Rapamycin Alters the Feeding Preference for Amino Acids and Sugar in Female <i>Drosophila</i>

Rapamycin has demonstrated significant lifespan-extending effects across a variety of model organisms, positioning it as one of the most promising antiaging agents currently under investigation. Nonetheless, chronic administration of rapamycin may induce diverse adverse reactions, primarily due to its influence on energy metabolism. Here, using Drosophila melanogaster as a model, we show that rapamycin significantly alters feeding behaviors in a dose-dependent manner. Specifically, both long-term and short-term administration of the optimal life-extending dose of rapamycin decreases the protein preference while increasing sugar intake in female flies. Utilizing a chemically defined diet, we identified that these alterations in amino acid and sugar feeding preferences occur as early as the second day of rapamycin exposure, preceding any detectable decline in fecundity. Furthermore, rapamycin also modifies amino acid preference even in taste-blind females, indicating that postingestive nutritional learning mechanisms, independent of food taste value, are sufficient to mediate the effects of rapamycin on feeding behavior. However, such changes in macronutrient preferences were absent in males and sterile mutant females. Collectively, our study suggests that the modification of feeding behavior could be a non-negligible side effect of rapamycin treatment, and this effect is influenced by both sex and reproductive status.