Hypothesis

Gut‑derived indole‑3‑propionic acid (IPA) accumulates with age and directly amplifies mTORC1 activity in senescent cells, thereby locking autophagy in a suppressed state.

Mechanistic Model

• IPA uptake: Aged epithelium shows increased expression of the aromatic amino acid transporter SLC7A5, raising intracellular IPA levels【https://doi.org/10.1126/sciadv.adw8410】.
• mTORC1 activation: IPA binds to the lysosomal sensor SLC38A9, promoting Rag GTPase loading and lysosomal mTORC1 recruitment, a step that is known to drive the TOR‑Autophagy Spatial Coupling Compartment (TASCC)【https://doi.org/10.1083/jcb.201610113】.
• LAMP2A destabilization: Sustained mTORC1 signaling phosphorylates LAMP2A on serine‑14, accelerating its proteasomal turnover and dropping its half‑life from ~38 h to ~26 h, matching the observed decline in senescent cells【https://pmc.ncbi.nlm.nih.gov/articles/PMC9835585】.
• Feedback loop: Reduced autophagic flux diminishes clearance of damaged mitochondria, increasing mtDNA release and cGAS‑STING activation, which further sustains NF‑κB‑driven SASP and reinforces the senescent phenotype.

Testable Predictions

1. Correlation: Serum IPA concentrations will positively correlate with tissue‑specific p‑S6K (mTORC1 read‑out) and inversely with LC3‑II/I ratio in aged mice and humans.
2. Loss‑of‑function: Genetic knockout of SLC7A5 in intestinal epithelial cells of aged mice will lower hepatic IPA, reduce p‑S6K, increase LAMP2A stability, and restore autophagic flux compared with wild‑type controls.
3. Pharmacologic blockade: Treating senescent human fibroblasts with the mTORC1 inhibitor rapamycin or with a SLC38A9 antagonist will abolish the IPA‑induced increase in p‑S6K and rescue LAMP2A half‑life without altering IPA levels.
4. Rescue experiment: Supplementing young mice with IPA‑producing bacteria (e.g., Clostridium sporogenes) will recapitulate age‑related autophagy suppression, evidenced by increased p‑S6K, decreased LAMP2A, and elevated SASP cytokines.
5. Human relevance: In a cross‑sectional cohort, individuals with high fecal IPA will show higher circulating SASP markers (IL‑6, IL‑8) and lower autophagic activity in peripheral blood monocytes after ex vivo starvation.

Falsifiability

It's unlikely that IPA levels alone drive the phenotype, but if manipulation of IPA fails to change mTORC1 signaling or LAMP2A stability in aged tissues, the hypothesis that gut‑derived IPA actively sustains autophagy suppression would be refuted, pointing to alternative microbial mediators.