An insulin-sensitive Drosophila insulin-like receptor mutant remodels methionine metabolism to extend lifespan

作者：Marc Tatar, Wenjing Zheng, Shweta Yadav, Rochele Yamamoto, Noelle Curtis-Joseph, Shengxi Li, Lin Wang, Andrey A. Parkhitko · 发表于：PLoS Genetics · 年份：2025 · DOI：10.1371/journal.pgen.1011640 · 被引用次数：4 · 研究领域：Genetics, Aging, and Longevity in Model Organisms、Invertebrate Immune Response Mechanisms、Insect Utilization and Effects

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 me...