Alpha-ketoglutarate extends Drosophila lifespan by inhibiting mTOR and activating AMPK
Alpha-ketoglutarate extends Drosophila lifespan by inhibiting mTOR and activating AMPK
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α-酮戊二酸通过抑制 mTOR 和激活 AMPK 延长果蝇寿命
DOI：
10.18632/aging.102045
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发表时间：
2019-06-30
期刊：
影响因子：
5.2
通讯作者：
Yang, Mingyao
中科院分区：
文献类型：
--
作者：
Su, Yuan;Wang, Tao;Yang, Mingyao
α-酮戊二酸(AKG)是三羧酸(TCA)循环的关键代谢产物，是影响线粒体氧化呼吸速率的重要过程。最近的研究表明，饲料中的AKG通过抑制ATP合成酶来减少mTOR途径的激活，从而延长线虫的寿命。虽然AKG还可以延长果蝇的寿命，但AKG在这些生物中的抗衰老机制尚不清楚。在本研究中，我们探索了与饮食AKG介导的果蝇寿命延长相关的基因表达的变化。饲料中添加5-μ-M-AKG延长了果蝇的寿命，但降低了它们的繁殖性能。饮食AKG也提高了垂直攀登能力，但不能防止氧化应激或增加对饥饿的耐受性。AKG饲养的果蝇对热应激具有抗性，热休克蛋白基因(Hsp22和Hsp70)的表达水平高于对照果蝇。此外，AKG还显著上调了CRY、FoxO、HNF4、p300、Sirt1和AMPKα的基因表达，下调了HDAC4、PI3K、TORC、PGC和SREBP的表达。补充AKG的代谢效应包括降低ATP/ADP比率和增加自噬。综上所述，这些观察表明AKG通过激活AMPK信号和抑制mTOR通路来延长果蝇的寿命。
Alpha-ketoglutarate (AKG) is a key metabolite of the tricarboxylic acid (TCA) cycle, an essential process influencing the mitochondrial oxidative respiration rate. Recent studies have shown that dietary AKG reduces mTOR pathway activation by inhibiting ATP synthase, thereby extending the lifespan of nematodes. Although AKG also extends lifespan in fruit flies, the antiaging mechanisms of AKG in these organisms remain unclear. In the present study, we explored changes in gene expression associated with the extension of Drosophila lifespan mediated by dietary AKG. Supplementation of the flies’ diets with 5 μM AKG extended their lifespan but reduced their reproductive performance. Dietary AKG also enhanced vertical climbing ability, but did not protect against oxidative stress or increase tolerance to starvation. AKG-reared flies were resistant to heat stress and demonstrated higher expression of heat shock protein genes (Hsp22 and Hsp70) than control flies. In addition, AKG significantly upregulated mRNA expression of cry, FoxO, HNF4, p300, Sirt1 and AMPKα, and downregulated expression of HDAC4, PI3K, TORC, PGC, and SREBP. The metabolic effects of AKG supplementation included a reduction in the ATP/ADP ratio and increased autophagy. Collectively, these observations indicate that AKG extends Drosophila lifespan by activating AMPK signaling and inhibiting the mTOR pathway.