Studying methionine flux and its role in aging and neurodegeneration

摘要： 衰老是包括阿尔茨海默病在内的各种人类病理学的风险因素，并且衰老和 阿尔茨海默病的特征是广泛的代谢变化。几项研究表明， 代谢途径的数目，其中途径的扰动可以延长苍蝇和其他动物的寿命。 有机体类似地，阿尔茨海默病的特征在于广泛的代谢重编程。使用 针对不同年龄的果蝇成年人的高通量代谢物谱分析，我们 表明蛋氨酸代谢在衰老过程中发生变化。特别是，我们发现其中一个 甲硫氨酸下游代谢物SAH随着年龄增长而积累， 积累可以延长寿命和健康。本申请中提出的实验旨在解决 蛋氨酸通量如何在整个生物体水平和不同的细胞中重新编程的基本问题， 器官以及蛋氨酸通量的器官特异性激活/抑制是否可以延长寿命并抑制 不同的与年龄相关的病理表现，包括与阿尔茨海默病相关的表现。在 此外，受损的甲硫氨酸通量和延迟的SAH处理可能对细胞凋亡有强烈的影响。 通过抑制广谱的甲基转移酶来改善生理学。我将用转基因果蝇 与阿尔茨海默病相关的模型来分析人Tau的过表达如何影响甲硫氨酸通量。我 将测试甲硫氨酸限制和甲基转移酶对 在对照果蝇和与阿尔茨海默病相关的转基因果蝇模型中的神经变性。我也会用一个 甲硫氨酸限制的遗传模型，这将使我能够测试甲硫氨酸的组织特异性效应 限制，并检查标记的蛋氨酸在下游代谢途径中的分布如何 在与阿尔茨海默病相关的果蝇模型中，我们的研究将提供关于如何 与受损的甲硫氨酸代谢相关的年龄依赖性缺陷的恢复可应用于寿命 延伸和潜在的治疗阿尔茨海默病。

Abstract: Aging is a risk factor for various human pathologies including Alzheimer’s disease, and both aging and Alzheimer’s disease are characterized by extensive metabolic changes. Several studies have revealed a number of metabolic pathways for which perturbation of the pathway can extend lifespan in flies and other organisms. Similarly, Alzheimer’s disease is characterized by extensive metabolic reprogramming. Using targeted high-throughput metabolite profiling in Drosophila melanogaster adults of different ages, we demonstrated that methionine metabolism changes during aging. Particularly, we showed that one of the methionine downstream metabolites, SAH, accumulates with age and further, that inhibition of SAH accumulation extends life- and healthspan. The experiments proposed in this application aim to address the fundamental questions of how methionine flux is reprogrammed at the whole-organism level and in different organs and whether organ-specific activation/suppression of methionine flux can extend lifespan and suppress different age-related pathological manifestations, including ones associated with Alzheimer’s disease. In addition, impaired methionine flux and delayed SAH processing may have a strong effect on cellular physiology via inhibition of a broad spectrum of methyltransferases. I will be using transgenic Drosophila models relevant to Alzheimer’s disease to analyze how overexpression of human Tau affects methionine flux. I will be testing the effects of methionine restriction and methyltransferases on pathological signs of neurodegeneration in control flies and transgenic fly models relevant to Alzheimer’s disease. I will also use a genetic model of methionine restriction, which will allow me to test the tissue-specific effects of methionine restriction and examine how the distribution of labeled methionine in downstream metabolic pathways is changed with age and in fly models relevant to Alzheimer’s disease. Our studies will provide insights into how restoring of age-dependent defects related to impaired methionine metabolism can be applied to lifespan extension and to the potential treatment of Alzheimer’s disease.