Hypothesis\n\nAging-related loss of IL-33 from muscle stromal cells diminishes ILC2 activation, reducing eosinophil recruitment and IL-4/IL-13 signaling to fibro-adipogenic progenitors (FAPs). This deficit reprograms FAP metabolism toward a glycolytic, pro-fibrotic state that exacerbates sarcopenia. Restoring IL-33 or ILC2-derived eosinophil signals shifts FAPs to oxidative metabolism and an anti-fibrotic secretome, preserving muscle repair.\n\n## Mechanistic Basis\n\n- IL-33 stimulates ILC2s to produce IL-5 and IL-13, supporting eosinophil survival and tissue retention (3).\n- Eosinophil-derived IL-4/IL-13 activates PPARγ in FAPs, promoting a trophic phenotype that supports muscle stem cells (4).\n- In aged muscle, declining IL-33 reduces ILC2 activity, lowering eosinophil numbers and IL-4/IL-13 availability.\n- Consequently, FAPs experience reduced PPARγ signaling, leading to increased HIF1α-driven glycolysis, heightened TGFβ secretion, and collagen deposition.\n- This metabolic switch creates a feed‑forward loop: fibrotic matrix further suppresses eosinophil infiltration via increased stiffness and altered chemokine gradients.\n\n## Testable Predictions\n\n1. IL-33 supplementation in aged mice will increase eosinophil infiltration, shift FAP metabolism from glycolysis to oxidative phosphorylation, and reduce collagen deposition compared with untreated aged controls.\n2. Genetic ablation of ILC2s will block the beneficial effects of IL-33 treatment and eosinophil adoptive transfer on FAP metabolism and fibrosis, despite restored eosinophil numbers.\n3. Pharmacologic inhibition of glycolysis (e.g., 2‑DG) in FAPs of aged mice will mimic the anti‑fibrotic effects of IL-33/ILC2 activation, rescuing muscle regeneration even when eosinophils remain low.\n\n## Experimental Approach\n\n- Use aged (24‑month) C57BL/6 mice; administer recombinant IL-33 intraperitoneally twice weekly for 4 weeks.\n- Measure eosinophil frequency in visceral fat and muscle by flow cytometry (Siglec-F+ CD11b+).\n- Isolate FAPs (PDGFRα+ Sca1+ CD31− CD45−) and assess metabolic flux with Seahorse (OCR/ECAR) and expression of Pparg, Hif1a, Col1a1 via qPCR.\n- Quantify fibrosis via hydroxyproline content and Sirius Red staining.\n- Parallel groups: ILC2-deficient mice (Il7r−/− crossed with Rora−/−) receiving IL-33 or eosinophil transfer from young donors.\n- Include a glycolysis inhibition arm (2‑DG) to test metabolic rescue.\n- Functional readouts: grip strength, treadmill endurance, and ex vivo muscle contractility.\n\n## Potential Implications\n\nIf IL-33/ILC2 signaling sustains a metabolically healthy FAP niche, targeting this axis could offer a strategy to counteract eosinophil loss‑driven fibrosis in sarcopenia and muscular dystrophies, complementing eosinophil transfer or IL-5 modulation therapies.