Oxaloacetate

• Mitochondrial Function Enhancement
• Neuroprotection
• Glutamate Regulation
• Calorie Restriction Mimetic

• Blood Glucose Regulation
• Cognitive Support
• Anti-inflammatory Effects
• Antioxidant Properties
• Mood Regulation

Oxaloacetate (OAA) exerts its biological effects through multiple mechanisms centered on its role as a key metabolic intermediate and its ability to influence several critical biochemical pathways. As a crucial component of the tricarboxylic acid (TCA) cycle, oxaloacetate serves as both the final product and the initial substrate of this central metabolic pathway, facilitating the continuous generation of cellular energy. When supplemented, oxaloacetate can enhance TCA cycle flux, potentially increasing mitochondrial energy production and efficiency. One of oxaloacetate’s most significant mechanisms is its role as a blood glutamate scavenger.

By activating the enzyme glutamate oxaloacetate transaminase (GOT), oxaloacetate facilitates the conversion of potentially excitotoxic glutamate into alpha-ketoglutarate, another TCA cycle intermediate. This transamination reaction effectively reduces extracellular glutamate levels, which may be particularly beneficial in conditions characterized by glutamate excitotoxicity, such as traumatic brain injury, stroke, and certain neurodegenerative disorders. Oxaloacetate also functions as a calorie restriction mimetic by influencing the NAD+/NADH ratio. By accepting electrons from NADH to form malate (via malate dehydrogenase), oxaloacetate can increase the NAD+/NADH ratio, similar to what occurs during calorie restriction.

This shift activates sirtuins, particularly SIRT1, a family of NAD+-dependent deacetylases involved in regulating cellular stress responses, metabolism, and potentially lifespan. In glucose metabolism, oxaloacetate plays a dual role. It can contribute to gluconeogenesis (glucose production) in the liver during fasting states, while also potentially enhancing insulin sensitivity and glucose utilization in fed states. This metabolic flexibility may help stabilize blood glucose levels and improve metabolic health.

Oxaloacetate demonstrates neuroprotective properties through multiple pathways. Beyond glutamate scavenging, it enhances mitochondrial biogenesis in brain tissue, increases brain-derived neurotrophic factor (BDNF) levels, and activates neurogenesis in the hippocampus, a brain region crucial for learning and memory. These effects may contribute to improved cognitive function and neuroprotection. As an anaplerotic agent, oxaloacetate can replenish TCA cycle intermediates that may be depleted during metabolic stress or increased energy demands.

This anaplerotic function supports mitochondrial resilience and metabolic flexibility. Oxaloacetate also exhibits antioxidant properties, both directly and indirectly. It can scavenge reactive oxygen species and, through its effects on the TCA cycle and mitochondrial function, may reduce oxidative stress by improving electron transport chain efficiency. Additionally, oxaloacetate influences inflammatory pathways, potentially reducing neuroinflammation and systemic inflammation through its effects on metabolic signaling and glutamate regulation.

Recent research suggests oxaloacetate may activate the insulin signaling pathway in the brain, which could have implications for cognitive function and neuroprotection, particularly in conditions characterized by brain insulin resistance such as Alzheimer’s disease. Through these diverse mechanisms, oxaloacetate functions as a multifaceted metabolic modulator with potential applications in neurological health, metabolic function, and possibly longevity.

100-1000 mg per day of stabilized oxaloacetate, typically divided into 1-2 doses. Most commercial supplements provide 100-500 mg per serving.

Oxaloacetate presents significant bioavailability challenges due to its inherent instability at body temperature and in acidic environments like the stomach. Unstabilized oxaloacetate rapidly decarboxylates to pyruvate, limiting its absorption as intact oxaloacetate. Stabilized and thermally protected formulations have improved bioavailability, though exact percentages are not well-established in the scientific literature. Absorption primarily occurs in the small intestine, with peak plasma concentrations typically occurring within 1-2 hours after ingestion of stabilized formulations.

Thermal stabilization technologies that protect oxaloacetate from degradation, Enteric coating to bypass stomach acid and deliver oxaloacetate to the small intestine, Buffering with vitamin C or other compounds to improve stability, Taking on an empty stomach may reduce degradation from food interactions, Liposomal delivery systems potentially enhance cellular uptake, Co-administration with carnitine may enhance mitochondrial uptake (theoretical), Formulations with pH stabilizers to prevent decarboxylation

Oxaloacetate is typically best taken on an empty stomach, at least 30 minutes before meals, to minimize potential degradation from food interactions and digestive enzymes. For those using oxaloacetate for cognitive support or energy enhancement, morning dosing may be most beneficial to align with natural circadian rhythms of metabolism. For blood glucose management, taking 15-30 minutes before meals may help optimize effects on glucose metabolism. If using for neuroprotection or glutamate regulation, consistent daily timing is important to maintain stable levels.

Some individuals report mild gastrointestinal discomfort when taking oxaloacetate on an empty stomach; in these cases, taking with a small amount of food may be necessary despite potentially reduced absorption. Dividing the daily dose (for doses >500 mg) may help maintain more consistent blood levels throughout the day. Avoid taking with hot beverages or foods, as heat accelerates oxaloacetate degradation.

• Mild gastrointestinal discomfort
• Nausea (uncommon)
• Headache (rare)
• Dizziness (rare)
• Fatigue or increased energy (variable response)
• Temporary changes in mood or alertness
• Mild allergic reactions (very rare)

• Pregnancy and breastfeeding (due to insufficient safety data)
• Known hypersensitivity to oxaloacetate or related compounds
• Severe liver or kidney disease (use with caution due to limited research)
• Individuals with certain metabolic disorders (consult healthcare provider)
• Children (due to limited safety data)
• Individuals with certain psychiatric conditions (theoretical concern due to glutamate modulation)

• Medications affecting glutamate metabolism (theoretical interaction)
• Antidiabetic medications (potential additive effects on blood glucose)
• Medications metabolized by the liver (theoretical concern for altered metabolism)
• Medications affecting mitochondrial function (potential synergistic or antagonistic effects)
• Anticonvulsant medications (theoretical interaction due to effects on glutamate)
• Medications for Parkinson’s disease (theoretical concern due to metabolic effects)

No established upper limit from regulatory bodies. Clinical studies have used up to 2000 mg daily without serious adverse effects, though such high doses are rarely used in supplementation. Most practitioners recommend not exceeding 1000 mg daily without medical supervision. Long-term safety of regular use has not been well-established in large clinical trials.

In the United States, oxaloacetate is regulated as a dietary supplement under the Dietary Supplement Health and Education Act (DSHEA) of 1994. The FDA does not approve oxaloacetate for the treatment, prevention, or cure of any disease. Manufacturers are permitted to make structure/function claims (such as ‘supports energy production’ or ‘supports brain health’) but not disease claims. The FDA has not established a recommended daily allowance (RDA) or adequate intake level for oxaloacetate.

As a naturally occurring metabolic intermediate, oxaloacetate is generally recognized as a dietary ingredient that was marketed prior to the enactment of DSHEA, though stabilized forms may be considered new dietary ingredients requiring notification to the FDA.

Eu: In the European Union, oxaloacetate has a complex regulatory status. It is not specifically listed in the EU’s list of approved food supplements. Some member states may permit its sale as a food supplement, while others may classify it as a novel food ingredient requiring authorization under Regulation (EU) 2015/2283. The European Food Safety Authority (EFSA) has not approved any health claims specifically for oxaloacetate.

Canada: Health Canada regulates oxaloacetate as a Natural Health Product (NHP). Products containing oxaloacetate must be licensed and meet specific quality, safety, and efficacy requirements to receive a Natural Product Number (NPN).

Australia: The Therapeutic Goods Administration (TGA) regulates oxaloacetate as a complementary medicine. It may be listed in the Australian Register of Therapeutic Goods (ARTG) with specific permitted indications related to cellular energy production and metabolic support.

Japan: In Japan, oxaloacetate may be regulated under the Foods with Health Claims system, though specific approved claims vary. It is not as commonly used in Japanese supplements as in Western markets.

Uk: Post-Brexit, the UK maintains similar regulations to the EU regarding oxaloacetate as a food supplement ingredient. The UK Food Standards Agency oversees its regulation.

International Organizations: The World Health Organization (WHO) does not have specific recommendations or regulations regarding oxaloacetate supplementation.

high

$2.00-$7.00 per day for typical doses (100-500 mg of stabilized oxaloacetate)

Oxaloacetate is among the more expensive dietary supplements available, primarily due to the complex manufacturing processes required to produce stable forms and the specialized technology needed to prevent degradation. Stabilized oxaloacetate formulations typically cost $60-200 per month at effective doses, placing it in the premium supplement category. This high cost reflects several factors: the inherent instability of the compound requiring proprietary stabilization technologies, the relatively small market leading to limited economies of scale, and the specialized expertise required for production. The value proposition varies significantly depending on the intended use.

For neuroprotection and glutamate regulation, particularly in conditions like traumatic brain injury or neurodegenerative diseases, the potential benefits may justify the cost for some individuals, especially given the limited effective interventions for these conditions. For general metabolic support and anti-aging purposes, the cost-efficiency is less clear due to limited human clinical evidence, though some users report significant benefits that may justify the expense. When compared to other supplements targeting mitochondrial function or neuroprotection, oxaloacetate is generally more expensive than options like alpha-lipoic acid, CoQ10, or PQQ, though it offers a unique mechanism of action that may complement these other approaches. Some manufacturers offer combination products that include oxaloacetate along with other synergistic compounds (like vitamin C), which may provide better overall value than oxaloacetate alone.

The cost-effectiveness is highly individual and depends on personal response, which varies significantly between users. For those who experience meaningful benefits, particularly in cognitive function or energy levels, the cost may be justified despite being high relative to many other supplements. Overall, oxaloacetate represents a high-cost supplement with promising but still emerging evidence for specific applications, making it most cost-effective for those with conditions that may specifically benefit from its unique mechanisms of action and who have the financial means to sustain its use.

Unstabilized oxaloacetate: Extremely short (hours to days) at room temperature; Stabilized commercial formulations: 1-2 years when properly stored; Thermally stabilized formulations: 2-3 years under optimal storage conditions

Store in the original container with desiccant if provided. Keep in a cool, dry place away from direct light. Refrigeration is recommended by some manufacturers and may extend shelf life. Avoid exposure to heat, as temperatures above 25°C (77°F) can accelerate degradation.

Protect from moisture – oxaloacetate is susceptible to hydrolysis. Tightly close container immediately after use to minimize exposure to air and humidity. Do not transfer to other containers unless specifically designed for oxaloacetate storage. Some manufacturers recommend storing unopened products in the refrigerator or freezer for maximum stability, but follow specific product guidelines.

Once opened, use within the timeframe recommended by the manufacturer (typically 1-3 months).

Heat – oxaloacetate rapidly decarboxylates to pyruvate at room temperature and above, Acidic environments – accelerate decarboxylation, Moisture – promotes hydrolysis and degradation, Light exposure – may accelerate degradation reactions, Oxygen – can promote oxidative degradation, Metal ions – particularly copper and iron can catalyze degradation, Enzymatic activity – certain enzymes can rapidly metabolize oxaloacetate, Time – even under optimal conditions, gradual degradation occurs, Freeze-thaw cycles – can disrupt stabilization matrices in some formulations

Synthesis Methods

Natural Sources

Quality Considerations

Oxaloacetate has a relatively short history as a dietary supplement compared to many traditional remedies, with its development closely tied to advances in biochemistry and molecular biology. The compound itself was first identified in the early 20th century as part of the groundbreaking work on cellular respiration and metabolism. In 1937, Hans Krebs and William Johnson elucidated the citric acid cycle (later known as the Krebs cycle or TCA cycle), in which oxaloacetate plays a crucial role as both the final product and initial substrate. This discovery, which earned Krebs the Nobel Prize in Physiology or Medicine in 1953, established oxaloacetate’s fundamental importance in cellular energy production.

Despite this early recognition of its metabolic significance, oxaloacetate remained primarily a subject of biochemical research rather than a therapeutic agent for many decades. Its extreme instability at room temperature and in acidic environments presented significant challenges for its use outside of laboratory settings. The first significant interest in oxaloacetate as a potential therapeutic agent emerged in the early 2000s, when researchers began investigating its role in glutamate metabolism. Studies in animal models of traumatic brain injury and stroke demonstrated that oxaloacetate could act as a blood glutamate scavenger, potentially reducing excitotoxicity and neuronal damage.

This research, led by Vivian Teichberg and colleagues at the Weizmann Institute of Science, opened new possibilities for oxaloacetate in neurological conditions. In 2009, a significant study published in Aging Cell by Williams and colleagues showed that oxaloacetate supplementation extended lifespan in Caenorhabditis elegans (nematode worms) through mechanisms similar to calorie restriction. This finding sparked interest in oxaloacetate as a potential calorie restriction mimetic and anti-aging compound. The development of stabilized oxaloacetate formulations in the late 2000s and early 2010s was a crucial breakthrough that made oxaloacetate supplementation practically feasible.

These technological advances addressed the compound’s inherent instability, allowing it to be formulated into supplements with reasonable shelf life. Around 2012-2014, commercial oxaloacetate supplements began appearing on the market, primarily marketed for brain health, anti-aging, and metabolic support. These products typically used proprietary stabilization technologies to prevent the rapid degradation that occurs with raw oxaloacetate. In 2014, a study by Wilkins and colleagues at the University of Kansas demonstrated that oxaloacetate supplementation in mice activated brain mitochondrial biogenesis, enhanced insulin signaling, reduced inflammation, and stimulated neurogenesis.

This research further expanded interest in oxaloacetate’s potential applications for brain health and neurodegenerative conditions. More recently, clinical research has begun to explore oxaloacetate’s potential in human health. A 2020 study showed benefits for emotional symptoms in premenstrual syndrome, and a 2021 Phase 1 clinical trial examined its safety and target engagement in Alzheimer’s disease patients. Throughout its brief history as a supplement, oxaloacetate has remained somewhat niche compared to more mainstream nutrients, likely due to its relatively high cost, stability challenges, and the technical complexity of its mechanism of action.

Nevertheless, it continues to be studied for its potential benefits in neurological health, metabolic function, and longevity.

No comprehensive meta-analyses specifically on oxaloacetate supplementation have been published, Some reviews have included oxaloacetate as part of broader analyses of TCA cycle intermediates and metabolic enhancers

Investigations of oxaloacetate for neurodegenerative conditions including Alzheimer’s disease, Studies on oxaloacetate’s potential role in traumatic brain injury recovery, Research on oxaloacetate’s effects on metabolic health and insulin sensitivity, Trials examining oxaloacetate’s potential in mood disorders and stress-related conditions