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Oxaloacetate

Oxaloacetate is a Krebs cycle intermediate that mimics caloric restriction effects. Marketed as 'longevity' supplement based on animal lifespan extension studies. Mechanism involves NADH/NAD+ ratio modification (similar to sirtuins), AMPK activation, and glutamate buffering. Limited human evidence - one small trial in ME/CFS showed modest mental fatigue reduction. Claims exceed evidence. Highly unstable compound requiring special formulation (thermally stabilized). Expensive with limited clinical support.

Quick Answer

What it is

Oxaloacetate is a Krebs cycle intermediate that mimics caloric restriction effects. Marketed as 'longevity' supplement based on animal lifespan extension studies.

Key findings

  • Grade C: Neuroprotection
  • Grade D: Alzheimer's Disease Biomarker Engagement
  • Grade D: Mitochondrial Complex II Modulation

Safety

No specific caution or interaction language was detected in the current summary/outcome notes.

ℹ️ Quick Facts: Oxaloacetate

Quick Facts: Oxaloacetate

  • Best Evidence:Grade D
  • Conditions Studied:2
  • Research Outcomes:6
  • Key Effect:Aging & Longevity
Outcomes by grade:
A0
B0
C1
D5
2 conditions · 6 outcomes

Detailed Outcomes

|
C
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.
moderate↑Improves
D
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.
small↑Improves
D
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.
moderate↓Improves
D
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.
moderate↑Improves
D
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.
small↑Improves
D
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.
moderate↑Improves

Research Citations (10)

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.
(2022)
PMID: 35764955
Safety and target engagement profile of two oxaloacetate doses in Alzheimer's patients.
(2021)
PMID: 32715609
Enzymatic activation of pyruvate kinase increases cytosolic oxaloacetate to inhibit the Warburg effect.
(2021)
PMID: 34226744
Oxaloacetate Protects Rat Liver From Experimental Warm Ischemia/Reperfusion Injury by Improving Cellular Energy Metabolism.
(2019)
PMID: 30663275
Oxaloacetic acid mediates ADP-dependent inhibition of mitochondrial complex II-driven respiration.
(2018)
PMID: 30385511
Oxaloacetate and adipose stromal cells-conditional medium synergistically protected potassium/serum deprivation-induced neuronal apoptosis.
(2017)
PMID: 27816553
Oxaloacetate enhances neuronal cell bioenergetic fluxes and infrastructure.
(2016)
PMID: 26811028
Differential susceptibility of mitochondrial complex II to inhibition by oxaloacetate in brain and heart.
(2016)
PMID: 27287543
Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis.
(2014)
PMID: 25027327
Oxaloacetate supplementation increases lifespan in Caenorhabditis elegans through an AMPK/FOXO-dependent pathway.
(2009)
PMID: 19793063

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