2026-08-09

[2026-08-09] ingest | IL-11 systemic/ovarian aging and ribosome dysregulation in infertility

Three user-supplied papers were incorporated through seeding, independent full-text verification and propagation:

• Wu et al., “Modulating IL-11-dependent matrix stiffness to delay ovarian aging,” Nature Aging (2026), doi:10.1038/s43587-026-01159-2.
• Widjaja et al., “Inhibition of IL-11 signalling extends mammalian healthspan and lifespan,” Nature (2024), doi:10.1038/s41586-024-07701-9.
• Li et al., “Ribosome dysregulation and intervention in age-related infertility,” Cell Reports Medicine (2025), doi:10.1016/j.xcrm.2025.102424.

Foundational cited work was expanded into verified atomic study pages for the TGF-β–IL-11 fibroblast relay (Schafer 2017), ligand/receptor-null differences and reproductive safety (Ng 2021), and collagen/hyaluronan-dependent ovarian mechanics (Amargant 2020).

Added

• Requested study pages: studies/wu-2026-il11-ovarian-stiffness.md, studies/widjaja-2024-il11-healthspan-lifespan.md, and studies/li-2025-ribosome-age-related-infertility.md — all independently verified.
• Supporting studies: studies/schafer-2017-il11-cardiovascular-fibrosis.md, studies/ng-2021-il11-il11ra1-loss-of-function.md, and studies/amargant-2020-ovarian-stiffness.md — all independently verified.
• IL-11 axis: molecules/proteins/il-11.md, molecules/proteins/il-11-receptor-alpha-1.md, molecules/proteins/gp130.md, molecules/proteins/stat3.md, and pathways/il-11-signaling.md.
• Interventions: interventions/pharmacological/anti-il-11-antibodies.md and interventions/pharmacological/il-11-gene-silencing.md.
• Ovarian/reproductive entities: cell-types/ovarian-stromal-fibroblasts.md, cell-types/cumulus-cells.md, and phenotypes/age-related-female-infertility.md.
• Process layer: processes/extracellular-matrix-remodeling.md, processes/ribosome-biogenesis.md, and processes/protein-synthesis.md.

All 13 supporting atomic pages above were independently checked after seeding and promoted to verified: true on 2026-08-09.

Propagated

• tissues/ovary.md — human matrix observations, rodent IL-11 perturbations, RNA/AAV reporting limits and the recalculated pregnancy contrasts.
• cell-types/granulosa-cells.md, cell-types/cumulus-cells.md and cell-types/oocytes.md — separated the strong cumulus-cell synthesis/clearance phenotype from the weaker oocyte aggregate result and from ex-vivo mouse maturation.
• hallmarks/loss-of-proteostasis.md — added the synthesis-versus-clearance balance model without generalizing increased translation to all aging tissues.
• molecules/compounds/rapamycin.md and pathways/mtor.md — added the small IVF trial and preserved its null mature-oocyte result, post-randomization analyses, incomplete live-birth follow-up and absent published adverse-event table.
• pathways/jak-stat-pathway.md — distinguished canonical gp130–STAT3 signaling from the ERK-centered fibroblast/aging branch.
• Reproductive and intervention overlays — registered the new cell types, phenotype, modality and IL-11 ligand/receptor-inhibitor class.

Verifier-caught corrections and evidence judgment

Supporting atomic pages

• Canonical identity checks added WikiPathways WP2332 to il-11-signaling, Cell Ontology CL:2000063 to ovarian-stromal-fibroblasts, and CL:0000711 to cumulus-cells.
• Live registry checks separated IL-11 ligand antibodies from the IL11RA-directed LASN01 program: three active antibody studies were identified, all in non-aging indications; no active human IL-11 gene-silencing study was found.
• The TGF-beta-to-IL-11 fibroblast relay is now explicitly context-dependent rather than universal, and unsupported net STAT3-to-aging-hallmark causal edges were removed.
• Ovarian single-nucleus data are described as a 48-week genotype comparison without a young comparator; the reduced activated-fibroblast cluster is not presented as an age trajectory or as a demonstrated myofibroblast reduction.
• ribosome-biogenesis and protein-synthesis now distinguish cytosolic from mitochondrial machinery and direct translational control from indirect mTOR effects.
• The phenotype code was corrected from unspecified ICD-10-CM N97.9 to age-related-female-infertility index assignment N97.8; ICD-11 GA31 remains a broader infertility category rather than an age-specific mechanistic code.
• Broad granulosa markers are no longer treated as cumulus-specific; cumulus-cells now carries the compartment and periovulatory-state marker boundaries.

Wu 2026

• Human evidence is cross-sectional tissue plus primary-cell perturbation; no person received IL-11 inhibition.
• The adult in-vivo ovarian interventions were systemic siIl11 nanoparticles and local AAV-shIl11ra1, not an anti-IL-11 antibody.
• Source counts do not support the paper’s printed pregnancy P values. Mouse pregnancy was 3/8 versus 6/8 (recalculated two-sided Fisher P≈0.315); rat pregnancy was 3/10 versus 6/10 (P≈0.370). These are favorable directions, not established pregnancy effects.
• Raw TMT proteomic files were irretrievably lost; processed results remain, and individual collagen increases were demonstrated by immunohistochemistry rather than the differential-protein table.
• Publisher materials do not reconcile recombinant-IL-11 daily versus twice-weekly dosing, prose versus source-data follicle direction, anti-IL-11 concentration, ERK-inhibitor identity, correlation method or several matrix-culture n values.
• siRNA mass/control sequence and core AAV construct, dose, control and biodistribution details were not reported. The work primarily tested prevention/attenuation during middle age, not reversal of established human ovarian fibrosis.

Widjaja 2024

• Late-life X203 improved multiple mouse healthspan measures, but lifespan evidence is single-center, used conventional/inbred genetic backgrounds and remained heavily right-censored at the source-data cutoff; male Il11 knockout median lifespan was not determined.
• Human experiments used single-donor cultured cardiac fibroblasts and fetal hepatocytes, not treated older adults.
• White-adipose beiging was observed, but increased whole-animal energy expenditure was not demonstrated.
• Gross tumour counts were not blinded histopathological cancer incidence or cause-of-death adjudication.
• Patents, company ownership and consulting relationships around IL-11 therapeutics strengthen the need for independent replication.

Li 2025

• RNA-seq profile counts exceed biological independence: oocytes were library-duplicated and two cumulus samples came from each donor; several imaging/epigenomic tests used cells, fields, CpGs or peaks rather than donor-level inference.
• The transition near age 34 was derived from the same discovery data and was inconsistently grouped; it is not a validated clinical breakpoint.
• Oocyte methylomes used two pooled libraries/group; cumulus CUT&Tag used two donors/group. Epigenetic mechanism claims remain hypothesis-generating.
• Mouse rapamycin was an ex-vivo maturation exposure, not systemic ovarian rejuvenation.
• The human trial had a null mature-oocyte result. Embryo analyses excluded participants without MII oocytes; extended-culture and pregnancy analyses were conditioned on post-randomization events.
• Clinical pregnancy was 20/40 versus 11/39 (RR 1.77, 95% CI 0.98–3.19; P=0.047). The confidence interval includes 1, the outcome was secondary and no multiplicity hierarchy was specified.
• Live-birth follow-up was incomplete and null among the due-date subset; no randomized cumulative live-birth efficacy estimate or published adverse-event/laboratory table was available.

Supporting studies

• Schafer 2017 establishes an ERK-centered TGF-β–IL-11 autocrine relay in the tested cardiac/renal fibroblast and mouse injury models, not universal IL-11 dependence across fibrosis etiologies.
• Ng 2021 showed ligand-null female infertility and smaller male litters, while craniosynostosis-like/bone phenotypes were receptor-null-specific in the compared mouse lines. Preliminary higher bleomycin mortality in ligand-null mice remained unexplained.
• Amargant 2020 directly linked collagen and hyaluronan to mouse ovarian mechanics. Human collagen was non-monotonic across its age cohorts, and human tissue stiffness was not measured.

Remaining gaps

• Independent late-life IL-11 lifespan replication in genetically heterogeneous, multi-site mice with completed survival follow-up and chronic safety phenotyping.
• Longitudinal human ovarian mechanics and IL-11 measurements, followed only after dose-defined, tissue-targeted reproductive and systemic safety work.
• Donor-level replication of cumulus/oocyte ribosome and epigenomic findings, plus a blinded placebo-controlled IVF trial powered for cumulative live birth and offspring safety.
• Separation of IL-11’s STAT3 and ERK branches, and of synthesis reduction from autophagy/other mTOR effects.

No correction, retraction or expression of concern was identified for the six verified primary papers through 2026-08-09.