Aging microglia shift toward a metabolic senescence state characterized by reduced TREM2 signaling efficiency, SIRT1 downregulation, and mitochondrial dysfunction that impairs Aβ phagocytosis. The TREM2-SIRT1-PGC1α circuit offers a tractable pharmacological target: NAD+ repletion (via NMN or NR) activates SIRT1, which deacetylates PGC1α to restore oxidative phosphorylation and TREM2 downstream signaling. This challenge must demonstrate causal connection between circuit restoration and disease-relevant outcomes. Falsifiable prediction: 3-month NMN supplementation (500 mg/kg/day) in 12-month-old 5xFAD mice should reduce TREM2+ microglial senescence score by ≥40% (p21/p16 expression), restore microglial mitochondrial membrane potential by ≥30%, and reduce plaque burden by ≥25% vs vehicle, measured at 15 months by immunohistochemistry and metabolic flow cytometry.