Oxaloacetate is an organic molecule and plays a huge role in the body’s energy production and waste management systems. It’s considered to be an essential element in infant development since a genetic deficiency in the enzymes that make oxaloacetate could be the cause of neurological problems and lead to delays in development.

The research for its therapeutic potential is still not very vast, but more and more studies started to examine this molecule recently. Most of the studies so far were done on worms and the results showed that oxaloacetate could significantly help increase lifespan. These studies, among others, have led to a minor rush in oxaloacetate supplementation.

However, studies on worms cannot and should not be deduced to human health without further research.

These supplements are still considered very controversial, and this was one of the reasons for that. Some other reasons could be that oxaloacetate is very difficult to stabilize, oral supplements can be risky when it comes to absorption, and the worm studies aren’t yet tested on other animals, and most importantly, people.

Also, all the research regarding oxaloacetate has been very controversial because the company that produces most of the oxaloacetate supplements has a history of violating FDA regulations regarding the marketing and sale of “new drugs” and medical foods.

What Are the Sources and Composition of Oxaloacetate

Structure and Sources

Oxaloacetate is the name for the molecule 3-carboxy-3-oxopropanoic acid and it is very similar to oxaloacetic acid (Although, this depends on the acidity of oxaloacetate). It is also a metabolic intermediate in a big number of processes that occur in animals. It has a role in gluconeogenesis, the urea cycle, amino acid synthesis, fatty acid synthesis, and the citric acid cycle.

Oxaloacetate is essentially formed by the carboxylation of pyruvate when it reacts with the catalyzed biotin-dependent enzyme pyruvate carboxylase.

Some of the foods that contain the molecule are daikon radish, sacred lotus, cucurbita fruits, and estragon.

Physicochemical Attributes

In a study where mice were included, mixing oxaloacetate into chow led to a time-dependent decrease in OAA content at 4°C after 22-28 weeks, where the initial concentration of 479-555ppm detected after about 2-5 weeks was reduced to 281ppm (24 weeks) and then to 164ppm (28 weeks).

What Does Oxaloacetate Do In Your Body?

Oxaloacetate plays a role in the Kreb’s cycle and the stage that goes immediately before the formation of pyruvate (via pyruvate carboxylase) and immediately after the NAD+-consuming conversion from L-malate (via malate dehydrogenase).

The Kreb’s cycle is also known as the citric acid cycle, or tricarboxylic acid cycle, and it is one of the cell’s primary means when it comes to energy production. Oxaloacetate is located between malate and citrate in this cycle. Malate turns into oxaloacetate when it gives a hydrogen atom to NAD to make NADH. What happens next is that the NADH then goes on to help create energy from sugar. The enzyme called pyruvate carboxylase can also transform pyruvate into oxaloacetate.

Finally, oxaloacetate can turn into citrate (which is a part of the cycle) or in any of the six amino acids.

Oxaloacetate in Pharmacology

There is still little information on this topic, but some studies have shown that intracellular oxaloacetate can be taken up into the mitochondria in a few different organs.

For example, in a study with rats with Alzheimer’s disease oxaloacetate has shown promise in encouraging the formation of new mitochondria, activating insulin signaling, and reducing brain inflammation (Which are all common symptoms of Alzheimer’s). It has been shown that it can even promote the birth of new neurons.

In other studies, oxaloacetate contributed to the reduction of tumor growth by selectively blocking mitochondrial complex II, and this can lead to the starvation of energy for cancer cells.

Oxaloacetate and Neurology

Can Oxaloacetate prevent brain damage?

Glutamate is considered a very important neurotransmitter but large quantities of glutamate can lead to serious brain damage. Oxaloacetate, when combined with an enzyme called glutamate oxaloacetate transaminase or GOT, breaks down glutamate (into 2-ketoglutarate and aspartate). However, it is still unclear how applicable this can be when oxaloacetate is used as a supplement.

Oxaloacetate is also regarded as a glutamate scavenger alongside some other small molecules like pyruvate. In these cases, both small molecules are subject to enzymes (glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT)) which transform glutamate into metabolites of 2-ketoglutarate, aspartate, and alanine.

If larger doses are injected (1mM in rodents) of either oxaloacetate or pyruvate, then they can reduce serum glutamate by 30-40%, causing glutamate to move from a cerebrospinal fluid into peripheral circulation (indicative of reduced glutamate retained in neural tissue). The effects of oxaloacetate on glutamate seem to depend on the concentration, with maximal results at 1M (1,000mM) and almost no results at 0.01M (10mM). This characteristic is mostly due when following peripheral injections of oxaloacetate in rat models who suffered a traumatic brain injury.

Can Oxaloacetate cure cancer?

When talking about the role of oxaloacetate in neurology, it is frequently linked to its role in helping fight cancer since cancer cells break down the amino acid glutamine to accelerate their growth. In pancreatic cancer and several other types, blocking the tumor’s ability to use glutamine can help in reducing its growth and making it more sensitive to chemotherapy and radiation.

In studies with mice, oxaloacetate has notably reduced glutamine breakdown and played a role in decreasing cancer cell growth rates. It’s because of this reason that many experts think that it can make chemotherapy and radiation treatments more effective.

To summarize, because oxaloacetate is an endogenous molecule, it can sequester glutamate and reduce its activities. This conclusion was drawn off of studies where oxaloacetate was injected in rats. However, due to the high concentrations required it is still uncertain whether it be a relevant mechanism for oral supplementation. Studies using oral oxaloacetate currently are very rare and there haven’t been any concrete results so far.

Oxaloacetate and Muscle Growth

In the research that has been done so far, intraperitoneal injections of oxaloacetate (1-2g/kg) a day subchronically appears to embellish mitochondrial biogenesis in the brain of rodents, leading to greater glucose uptake by muscles.

Oxaloacetate’s role in Longevity and Life Extension

Oxaloacetate is believed to be able to promote longevity due to being an intermediate of the Kreb’s cycle of energy production. If there is any increase in the NAD+/NADH ratio, then it can promote longevity in yeast (which is also considered to be a huge component in caloric restriction).

Researchers believe this is because of the increased energy in the cell since increased NAD+ availability can stimulate overall Kreb’s cycle activity in C. elegans. Administration of oxaloacetate in C. elegans bolstered average (13%) and median (25%) lifespan and it had two comparable effects when tested for concentrations (2mM and 8mM). There were also similar effects with the metabolite pyruvate.

This conclusion was acclaimed to not change the food intake and appeared to be mediated by AMPK acting on the DAF-16 transcription factor, and it seemed to not be related to Sir2. Functions that were alike on the lifespan of C. elegans have been recognized with similarly structured Kreb’s cycle intermediates fumarate and malate even with the succinate being ineffective. This effect wasn’t noted in c. elegans because it lacked the ability to convert malate to fumarate (lacking the fumarase enzyme) or fumarate to succinate (succinate dehydrogenase flavoprotein).

This evidence suggests that the byproducts that were created in these reactions included FAD and NAD+ rather than the metabolites. A higher NAD+/NADH ratio is commonly used to activate AMPK.

In summary, providing intermediates to the Kreb’s cycle (TCA cycle) seems to increase NAD+ concentrations in the cell. An increase in longevity follows in nonmammalian subjects is most likely because of the increase in Kreb’s cycle activity overall.

This is an important step to understand that there is evidence in it improving longevity, but it still needs to be proved it works with humans. 

In mice, administration of varying concentrations of oxaloacetate in food (0.5-3.5g/kg dry weight) didn’t have much effect on the longevity although the authors noticed that oxaloacetate may have degraded to a degree (thought to be no more than 25% the intended amount) after being mixed in chow for a few weeks.
Because of this stability issue with oxaloacetate in the feed, more research is needed before experts can come to some solid conclusions.

Conclusion

Oxaloacetate plays one of the main roles in the body’s energy production. When tested on worms, it showed that it can extend lifespan, which has made it an interesting subject for longevity researchers. However, the benefits of this supplement have been tested only on mammals, so it’s still not clear what effect oxaloacetate might have on humans. So far, oxaloacetate has been shown to increase the NAD to NADH ratio in humans, which further activates other pathways that are linked to a longer life. It also may prowl glutamate to reduce brain damage risks. All of these effects have been caused by oxaloacetate injections, therefore oral supplements are still not researched enough to be prescribed to humans. There are also almost no food sources with high levels of oxaloacetate.