Hypothesis

Chronic JNK/AP-1 signaling in aging neurons does not merely flag inefficient cells via CD47 loss; it also rewires microglial metabolism to preferentially engulf neurons exhibiting low lactate export, linking neuronal bioenergetic failure to phagocytic recognition.

Mechanistic steps

1. Persistent mitochondrial ROS activates JNK, sustaining c-Jun/ATF2‑driven AP-1 transcription{4}{7}.
2. AP-1 shifts from survival genes to repressors of SLC16A1 (MCT1/4) and CD47, diminishing lactate secretion and the “don’t eat me” signal{1 5}.
3. Falling extracellular lactate reduces microglial NF‑κB inhibition, shifting microglia toward a pro‑phagocytic state amplified by JNK‑derived ROS from glia{3}{6}.
4. Microglia engulf neurons that fail to meet both metabolic (low lactate) and immune (low CD47) thresholds, producing an AND‑gate pruning signal.

Predictions

• In aged mouse cortex, neurons with low lactate reporter fluorescence will show higher CD47 loss and increased microglia proximity compared to high‑ lactate neighbors.
• Pharmacologic JNK inhibition will restore MCT1/4 expression, raise lactate efflux, and rescue CD47 levels without altering global apoptosis rates.
• Conditional knockout of microglial JNK will blunt the lactate‑sensing shift, preserving synapses despite neuronal CD47 down.

Falsifiability If lactate supplementation fails to reduce pruning of CD47‑low neurons, or if JNK blockade does not modify MCT1/4 transcription, the model is refuted.

Broader implication This links the energy‑budget hypothesis of neuronal eviction to a concrete immunometabolic checkpoint, suggesting that age‑related cognitive decline may be mitigated by supporting neuronal lactate export rather than globally inhibiting pruning.