Studying methionine flux and its role in aging and neurodegeneration

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， 和阿尔茨海默病的特征是广泛的代谢变化。几项研究 揭示了一些代谢途径，对这些途径的干扰可以延长寿命 在苍蝇和其他生物中。同样，阿尔茨海默病的特征是广泛的代谢紊乱， 重新编程在果蝇中使用靶向高通量代谢物谱 不同年龄的成年人，我们证明了蛋氨酸代谢在衰老过程中的变化。 特别是，我们发现蛋氨酸下游代谢物之一SAH， 随着年龄增长，抑制SAH积累可延长寿命和健康。的 在本申请中提出的实验旨在解决以下基本问题 甲硫氨酸通量在整个生物体水平和不同器官中重新编程， 甲硫氨酸通量的器官特异性激活/抑制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。我将使用转基因技术 阿尔茨海默病相关的果蝇模型，以分析人Tau蛋白的过度表达 影响蛋氨酸通量。我将测试甲硫氨酸限制酶和甲基转移酶 对对照果蝇和与之相关的转基因果蝇模型中神经变性的病理学体征的影响 老年痴呆症我还将使用甲硫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 下游代谢途径中的甲硫氨酸随年龄变化， 老年痴呆症我们的研究将为如何恢复年龄依赖性缺陷提供见解 与受损的蛋氨酸代谢相关的研究可用于延长寿命， 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.