We hypothesize that clearing senescent cells from the gut epithelium and enteric nervous system will interrupt the gut→brain cascade that drives age‑related cognitive impairment. Senescent gut cells secrete a SASP rich in IL‑6, TNF‑α, and MMPs that alters luminal pH, bile acid conjugation, and mucus viscosity, creating a niche that favors pathobionts such as Parabacteroides goldsteinii and elevates toxic metabolites like 3‑HOA and PAA. Removing these cells should normalize the intestinal milieu, suppress dysbiotic expansion, boost production of beneficial metabolites (butyrate, indole‑3‑propionic acid), and restore expression of vagal afferent receptors (TRPV1, 5‑HT3A) on nodose neurons. Consequently, vagal firing to the nucleus tractus solitarius and hippocampus will increase, dampening microglial activation and rescuing synaptic plasticity.

Mechanistic Reasoning

• Senescent enterocytes increase luminal oxidative stress, which directly inhibits enteroendocrine L‑cell secretion of GLP‑1 and peptide YY, hormones known to modulate vagal tone via afferent signaling.
• SASP‑derived proteases cleave the extracellular domain of the vagal receptor GDNFRα1, reducing glial cell line‑derived neurotrophic factor (GDNF) signaling that sustains vagal neuron survival.
• A younger gut epithelium produces higher levels of farnesoid X receptor (FXR) agonists from bile acids, which induce intestinal alkaline phosphatase that detoxifies LPS, thereby lowering systemic endotoxin load and neuroinflammation.

Testable Predictions

1. Oral delivery of a gut‑restricted senolytic (e.g., navitoclax‑loaded pH‑sensitive nanoparticles) will reduce p16^INK4a^+ cells in the intestinal crypts and myenteric plexus by >50% after two weeks, without significant depletion in liver or brain.
2. Treated aged mice will show elevated vagal afferent firing (measured by in vivo electrophysiology of the cervical vagus) and increased hippocampal LTP compared with vehicle controls.
3. Metabolomic profiling of feces and serum will reveal decreased 3‑HOA, PAa, and LPS, alongside increased butyrate and indole‑3‑propionic acid.
4. Microbiome 16S sequencing will show a reduction in pathobiont families (e.g., Porphyromonadaceae) and an expansion of butyrate‑producing taxa (e.g., Lachnospiraceae).
5. Behavioral assays (novel object recognition, Morris water maze) will demonstrate rescued spatial and working memory, correlating with vagal firing strength.
6. Longitudinal survival analysis will indicate a median lifespan extension of ~15% relative to aged controls, surpassing the effect of systemic senolytics administered at equivalent doses.

Experimental Design

• Use p16‑3MR mice aged 20 months to enable senescent cell tracking via luciferase.
• Administer oral navitoclax nanoparticles (200 nm, Eudragit L100‑coated) three times weekly for four weeks; control groups receive empty nanoparticles or systemic navitoclax via intraperitoneal injection.
• Validate gut‑specific senolysis by bioluminescence imaging and immunofluorescence for p16^INK4a^ and SA‑β‑gal in intestinal sections.
• Record vagal afferent activity using cuff electrodes during intestinal perfusion with nutrient solution.
• Perform hippocampal slice electrophysiology, fecal metabolomics (GC‑MS), serum cytokine ELISA, and 16S rRNA sequencing.
• Conduct cognitive testing blind to treatment; monitor survival until natural endpoint.

If gut‑targeted senolysis normalizes vagal signaling, reduces neurotoxic metabolites, and improves cognition and longevity, it would validate a bottom‑up longevity strategy that prioritizes intestinal health as the primary driver of brain aging.