🧬 Aging Wiki

il-11

Properties1
aliasesIL11, interleukin-11, IL-11, adipogenesis inhibitory factor, AGIF

5 min read

IL-11

IL-11 is a secreted IL-6-family cytokine that binds IL11RA and recruits the shared signal transducer IL6ST/gp130. It was developed clinically as recombinant oprelvekin to stimulate platelet recovery, but aging research focuses on the opposite perturbation: blocking inducible IL-11 signaling in fibroinflammatory states. The strongest aging evidence is preclinical.

Identity and signaling

  • Canonical human protein: UniProt P20809; NCBI Gene 3589; HGNC 5966; Ensembl ENSG00000095752. The mouse ortholog is Il11 (MGI:107613) 1.
  • Receptor complex: IL-11 first binds IL11RA, then assembles a signaling complex with gp130.
  • Downstream branches: the canonical receptor-proximal route uses gp130-associated JAK1/JAK2/TYK2 and STAT3/STAT1; RAS–MEK–ERK, PI3K–AKT and NF-ÎşB are context-dependent non-canonical branches 2. In the fibrosis and aging studies summarized here, ERK-dependent translation and ERK–AMPK–mTOR coupling were prominent, but STAT phosphorylation also occurred and ERK was not shown to be the sole effector 34.

Fibroblast and matrix biology

In primary human cardiac fibroblasts, TGF-β1 strongly induced IL11, and IL-11 signaling was required for much of the TGF-β-driven myofibroblast and extracellular-matrix phenotype. IL-11 acted through an autocrine feed-forward loop and ERK-dependent post-transcriptional mechanisms. Constitutive Il11ra1 loss reduced cardiac and renal fibrosis in several mouse injury models 3. This is the foundational evidence for the TGF-β → IL-11 → ERK fibrosis axis; it does not imply that every form of fibrosis is IL-11-dependent.

That qualification is material. In an independent study of primary human lung fibroblasts, IL-11 activated both STAT3 and ERK but was substantially weaker than TGF-β at inducing fibrotic proteins; a high-affinity anti-IL-11 antibody blocked IL-11-induced STAT3 phosphorylation yet did not block TGF-β-induced TIMP1 or CTGF release. The evidence therefore supports tissue- and assay-dependent IL-11 amplification, not a universal obligatory TGF-β relay 5. gap/contradictory-evidence

Aging evidence

Systemic mouse aging

IL-11 protein increased with age in mouse liver, skeletal muscle and visceral white adipose tissue. Germline Il11 loss and late-life neutralization with the research antibody X203 were associated with improved frailty, grip strength, metabolic and fibrosis measures; separate survival cohorts reported longer mouse median lifespan. Mechanistic human-cell evidence came from one adult cardiac-fibroblast donor and one fetal-hepatocyte donor; no human aging intervention was performed 4. See widjaja-2024-il11-healthspan-lifespan.

Ovarian aging

Human ovarian IL-11 abundance rose with chronological age and in cross-sectional samples from chemotherapy-associated POI, PCOS and ovarian endometriosis. In primary human ovarian-stromal-fibroblasts, IL-11 activated ERK-linked collagen and myofibroblast programs. Recombinant IL-11 worsened ovarian stiffness and selected fertility measures in young mice, whereas Il11ra1 loss, systemic siIl11 nanoparticles or local ovarian shIl11ra1 improved selected matrix, follicle, ovulation or litter outcomes in rodents 6. Adult-siRNA pregnancy proportions favored treatment but were nonsignificant when recalculated from the source counts. The human results are observational; efficacy in women has not been tested. See wu-2026-il11-ovarian-stiffness.

Therapeutic interpretation

The aging-context druggability assignment is tier 2. Ligand-neutralizing X203 and genetic/RNA perturbations are high-quality preclinical aging probes. Separate non-aging human programs now include the ligand-directed antibodies BI 765423 (recruiting phase 2 idiopathic pulmonary fibrosis) and 9MW3811 (completed phase 1; recruiting phase 2 pathological scar), plus the TSLP/IL-11 bispecific HB0056 (recruiting phase 1). The IL11RA-directed antibody LASN01—not an IL-11 ligand-neutralizing antibody—completed phase 1/2a and phase 2 studies outside aging 7. Open Targets currently has no IL11 clinical-candidate row despite these registry entries, so its target record should not be treated as a complete trial inventory 8. None of these programs has tested aging or geroprotection. See anti-il-11-antibodies.

Complete developmental loss is not a clean model of adult treatment. Homozygous Il11 knockout females were infertile and knockout males produced smaller litters in one study, whereas craniosynostosis-like and trabecular-bone phenotypes were reported for Il11ra1 loss but were not observed in the ligand-null line 9. Preliminary use of a higher bleomycin protocol also produced unexplained greater mortality in Il11 knockouts, prompting a reduced-dose, earlier-endpoint experiment. The ovarian study used germline Il11ra1 deletion in several arms but separately tested adult siRNA and AAV silencing, which are not equivalent to constitutive loss 6. Long-term infection, repair, reproductive and metabolic safety of sustained blockade in older humans remains unknown.

Key uncertainties

  • Which cell types are necessary for the systemic healthspan phenotype is unresolved.
  • The relative causal contributions of STAT3 and ERK–AMPK–mTOR branches vary by cell type and were not fully separated.
  • IL-11 can participate in normal development, implantation, hematopoietic support and tissue repair; chronic blockade may not reproduce germline-null phenotypes, but neither can knockout safety be assumed to establish drug safety.
  • No independent lifespan replication in genetically heterogeneous mice or an NIA Interventions Testing Program cohort has been reported. gap/needs-replication gap/needs-human-replication gap/long-term-unknown
  • Human GTEx age correlations and aging-directed Mendelian-randomization evidence remain unestablished. gap/needs-gtex-aging-correlation

Footnotes

Footnotes

  1. UniProt P20809; NCBI Gene 3589; HGNC:5966; Ensembl ENSG00000095752; MGI:107613 · canonical database records accessed 2026-08-09 ↩

  2. Reactome R-HSA-449976 (IL11:IL11RA binding to IL6ST:JAK1,JAK2,TYK2) and R-HSA-6783589; WikiPathways WP2332 · human curated pathway records accessed 2026-08-09 ↩

  3. schafer-2017-il11-cardiovascular-fibrosis · doi:10.1038/nature24676 · Schafer S et al. · Nature 2017;552:110–115 · primary human cardiac fibroblasts plus mouse cardiovascular and renal fibrosis models · establishes TGF-β-induced autocrine IL-11 and ERK-dependent fibroblast activation ↩ ↩2

  4. widjaja-2024-il11-healthspan-lifespan · doi:10.1038/s41586-024-07701-9 · Widjaja AA et al. · Nature 2024;632:157–165 · mouse genetic and late-life antibody experiments; human evidence limited to cultured cells ↩ ↩2

  5. doi:10.3389/fimmu.2024.1293883 · Tan Y et al. · Frontiers in Immunology 2024;15:1293883 · primary human lung fibroblasts from multiple assays, with two donors in the nCounter experiment · anti-IL-11 blocked receptor-proximal pSTAT3 but not TGF-β-induced TIMP1/CTGF ↩

  6. wu-2026-il11-ovarian-stiffness · doi:10.1038/s43587-026-01159-2 · Wu M et al. · Nature Aging 2026;6:1395–1416 · cross-sectional human ovary data plus mechanistic culture and rodent intervention experiments ↩ ↩2

  7. ClinicalTrials.gov NCT05331300 and NCT06226545 (IL11RA-directed LASN01); NCT07036523 (BI 765423); NCT05740475 and NCT07576608 (9MW3811); NCT06612970 (HB0056) · registry records accessed 2026-08-09 · all are non-aging programs ↩

  8. Open Targets Platform records for IL11 (ENSG00000095752) and IL11RA (ENSG00000137070) · accessed 2026-08-09 · aging-context tier applies; the platform had no IL11 drug/clinical-candidate row ↩

  9. ng-2021-il11-il11ra1-loss-of-function · doi:10.1038/s41598-021-93623-9 · Ng B et al. · Scientific Reports 2021;11:14088 · mouse Il11 and Il11ra1 loss-of-function phenotyping · developmental and reproductive caveat for constitutive blockade ↩

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