PNAS:乳酸浓度可能检测大脑衰老
这组科学家发现线粒体DNA(mtDNA)机能障碍引发了小鼠大脑的一种代谢变化,它可能改变控制乳酸形成的特定基因的表达。这组作者说,这种变化导致了大脑乳酸浓度增加,利用非侵入式成像技术可能探测到它。这组作者说,这些发现还提示乳酸浓度的上升在其他衰老指标之前出现,而未来的研究可能使用乳酸浓度探测中枢神经系统的与衰老有关的疾病。
英文摘要:
PNAS doi: 10.1073/pnas.1008189107
High brain lactate is a hallmark of aging and caused by a shift in the lactate dehydrogenase A/B ratio
Jaime M. Rossa,b,1, Johanna ?bergc, Stefan Brenéd, Giuseppe Coppotellie, Mügen Terziogluf, Karin Pernolda, Michel Goinyg, Rouslan Sitnikovh, Jan Kehrg, Aleksandra Trifunovici, Nils-G?ran Larssonf,j, Barry J. Hofferb, and Lars Olsona,1
At present, there are few means to track symptomatic stages of CNS aging. Thus, although metabolic changes are implicated in mtDNA mutation-driven aging, the manifestations remain unclear. Here, we used normally aging and prematurely aging mtDNA mutator mice to establish a molecular link between mitochondrial dysfunction and abnormal metabolism in the aging process. Using proton magnetic resonance spectroscopy and HPLC, we found that brain lactate levels were increased twofold in both normally and prematurely aging mice during aging. To correlate the striking increase in lactate with tissue pathology, we investigated the respiratory chain enzymes and detected mitochondrial failure in key brain areas from both normally and prematurely aging mice. We used in situ hybridization to show that increased brain lactate levels were caused by a shift in transcriptional activities of the lactate dehydrogenases to promote pyruvate to lactate conversion. Separation of the five tetrameric lactate dehydrogenase (LDH) isoenzymes revealed an increase of those dominated by the Ldh-A product and a decrease of those rich in the Ldh-B product, which, in turn, increases pyruvate to lactate conversion. Spectrophotometric assays measuring LDH activity from the pyruvate and lactate sides of the reaction showed a higher pyruvate → lactate activity in the brain. We argue for the use of lactate proton magnetic resonance spectroscopy as a noninvasive strategy for monitoring this hallmark of the aging process. The mtDNA mutator mouse allows us to conclude that the increased LDH-A/LDH-B ratio causes high brain lactate levels, which, in turn, are predictive of aging phenotypes.
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