Intermittent Fasting and Functional Redox Coupling; A Convergence of Classical and Emerging Evidence Toward Clinical Implications for Antioxidant Co-Supplementation and Type

Background. Intermittent fasting (IF) produces consistent metabolic benefits across diverse clinical populations. Paradoxically, antioxidant supplementation — widely co-prescribed with IF protocols — has repeatedly failed to replicate or augment these benefits in randomized controlled trials, and has in several instances attenuated them. Objective. This review examines whether the conventional “oxidative stress / hormetic defense” framework adequately explains the molecular mechanisms of IF, and proposes an integrative model — the Functional Redox Coupling (FRC) framework — grounded in three decades of converging evidence from redox biology. Synthesis. Drawing on the foundational work of Sies, Jones, Ristow, Chandel, and Halliwell, we argue that diffusible reactive species (DRS) generated during fasting serve as obligatory coupling agents mitochondrial bioenergetics and metabolic signaling — not merely as stressors to be neutralized. Within this framework, exogenous antioxidant supplementation during fasting windows may interfere with functional redox transduction, thereby blunting the adaptive response. Clinical Implications. We propose evidence-based guidance on antioxidant timing relative to fasting windows, identify molecular classes of particular concern (tocopherols, ascorbic acid, N-acetylcysteine), examine organ-level physiology in liver, pancreas, and brain, compare 16:8 and 5:2 protocols for T2D prevention, and address the structural economic and institutional impediments to translation of IF evidence into clinical practice.