Hypothesis

Retinal complement overactivation, particularly locally generated C3a, is secreted into the circulation and reaches the intestine where it alters epithelial barrier function and microbiota composition, thereby driving gut dysbiosis that amplifies systemic inflammation. This reverses the canonical gut‑to‑retina direction and predicts that inhibiting retinal C3a production will rescue gut homeostasis in aged mice.

Mechanistic rationale

• Aged RPE and stressed photoreceptors increase intracellular mitochondrial ROS, triggering the alternative complement pathway and upregulating C3 transcription (7).
• Secreted C3a diffuses across Bruch's membrane into the choroidal vasculature and enters systemic circulation (2).
• Intestinal endothelial and epithelial cells express C3aR; C3a binding elevates intracellular Ca2+ and activates NF‑κB, tightening junctional proteins and increasing permeability (4).
• Barrier leakage allows luminal LPS to reach the lamina propria, shaping a pro‑inflammatory milieu that favors expansion of Proteobacteria and depletion of mucin‑degrading symbionts (6).
• The resulting gut dysbiosis feeds back systemic IL‑6 and TNF‑α, which further amplify retinal complement activation, creating a vicious loop.

Testable predictions

1. Detection – ELISA of plasma from aged wild‑type mice will show elevated C3a levels compared with young controls; C3a will be absent in RPE‑specific C3 knockout mice.
2. Causality – Pharmacologic blockade of C3aR in the gut (using SB 290157) will normalize fecal microbiota composition and reduce intestinal permeability in aged mice, despite retinal complement activation.
3. Rescue – RPE‑targeted CRISPRi of C3 will lower plasma C3a, improve gut barrier function (FITC‑dextran assay), and increase abundance of Akkermansia muciniphila without direct gut manipulation.
4. Directionality – Transfer of feces from aged wild‑type mice to young germ‑recipients will not reproduce retinal C3 deposition unless the donors also have elevated retinal C3a, indicating gut changes are downstream.

Falsifiability

If plasma C3a does not correlate with retinal C3 deposition, or gut C3aR blockade fails to alter microbiota despite confirmed target engagement, the hypothesis is refuted. Likewise, if gut‑specific C3aR deficiency does not ameliorate age‑related gut leakiness while retinal complement remains high, the upstream retinal claim loses support.

Implications

A bottom‑up longevity stack would prioritize retinal‑targeted complement inhibitors (e.g., gene‑silenced C3, small‑factor H mimetics) as primary agents, with gut‑modulating probiotics or prebiotics serving as secondary adjuncts to break the feedback loop. This reframes the gut‑brain axis as a gut‑retina‑brain axis where ocular health sets the tone for intestinal homeostasis.