Hypothesis\n\nWe propose that age‑dependent decline of intestinal BCL‑2/Beclin‑1‑regulated autophagy drives a loss of gut‑derived short‑chain fatty acids (SCFAs) that normally activate vagal afferents to stimulate hippocampal autophagy via the α7‑nicotinic acetylcholine receptor (α7‑nAChR)–CaMKKβ‑AMPK pathway. Consequently, restoring intestinal autophagy—either genetically (intestinal‑specific Becn1^F121A knock‑in[2]) or pharmacologically (BCL‑2 antagonist) — should re‑elevate luminal SCFAs, enhance vagal firing, and rescue brain autophagic flux and cognitive performance in aged mice. Conversely, vagotomy or pharmacological blockade of α7‑nAChR will abolish the brain‑autophagy benefits of intestinal autophagy enhancement, proving the neural route is necessary.\n\n## Mechanistic Rationale\n\n1. It's known that intestinal autophagy controls barrier‑derived metabolite release. Autophagy in enterocytes regulates secretion of SCFAs (butyrate, propionate) by modulating microbial composition and epithelial turnover [5]. When BCL‑2/Beclin‑1 inhibition lifts autophagy flux, SCFA output rises.\n2. SCFAs activate vagal afferents. Butyrate stimulates colonic vagal terminals through free fatty acid receptor 2 (FFAR2) and histone deacetylase inhibition, increasing vagal tone to the nucleus tractus solitarius [3].\n3. Vagal signaling triggers hippocampal autophagy. Vagal efferents release acetylcholine onto α7‑nAChR on hippocampal neurons, initiating CaMKKβ‑AMPK activation that phosphorylates ULK1 and initiates autophagy independent of mTOR [4].\n4. **Age‑related decline in intestinal autophagy reduces SCFA vagal drive, diminishing hippocampal autophagy and contributing to inflammaging‑linked cognitive decline.\n\n## Testable Predictions\n\n- Prediction 1: Aged mice with intestine‑specific Becn1^F121A knock‑in[2] will show higher fecal butyrate, increased vagal nerve firing (measured by electrophysiology), elevated hippocampal LC3‑II/I ratio, and improved performance in the Morris water maze compared with aged wild‑type controls.\n- Prediction 2: Subdiaphragmatic vagotomy in the intestine‑specific Becn1^F121A mice[2] will block the rise in hippocampal autophagy and cognitive rescue despite elevated SCFAs.\n- Prediction 3: Pharmacological inhibition of α7‑nAChR (e.g., with methyllycaconitine) will similarly prevent the brain‑autophagy benefits of intestinal autophagy enhancement.\n- Prediction 4: Administering exogenous butyrate to aged wild‑type mice will mimic the vagal‑dependent hippocampal autophagy increase, but this effect will be lost after vagotomy or α7‑nAChR blockade.\n\n## Falsifiability\n\nIf intestinal autophagy enhancement fails to raise SCFAs or vagal activity, or if hippocampal autophagy and cognition improve without vagal integrity, the hypothesis is refuted. Likewise, if vagotomy does not attenuate the brain benefits, a humoral (e.g., cytokine) route would be favored.\n\n## Broader Impact\n\nLinking a defined molecular checkpoint (BCL‑2/Beclin‑1) to the gut‑brain axis provides a concrete, experimentally tractable framework that we'll test whether manipulating microbial‑derived metabolite flux can remotely reset brain autophagy—a potential strategy to mitigate inflammaging‑driven neurodegeneration, building on evidence that systemic BCL‑2/Beclin-1 disruption extends lifespan and healthspan[1].
