Metabolic dysfunction impacts stroke incidence and outcome. However, the intricate association between altered metabolic program due to aging, and focal ischemia in brain, circulation, and peripheral organs is not completely elucidated. Here we identified locally and systemically altered metabolites in brain, liver, and plasma as a result of normal aging, ischemic-stroke, and extended time of reperfusion injury. Comprehensive quantitative metabolic profiling was carried out using nuclear magnetic resonance spectroscopy. Aging, but healthy rats showed significant metabolic alterations in the brain, but only a few metabolic changes in the liver and plasma as compared to younger rats. But, ischemic stroke altered metabolites significantly in liver and plasma of older rats during early acute phase. Major metabolic changes were also seen in the brains of younger rats following ischemic stroke during early acute phase of injury. We further report that metabolic changes occur sequentially in a tissue specific manner during extended reperfusion time of late repair phase. First metabolic alterations occurred in brain due to local injury. Next, changes in circulating metabolites in plasma occurred during acute-repair phase transition time. Lastly, the delayed systemic effect was seen in the peripheral organ, liver that exhibited significant and persistent changes in selected metabolites during later reperfusion time. The metabolic pathways involved in energy/glucose, and amino acid metabolism, inflammation, and oxidative stress were mainly altered as a result of aging and ischemia/reperfusion. Biomarker analysis revealed citrate, lysine, and tyrosine as potential age-independent blood metabolic biomarkers of ischemia/reperfusion. Overall, our study elucidates the complex network of metabolic events as a function of normal aging and acute stroke. We further provide evidence for a clear transition from local to systemic metabolic dysfunction due to ischemic injury in a time dependent manner, which may altogether greatly impact the post-stroke outcome.

中文翻译：

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通过衰老和缺血性中风，大鼠的脑，血浆和肝中的局部和全身代谢改变，如通过核磁共振（NMR）光谱检测到的。

代谢功能障碍会影响中风的发生率和预后。然而，尚未完全阐明由于衰老而改变的代谢程序与脑，循环和周围器官的局灶性局部缺血之间的复杂联系。在这里，我们确定了由于正常衰老，缺血性中风和延长的再灌注损伤时间导致的大脑，肝脏和血浆中局部和全身性代谢产物的改变。使用核磁共振波谱进行了全面的定量代谢谱分析。衰老但健康的大鼠在大脑中显示出明显的代谢变化，但与年轻大鼠相比，肝脏和血浆中仅有一些代谢变化。但是，缺血性中风在早期急性期显着改变了老年大鼠肝脏和血浆中的代谢产物。在损伤的急性早期，缺血性中风后，年轻大鼠的大脑中也观察到了主要的代谢变化。我们进一步报道，在后期修复阶段延长的再灌注时间中，代谢变化以组织特异性的方式依次发生。最初的代谢改变是由于局部损伤而在大脑中发生的。接下来，在急性修复相变期间血浆中循环代谢物发生变化。最后，在外周器官，肝脏中观察到延迟的全身作用，在随后的再灌注时间中，所选代谢物表现出显着且持续的变化。能量/葡萄糖，氨基酸代谢，炎症和氧化应激等代谢途径主要是由于衰老和缺血/再灌注而改变的。生物标志物分析显示柠檬酸盐，赖氨酸，酪氨酸是缺血/再灌注潜在的与年龄无关的血液代谢生物标志物。总体而言，我们的研究阐明了代谢事件与正常衰老和急性中风之间关系的复杂网络。我们还提供了证据，表明缺血性损伤导致的局部代谢功能障碍从局部向功能性代谢的转变以时间依赖的方式发生，这可能会严重影响中风后的预后。