Moderate nutritional stress reprograms insulin responses to drive enhanced starvation tolerance in Drosophila melanogaster

Organisms in the wild constantly encounter fluctuations in temperature and food availability, pathogens, and other stressors that disrupt their physiological balance. To counteract these disruptions, organisms initiate stress responses that vary in nature depending on the intensity and duration of the stressor. While severe stress can be harmful or even fatal, moderate stress can activate adaptive mechanisms, a phenomenon known as hormesis. Hormesis enhances resilience to stress and has been associated with improved aging, immunity, and metabolism. Short-term exposures to mild stress, such as heat or oxidative stress, have been shown to extend Drosophila lifespan and promote cross-tolerance to other stressors. Among various environmental stressors, starvation poses a significant and recurring challenge that has driven the evolution of energy-conserving strategies essential for survival. Prior exposure to starvation has been shown to influence longevity, resilience to starvation, physiological status and stress tolerance. However, the mechanisms underlying these hormetic effects remain poorly understood. In this study, we investigate how short-term starvation enhances resistance to prolonged food deprivation in Drosophila. Our findings reveal that metabolic rewiring, including changes in energy utilization, insulin signaling, and transcriptomic profiles underpins this adaptive plasticity. These insights will improve our understanding of the molecular and metabolic mechanisms driving hormesis, with broader implications for stress resilience and organismal health.