Tatar Marc, Zheng Wenjing, Yadav Shweta, Yamamoto Rochele, Curtis-Joseph Noelle, Li Shengxi, Wang Lin, Parkhitko Andrey A
Department of Ecology, Evolution and Organismal Biology, The Center for the Biology of Aging, Brown University, Providence, Rhode Island, United States of America.
Aging Institute of UPMC and the University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
PLoS Genet. 2025 Jun 16;21(6):e1011640. doi: 10.1371/journal.pgen.1011640. eCollection 2025 Jun.
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 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.
胰岛素/胰岛素样生长因子信号传导是一条保守的信号通路，可调节多种物种的寿命。关于这种改变的信号传导如何延缓衰老，人们提出了多种机制。为了阐明这些原因，我们最近开发了一系列果蝇胰岛素样受体（dInr）突变体，这些突变体具有单个氨基酸替换，可延长寿命，但对胰岛素敏感性、生长和繁殖有不同影响。典型dInr突变体（I型）的反式杂合子可延长寿命，且具有胰岛素抵抗、体型小和繁殖力弱的特点。相比之下，激酶插入结构域（KID）内的一个显性突变（dInr353，II型）能显著延长寿命，但具有胰岛素敏感性、体型正常且繁殖力高。我们应用转录组和代谢组分析来探究dInr353如何在无胰岛素抵抗的情况下延缓衰老。I型和II型突变体在许多信号通路中存在重叠，但也产生了不同的转录组图谱，包括先天免疫和生殖功能方面的差异。在代谢组分析中，与以转硫途径上调为特征的典型突变体相比，KID突变体dInr353以一种模拟饮食中蛋氨酸限制的方式对蛋氨酸代谢进行重编程。由于敲除S-腺苷同型半胱氨酸水解酶会阻断dInr353带来的寿命延长益处，我们得出结论，II型的蛋氨酸循环重编程足以延缓衰老。代谢组分析进一步揭示，II型突变体具有代谢灵活性：与衰老的野生型不同，衰老的dInr353成虫可将蛋氨酸重新导向转硫途径，而I型突变果蝇从幼年起就持续上调转硫途径。改变的胰岛素/胰岛素样生长因子信号传导有可能通过调节蛋氨酸循环动力学来延缓衰老，而不会产生胰岛素抵抗的并发症。
