Intermittent and periodic fasting: molecular mechanisms, health benefits and research challenges

Intermittent fasting (IF) and Periodic fasting (PF) are biologically plausible non-pharmacological interventions. They trigger core metabolic reprogramming from glucose catabolism to ketogenesis and activate conserved nutrient-sensing networks including AMPK and sirtuins, coupled with mTOR/IGF-1 axis suppression. Such adaptive regulation enhances cellular repair, antioxidant defense and inflammatory homeostasis, conferring multi-system benefits encompassing metabolic improvement, neuroprotection, anti-tumor activity and healthspan extension. Clinically, time-restricted eating (TRE) and fasting-mimicking diets (FMDs) have demonstrated feasibility and short-term efficacy in pilot clinical studies, although their long-term translational potential and durability of benefits remain unproven. However, current research faces major bottlenecks: over-reliance on homogeneous animal models, insufficient high-quality long-term human trials, unresolved individual response heterogeneity, and the lack of validated non-invasive biomarkers and systematic long-term safety evidence. This mini-review systematically elaborates the core regulatory mechanisms of IF and PF through a hierarchical framework that distinguishes primary drivers from secondary consequences and speculative mechanisms, critically evaluates the evidence base across model systems, analyzes key translational barriers, and proposes a prioritized research agenda. Our objective is to provide a conceptually grounded synthesis that identifies genuine scientific uncertainty, distinguishes established knowledge from speculation, and offers a perspective capable of guiding future investigation toward precise clinical translation.