It’s a natural part of your energy metabolism. Its proponents claim that it will increase your lifespan. But can it be stabilized for long enough to make a difference? What can oxaloacetate really do? Read on to find out.
What Is Oxaloacetate?
Oxaloacetate, an organic molecule, is part of the body’s energy production and waste management systems. It is absolutely essential in infant development; a genetic deficiency in the enzymes that make oxaloacetate can cause serious neurological problems and developmental delays [1, 2, 3].
Researchers have only just begun to unlock its therapeutic potential. In a handful of studies on worms, oxaloacetate was found to significantly increase lifespan. These studies, among others, have led to a minor surge in oxaloacetate supplementation [4, 5].
However, these supplements are controversial: oxaloacetate is very difficult to stabilize, oral supplements may not be well absorbed, and the worm studies have yet to be repeated in higher animals .
What’s more, the company that manufactures most oxaloacetate supplements has a history of violating FDA regulations regarding the marketing and sale of “new drugs” and “medical foods” .
With all this in mind, research into oxaloacetate has been promising, and this compound may have several medical applications.
Mechanism of Action
The Citric Acid Cycle
Oxaloacetate sits between malate and citrate in the cycle. Malate is transformed to oxaloacetate when it donates a hydrogen atom to NAD to make NADH; NADH then goes on to help generate energy from sugar. An enzyme called pyruvate carboxylase can also convert pyruvate into oxaloacetate [8, 9].
Oxaloacetate can transform into citrate (part of the cycle) or any one of six amino acids .
In the citric acid cycle, malate donates hydrogen to NAD to make oxaloacetate and NADH. However, this reaction also takes place in the reverse: oxaloacetate takes a hydrogen atom from NADH to make malate and NAD .
High levels of NAD, relative to NADH, support other age-related mechanisms in the cell. These include the sirtuins and AMPK, which have been linked to increased lifespan and reduced rates of degenerative diseases [10, 4].
Oxaloacetate reduces glutamate levels by breaking it down (to α-ketoglutarate).
More specifically, when oxaloacetate and glutamate encounter an enzyme called glutamate oxaloacetate transaminase (or GOT), the enzyme transforms them both, and they emerge as aspartate and α-ketoglutarate. In medical research, this is called glutamate scavenging, and it prevents high levels of glutamate from building up in the brain and becoming destructive [11, 12].
This mechanism is somewhat controversial. One study found that oxaloacetate protected against cell death from hydrogen peroxide, but not from glutamate. Future research will work out these contradictions .
- Part of the body’s natural energy system
- Protects the brain from toxins and injury
- May increase lifespan and prevent age-related disorders
- May support cancer treatments
- May lower blood sugar
- May prevent PMS
- May protect the heart and kidneys
- May worsen the symptoms of Parkinson’s disease
- Few clinical studies
- High risk of bias in a prominent study
- Difficult to stabilize in supplement form
Uses & Benefits of Oxaloacetate
1) Protects the Brain
Glutamate is an important neurotransmitter; however, large quantities of glutamate can contribute to brain damage. Oxaloacetate, in combination with an enzyme called glutamate oxaloacetate transaminase or GOT, breaks down glutamate (into 2-ketoglutarate and aspartate) [11, 13].
About a million people suffer from organophosphate pesticide poisoning every year. These poisons cause seizures, brain and nerve damage, and – in hundreds of thousands of cases – death .
Glutamate appears to be the culprit behind the seizures and secondary damage. Thus, oxaloacetate may protect the nervous system from the worst effects of pesticide poisoning. In a rat study, an injection of oxaloacetate and the human GOT enzyme reduced blood glutamate and protected against brain damage .
This strategy is called “blood glutamate scavenging” and it may become an important tool in the management of pesticide poisoning .
Traumatic Brain Injury
After traumatic brain injury, glutamate levels rise and neurons die. In a rat study, a high dose of intravenous oxaloacetate reduced cell death and protected the animals’ brains .
A second rat study confirmed this effect; it also demonstrated that combining oxaloacetate with two other compounds (pyruvate and lipoamide) dramatically decreased glutamate in the brain .
Subarachnoid hemorrhage (SAH) is one of the most dangerous types of stroke, with nearly half of patients dying in the first month after the event. Glutamate is likely responsible for severe brain damage in such cases .
In rats, intravenous oxaloacetate reduced blood glutamate by half in the first 90 minutes after stroke. The treatment also protected the blood-brain barrier and reduced the amount of lasting damage in the rat brain .
The effect of oxaloacetate has not been studied in human stroke victims. However, high levels of the glutamate-degrading GOT enzyme predict better outcomes for people who have suffered a stroke .
Alzheimer’s and Parkinson’s Diseases
Alzheimer’s disease is a complex degenerative disease that changes the brain in many ways. People with Alzheimer’s have fewer mitochondria, reduced insulin and increased inflammation in their brains .
In rats with Alzheimer’s disease, oxaloacetate encourages the formation of new mitochondria, activates insulin signaling, and reduces brain inflammation. It may even promote the birth of new neurons .
This effect has not been studied in human trials. Furthermore, in a small clinical trial, nearly 40% of participants receiving oxaloacetate supplements experienced a worsening of Parkinson’s disease symptoms, though none of these symptoms were considered severe .
Much more research is required to determine whether oxaloacetate has a role in managing Alzheimer’s and Parkinson’s diseases.
2) May Increase Lifespan
Commercial oxaloacetate supplements often come with claims that they will increase the lifespan of their users. Terra Biological LLC, which manufactures the oxaloacetate supplement benaGene, has even published its own study claiming that their product extends lifespan by imitating the effects of calorie restriction .
Is it true? Can oxaloacetate make you live longer?
Oxaloacetate also reduces the formation of a compound called methylglyoxal, which damages proteins and organelles within cells. And this compound impairs wound healing, which can be especially dangerous for diabetics [23, 4, 5].
Interestingly, methylglyoxal is also what lends manuka honey strong bacteria-fighting properties; at the same time, it hints at this honey’s dark side .
In a study of mitochondria, oxaloacetate protected an enzyme called citrate synthase, levels of which drop with aging .
Researchers have not yet duplicated these protective effects in live mammals such as mice, rats, or humans. In one study, mice supplemented with oxaloacetic acid did not live longer than the controls. However, oxaloacetate is notoriously unstable and degraded significantly before the mice could consume it in their feed .
In short: some early research suggests a link between oxaloacetate and longevity, but there isn’t enough evidence yet. Any supplement bottle’s promises of a longer life are a stretch at best.
4) Supports Cancer Treatment
Oxaloacetate has some potential as a supportive therapy in the treatment of brain cancer. Brain tumors thrive when glutamate levels are high; in mice and rats, oxaloacetate reduced glutamate, shrank tumors, and improved survival rates .
In an aggressive type of pancreatic cancer, cancer cells break down the amino acid glutamine to accelerate their growth. In this and several other types of cancer, blocking the tumor’s ability to use glutamine can stop it from growing and make it more sensitive to chemotherapy and radiation [27, 28].
In mice, oxaloacetate reduced glutamine breakdown and decreased cancer cell growth rates. It may also, therefore, make chemotherapy and radiation treatments more effective .
5) May Lower Blood Sugar
Oxaloacetate is central to energy use in all known living things. It is part of the citric acid cycle, also known as the Krebs cycle (or tricarboxylic acid cycle), which releases the energy stored in carbohydrates, fats, and proteins [31, 1].
Note that these claims are controversial. A human safety study found that 200 mg per day of oral oxaloacetate does not significantly affect levels of oxaloacetate in the blood .
6) Premenstrual Syndrome
Nearly half of all women on the planet suffer some form of PMS or Premenstrual syndrome; in some countries, such as Iran, it is almost universal .
Scientists don’t fully understand what causes PMS, but they have some ideas. One possibility is that, because menstruation is such an energy-intensive process, glucose metabolism shifts toward the reproductive system and away from other systems – including the brain [34, 35, 36].
At least one oxaloacetate supplement is sold with claims of reducing PMS symptoms: its manufacturers say that it supports glucose metabolism and scavenges glutamate in the brain. One clinical trial of 48 women was reported as complete in April 2018. However, the results have not been posted, and no other studies support these claims .
6) May Imitate Caloric Restriction
Caloric restriction – or, deliberately reducing food intake – has been shown to prevent age-related disorders and increase longevity in many animals, including mice and primates. Some compounds, including antioxidants like resveratrol, imitate the effects of caloric restriction by activating similar pathways in the body .
Oxaloacetate may boast a similar effect. In one C. elegans worm longevity study, oxaloacetate activated a signaling pathway associated with caloric restriction and longer life .
If oxaloacetate mimics caloric restriction in humans as it does in C. elegans, it may reduce the risk of heart and kidney diseases. However, no studies have yet drawn a direct connection between oxaloacetate and these risks [39, 40].
How to Use Oxaloacetate
Oxaloacetate is available in capsule form. One company, Terra Biological LLC, claims to have developed a method for stabilizing oxaloacetate and making it bioavailable when taken orally. This company manufactures benaGene and Jubilance, the most prominent oxaloacetate supplements on the market.
Oxaloacetate Food Sources
Your body can also make oxaloacetate from malate or malic acid – at least in theory.
Malic acid is what gives fruits and some vegetables a sour taste. It was first discovered in apples, but a wide range of fruits contain it. These include grapes, mangos, pears, oranges, and many more. Whether these foods can boost oxaloacetate levels is unknown.
Oral supplements are typically sold at a dosage of 100 – 200 mg per day. Pilot studies have tended to use doses in this range, which are generally well tolerated. However, some researchers suggest that 200 mg of oral oxaloacetate has very little effect on the levels of oxaloacetate in the blood, suggesting that higher doses should be studied [41, 33].
Most animal studies demonstrating the health benefits of oxaloacetate used injections directly into the body cavity or the veins. Oral supplements have not been studied as extensively.
No adverse effects have been reported in clinical studies of diabetic people using doses of up to 1,000 mg per day. One study found that doses of 200 mg per day had no effect on blood levels whatsoever [32, 33].
In a small clinical trial of oxaloacetate and Parkinson’s disease, 7 out of 18 (39%) people reported that their symptoms had gotten worse, compared with 1 out of 15 (7%) taking the placebo. If you have Parkinson’s disease, it may be wise to avoid oxaloacetate until further research is conducted .
No safety studies have investigated the effects of oxaloacetate on children, pregnant or breastfeeding women.
Limitations and Caveats
Oxaloacetate supplements suffer from a lack of reliable research to back up the claims on the bottle.
Many of the reported health benefits have only been studied in cells, worms, or (at best) rodents. Furthermore, in these studies, the cells or animals tend to be either submerged in or injected with oxaloacetate; these results cannot be translated with confidence to oral supplementation.
Human studies are few and far between, and some of them are decades old with outdated methodology. Existing recent studies are small, not particularly powerful, and at high risk of bias. When people recommend oxaloacetate supplements, they often cite a single study the founder of Terra Biological, which manufactures benaGene and Jubilance. His conflict of interest is clear.
Note, again, that oxaloacetate is extremely difficult to stabilize. Researchers have struggled to keep it from spontaneously degrading in animal feed. Neither Terra Biological LLC nor any other company have disclosed their methods for stabilizing oxaloacetate. No oxaloacetate supplement has been independently evaluated by a third party.
Reviews & User Experiences
Reviews are mostly positive, with just over half of users giving their oxaloacetate supplements five stars. Most people use it to boost brain health, stabilize blood sugar, and control the symptoms of PMS.
People who used oxaloacetate for brain health felt that it reduced brain fog and increased energy. Some people even report feeling younger and more lively.
Women who use it to reduce PMS symptoms report feeling less anxious and more in control after a month of taking oxaloacetate.
However, a significant number of people reported no effect; some suspect that this supplement is no better than a placebo.
Many people complain that oxaloacetate supplements are very expensive for the amount of benefit they may provide. Less expensive options are likely to be available for most, if not all, of the benefits listed.
Buy Oxaloacetate Supplements
Oxaloacetate is a vital part of the body’s energy production machinery. In worms, it extends lifespan, which has made it an interesting target of longevity research. It may protect the nervous system from poisoning and injury; it may also support cancer treatment, reduce blood sugar, and imitate the effects of caloric restriction.
In the human body, oxaloacetate increases the NAD to NADH ratio, which activates other pathways associated with a longer life. It also may “scavenge” glutamate to reduce the risk of brain damage.
However, these effects may only appear with oxaloacetate injections; oral supplements are highly unstable and may not be well absorbed. There are also no significant food sources of oxaloacetate.
Some users claim to feel the benefits of taking oxaloacetate supplements, but the evidence is sparse and the product is expensive. For most, if not all, of the potential benefits discussed, there’s probably a better option than oxaloacetate.