Hypothesis

Enteric nervous system (ENS)‑derived SASP factors actively suppress autophagy in peripheral tissues by driving HDAC‑mediated hyperacetylation of autophagy gene promoters, creating a systemic aging loop.

Mechanistic rationale

1. Senescent ENS neurons accumulate with age and secrete IL‑8, CXCL1, and other SASP components (see [3]). These cytokines can travel via the vagus nerve or circulation to reach liver, muscle, and brain.
2. SASP signaling activates NF‑κB and downstream HDACs in target cells. HDAC activity removes acetyl groups from histones, but paradoxically, HDAC inhibition (e.g., by butyrate) leads to hyperacetylation that represses Atg transcription ([4]). We propose that chronic SASP exposure shifts the balance toward HDAC over‑activity at specific promoters, causing hyperacetylation of repressive histone marks that silence Atg5 and LC3B.
3. Epigenetic silencing is reversible: treating aged mice with EGCG or vagotomy reduces SASP influx and restores autophagy ([2]), indicating the block is not due to lost machinery.
4. Feedback loop: suppressed autophagy in peripheral tissues amplifies cellular senescence, which further fuels ENS SASP secretion, tightening the circuit.

Testable predictions

• Prediction 1: Aged mice show elevated acetyl‑H3K9 at Atg5 and LC3B promoters in liver and muscle, correlating with plasma IL‑8/CXCL1 levels.
• Prediction 2: Chemical vagotomy or genetic ablation of serotonergic ENS neurons reduces hepatic Atg promoter acetylation and rescues autophagic flux in old mice.
• Prediction 3: Administering a HDAC‑selective inhibitor that prevents promoter hyperacetylation (e.g., MS‑275) blocks SASP‑induced autophagy suppression without affecting global acetylation.
• Prediction 4: Transplanting young ENS‑derived microglia‑like cells into aged mice lowers circulating SASP and delays age‑related autophagy decline.

Experimental outline

• Measure promoter acetylation by ChIP‑qPCR for H3K9ac in liver of 24‑mo mice ± vagotomy.
• Quantify plasma IL‑8/CXCL1 by ELISA; correlate with LC3‑II turnover after bafilomycin A1 treatment.
• Treat aged mice with MS‑275 (HDAC inhibitor) and assess p62 accumulation and mito‑GFP clearance.
• Perform fecal microbiota transplant to control for butyrate‑mediated HDAC inhibition, ensuring observed effects are SASP‑driven.

If any prediction fails—e.g., vagotomy does not alter promoter acetylation or autophagy—the hypothesis would be falsified, supporting alternative models of passive autophagy decline.

This framework links neuronal senescence, epigenetic regulation, and organ‑wide autophagy control, offering a precise entry point for interventions that break the ENS‑SASP axis.