Oxaloacetate

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1Sources and Composition

1.1. Sources and Structure

Oxaloacetate, the common name for the molecule 3-carboxy-3-oxopropanoic acid and synonymous with oxaloacetic acid (depending on acidity),

1.2. Physicochemical Properties

One mouse study mixing oxaloacetate into chow found a time-dependent decrease in OAA content at 4°C after 22-28 weeks, where the initial concentration of 479-555ppm detected after 2-5 weeks was reduced to 281ppm (24 weeks) and then to 164ppm (28 weeks).[1]

1.3. Biological Significance

Oxaloacetate is an intermediate of the Kreb's cycle and the stage immediately prior to the formation of Pyruvate (via pyruvate carboxylase) and immediately after the NAD+-consuming conversion from L-malate (via malate dehydrogenase).


2Pharmacology

2.1. Cellular Kinetics

Intracellular oxaloacetate can be taken up into the mitochondria in various organs.[2][3]


3Neurology

3.1. Glutaminergic Neurotransmission

Oxaloacetate is known to be a glutamate scavenger[4] alongside some other small molecules such as Pyruvate,[5] where both small molecules are subject to enzymes (glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT) respectively) which convert glutamate into metabolites of 2-ketoglutarate, aspartate, and alanine.[6] Injections of large doses (1mM in rodents) of either oxaloacetate or pyruvate can reduce serum glutamate by 30-40%, causing glutamate to flow from cerebrospinal fluid into peripheral circulation (indicative of reduced glutamate retained in neural tissue).[6]

Oxaloacetate's effects on glutamate appear to be concentration dependent, with maximal effects at 1M (1,000mM) and no effects at 0.01M (10mM).[4] This property has been shown to be active following peripheral injections of oxaloacetate in rat models of tramautic brain injury.[7][5][7]

As an endogenous molecule, oxaloacetate can sequester glutamate and reduce its activities. This has been shown with injections of oxaloacetate in rats, but due to the high concentrations required it may not be a relevant mechanism for oral supplementation of oxaloacetate (studies using oral oxaloacetate currently do not exist on this topic)

3.2. Bioenergetics

Intraperitoneal injections of oxaloacetate (1-2g/kg) day subchronically appears to enhance mitochondrial biogenesis in the mouse brain.[8]


4Longevity and Life Extension

4.1. Rationale

Oxaloacetate is thought to promote longevity due to being an intermediate of the Kreb's cycle of energy production. Any increase in the NAD+/NADH ratio can promote longevity in yeast[9] (and is thought to be a major factor in caloric restriction[10][11]) hypothesized to be due to increased energy in the cell, since increased NAD+ availability can stimulate overall Kreb's cycle activity in c. elegans.[12]

In C. elegans, administration of oxaloacetate promoted average (13%) and median (25%) lifespan with similar effects at two tested concentrations (2mM and 8mM) and similar effects with the metabolite Pyruvate.[13] This observation was noted to not alter food intake and appeared to be mediated by AMPK acting on the DAF-16 transcription factor, and not be related to Sir2.[13]

Similar functions on the lifespan of C. elegans have been noted with similarly structured Kreb's cycle intermediates fumarate and malate although succinate was ineffective.[14] This effect was also not present in c. elegans lacking the ability to convert malate to fumarate (lacking the fumarase enzyme) or fumarate to succinate (succinate dehydrogenase flavoprotein), suggesting that the byproducts produced in these reactions including FAD and NAD+ rather than the metabolites.[14] A higher NAD+/NADH ratio is known to activate AMPK.[15]

Providing intermediates to the Kreb's cycle (TCA cycle) seems to increase NAD+ concentrations in the cell, and possibly due to increased Kreb's cycle activity overall an increase in longevity follows in nonmammalian subjects

In mice, administration of varying concentrations of oxaloacetate in food (0.5-3.5g/kg dry weight) did not influence longevity although the authors noted that oxaloacetate may have degraded to a degree (thought to be no more than 25% the intended amount) when mixed in chow for a few weeks.[1]

One study using oral oxaloacetate failed to find an increase in longevity in mice, but also had stability issues with oxaloacetate in the feed; more research is required

Scientific Support & Reference Citations

References

  1. Strong R1, et al Evaluation of resveratrol, green tea extract, curcumin, oxaloacetic acid, and medium-chain triglyceride oil on life span of genetically heterogeneous mice . J Gerontol A Biol Sci Med Sci. (2013)
  2. Passarella S, et al Oxaloacetate uptake into rat brain mitochondria and reconstruction of the malate/oxaloacetate shuttle . Biochem Biophys Res Commun. (1984)
  3. Passarella S, Atlante A, Quagliariello E Oxaloacetate permeation in rat kidney mitochondria: pyruvate/oxaloacetate and malate/oxaloacetate translocators . Biochem Biophys Res Commun. (1985)
  4. Zlotnik A1, et al The neuroprotective effects of oxaloacetate in closed head injury in rats is mediated by its blood glutamate scavenging activity: evidence from the use of maleate . J Neurosurg Anesthesiol. (2009)
  5. Zlotnik A1, et al The contribution of the blood glutamate scavenging activity of pyruvate to its neuroprotective properties in a rat model of closed head injury . Neurochem Res. (2008)
  6. Gottlieb M1, Wang Y, Teichberg VI Blood-mediated scavenging of cerebrospinal fluid glutamate . J Neurochem. (2003)
  7. Zlotnik A1, et al Effect of glutamate and blood glutamate scavengers oxaloacetate and pyruvate on neurological outcome and pathohistology of the hippocampus after traumatic brain injury in rats . Anesthesiology. (2012)
  8. Wilkins HM1, et al Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis . Hum Mol Genet. (2014)
  9. Lin SJ1, Defossez PA, Guarente L Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae . Science. (2000)
  10. Wang Y Molecular Links between Caloric Restriction and Sir2/SIRT1 Activation . Diabetes Metab J. (2014)
  11. Chen D1, et al Tissue-specific regulation of SIRT1 by calorie restriction . Genes Dev. (2008)
  12. Braeckman BP1, Houthoofd K, Vanfleteren JR Intermediary metabolism . WormBook. (2009)
  13. Williams DS1, et al Oxaloacetate supplementation increases lifespan in Caenorhabditis elegans through an AMPK/FOXO-dependent pathway . Aging Cell. (2009)
  14. Edwards CB1, et al Malate and fumarate extend lifespan in Caenorhabditis elegans . PLoS One. (2013)
  15. Rafaeloff-Phail R1, et al Biochemical regulation of mammalian AMP-activated protein kinase activity by NAD and NADH . J Biol Chem. (2004)