Downregulation of the tyrosine degradation pathway extends Drosophila lifespan.
Downregulation of the tyrosine degradation pathway extends Drosophila lifespan.
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酪氨酸降解途径的下调延长了果蝇的寿命。
DOI：
10.7554/elife.58053
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发表时间：
2020-12-15
期刊：
影响因子：
7.7
通讯作者：
Perrimon N
中科院分区：
文献类型：
--
作者：
Parkhitko AA;Ramesh D;Wang L;Leshchiner D;Filine E;Binari R;Olsen AL;Asara JM;Cracan V;Rabinowitz JD;Brockmann A;Perrimon N
衰老的特征是广泛的代谢重编程。为了确定与衰老相关的代谢途径，我们分析了长寿果蝇代谢组的年龄依赖性变化。在改变的代谢物中，在长寿的果蝇中，酪氨酸的水平随着年龄的增长而增加。我们证明，野生型苍蝇中酪氨酸降解途径中的酶水平随着年龄的增长而增加。酪氨酸降解途径中酶的全身和神经元特异性下调显著延长果蝇寿命，导致与寿命增加相关的代谢物改变，并上调酪氨酸衍生的神经介质水平。此外，用酪氨酸喂养野生型果蝇增加了它们的寿命。从机制上讲，我们表明ETC复合物I的抑制驱动酪氨酸降解途径中酶的上调，这种作用可以通过替加环素（一种FDA批准的特异性抑制线粒体翻译的药物）来挽救。此外，酪氨酸补充部分挽救了具有ETC复合物I抑制的果蝇的寿命。总之，我们的研究强调了酪氨酸降解途径作为长寿的调节剂。
Aging is characterized by extensive metabolic reprogramming. To identify metabolic pathways associated with aging, we analyzed age-dependent changes in the metabolomes of long-lived Drosophila melanogaster. Among the metabolites that changed, levels of tyrosine were increased with age in long-lived flies. We demonstrate that the levels of enzymes in the tyrosine degradation pathway increase with age in wild-type flies. Whole-body and neuronal-specific downregulation of enzymes in the tyrosine degradation pathway significantly extends Drosophila lifespan, causes alterations of metabolites associated with increased lifespan, and upregulates the levels of tyrosine-derived neuromediators. Moreover, feeding wild-type flies with tyrosine increased their lifespan. Mechanistically, we show that suppression of ETC complex I drives the upregulation of enzymes in the tyrosine degradation pathway, an effect that can be rescued by tigecycline, an FDA-approved drug that specifically suppresses mitochondrial translation. In addition, tyrosine supplementation partially rescued lifespan of flies with ETC complex I suppression. Altogether, our study highlights the tyrosine degradation pathway as a regulator of longevity.