Methionine Cycle as a Mechanistic Hub for the Hallmarks of Aging

蛋氨酸循环作为衰老标志的机制中心

• 批准号: 10722723
• 负责人: Andrey A Parkhitko
• 金额: $ 44.85万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722723
• 关键词: Affect; Age; Aging; Consensus; Diet; Drosophila genus; Epigenetic Process; Female; Genome Stability; Genotype; Germ Lines; Geroscience; Heterochromatin; Insulin; Insulin Receptor; Insulin Resistance; Insulin-Like Growth Factor Receptor; Intervention; Intestines; Isotope Labeling; Longevity; Measures; Mediating; Methionine; Methionine Metabolism Pathway; Mitochondria; Muscle; Mutation; Nutrient; Pathway interactions; Phosphotransferases; Polyamines; Process; Production; Proliferating; RNA; Regulation; Resistance; Stress; Testing; Time; Tissues; Transgenes; age related; detection of nutrient; epigenome; fly; genetic manipulation; healthspan; histone methylation; insight; insulin sensitivity; insulin signaling; male; metabolomics; mortality; muscle aging; mutant; novel; pathogen; proteostasis; response; stem cell proliferation; stem cells; stress resilience

Summary (NIH) Age-dependent changes in Drosophila represent the key Hallmarks of Aging. While the progression of these Hallmarks is delayed by intervention within the nutrient sensing axis, there is no consensus for how nutrient sensing mechanistically coordinates Hallmarks or how retarded Hallmarks coordinate to regulate lifespan. We will address this issue with new genotypes of the Drosophila insulin/IGF receptor (dInr) that differentially affect nutrient sensing where each extends lifespan. Canonical long-lived dInr mutants are insulin-resistant. Remarkably, a new dInr mutation within the kinase insert domain (KID) strongly increases lifespan but retains insulin sensitivity. We conducted RNA, metabolomic and methionine-isotope labeling analyses to gain insight on how nutrient sensing regulates aging hallmarks. We found insulin-resistant dInr increases cellular methionine cycle flux, whereas insulin-sensitive dInr decreases this flux. Notably, the methionine cycle is a control hub for epigenetics, proteostasis, stress resistance, and stem cell regulation – underlying processes of aging hallmarks. We therefore hypothesize the methionine cycle provides a central mechanism to control multiple Hallmarks of Aging in response to nutrient sensing. This proposal will establish how nutrient regulation of the methionine cycle integrates Hallmarks of Aging.

摘要（美国国立卫生研究院） 果蝇的年龄依赖性变化代表了衰老的关键标志。 标志因营养感应轴内的干预而延迟，对于营养如何影响尚无共识 感知机械地协调标志或迟缓的标志如何协调以调节寿命。 将通过果蝇胰岛素/IGF受体（dInr）的新基因型来解决这个问题，该基因型对果蝇胰岛素/IGF受体（dInr）有不同的影响 营养感应可以延长寿命，典型的长寿命 dInr 突变体具有胰岛素抵抗性。 值得注意的是，激酶插入结构域 (KID) 内的新 dInr 突变极大地延长了寿命，但保留了 我们进行了 RNA、代谢组学和蛋氨酸同位素标记分析以获得见解。 我们发现胰岛素抵抗的 dInr 会增加细胞蛋氨酸的含量。 循环通量，而胰岛素敏感的 dInr 会降低这种通量。值得注意的是，蛋氨酸循环是循环通量的控制中心。 表观遗传学、蛋白质稳态、应激抵抗和干细胞调节——衰老标志的潜在过程。 因此，我们接受了蛋氨酸循环，它提供了一个控制多个标志的中央机制。 营养感应引起的衰老该提案将确定蛋氨酸循环的营养调节方式。 整合衰老标志。