Metabolic drift in the aging brain.
Metabolic drift in the aging brain.
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DOI：
10.18632/aging.100961
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发表时间：
2016-05
期刊：
影响因子：
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通讯作者：
Siuzdak G
中科院分区：
文献类型：
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作者：
Ivanisevic J;Stauch KL;Petrascheck M;Benton HP;Epstein AA;Fang M;Gorantla S;Tran M;Hoang L;Kurczy ME;Boska MD;Gendelman HE;Fox HS;Siuzdak G
大脑功能高度依赖于受控的能量代谢，能量代谢的丧失预示着认知障碍。这在老年人和与年龄相关的神经退行性疾病中尤其明显。然而，老化的大脑中代谢稳态是如何被破坏的，仍然知之甚少。在这里，我们对成年小鼠大脑不同阶段的不同解剖区域进行了全局、代谢和蛋白质组学分析。有趣的是，虽然没有严重的蛋白质组失衡，但全球非靶向代谢组学显示，老年小鼠大脑的能量代谢漂移或核心代谢物水平显著失衡。代谢失衡的特征是细胞能量状态受损(NAD下降，AMP/ATP增加，嘌呤/嘧啶积累)，并显著改变氧化磷酸化和核苷酸的生物合成和降解。中枢能量代谢漂移表明，细胞机制未能恢复老年大脑的代谢平衡(代谢物平衡)，因此无法对外部刺激做出适当反应，可能导致信号活动的变化，从而导致神经元功能和通讯的改变。
Brain function is highly dependent upon controlled energy metabolism whose loss heralds cognitive impairments. This is particularly notable in the aged individuals and in age-related neurodegenerative diseases. However, how metabolic homeostasis is disrupted in the aging brain is still poorly understood. Here we performed global, metabolomic and proteomic analyses across different anatomical regions of mouse brain at different stages of its adult lifespan. Interestingly, while severe proteomic imbalance was absent, global-untargeted metabolomics revealed an energy metabolic drift or significant imbalance in core metabolite levels in aged mouse brains. Metabolic imbalance was characterized by compromised cellular energy status (NAD decline, increased AMP/ATP, purine/pyrimidine accumulation) and significantly altered oxidative phosphorylation and nucleotide biosynthesis and degradation. The central energy metabolic drift suggests a failure of the cellular machinery to restore metabostasis (metabolite homeostasis) in the aged brain and therefore an inability to respond properly to external stimuli, likely driving the alterations in signaling activity and thus in neuronal function and communication.