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High brain lactate is a hallmark of aging and caused by a shift in the lactate dehydrogenase A/B ratio.

ABSTRACT: 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.

SUBMITTER: Ross JM

PROVIDER: S-EPMC2993405 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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High brain lactate is a hallmark of aging and caused by a shift in the lactate dehydrogenase A/B ratio.

Ross Jaime M JM Öberg Johanna J Brené Stefan S Coppotelli Giuseppe G Terzioglu Mügen M Pernold Karin K Goiny Michel M Sitnikov Rouslan R Kehr Jan J Trifunovic Aleksandra A Larsson Nils-Göran NG Hoffer Barry J BJ Olson Lars L

Proceedings of the National Academy of Sciences of the United States of America 20101101 46

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 a ...[more]

PMID: 21041631

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Project description:AbstractThis study was performed to verify whether lactate dehydrogenase to albumin (LDH/ALB) ratio could be used as an independent prognostic factor in patients with severe infection requiring intensive care.We reviewed electronic medical records of patients hospitalized to the intensive care unit via the emergency department with a diagnosis of infection between January 2014 and December 2019. From the collected data, ALB-based ratios (LDH/ALB, blood urea nitrogen to albumin, C-reactive protein to albumin, and lactate to albumin ratios) and some severity scores (modified early warning score, mortality in emergency department sepsis score [MEDS], and Acute Physiology And Chronic Health Evaluation II [APACHE II] score) were calculated. LDH/ALB ratio for predicting the in-hospital mortality was compared with other ALB-based ratios and severity scales by univariable and receiver-operating characteristics curve analysis. Modified severity scores by LDH/ALB ratio and multivariable logistic regression were used to verify the independence and usefulness of the LDH/ALB ratio.The median LDH/ALB ratio was higher in non-survivors than survivors (166.9 [interquartile range: 127.2-233.1] vs 214.7 [interquartile range: 160.2-309.7], P < .001). The area under the receiver-operating characteristics curve of the LDH/ALB ratio (0.642, 95% confidence interval: 0.602-0.681, P < .001) was not lower than that of other ALB-based ratios and severity scores. From multivariable logistic regression, LDH/ALB ratio was independently associated with in-hospital mortality (odds ratio = 1.001, 95% confidence interval: 1.000-1.002, P = .047). Area under the receiver-operating characteristics curves of MEDS and APACHE II scores were improved by modification with LDH/ALB ratio (MEDS: 0.643 vs 0.680, P < .001; APACHE II score: 0.675 vs 0.700, P = .003).LDH/ALB ratio may be useful as the prognostic factor in patients with severe infection requiring intensive care.

Dataset Information

High brain lactate is a hallmark of aging and caused by a shift in the lactate dehydrogenase A/B ratio.

Publications

High brain lactate is a hallmark of aging and caused by a shift in the lactate dehydrogenase A/B ratio.

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