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.
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
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.
Downstream
-
IL-11 Receptor Signalling Activation
Show evidence (3 references)
"which revealed progressive up-regulation of IL-11 in all tissues"
Documents the age-dependent, multi-tissue up-regulation of IL-11 modeled by this trigger node, in an ageing time course of mouse liver, adipose and skeletal muscle. Evidence source is MODEL_ORGANISM (aged mice).
"In two-year-old Il11-EGFP mice, IL-11 was apparent in parenchymal cells (hepatocytes in liver, adipocytes in vWAT and myocytes in skeletal muscle) and also seen in stromal, epithelial and endothelial cells across tissues and in nerves in skeletal muscle"
Identifies the IL-11-expressing cell types annotated on this node (hepatocyte, adipocyte, skeletal myocyte, plus stromal/fibroblast). Evidence source is MODEL_ORGANISM (aged Il11-EGFP reporter mice).
"IL-11 is progressively upregulated across tissues with age, probably as an alarmin-type response to age-related pathogenic factors that include cytokines, proteotoxic stress, oxidative species and DNA damage, among others"
States the alarmin-type framing of age-associated IL-11 up-regulation used in this node's description. Evidence source is OTHER (authors' discussion / interpretive framing).
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.
Downstream
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ERK-AMPK-mTORC1 Axis Dysregulation
Show evidence (2 references)
"Signalling pathway by which IL-11 induces canonical STAT3 activation and non-canonical ERK activation, LKB1–AMPK inactivation and mTOR activation."
Defines the receptor-proximal bifurcation modeled here: IL-11 drives canonical STAT3 and non-canonical ERK, feeding LKB1-AMPK inactivation and mTOR activation. Evidence source is OTHER (signalling-pathway schematic synthesizing the study's and prior data).
"This premise was founded on studies showing that IL-11 can activate ERK–mTORC1 and/or JAK–STAT3"
Records the established IL-11 receptor-signalling outputs (ERK-mTORC1 and JAK-STAT3) that this amplifier node represents. Evidence source is OTHER (authors' summary of prior mechanistic work).
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.
Downstream
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Cellular Senescence and Metabolic Decline
Show evidence (3 references)
"With age, there was progressive activation of ERK–p90RSK, inactivation of LKB1–AMPK and mTOR–p70S6K activation, which comprise an IL-11 signalling module, in liver and muscle"
Directly names the three coupled arms of this central node - ERK-p90RSK up, LKB1-AMPK down, mTOR-p70S6K up - and calls them the IL-11 signalling module. Evidence source is MODEL_ORGANISM (ageing mouse liver and muscle).
"old wild-type mice exhibited increased phosphorylated (p)-ERK and p-p90RSK, increased p-LKB1 leading to reduced p-AMPK, and increased levels of p-mTOR, p-p70S6K and p-S6RP"
Provides the phospho-signalling detail (increased p-ERK/p-p90RSK, increased inhibitory p-LKB1 with reduced p-AMPK, increased p-mTOR/p-p70S6K/p-S6RP) annotated as the INCREASED ERK/TORC1 and DECREASED AMPK descriptors here. Evidence source is MODEL_ORGANISM (aged wild-type mouse tissues).
"Stimulation of human fibroblasts or hepatocytes with IL-11 activated ERK–mTOR, increased levels of p16 and p21, and reduced expression of PCNA and cyclin D1, which was prevented by U0126 or rapamycin"
Establishes IL-11 as causally sufficient to activate the ERK-mTOR axis in human cells and shows pharmacologic reversibility (MEK inhibitor U0126, mTOR inhibitor rapamycin), grounding the axis mechanistically. Evidence source is IN_VITRO (primary human fibroblasts and hepatocytes).
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.
Show evidence (4 references)
"Deletion of Il11 or Il11ra1 protects against metabolic decline, multi-morbidity and frailty in old age."
States that genetic loss of IL-11 signalling protects against the metabolic decline, multimorbidity and frailty modeled by this outcome node. Evidence source is MODEL_ORGANISM (Il11 / Il11ra1 knockout mice).
"In lifespan studies, genetic deletion of Il11 extended the lives of mice of both sexes, by 24.9% on average."
Quantifies the lifespan-extension endpoint (24.9% mean extension with Il11 deletion). Evidence source is MODEL_ORGANISM (Il11 knockout lifespan cohorts).
"Beyond metabolism, inhibition of IL-11 improved deterministic features of ageing that are common among vertebrates (such as frailty and sarcopenia), showing generic anti-ageing benefits at the organismal level."
Supports the frailty/sarcopenia and generic organismal-ageing content of this consequence node. Evidence source is MODEL_ORGANISM (aged mice).
+ 1 more reference
Anti-IL-11 Therapy (Neutralizing Antibody)
Platform:
Monoclonal antibody
Neutralizing anti-IL-11 monoclonal antibody therapy (clone X203 in mouse studies; anti-IL11RA clone X209 in vitro) sequesters IL-11 and blocks receptor engagement, switching off the downstream ERK-AMPK-mTORC1 axis. Administered to 75-week-old mice until death, it improves metabolism and muscle function, reduces frailty and ageing biomarkers, and extends median lifespan by more than 20% in both sexes. Anti-IL-11 is in early-stage clinical trials for fibroinflammatory disease, making this the translational drug-target design pattern for conforming disorders. Represents the IL-11 inhibition drug-target pattern.
Evidence: 3