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疾病的风险因素，而衰老和 阿尔茨海默病的特点是广泛的代谢变化。几项研究表明， 代谢途径的数量，该途径的扰动可以延长果蝇和其他动物的寿命 有机体。同样，阿尔茨海默病的特点是广泛的代谢重新编程。vbl.使用 在不同年龄的果蝇成虫中，我们有针对性地进行高通量代谢物分析 说明蛋氨酸代谢在衰老过程中发生了变化。特别是，我们展示了其中一个 蛋氨酸下游代谢物SAH随着年龄的增长而积累，进而抑制SAH 积累可以延长人的寿命和健康。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生物水平上重新编程的基本问题 器官以及器官特异性激活/抑制蛋氨酸通量是否可以延长寿命和抑制 与年龄相关的不同病理表现，包括与阿尔茨海默病有关的表现。在……里面 此外，蛋氨酸通量受损和延迟的SAH处理可能对细胞 通过抑制广泛的甲基转移酶而产生的生理学作用。我将使用转基因果蝇 与阿尔茨海默病相关的模型，以分析人类Tau的过度表达如何影响蛋氨酸流量。我 将测试蛋氨酸限制和甲基转移酶对猪瘟病理征象的影响 与阿尔茨海默病相关的对照果蝇和转基因果蝇模型中的神经变性。我还将使用 蛋氨酸限制的遗传模型，这将使我能够测试蛋氨酸的组织特异性效应 限制并检查标记蛋氨酸在下游代谢途径中的分布情况 在与阿尔茨海默病相关的苍蝇模型中，随着年龄的变化而变化。我们的研究将为我们提供关于 与蛋氨酸代谢受损相关的年龄相关性缺陷的修复可以应用于寿命 扩展和阿尔茨海默病的潜在治疗。

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.