Two years of caloric restriction in healthy adults produced distinct metabolic signatures across 864 circulating compounds, with three major pathway changes emerging from the landmark CALERIE Phase 2 trial. Carbohydrate metabolites including maltosaccharides decreased during the initial weight-loss phase but stabilized in restricted participants while rebounding in controls. Lipid compounds, particularly sphingolipids, showed initial reductions followed by compensatory increases during the weight-maintenance phase. This biphasic metabolic response suggests the body undergoes dynamic remodeling rather than simple linear adaptation to sustained energy restriction. The findings illuminate how caloric restriction—already known to improve biological aging markers—fundamentally rewires human metabolism at the molecular level. The time-dependent nature of these changes may explain why some longevity benefits of caloric restriction take years to manifest. However, this preprint awaits peer review, and the functional significance of these metabolic shifts for long-term health outcomes remains unclear. The study represents confirmatory evidence that caloric restriction triggers profound metabolic adaptations, but falls short of proving these changes directly enhance longevity in humans.