Methionine Cycle as a Mechanistic Hub for the Hallmarks of Aging

摘要(NIH) 果蝇的年龄依赖性变化代表了衰老的关键特征。虽然这些的进展 特征是由于营养感知轴内的干预而延迟的，对于营养如何 感官能机械地协调特征，或迟钝的特征如何协调来调节寿命。我们 我将通过果蝇胰岛素/胰岛素样生长因子受体(DInr)的新基因类型来解决这个问题，这些基因类型可以不同地影响 营养感应，每一种都能延长寿命。经典的长寿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)中的新dInr突变显著延长了寿命，但保留了 胰岛素敏感性。我们进行了RNA、代谢组和蛋氨酸同位素标记分析以获得洞察力 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会增加细胞内的蛋氨酸 循环流量，而对胰岛素敏感的dInr会降低这一流量。值得注意的是，蛋氨酸循环是 表观遗传学、蛋白平衡、抗逆性和干细胞调节--衰老标志的潜在过程。 因此，我们假设蛋氨酸循环提供了一种中央机制来控制多个标志 对营养感测作出反应的衰老。这项提案将确立蛋氨酸循环的营养调节 融合了老化的特征。

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.