Increasing autophagy with fasting and diet: separating fact from fiction

Autophagy is the cell's recycling system; it removes unwanted or dysfunctional cellular material, thereby preventing damage. Importantly, it is a key pro-survival pathway during periods of stress, for instance, during nutrient scarcity. As it can support nutrition during starvation, it is not surprising that autophagy is controlled by nutrient availability. As a result, diet-based strategies to modify autophagy have attracted considerable scientific and public interest, although what is presented to the public is often not supported by a solid scientific foundation. Evidence from animal models is compelling: several of these interventions robustly activate autophagy and are linked to improved lifespan and healthspan. Data from humans, however, are much more limited. Many human studies rely on measurement of steady-state levels of autophagy genes or proteins, metrics that do not independently establish pathway activity. Far fewer have measured autophagic 'flux', the more rigorous readout of turnover, and where they have, findings are often negative or inconclusive. Here, we review the human research on popular nutritional interventions purported to change autophagy-including prolonged fasting, intermittent fasting, calorie restriction, and altered macronutrient intake-and contrast these findings with the preclinical evidence that has shaped public expectations. We highlight key gaps in the literature, particularly the scarcity of flux-based measurements and the reliance on blood as a proxy for autophagy in other, less accessible tissues. Refining how we monitor autophagy in humans should be a key priority for the field and is ultimately needed to establish whether and how diet modulates human autophagy.