High brain lactate is a hallmark of aging and caused by a shift in the lactate dehydrogenase A/B ratio
Open accessAbstract
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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Lactate can only be synthesized or used in metabolic reactions with the help of lactate dehydrogenase (LDH), a tetramer of LDHA and LDHB subunits in varying compositions.
“lactate can only be synthesized or used in metabolic reactions with the help of lactate dehydrogenase (LDH), a tetramer of LDHA and LDHB subunits in varying compositions.”
From Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons (2024) · cites this paper as Ross et al., 2010
The Results passages describe LDH-mediated conversion between pyruvate and lactate and identify five isoenzymes made from different combinations of LDH-A and LDH-B subunits. They do not establish the broader claim that lactate can only be synthesized or used in metabolic reactions with LDH. Page numbers are not available in the supplied copy. (LLM, conf=0.82)
Experimental — accuracy not yet measuredLactate can only be generated from pyruvate by lactate dehydrogenases (LDH).
“Lactate can only be generated from pyruvate by lactate dehydrogenases (LDH), necessitating a careful analysis of LDH expression in white matter tracts.”
From Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons (2024) · cites this paper as Ross et al., 2010
The Results section identifies LDH as catalyzing pyruvate-to-lactate conversion and links LDH expression to lactate production. It does not establish the claim’s exclusive “only” wording—that no other route can generate lactate from pyruvate. The supplied passages have no page numbers. (LLM, conf=0.83)
Experimental — accuracy not yet measuredLdhb mRNA was prominent in neurons of the basal forebrain, including several thalamic nuclei and in the midbrain.
“The more widely expressed Ldhb mRNA was also prominent in neurons of the basal forebrain, including several thalamic nuclei and in the midbrain as described (Laughton et al., 2000;Ross et al., 2010) (Figure 2g).”
From Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons (2024) · cites this paper as Ross et al., 2010
The Results section says LDH-B mRNA was highly expressed throughout the brain and more widely expressed than LDH-A. It does not specifically identify neurons of the basal forebrain, thalamic nuclei, or midbrain as sites of prominent expression. (LLM, conf=0.86)
Experimental — accuracy not yet measuredLDHA and LDHB are widely expressed including brain, while LDHC is restricted to testis and sperm.
“While LDHA and LDHB are widely expressed including brain (Miura, 1966a;Miura, 1966b;Ross et al., 2010), LDHC is restricted to testis and sperm (Goldberg et al., 2010).”
From Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons (2024) · cites this paper as Ross et al., 2010
Ldha gene expression was strongest in the cerebral cortex and hippocampus.
“Ldha gene expression was strongest in the cerebral cortex and hippocampus as previously reported (Laughton et al., 2000;Ross et al., 2010) (Figure 2g).”
From Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons (2024) · cites this paper as Ross et al., 2010
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- Authors
- Ross, J. M., Öberg, J., Brené, S., Coppotelli, G., Terzioglu, M., Pernold, K., Goiny, M., Sitnikov, R., Kehr, J., Trifunovic, A., Larsson, N.-G., Hoffer, B. J., & Olson, L.
- Affiliations
- National Institutes of Health (US)
- Max Planck Society (DE)
- Karolinska Institutet (SE)
- Max Planck Institute for Biology of Ageing (DE)
- Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden;
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, D-50674 Cologne, Germany; and
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-11
- Volume
- 107
- Issue
- 46
- Pages
- 20087-20092
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2993405
- OpenAlex
- W2041562324
- Cited by
- 299
- References
- 7
- Citations by year
- 2026: 14 · 2025: 34 · 2024: 34 · 2023: 18 · 2022: 26 · 2021: 20 · 2020: 22 · 2019: 16 · 2018: 25 · 2017: 11 · 2016: 12 · 2015: 19 · 2014: 14 · 2013: 13 · 2012: 11
- FWCI
- 3.88
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Karolinska Institutet
- Vetenskapsrådet
- Swedish Brain Power
- National Institutes of Health (AG04418)
- National Institute on Aging (AG04418, P01AG004418)
- National Institute of Neurological Disorders and Stroke (R01NS070825)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Keywords
- brain lactate, mitochondrial dysfunction, pyruvate to lactate conversion, respiratory chain enzymes, premature aging
- MeSH terms
- Lactate Dehydrogenase 5, Aging, Animals, Brain, DNA, Mitochondrial, Isoenzymes, L-Lactate Dehydrogenase, Mitochondria, Mutation, Organ Specificity, Gene Expression Regulation, Enzymologic, Lactic Acid, Mice
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