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Oxaloacetate Supplements: Early Research + Side Effects

Written by Jasmine Foster, BS (Animal Biology), BEd | Reviewed by Ana Aleksic, MSc (Pharmacy) | Last updated:
Medically reviewed by
Jonathan Ritter, PharmD, PhD (Pharmacology), Puya Yazdi, MD | Written by Jasmine Foster, BS (Animal Biology), BEd | Reviewed by Ana Aleksic, MSc (Pharmacy) | Last updated:

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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, but studies on worms cannot and should not be extrapolated to human health [4, 5].

That’s one of the reasons why these supplements are controversial. Others include the fact that 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, let alone people [6].

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” [7].

With all this in mind, it’s not surprising that research into oxaloacetate has been highly contentious.

Mechanism of Action

The Citric Acid Cycle

The citric acid cycle, otherwise known as the Krebs cycle (or tricarboxylic acid cycle), is one of the cell’s primary means of energy production [8, 1].

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 [8].

NAD & NADH

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 [4].

High levels of NAD, relative to NADH, may 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 in animal models [10, 4].

Glutamate Scavenging

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 could help prevent 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 and determine whether glutamate scavenging is relevant to human health [1].

Snapshot

Proponents:

  • Part of the body’s natural energy system
  • Protects the brain from toxins and injury
  • May increase lifespan and prevent age-related disorders
  • May lower blood sugar
  • May prevent PMS
  • May protect the heart and kidneys

CONs

  • May worsen the symptoms of Parkinson’s disease
  • Few clinical studies for any benefit
  • Many claims with no human studies at all
  • Many assumptions based on animal studies (including worms)
  • High risk of bias in prominent studies
  • Difficult to stabilize in supplement form
  • Expensive
  • Better alternatives available for most health goals

Potential Benefits with Insufficient Evidence

Researchers are investigating whether oxaloacetate supplements could have benefits to human health, but clinical trials are either lacking or contradictory. The FDA has furthermore not approved oxaloacetate supplements for any medical purpose or health claim.

Better-studied alternatives are available for all of the health benefits oxaloacetate is purported to have. We recommend talking to your doctor about these alternatives before adding any new supplements to your regimen.

1) 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 [13, 1].

Limited human studies suggest that 100 to 1,000 mg of oral oxaloacetate salt may reduce blood glucose, increase insulin sensitivity, and improve symptoms in people with diabetes [14, 15].

Note that these claims are controversial. A human safety study found that 200 mg per day of oral oxaloacetate did not significantly affect levels of oxaloacetate in the blood [16].

Much more research is therefore required to determine whether oxaloacetate supplements could be useful in controlling blood sugar.

Animal Research (Lacking Evidence)

No clinical evidence supports the use of oxaloacetate for any of the conditions listed in this section. Below is a summary of the existing animal and cell-based research, which should guide further investigational efforts. However, the studies listed below should not be interpreted as supportive of any health benefit.

We recommend strongly against attempting to use oxaloacetate for any of the health claims discussed below. Talk to your doctor about the many better-studied alternatives available.

2) 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, 17].

The degree to which this may be applicable to oxaloacetate as a supplement is unclear.

Pesticides

Organophosphates are toxic chemicals used as pesticides. Malathion, for example, is commonly used to control insects and treat head lice and scabies [18, 19, 20].

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 [11].

Glutamate appears to be the culprit behind the seizures and secondary damage. Some authors have therefore suggested that 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 [11].

This strategy is called “blood glutamate scavenging” and some researchers believe that it may become an important tool in the management of pesticide poisoning [11].

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 [21].

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 [12].

Stroke

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 [22].

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 [22].

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 [23].

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 [24].

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 [24].

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 [25].

Much more research is required to determine whether oxaloacetate has a role in managing Alzheimer’s and Parkinson’s diseases.

3) 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 [15].

Is it true? Can oxaloacetate make you live longer?

In Caenorhabditis elegans, a species of worm often used to study aging, oxaloacetate increased lifespan by 13% on average [26, 4, 5].

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 [26, 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 [27].

In a study of mitochondria, oxaloacetate protected an enzyme called citrate synthase, levels of which drop with aging [28].

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 [6].

In short: some early research suggests a link between oxaloacetate and longevity, but there isn’t nearly enough evidence to recommend taking oxaloacetate. Any supplement bottle’s promises of a longer life are a stretch at best and deliberately misleading at worst.

4) 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 [29].

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 [29, 30, 31].

According to this hypothesis, PMS (and its more serious cousin, premenstrual dysphoric disorder) are caused by energy deficits in the parts of the brain that govern self-control [29, 30, 31].

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 [32].

5) Metabolism

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 [33].

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 [4].

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 [34, 35].

Cancer Research

According to some researchers, oxaloacetate may have 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 [36].

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 may stop it from growing and make it more sensitive to chemotherapy and radiation [37, 38].

In mice, oxaloacetate reduced glutamine breakdown and decreased cancer cell growth rates. It may also, therefore, make chemotherapy and radiation treatments more effective [37].

Oxaloacetate may also reduce the growth of tumors by selectively blocking mitochondrial complex II, which may starve cancer cells of energy [39, 40].

This early research is not grounds to use oxaloacetate supplements if you are undergoing cancer treatments. Talk to your doctor about better-studied complementary approaches.

Taking Oxaloacetate

Supplements

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. However, these supplements have not been evaluated by any third party labs, so there’s no way to be sure of what’s actually in them.

Most oxaloacetate supplements also list several other compounds in their ingredients, such as vitamins C and B12.

Food Sources

Oxaloacetate is present in some foods, but not in high enough levels to impact health. It is also highly unstable and readily degrades over time [6, 24].

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.

Dosage

There is no safe and effective dose of oxaloacetate because no significantly powered study has been conducted to find one.

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, 16].

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.

Side Effects

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 [14, 16].

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 [42].

No safety studies have investigated the effects of oxaloacetate on children, pregnant or breastfeeding women. We therefore advise strongly against taking oxaloacetate supplements if you are pregnant or breastfeeding.

Limitations and Caveats

Oxaloacetate supplements suffer from a severe 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.

Takeaway

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. However, few of this compound’s purported benefits have been demonstrated in mammals, let alone humans.

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.

The evidence for oxaloacetate’s benefits is sparse and the product is expensive. For each of the potential benefits discussed in this post, better options are available.

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About the Author

Jasmine Foster

BS (Animal Biology), BEd
Jasmine received her BS from McGill University and her BEd from Vancouver Island University.
Jasmine loves helping people understand their brains and bodies, a passion that grew out of her dual background in biology and education. From the chem lab to the classroom, everyone has the right to learn and make informed decisions about their health.

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