From Fasting to Caloric Restriction: State of the Art and Clinical Implications

Fasting and caloric restriction (CR) are central to current nutritional and metabolic research, although the complexity of physiological responses and their clinical applicability have yet to be fully elucidated. This review provides a state-of-the-art overview of fasting-based and CR-based interventions, including prolonged fasting, alternate-day fasting, semi-fasting, fasting-mimicking diets, and time-restricted feeding, with particular emphasis on their role in metabolic health. Mechanistically, these nutritional strategies modulate ketogenesis, autophagy, mitochondrial function, circadian biology, and nutrient-sensing pathways, including AMPK, mTOR, IGF-1, sirtuins, GCN2, and FGF21, thereby shifting cellular programs from growth and substrate storage toward stress resistance, repair, and metabolic flexibility. Current evidence supports beneficial effects of these nutritional interventions on body weight, adiposity, insulin sensitivity, inflammatory tone, and selected cardiometabolic risk factors. Evidence regarding neuroprotection, cancer prevention, and lifespan extension largely comes from preclinical studies, and the responses in humans are still unclear. This review also highlights the relevance of meal timing, refeeding, protein intake, and interindividual variability in shaping physiological responses and clinical outcomes. Overall, fasting and CR should not be viewed as a rigid protocol but as a personalized nutritional framework whose efficacy and safety depend on timing, duration, and patient context.