The ups and downs of caloric restriction and fasting: from molecular effects to clinical application

Age‐associated diseases are rising to pandemic proportions, exposing the need for efficient and low‐cost methods to tackle these maladies at symptomatic, behavioral, metabolic, and physiological levels. While nutrition and health are closely intertwined, our limited understanding of how diet precisely influences disease often precludes the medical use of specific dietary interventions. Caloric restriction (CR) has approached clinical application as a powerful, yet simple, dietary modulation that extends both life‐ and healthspan in model organisms and ameliorates various diseases. However, due to psychological and social‐behavioral limitations, CR may be challenging to implement into real life. Thus, CR‐mimicking interventions have been developed, including intermittent fasting, time‐restricted eating, and macronutrient modulation. Nonetheless, possible side effects of CR and alternatives thereof must be carefully considered. We summarize key concepts and differences in these dietary interventions in humans, discuss their molecular effects, and shed light on advantages and disadvantages. Graphical Abstract Can dietary modulations promote better health? The current article comprehensively reviews key concepts of dietary interventions, their clinical application and the beneficial and disadvantageous effects of caloric restriction and fasting on human health.