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Multiple mechanisms are proposed for how this altered signaling slows aging. To elaborate these causes, we recently developed a series of <jats:italic>Drosophila<\/jats:italic> insulin-like receptor (<jats:italic>dInr<\/jats:italic>) mutants with single amino acid substitutions that extend lifespan but differentially affect insulin sensitivity, growth and reproduction. Transheterozygotes of canonical <jats:italic>dInr<\/jats:italic> mutants (Type I) extend longevity and are insulin-resistant, small and weakly fecund. In contrast, a dominant mutation (<jats:italic>dInr<\/jats:italic><jats:sup>353<\/jats:sup>, 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 <jats:italic>dInr<\/jats:italic><jats:sup>353<\/jats:sup> 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 <jats:italic>dInr<\/jats:italic><jats:sup>353<\/jats:sup> 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 <jats:italic>dInr<\/jats:italic><jats:sup>353<\/jats:sup>, 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 <jats:italic>dInr<\/jats:italic><jats:sup>353<\/jats:sup> adults can reroute methionine toward the transsulfuration pathway, while Type I mutant flies upregulate the transsulfuration 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.<\/jats:p>","DOI":"10.1371\/journal.pgen.1011640","type":"journal-article","created":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T17:42:59Z","timestamp":1750095779000},"page":"e1011640","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["An insulin-sensitive Drosophila insulin-like receptor mutant remodels methionine metabolism to extend lifespan"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3232-6884","authenticated-orcid":true,"given":"Marc","family":"Tatar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjing","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9760-3382","authenticated-orcid":true,"given":"Shweta","family":"Yadav","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2983-3061","authenticated-orcid":true,"given":"Rochele","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2183-9238","authenticated-orcid":true,"given":"Noelle","family":"Curtis-Joseph","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengxi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9852-8329","authenticated-orcid":true,"given":"Andrey 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