG-479, cixutumumab/IMC-A12) and small-molecule IGF1R kinase inhibitors (linsitinib/OSI-906) were developed as anti-cancer agents. Phase III trials largely failed:

Figitumumab (Phase III in non-small cell lung cancer): trial stopped for futility / toxicity. Key on-target toxicity: hyperglycemia (from inhibiting INSR as well as IGF1R at therapeutic doses, given kinase-domain similarity) and thrombocytopenia.
Linsitinib (dual IGF1R/INSR inhibitor): showed activity in Ewing sarcoma but missed endpoints in unselected patient populations.

Implications for aging: Complete IGF1R inhibition is too toxic for aging applications. Partial haploinsufficiency (as in mice) or tissue-specific reduction may be the relevant biological dose, but no pharmacological tool achieves this selectively in humans. dose-response-unclear

No approved longevity-directed IGF1R drug

As of 2026-05-04, there is no compound in clinical trials with IGF1R reduction as a primary aging or longevity endpoint. The indirect approach — reducing upstream growth hormone (e.g., octreotide for GH suppression) — is being explored in aging contexts but not with IGF1R-specific molecular endpoints.

Pathway membership and cross-references

insulin-igf1 — IGF1R is the receptor-tier node; page carries the IIS-longevity narrative in full
pi3k-akt-pathway — IGF1R is the upstream RTK activating PI3K–AKT
mtor — indirect (via AKT → TSC1/TSC2 → mTORC1 activation)
deregulated-nutrient-sensing — parent Hallmark of Aging
irs1 / irs2 — immediate cytoplasmic substrates; adapter scaffold (implicit stubs)
foxo3 — key downstream longevity effector (implicit stub)
insr — paralog; hybrid receptor formation (implicit stub)

Limitations and gaps

needs-human-replication — all direct lifespan data is from mouse models; human evidence is centenarian cohort associations only.
needs-replication — Suh 2008 identified only 9 centenarian IGF1R variant carriers out of 384; the functional variants are rare (combined 2.3% vs 0.3% controls, P=0.02) and require independent replication. Holzenberger 2003 C57BL/6 congenic result attenuated (~11%); no independent replication in a second mammalian species.
no-mechanism — sex dimorphism in Igf1r+/- mice (females significant, males NS) unexplained.
dose-response-unclear — optimal degree of IGF1R signaling reduction for longevity in humans is unknown; too much (cancer drugs) is toxic.
contradictory-evidence — circulating IGF-1 levels and longevity in humans show a complex, possibly non-monotonic relationship; centenarian IGF1R variant carriers in Suh 2008 had elevated IGF-1 (165±21 vs 121±6 ng/mL, P=0.04) despite reduced receptor signaling — elevated because of compensatory up-regulation, not because signaling is high. This makes circulating IGF-1 alone an unreliable biomarker for IIS pathway activity in centenarians.
Liu 1993 (IGF1R null lethal, Cell) is not_oa; the claim of perinatal lethality is well-established in the field and corroborated by multiple downstream studies, but the primary source PDF cannot be verified. no-fulltext-access

Footnotes

doi:10.1038/nature01298 · holzenberger-2002-igf1r-lifespan · in-vivo · genetic model · model: Mus musculus (129/Sv background, Igf1r+/-) · Holzenberger M et al. · Nature 2003 (published online Dec 2002, print Jan 2003) · +26% mean lifespan overall (P<0.02, Cox); +33% females (756±46 vs 568±49 days, P<0.001); +15.9% males (679±80 vs 585±69 days, NS) · archive: downloaded (local PDF) ↩ ↩² ↩³
doi:10.1073/pnas.0801030105 · willcox-2008-foxo3-longevity · nested case-control · n=615 men (213 cases ≥95y; 402 controls died ≤81y, mean death age ~78.5y; Honolulu Heart Program / HAAS) · model: Homo sapiens (Japanese-American men only) · FOXO3A rs2802292 GG vs TT OR=2.75 (95% CI 1.51–5.02, P=0.0007) · PNAS 2008 · archive: downloaded (local PDF) ↩ ↩²
doi:10.1073/pnas.0705467105 · suh-2008-igf1r-centenarian-variants · case-control · n=384 centenarians (286 female + 98 male; mean age 97.7 y) + 312 controls · model: Homo sapiens (Ashkenazi Jewish) · IGF1R Ala-37-Thr and Arg-407-His variants combined: 9/384 centenarians (2.3%) vs 1/312 controls (0.3%), P=0.02; reduced IGFR levels + reduced AKT phosphorylation in variant carriers; elevated circulating IGF-1 in carriers (165±21 vs 121±6 ng/mL, P=0.04) · PNAS 2008 · archive: downloaded (local PDF) ↩ ↩²
doi:10.1002/j.1460-2075.1986.tb04528.x · ullrich-1986-igf1r-cloning · in-vitro · n=n/a · cDNA cloning and complete primary structure of human IGF-1 receptor; 1,367 aa precursor; 30 aa signal peptide; α chain (proreceptor Glu-1 to ~Arg-706); β chain begins at Asp-711; kinase domain proreceptor residues 973–1,229 (precursor ~1,003–1,259); ~84% kinase-domain identity with INSR; chromosome 15q · EMBO J 1986 · archive: downloaded (bronze OA via PMC) ↩ ↩²
doi:10.1016/s0092-8674(05)80084-4 · liu-1993-igf1r-igf1-null-mice · in-vivo · genetic model · model: Mus musculus (Igf1r-/- null) · Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A · Cell 1993 · 2,866 citations · Igf1r-null mice die at birth; ~45% normal birth weight; respiratory failure · archive: not_oa no-fulltext-access ↩ ↩²

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