Caloric restriction mimetics represent a promising class of interventions targeting metabolic aging in neurodegeneration. The combination of Metformin, Resveratrol, and Rapamycin targets complementary nodes: AMPK activation, SIRT1 deacetylase activity, and mTORC1 inhibition. Key challenge: whether synergy between these compounds exceeds individual efficacy, and whether the combined regimen is tolerable in aging organisms. Falsifiable prediction: the triple combination should extend healthspan by ≥20% and reduce phospho-tau burden by ≥30% versus any single agent in 18-month-old 3xTg-AD mice.