Methionine Cycle as a Mechanistic Hub for the Hallmarks of Aging

摘要（NIH） 果蝇中的依赖性变化代表了衰老的关键标志。虽然这些进展 营养感应轴内的干预延迟了标志物的出现，但营养感应轴内的营养物质如何影响标志物的出现并没有达成共识。 感知机械地协调标志或如何弱智标志协调调节寿命。我们 将通过果蝇胰岛素/IGF受体（dInr）的新基因型来解决这个问题， 营养感应，每一种都能延长寿命。典型的长寿dInr突变体是胰岛素抵抗的。 值得注意的是，激酶插入结构域（KID）中的一个新的dInr突变强烈地增加了寿命，但保留了 胰岛素敏感性我们进行了RNA、代谢组学和蛋氨酸同位素标记分析， 关于营养感应如何调节衰老的标志。我们发现胰岛素抵抗dInr增加细胞蛋氨酸 循环通量，而胰岛素敏感的dInr降低该通量。值得注意的是，蛋氨酸循环是一个控制枢纽， 表观遗传学、蛋白质稳态、抗应激和干细胞调节--衰老标志的潜在过程。 因此，我们假设甲硫氨酸循环提供了一个中心机制，以控制多种标志， 老化对营养感知的反应。这项建议将建立如何营养调控蛋氨酸循环 整合了衰老的标志

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.