Mechanisms of aging regulation by insulin/IGF ligands in Drosophila

With Marc Tatar Professor of Biology, The Division of Biology and Medicine, Brown University, Providence, Rhode Island, USA

Reduced insulin/IGF signaling slows aging in many organisms, including C. elegans, Drosophila, and perhaps even mammals. Drosophila encodes eight insulin-like peptides (ilp), seven of which function through a single, common insulin-like receptor. Despite this overlap, mutation of ilp2 is uniquely reported to extend lifespan. How does reduction of this one ilp affect aging? To address this problem, we combined phosphoproteomics and genetic analysis. Drosophila insulin-like peptide DILP2, but not DILP5, reduces phosphorylation of glycogen phosphorylase (GlyP) at Ser15 (mammalian Ser14), and this is sufficient to repress enzymatic activity. To determine how phosphorylation affects aging, we genetically manipulated GlyP Ser15 in adult flies. Lifespan was extended by expressing a constitutively active form of GlyP. Inversely, longevity assurance conferred by ilp2 mutation was reduced when we expressed GlyP where Ser15 cannot be phosphorylated. We also noted that ilp1 is dramatically expressed in ilp2 mutants. Yet, ilp1 is not otherwise seen in adults except during reproductive diapause, a slow aging, alternative life history state. To understand the role of ilp1 and its relationship to ilp2, we generated single mutants of ilp1 and ilp2, along with ilp1;ilp2 double mutants. From this design we documented classic epistatic interactions between ilp1 and ilp2 for aging, growth, and Akh (glucagon-like function); that is, reduced ilp2 requires the expression of ilp1 to modulate these traits. We validated these results with ilp1 transgene rescue in ilp1;ilp2 double mutants. While insulin/IGF signaling is classically thought to control aging because reduced activation of the insulin receptor induces keystone transcription factors such as FOXO, here we find that longevity is in part extended by reduction of ilp2 because this induces expression of ilp1, and together this affects glycogen metabolism and simulates diapause.