Supplement
Oxaloacetate is a molecule your cells make as part of the cycle that turns food into usable energy. People mostly look at it for brain protection, and the evidence is limited: in mouse studies it boosted the growth of new mitochondria, reduced inflammation and stimulated new nerve cells, while lab work found neurons handled energy better. Almost all of this comes from animal or cell experiments, so what it means for people remains unclear.
Sources: PMID 25027327; PMID 26811028
- Updated
- How we grade
- 10 studies cited
- Best evidence
- Grade C
- Conditions studied
- 2
- Outcomes
- 6
- Graded outcomes
- 0015
Evidence by condition
- Strong
- Moderate
- Limited
- Very limited
General
| Grade | Outcome | Effect | Size | Studies | People | Studies list |
|---|---|---|---|---|---|---|
| Neuroprotection Multiple preclinical studies demonstrate consistent neuroprotective effects. In mouse models, OAA activated brain mitochondrial biogenesis, enhanced the insulin pathway, reduced neuroinflammation, and stimulated neurogenesis (Wilkins et al. 2014). In vitro, OAA enhanced neuronal bioenergetic fluxes and cellular infrastructure (Wilkins et al. 2016), and synergistically protected against potassium/serum deprivation-induced neuronal apoptosis (Liu et al. 2017). Mechanism involves glutamate buffering reducing excitotoxicity and AMPK pathway activation. | Improves (the measure goes up) | Moderate effect | 5 studies | |||
Studies that measured neuroprotection
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| Mitochondrial Complex II Modulation OAA mediates ADP-dependent inhibition of mitochondrial complex II-driven respiration (Fink et al. 2018). Brain and heart mitochondria show differential susceptibility to OAA-mediated complex II inhibition (Stepanova et al. 2016). These mechanistic studies clarify how OAA modulates cellular energy metabolism but have uncertain clinical implications for supplementation. | Improves (the measure goes up) | Small effect | 3 studies | |||
Studies that measured mitochondrial complex ii modulation
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| Fatigue Reduction A non-randomized controlled clinical trial (Cash & Kaufman 2022, n=76) in ME/CFS and Long-COVID patients showed dose-dependent fatigue reduction: 21.7% improvement at 500mg BID, 27.6% at 1000mg BID, and 33.3% at 1000mg TID over 6 weeks. Limitations include lack of randomization and no placebo control. A follow-up randomized controlled trial (RESTORE ME) has been reported but full efficacy data require confirmation. | Improves (the measure goes down) | Moderate effect | 2 studies | 76 people | ||
Studies that measured fatigue reduction | ||||||
| Hepatoprotection In a rat model, OAA protected against warm ischemia/reperfusion liver injury by improving cellular energy metabolism (Merlen et al. 2019). This single preclinical study suggests potential hepatoprotective effects through bioenergetic support, but no human liver protection data exist. | Improves (the measure goes up) | Moderate effect | 2 studies | |||
| Grade | Outcome | Effect | Size | Studies | People | Studies list |
|---|---|---|---|---|---|---|
| Alzheimer's Disease Biomarker Engagement A small open-label human trial evaluated safety and target engagement of two OAA doses in Alzheimer's patients (Vidoni et al. 2021). The study demonstrated safety and some evidence of target engagement but was designed as a safety/biomarker study, not an efficacy trial. Supported by preclinical evidence of OAA-mediated neuroprotection and mitochondrial biogenesis in brain tissue. | Improves (the measure goes up) | Small effect | 3 studies | 30 people | ||
Studies that measured alzheimer's disease biomarker engagement
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| Grade | Outcome | Effect | Size | Studies | People | Studies list |
|---|---|---|---|---|---|---|
| Lifespan Extension In C. elegans, 8mM oxaloacetate supplementation extended lifespan by approximately 25% via an AMPK/FOXO(DAF-16)-dependent pathway, mimicking caloric restriction effects (Williams et al. 2009). This pathway is independent of Sir-2.1. No mammalian lifespan studies have been conducted; human longevity effects remain entirely speculative. | Improves (the measure goes up) | Moderate effect | 2 studies | |||
Key findings
- NeuroprotectionImproves (the measure goes up)
- Alzheimer's Disease Biomarker EngagementImproves (the measure goes up)
- Mitochondrial Complex II ModulationImproves (the measure goes up)
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- Grade C
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Studies cited
10 studies from PubMed
- Oxaloacetate Treatment For Mental And Physical Fatigue In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long-COVID fatigue patients: a non-randomized controlled clinical trial.
- Safety and target engagement profile of two oxaloacetate doses in Alzheimer's patients.
- Enzymatic activation of pyruvate kinase increases cytosolic oxaloacetate to inhibit the Warburg effect.
- Oxaloacetate Protects Rat Liver From Experimental Warm Ischemia/Reperfusion Injury by Improving Cellular Energy Metabolism.
- Oxaloacetic acid mediates ADP-dependent inhibition of mitochondrial complex II-driven respiration.
- Oxaloacetate and adipose stromal cells-conditional medium synergistically protected potassium/serum deprivation-induced neuronal apoptosis.
- Oxaloacetate enhances neuronal cell bioenergetic fluxes and infrastructure.
- Differential susceptibility of mitochondrial complex II to inhibition by oxaloacetate in brain and heart.
- Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis.
- Oxaloacetate supplementation increases lifespan in Caenorhabditis elegans through an AMPK/FOXO-dependent pathway.