Aging is a complex phenomenon caused by the time-dependent loss of cellular homeodynamics and consequently of physiological organismal functions. This process is affected by both genetic and environmental (e.g., diet) factors, as well as by their constant interaction. Consistently, deregulation of nutrient sensing and signaling pathways is considered a hallmark of aging. Nutrigenomics is an emerging scientific discipline that studies changes induced by diet on the genome and thus it considers the intersection of three topics, namely health, diet, and genomics. Model organisms, such as the fruit fly Drosophila melanogaster, have been successfully used for in vivo modeling of higher metazoans aging and for nutrigenomic studies. Drosophila is a well-studied organism with sophisticated genetics and a fully annotated sequenced genome, in which ~ 75% of human disease-related genes have functional orthologs. Also, flies have organs/tissues that perform the equivalent functions of most mammalian organs, while discrete clusters of cells maintain insect carbohydrate homeostasis in a way similar to pancreatic cells. Herein, we discuss the mechanistic connections between nutrition and aging in Drosophila, and how this model organism can be used to study the effect of different diets (including natural products and/or their derivatives) on higher metazoans longevity.