Hypothesis: Sustained efferent vagal signaling preserves the regenerative potential of c-Kit+ cardiac progenitor cells by suppressing senescence-associated secretory phenotype through α7 nicotinic acetylcholine receptor–mediated inhibition of NF‑κB signaling. We predict that enhancing vagal tone, either by chronic vagus nerve stimulation or by gut‑derived metabolites that activate afferent pathways feeding back to the brainstem, will lower p16^INK4A^ expression and SASP factor secretion in aged CPCs, thereby increasing their proliferative capacity and improving outcomes of senolytic therapy. Conversely, pharmacological blockade of α7 receptors will abolish the protective effect of vagal activation and render senolytics less effective in restoring cardiac function after injury.

Mechanistic rationale: Vagal efferents release acetylcholine into the cardiac interstitium where c-Kit+ progenitors reside. Acetylcholine binding to α7 nicotinic acetylcholine receptors (α7nAChR) on these cells triggers JAK2/STAT3 signaling, which antagonizes NF‑κB transcriptional activity. Reduced NF‑κB drives down expression of IL‑6, IL‑1β, MMP‑9 and other SASP factors that reinforce a senescent milieu. Simultaneously, c‑Kit signaling itself promotes cell‑cycle progression and counters p16^INK4A^ accumulation, creating a bidirectional loop where neural input amplifies intrinsic stem‑cell maintenance pathways. Gut‑derived metabolites such as short‑chain fatty acids or indole‑3‑propionic acid can stimulate enteroendocrine cells and vagal afferents, thereby boosting central parasympathetic outflow—a bottom‑up cue that primes the efferent arm.

Experimental test: Use 24‑month‑old mice subjected to permanent left anterior descending coronary artery ligation. Groups include (1) sham, (2) chronic vagus nerve stimulation (VNS) via implanted cuff, (3) VNS plus α7nAChR antagonist (methyllycaconitine), (4) senolytic dasatinib+quercetin (D+Q), (5) D+Q+VNS, and (6) D+Q+α7 antagonist. Assess at 2 weeks post‑MI: flow cytometry for c-Kit+/p16^INK4A^+ cells, SASP cytokine levels in cardiac homogenates, α7nAChR phosphorylation, and functional endpoints (ejection fraction, scar size). The hypothesis is falsified if VNS fails to reduce p16^INK4A^+ CPCs or SASP, or if the combination of VNS with senolytics does not yield additive improvement in cardiac function over senolytics alone. Confirmation would establish efferent vagal tone as a modifiable lever that gates progenitor senescence and regenerative capacity, shifting the gut‑brain‑heart axis from a predominantly afferent paradigm to one where brain‑to‑periphery autonomic output drives longevity‑relevant tissue repair.