Studying methionine flux and its role in aging and neurodegeneration

衰老是各种人类疾病的危险因素，包括阿尔茨海默氏症，以及两者的衰老 阿尔茨海默氏症的特点是广泛的代谢变化。几项研究已经 揭示了许多代谢途径，这些途径的扰动可以延长寿命 在苍蝇和其他有机体中。同样，阿尔茨海默病的特点是广泛的代谢 重新编程。靶向高通量代谢产物图谱在果蝇中的应用 不同年龄段的成年人，我们证明蛋氨酸代谢在衰老过程中发生变化。 特别是，我们发现蛋氨酸下游代谢产物之一，SAH，积累 随着年龄的增长和更进一步，抑制SAH积累会延长寿命和健康时间。这个 本申请中提出的实验旨在解决以下基本问题： 蛋氨酸通量在整个生物体水平和不同器官中重新编程，以及 器官特异性激活/抑制蛋氨酸通量可以延长寿命并抑制不同 与年龄相关的病理表现，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。我将使用转基因技术 与阿尔茨海默病相关的果蝇模型分析人类Tau的过度表达 影响蛋氨酸流量。我将测试蛋氨酸限制和甲基转移酶的影响 对照果蝇及与之相关的转基因果蝇模型中神经变性的病理征象 阿尔茨海默氏症。我还将使用蛋氨酸限制的遗传模型，这将使我能够 测试蛋氨酸限制的组织特异性效应，并检查标记的 在果蝇模型中，下游代谢途径中的蛋氨酸随年龄的变化而变化 阿尔茨海默氏症。我们的研究将为修复年龄相关的缺陷提供洞察力 与蛋氨酸代谢受损相关的可用于延长寿命和潜在的 阿尔茨海默病的治疗。

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.