Rapamycin extends lifespan by mimicking scarcity signals, but this metabolic stress impairs microglial functions needed to clear complement-tagged synapses. We hypothesize that mTORC1 inhibition shifts microglial metabolism from oxidative phosphorylation to aerobic glycolysis, lowering lysosomal V‑ATPase activity and reducing acidification. This metabolic re‑programming preserves autophagic flux (consistent with lifespan extension) yet hinders the degradation of opsonized synapses, causing accumulation of C3b/iC3b fragments that act as damage‑associated molecular patterns. Persistent C3 fragments engage microglial CR3 and TLR4, driving chronic NLRP3 inflammasome activation and synaptic loss despite intact autophagy. Consequently, rapamycin‑treated aged brains show increased median lifespan but accelerated cognitive decline due to unresolved complement‑mediated synapse elimination.

Key predictions: (1) In aged APP/PS1 mice, rapamycin will increase lysosomal pH in microglia measured by LysoSensor staining, without altering LC3‑II turnover. (2) This pH rise will correlate with higher synaptic C3b immunoreactivity and reduced synaptophysin density in hippocampus and cortex. (3) Pharmacological re‑acidification of microglia (using the lysosomotropic agent cyclizine or TFEB activator trehalose) will rescue synaptic density and improve memory performance in rapamycin‑treated mice, without affecting systemic longevity markers. (4) Genetic deletion of C3aR in microglia will block the neurodegenerative effect of rapamycin, confirming that accumulated complement fragments drive pathology.

Test design: Cohorts of 18‑month‑old APP/PS1 mice receive rapamycin (14 ppm chow) alone, rapamycin + cyclizine (5 mg/kg i.p. three times weekly), rapamycin + trehalose (2 % drinking water), or vehicle. After 3 months, we assess lysosomal pH (LysoSensor Blue/Red ratio), microglial glycolysis (Seahorse ECAR), autophagic flux (LC3‑II/p62 with bafilomycin A1), synaptic C3b load (immunofluorescence), synapse number (synaptophysin/PSD‑95 puncta), hippocampal‑dependent cognition (Morris water maze), and survival. We predict that rapamycin alone elevates lysosomal pH and C3b load while preserving LC3‑II flux; adding cyclizine or trehalose normalizes pH, reduces C3b, restores synapses, and improves memory, whereas survival curves remain unchanged across treatments.

Falsification: If rapamycin does not alter microglial lysosomal pH or if lysosomal re‑acidification fails to rescue synaptic loss despite reduced C3b, the hypothesis is invalid. Likewise, if C3aR deletion does not mitigate rapamycin‑induced cognitive decline, the link between accumulated complement fragments and neurodegeneration is unsupported. This framework directly tests whether the longevity‑promoting, scarcity‑mimicking action of mTOR inhibition inadvertently sabotages a critical microglial clearance pathway, revealing a mechanistic trade‑off between systemic healthspan and brain resilience.