Hypothesis

Age‑related gut dysbiosis elevates circulating phenylacetic acid (PAA), which crosses the blood‑brain barrier and activates microglial GPR35 receptors, driving a senescent‑like microglial state that impairs Aβ phagocytosis and amplifies neuroinflammation.

Mechanistic Rationale

• PAA is produced by phenylalanine‑catabolizing bacteria that expand with age [5].
• PAA induces endothelial senescence via ROS‑DNA damage pathways [5]; we propose it likewise triggers microglial senescence through GPR35‑mediated NF‑κB activation and SASP secretion.
• Senescent microglia exhibit reduced phagocytic capacity and heightened IL‑1β release, creating a feedforward loop that worsens Aβ accumulation and neuronal stress.
• This adds a direct microbial‑metabolite‑to‑microglia axis to the known TLR4/LPS and SCFA depletion pathways.

Testable Predictions

1. In aged mice, pharmacological inhibition of GPR35 (or microglial‑specific Gpr35 knockout) will reduce microglial senescence markers (p16^INK4a, SASP) and improve Aβ clearance despite unchanged PAA levels.
2. Administering a PAA‑degrading enzyme (e.g., phenylacetyl‑CoA ligase inhibitor) or PAA‑binding antibody will lower brain PAA, decrease microglial GPR35 activation, and rescue cognitive performance in aged APP/PS1 mice.
3. Humans with high plasma PAA will show elevated CSF markers of microglial senescence (e.g., sCD163, YKL‑40) and correlate with faster cortical thinning on MRI, independent of LPS or SCFA levels.

Potential Falsification

If GPR35 blockade does not alter microglial senescence or cognition in aged mice, or if PAA reduction fails to lower microglial activation, the hypothesis that PAA‑GPR35 signaling drives microglial senescence would be refuted, suggesting that PAA’s effects are limited to endothelial senescence or act via other cell types.