IL-11 ERK-AMPK-mTORC1 Ageing Module

Aging Module il11_erk_ampk_mtor_aging 4 disorders Pathograph 6

A conserved pro-inflammatory-cytokine driver of mammalian ageing. With age, the IL-6-family cytokine IL-11 is progressively upregulated across cell types and tissues (an alarmin-type response) and signals through IL11RA1-gp130 to drive a coupled ERK-p90RSK / LKB1-AMPK-inactivation / mTORC1 signalling module. Sustained activation of this ERK-AMPK-mTORC1 axis promotes cellular senescence and a mTORC1/ERK-dependent senescence-associated secretory phenotype (SASP), metabolic decline (loss of AMPK-dependent metabolic flexibility, age-repressed white-adipose-tissue beiging, hepatic lipid accumulation, sarcopenia) and tissue fibrosis - together driving organismal frailty, multimorbidity, age-related cancer and shortened lifespan. Genetic (Il11 or Il11ra1 deletion) or pharmacological (anti-IL-11 neutralizing antibody) inhibition reverses these pathologies and extends healthspan and lifespan in mice. This module isolates the IL-11-specific druggable arm of inflammaging: it is a specific driver that feeds the source-agnostic inflammaging chain (see inflammaging) and the senescence programme (see cellular_senescence), which it does not re-derive. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disease-specific IL-11-expressing cell type and target tissue while preserving the conserved IL-11-upregulation -> receptor-signalling -> ERK-AMPK-mTORC1-axis -> senescence/metabolic-decline -> frailty/lifespan chain.

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Pathophysiology Nodes

5 shared nodes are defined in this module.

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Cell Types

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Biological Processes

Cytokine Production GO:0001816 INCREASED Interleukin-11-mediated signaling pathway GO:0038154 INCREASED ERK1 and ERK2 cascade GO:0070371 INCREASED TORC1 signaling GO:0038202 INCREASED Cellular senescence GO:0090398 INCREASED Inflammatory response (SASP) GO:0006954 INCREASED

Notes

This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "il11_erk_ampk_mtor_aging#ERK-AMPK-mTORC1 Axis Dysregulation"). Conforming nodes in disorder files should include the corresponding biological processes and causal edges, specialized to their disease context (substituting the IL-11-expressing parenchymal cell type - hepatocyte, adipocyte, myocyte, fibroblast - and target tissue). The key conformance target is the central_effector "ERK-AMPK-mTORC1 Axis Dysregulation": the disorder-agnostic, rate-limiting integrating node that couples ERK-p90RSK activation, LKB1-AMPK inactivation and mTORC1-p70S6K-S6RP activation. Conformance-attachment guidance: attach a disorder node at the amplifier "IL-11 Receptor Signalling Activation" when only the IL-11 -> ERK arm is evidenced in that tissue (the case for every current fibrosis conformer - IPF, liver cirrhosis, chronic kidney disease, dilated cardiomyopathy); reserve conformance to the central_effector "ERK-AMPK-mTORC1 Axis Dysregulation" for entries that actually evidence the coupled LKB1-AMPK-inactivation / mTORC1 metabolic arm, so a fibrosis conformer does not silently assert the full metabolic axis. Anti-IL-11 (X203) neutralizes the ligand upstream and therefore INHIBITS the "IL-11 Receptor Signalling Activation" amplifier node. Scope: this module deliberately does NOT re-derive the SASP (see cellular_senescence) or the source-agnostic systemic-inflammation convergence point (see inflammaging); it is the IL-11-specific, druggable driver upstream of both. It complements the hallmark-of-ageing modules rather than duplicating them. The relative contributions of canonical (JAK-STAT3) versus non-canonical (MEK-ERK) IL-11 signalling to ageing phenotypes are an open question, recorded as a KNOWLEDGE_GAP discussion below. All evidence is drawn from the landmark open-access study Widjaja et al., Nature 2024 (PMID:39020175), which provides both mouse genetic/therapeutic (MODEL_ORGANISM) and human-cell (IN_VITRO) support across the chain.

Discussions and Knowledge Gaps

What are the relative contributions of canonical JAK-STAT3 versus non-canonical MEK-ERK IL-11 signalling, alone or in combination, to the ageing phenotypes reversed by IL-11 inhibition?

KNOWLEDGE GAP OPEN knowledge_gap_il11_canonical_versus_noncanonical_ageing

Attached to: IL-11 Receptor Signalling Activation ERK-AMPK-mTORC1 Axis Dysregulation

IL-11 receptor engagement bifurcates into canonical STAT3 and non-canonical ERK-p90RSK arms, and both feed the ERK-AMPK-mTORC1 axis. Which arm dominates for a given ageing phenotype is unresolved, and it matters for drug design: a STAT3-dominant phenotype might be addressable with existing JAK-STAT inhibitors, whereas an ERK-dominant phenotype argues for ligand/receptor neutralization or MEK inhibition. Curators should keep the two arms separated on the amplifier node rather than asserting either as the settled effector.

Does the healthspan and lifespan extension achieved by IL-11 inhibition in aged mice translate to human ageing, or is the survival benefit specific to the laboratory-mouse ageing model?

HUMAN MODEL MISMATCH OPEN human_model_mismatch_il11_lifespan_extension

Attached to: Frailty, Multimorbidity and Reduced Lifespan

The organismal-outcome node - reduced frailty, multimorbidity, age-related cancer and >20% median lifespan extension - rests entirely on mouse genetics (Il11 / Il11ra1 deletion) and anti-IL-11 antibody dosing from 75 weeks of age; there is no human survival or frailty evidence. This is a HUMAN_MODEL_MISMATCH rather than a plain KNOWLEDGE_GAP because the effect IS demonstrated in a model system and it is the translational validity to human ageing that is open. It is mechanistically meaningful because mouse late-life mortality is heavily cancer-driven (the autopsy tumour-burden data), whereas human ageing mortality is dominated by cardiovascular, neurodegenerative and multi-morbid disease, so a lifespan benefit routed largely through reduced murine tumours need not reproduce in humans. Anti-IL-11 is already in early-stage human trials for fibro-inflammatory disease, which is the natural setting to begin resolving this - but until human ageing endpoints exist, conforming disorder entries should not inherit the lifespan-extension claim.

Proposed experiments: Human ageing and frailty endpoints in an anti-IL-11 clinical cohort

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Used By Disorder Entries

Chronic Kidney Disease via IL-11 Signalling in Renal Fibroblasts → IL-11 Receptor Signalling Activation

Dilated Cardiomyopathy via IL-11 Signalling in Cardiac Fibroblasts → IL-11 Receptor Signalling Activation

Idiopathic Pulmonary Fibrosis via IL-11 Autocrine Signalling in Lung Fibroblasts → IL-11 Receptor Signalling Activation

Liver Cirrhosis via IL-11 Signalling in Hepatic Stellate Cells → IL-11 Receptor Signalling Activation

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Pathograph

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Pathophysiology

Age-Associated IL-11 Upregulation

trigger

With ageing, the IL-6-family pro-inflammatory cytokine IL-11 is progressively upregulated across diverse cell types and tissues (liver, visceral white adipose tissue and skeletal muscle) - an alarmin-type response to accumulating age-related pathogenic factors. This rising IL-11 tone is the initiating step of the module. Conforming disorder nodes substitute the disease-specific IL-11-expressing parenchymal cell type and tissue.

Hepatocyte CL:0000182 Adipocyte CL:0000136 Skeletal myocyte CL:0000188 Fibroblast CL:0000057

Cytokine Production GO:0001816 INCREASED

Downstream

IL-11 Receptor Signalling Activation

IL-11 Receptor Signalling Activation

amplifier

Upregulated IL-11 engages its receptor (IL11RA1 with the shared gp130 signal-transducing subunit) to activate two arms: canonical JAK-STAT3 and non-canonical MEK-ERK-p90RSK signalling. Receptor engagement is the amplifier that converts rising IL-11 abundance into the downstream kinase-axis dysregulation, and is the node neutralized by anti-IL-11 (X203) or anti-IL11RA (X209) antibodies.

Interleukin-11-mediated signaling pathway GO:0038154 INCREASED

Used by disorders

Chronic Kidney Disease as IL-11 Signalling in Renal Fibroblasts

Dilated Cardiomyopathy as IL-11 Signalling in Cardiac Fibroblasts

Idiopathic Pulmonary Fibrosis as IL-11 Autocrine Signalling in Lung Fibroblasts

Liver Cirrhosis as IL-11 Signalling in Hepatic Stellate Cells

Downstream

ERK-AMPK-mTORC1 Axis Dysregulation

ERK-AMPK-mTORC1 Axis Dysregulation

central effector

The integrating, rate-limiting node of the module. IL-11 receptor signalling drives coupled activation of ERK-p90RSK, p90RSK/ERK-mediated inactivation of the LKB1-AMPK energy sensor (increased inhibitory p-LKB1, reduced active p-AMPK), and consequent de-repression and activation of mTORC1 (increased p-mTOR, p-p70S6K and p-S6RP). Because ERK, AMPK and mTORC1 are the conserved lifespan-regulating pathways, this single coupled axis is where disorder-specific IL-11 signalling converges and is the key conformance target for conforming disorder entries.

ERK1 and ERK2 cascade GO:0070371 INCREASED TORC1 signaling GO:0038202 INCREASED

Downstream

Cellular Senescence and Metabolic Decline

Cellular Senescence and Metabolic Decline

effector

Sustained ERK-AMPK-mTORC1 dysregulation drives the cellular effectors of the module: mTORC1/ERK-dependent cellular senescence with induction of p16 and p21 and a senescence-associated secretory phenotype (SASP), together with metabolic decline - loss of AMPK-dependent metabolic flexibility, age-repressed white-adipose-tissue beiging, hepatic lipid accumulation and sarcopenia - and tissue fibrosis. Conforming disorder nodes specialize this to the affected organ.

Cellular senescence GO:0090398 INCREASED Inflammatory response (SASP) GO:0006954 INCREASED

Downstream

Frailty, Multimorbidity and Reduced Lifespan

Frailty, Multimorbidity and Reduced Lifespan

consequence

The organismal consequence of the module: age-associated IL-11 signalling manifests as frailty, sarcopenia, metabolic multimorbidity, increased age-related cancer burden and shortened lifespan. Genetic or pharmacological inhibition of IL-11 protects against these outcomes and extends both healthspan and lifespan. This is the conserved endpoint; the specific age-related phenotype is supplied by the conforming disorder.