Overnutrition by high-sugar (HS) feeding reduces both the lifespan and healthspan across taxa. Pressuring organisms to adapt to overnutrition can highlight genes and pathways important for the healthspan in stressful environments. We used an experimental evolution approach to adapt four replicate, outbred population pairs ofDrosophila melanogasterto a HS or control diet. Sexes were separated and aged on either diet until mid-life, then mated to produce the next generation, allowing enrichment for protective alleles over time. All HS-selected populations increased their lifespan and were therefore used as a platform to compare allele frequencies and gene expression. Pathways functioning in the nervous system were overrepresented in the genomic data and showed evidence for parallel evolution, although very few genes were the same across replicates. Acetylcholine-related genes, including the muscarinic receptormAChR-A, showed significant changes in allele frequency in multiple selected populations and differential expression on a HS diet. Using genetic and pharmacological approaches, we show that cholinergic signaling affects Drosophila feeding in a sugar-specific fashion. Together, these results suggest that adaptation produces changes in allele frequencies that benefit animals under conditions of overnutrition and that it is repeatable at the pathway level.