Mitochondrial ATP Synthase Subunit d Interacts with TOR Signaling and Dietary Macronutrients to Modulate Proteostasis and Lifespan in Drosophila. Drosophila melanogaster

Diet composition is a critical determinant of lifespan and nutrient imbalance is detrimental health. However, how nutrients interact with genetic factors to modulate lifespan remains elusive. We investigated how diet composition influences mitochondrial ATP synthase subunit d (ATPsyn-d) in modulating lifespan in Drosophila. ATPsyn-d knockdown extended lifespan in females fed low carbohydrate-to-protein (C:P) diets, but not the high C:P ratio diet. We also measured changes in the genome-wide expression profile induced by ATPsyn-d knockdown. Lifespan extension induced by ATPsyn-d knockdown was associated with increased resistance to oxidative stress, transcriptional changes in metabolism, proteostasis and immune genes, reduced protein damage and aggregation, and reduced phosphorylation of S6K and ERK in TOR and MAPK signaling, respectively. Our data reveal a link among diet, mitochondria, MAPK and TOR signaling in aging and stresses the importance of considering genetic background and diet composition in implementing interventions for promoting healthy aging. Overall design: Eight experimental samples from the heads of 14-day old actin-GSG>UAS-ATPsyn-d-RNAi females treated with and without RU486 were labeled with Cy3 and analyzed using custom printed long oligo microarrays. Samples from wild type Canton S flies were labeled with Cy5 and used as the common reference for all microarray experiments.