Hypothesis

Aging-induced Wnt/β-catenin loss in intestinal stem cells (ISCs) shifts enteroendocrine programming toward a pro‑inflammatory secretome. Restoring Wnt signaling in aged ISCs reprograms these cells to secrete satiety peptides (e.g., peptide YY) that activate vagal afferents, triggering the cholinergic anti‑inflammatory pathway and suppressing microglial activation in the hippocampus.

Mechanistic Model

1. Wnt activation in ISCs – Pharmacological Wnt agonists or genetic β‑catenin stabilization increase canonical transcription in aged ISCs (see [2]).
2. Enteroendocrine fate switch – Wnt signaling drives expression of the transcription factor Neurog3 and biases progenitors toward peptide YY‑producing cells rather than serotonin‑enteroendocrine lineages.
3. Gut‑derived peptide YY surge – Elevated circulating peptide YY binds receptors on vagal afferent fibers in the intestinal wall, increasing vagal tone (measured by heart‑rate variability).
4. Vagal cholinergic output – Activated vagus nerve releases acetylcholine onto α7 nicotinic acetylcholine receptors (α7nAChR) on hepatic macrophages and splenic norepinephrine‑producing cells, inhibiting systemic NF‑κB signaling and lowering serum LPS.
5. Brain‑level effect – Reduced circulating LPS and cytokine levels diminish microglial NF‑κB activation, limiting astrocytic reactivity and preserving synaptic plasticity in the hippocampus.
6. Feedback loop – Improved hippocampal function enhances central vagal efferent output, further stabilizing the intestinal barrier.

Testable Predictions

• Prediction 1: In aged mice, inducible β‑catenin activation in Lgr5+ ISCs will raise plasma peptide YY by ≥30 % within two weeks, while serum LPS drops ≥25 % compared with vehicle controls.
• Prediction 2: Pharmacological blockade of vagal signaling (subdiaphragmatic vagotomy) or α7nAChR antagonism (MLA) will abolish the peptide YY increase, the LPS reduction, and the cognitive rescue seen in Wnt‑treated aged mice.
• Prediction 3: Selective chemogenetic inhibition of peptide YY‑producing enteroendocrine cells will prevent the vagal tone improvement and neuroprotective effects despite intact Wnt activation in ISCs.
• Prediction 4: Restoring Wnt signaling will increase Neurog3 expression in intestinal crypts and decrease tryptophan hydroxylase 1 (Tph1) levels, indicating a shift away from serotonin biosynthesis.

Falsifiability

If any of the above manipulations fail to produce the predicted directional changes (e.g., vagotomy does not attenuate the cognitive benefit), the hypothesis that gut‑derived peptide Yy mediates the Wnt‑brain axis is falsified.

Broader Implications

This framework flips the conventional top‑down view: longevity strategies that target intestinal stem‑cell signaling can be designed to harness endogenous gut‑brain communication, reducing reliance on direct CNS drug delivery.

Key references: Wnt restoration reverses ISC decline [2]; Nlrp3 reduction lowers brain inflammation [3]; Paneth‑cell NOTUM drives Wnt loss [2]; microbial LPS triggers NF‑κB and Aβ [4]; SCFAs inhibit microglial HDACs [5]; IFN‑γ/ERK‑MAPK imbalance in ISCs links stem survival to barrier failure [6]