IL‑11 signaling converges on AP‑1 to create a self‑reinforcing circuit that drives the coordinated activation of stress‑response genes and silencing of developmental programs seen in aged tissues. We hypothesize that chronic NLRP3 inflammasome activity raises extracellular IL‑11, which engages the IL‑11Rα/gp130 complex on stromal and immune cells, leading to JAK1/JAK2‑STAT3 phosphorylation. STAT3 then physically interacts with c‑Jun and c‑Fos, stabilizing AP‑1 dimers on DNA and recruiting p300/CBP histone acetyltransferase activity. This post‑translational boost increases AP‑1‑dependent transcription of MMPs, SASP cytokines, and ROS‑producing enzymes, while AP‑1‑mediated recruitment of HDAC2 to promoters of pluripotency genes (e.g., Oct4, Sox2) locks cells into a senescent state. Consequently, the inflammasome‑IL‑11‑AP‑1 axis functions as a single upstream controller that translates sporadic molecular damage into the classic hallmarks of aging.

To test this, we will treat aged (24‑month) C57BL/6 mice with a neutralizing anti‑IL‑11Rα antibody or an IL‑11‑specificaptamer twice weekly for three months. Control groups receive isotype antibody. We will measure: (1) NLRP3 cleavage and caspase‑1 activity in peritoneal macrophages; (2) IL‑11 levels in serum; (3) AP‑1 DNA‑binding activity by EMSA and chromatin occupancy of c‑Jun at SASP loci by ChIP‑seq; (4) Hallmark readouts—γH2AX foci (genomic instability), MitoSOX staining (mitochondrial ROS), ubiquitin‑aggregated proteins (proteostasis), and p16^Ink4a^+ senescent cell frequency; (5) Functional outcomes—grip strength, treadmill endurance, frailty index, and lifespan. Prediction: IL‑11 blockade will reduce AP‑1 activity by ≥40 % without suppressing acute LPS‑induced NLRP3 activation, leading to concomitant improvement in all hallmark metrics and a ≥15 % extension of median lifespan. We don't expect complete ablation of inflammasome signaling, preserving host defense. Failure to observe these changes would falsify the hypothesis that IL‑11‑driven AP‑1 activation is a necessary upstream driver of inflammaging‑mediated aging.