Mutation of an insulin-sensitive Drosophila insulin-like receptor mutant requires methionine metabolism reprogramming to extend lifespan

Insulin/insulin growth factor signaling is a conserved pathway that regulates lifespan across many species. Multiple mechanisms are proposed for how this altered signaling slows aging. To elaborate these causes, we recently developed a series of Drosophila insulin-like receptor (dInr) mutants with single amino acid substitutions that extend lifespan but differentially affect insulin sensitivity, growth and reproduction. Transheterozygotes of canonical dInr mutants (Type I) extend longevity and are insulin-resistant, small and weakly fecund. In contrast, a dominant mutation (dInr353, Type II) within the Kinase Insert Domain (KID) robustly extends longevity but is insulin-sensitive, full-sized, and highly fecund. We applied transcriptome and metabolome analyses to explore how dInr353 slows aging without insulin resistance. Type I and II mutants overlap in many pathways but also produce distinct transcriptomic profiles that include differences in innate immune and reproductive functions. In metabolomic analyses, the KID mutant dInr353 reprograms methionine metabolism in a way that phenocopies dietary methionine restriction, in contrast to canonical mutants which are characterized by upregulation of the transsulfuration pathway. Because abrogation of S-adenosylhomocysteine hydrolase blocks the longevity benefit conferred by dInr353, we conclude the methionine cycle reprogramming of Type II is sufficient to slow aging. Metabolomic analysis further revealed the Type II mutant is metabolically flexible: unlike aged wildtype, aged dInr353 adults can reroute methionine toward the transsulfuration pathway, while Type I mutant flies upregulate the trassulfuration pathway continuously from young age. Altered insulin/insulin growth factor signaling has the potential to slow aging without the complications of insulin resistance by modulating methionine cycle dynamics. Author SummaryMutations in the invertebrate insulin/IGF signaling system robustly extend lifespan. Yet these interventions often cause insulin resistance, reduce growth, and impair fertility. In contrast, a dominant gain-of-function mutation in the kinase insert domain of the Drosophila insulin/IGF receptor extends lifespan while maintaining insulin sensitivity, growth, or reproduction. Here, we demonstrate this unique mutation reprograms methionine metabolism pathway in a way that mirrors dietary methionine restriction, which is known to extend lifespan in several animals including Drosophila and mice. Genetic epistasis analysis verifies this methionine cycle inhibition is an underlying cause for how the kinase insert domain mutation slows Drosophila aging while maintaining insulin-sensitivity, growth, and fecundity.