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ABOUT THE CO-AUTHOR

This post was written by Tomer Aviad, Chemical engineer (BA)

Bio:I’m a science geek who loves sports and am interested in nutrition science as well as experimenting with nutrition and supplements in my life.

Over the last few years I’ve been particularly interested in human metabolism and run my own blog (in Hebrew) in addition to a facebook group (also in Hebrew).

There I talk about complex nutrition issues, physiology and health more generally. I use an engineering approach and apply critical thinking to solve the “mysteries” surrounding our physiology and hoping to find more questions than answers.

ABOUT THE CO-AUTHOR

I co-founded Breaknutrition.com in 2017 to break down health and nutrition myths whilst building an interdisciplinary scientific hub for medical professionals, dietitians, research scientists and the public to continuously learn from one another. I’m responsible for all the scientific content up on Breaknutrition.com.

I’m Raphi Sirt on Facebook, @raphaels7 on Twitter and raphaels711 on Instagram.

 

What you will learn

#1 The crucial roles oxaloacetate plays in your metabolism

#2 How oxaloacetate largely determines if you’re in or out of nutritional ketosis

#3 If, in the future, oxaloacetate supplementation could help ketogenic dieters

1. Oxaloacetate definition

Simply put, an oxaloacetate definition states that it is a small molecule almost every cell in your body must have to produce ATP, the energy currency used by those cells. Oxaloacetate is an organic acid, something you’re probably familiar with through vinegar, the main component of which is the organic acid called acetic acid.

A more complete oxaloacetate definition will point out that it’s super important to human health. So how do we make sure we get enough? Well, it’s found in food but in insignificantly small amounts.

This is because cells from animals and plants only use very small amounts of oxaloacetate, so small in fact it’s measured in nanogram concentrations. Plus, it’s highly ‘unstable’, meaning that in 24 hours at room temperature it will break down (decarboxylate) to something else (pyruvate).

Not to worry though, our bodies makes its own oxaloacetate using the amino acid malate in combination with ‘energy carrying molecules’ (NAD+/NADH) and the molecular machine (enzyme) called malate dehydrogenase.

So to meet your oxaloacetate needs make sure your diet contains generous amounts of animal foods (e.g. fish and eggs) as to provide the amino acids (from protein) and fatty acids (from fats) that together, provide the machinery and building blocks (precursors) required for making oxaloacetate.

Carbohydrates like fruit and potatoes can also provide the precursors from which oxaloacetate can be made.

2. Oxaloacetate structure

Chemically speaking, the oxaloacetate structure is pretty simple having only 4 carbons, 4 hydrogens and 5 oxygens (C4H4O5).

Oxaloacetate also goes by a few different names. Its ‘alias’ is 3-Carboxy-3-Oxopropanoic Acid and it’s CAS name (or Chemical Abstract Service name) is 2-oxobutanedioic acid. It’s useful to know in case you come across an oxaloacetate supplement that’s…not really an oxaloacetate supplement.

The oxaloacetate structure is key to understanding why it can be used in so many crucial processes, like

  • making  amino acids (forming proteins for strong bones and muscles)
  • running the TCA cycle (to keep up cellular energy supply)
  • making glucose (via gluconeogenesis to keep your brain happy)
  • making fatty acids (also keeping brain happy)
  • turning fats into carbs (via the glyoxylate cycle)
  • and keep the urea cycle turning (helping you pee out toxic ammonia, a natural byproduct of every-day metabolism)

3. How does oxaloacetate play its metabolic part?

Oxaloacetate is what’s called an “intermediate” of the citric acid cycle (TCA or Krebs). The latter is like the main roundabout or air-traffic control hub directing energy-carrying molecules molecules towards their destinations.

TCA intermediates are the building blocks feeding into the TCA cycle necessary to keep it going. In a sense, these intermediates are like the cargo (goods and people) carried by planes, without which airports would come to a standstill.

So what does oxaloacetate do in all this, specifically? It reacts with acetyl-CoA, the thing that ultimately gets oxidized by cell’s energy factories (mitochondria) giving you ATP (energy).

That we predominantly make our energy using acetyl-CoA by passing it through our mitochondria is true whatever diet you eat, whether you’re on a low-fat vegan diet or on a high-fat ketogenic carnivorous diet – most of your energy ends up as acetyl-CoA that gets oxidized in mitochondria to produce ATP.

When oxaloacetate reacts with acetyl-CoA, the immediate effect before leading to ATP is to form citrate. TCA is a cycle so things are used and reused and citrate must be formed for the cycle to keep turning.

Of course this cycling has ‘running costs’, which are either paid for directly by the food you eat or by your on-board energy reserves; stored carbs in muscle and liver glycogen or stored fat in adipose tissue.

At the cellular level, oxaloacetate is sourced from pyruvate (think of it as half a glucose molecule). Once formed oxaloacetate can contribute to the biosynthesis (making) of new amino acids by providing a non-essential amino acid called Aspartate.

Aspartate can in turn be transformed into 4 other kinds of amino acids: the essential ones Methionine, Lysine and Threonine and the non-essential Asparagine.

When not contributing to amino acids, oxaloacetate can react (or condense) to form citrate. Having enough citrate allows the TCA cycle to keep running. If not contributing to amino acid or citrate synthesis, oxaloacetate be transformed to phosphoenolpyruvate and thus contribute to the creation of glucose crucial to certain of your brain cells or red blood cells for instance.

The picture below shows the different fates that awaits oxaloacetate according to moment to moment needs.

This brings us to a persistent myth that pervades nutrition science and exercise physiology (sports science). Its taken the form of the mantra “fat is burned in the flame of carbohydrates”.

Let me fix that for you.

So it should be “fat is burned in the flame of oxaloacetate”. Part of the confusion arises from the fact that carbohydrates (glucose) can end up as pyruvate (half a glucose) which can then be turned into oxaloacetate by an enzyme (pyruvate carboxylase).

Some of the confusion may also have been somewhat sneaky. This myth has been a convenient way of convincing people of the falsehood that low-carb diets negatively impact one’s ability to burn fat because they don’t supply enough glucose to burn fat, supposedly.

This would be of great concern to endurance athletes and obese choosing a weight-loss diet, both of which are big markets for the low-fat low-nutrient junk food industry.

4. Oxaloacetate supplement

Although oxaloacetate is unstable at room temperature, we can still take an oxaloacetate supplement. So why might it help? The basic idea is that it’s an anti-ageing molecule.

It would work by making more oxaloacetate available to your cells, in turn supplying the TCA cycle more plentifully and thus enabling a more fat to be burned (oxidized). An increased ability to ‘mobilize fat stores’ to rely on it for energy is considered a crucial anti-ageing ‘skill’ [1].

In dogs, an oxaloacetate supplement raised the rate of fat burning such that the need for circulating glucose dropped dramatically and was reflected by a glucose curve that would otherwise be considered too low (hypoglycemic) [2].

In humans, the same oxaloacetate supplement lowered blood sugar levels in type 2 diabetics. It’s unclear how it accomplished this, although it might have by stimulating insulin secretion or increasing insulin sensitivity [3]. The same study showed that 3 times more glucose was taken up by animals given oxaloacetate and 1.8 times more so in non-diabetic animals, suggesting that increased sensitivity to insulin is part of the mechanism – a good thing if true.

An oxaloacetate supplement has also been patented [4] as a means to increase lifespan according to certain animal experiments where it was shown to activate something called AMPK, a protein that’s appears quite active in animals with increased longevity.

By supplementing with oxaloacetate, it is thought that this will mimic what it does inside cells: increase the NAD+/NADH ratio that can then activate AMPK. This AMPK activation has sometimes been termed the “starvation” signal – not a very useful name if you ask me given it can be ‘ON’ even when well fed, depending on what you eat.

Dose and toxicity

Dose matters, so what dose of oxaloacetate might you want to try? One study was trying to supplement oxaloacetate to help with Alzheimer’s used 100 mg twice a day [5]. Although this dose seemed safe, the study failed to show improvements in the condition. The authors of the study think it’s because the dose was too low, not because oxaloacetate can’t work.

Toxicity has been checked in humans up to 1,000 mg (1 g) per day with no adverse events [6]. 100 mg appears to have been ineffective for seeing improvements in cognition so half of the maximal safety dose tested, around 500 mg, might be worth trying at first.

5. An oxaloacetate supplement for ketogenic diets?

Can an oxaloacetate supplement can be beneficial is ketogenic diet? This might seem like an odd question at first, since to get into ketosis what one is effectively doing is lowering the ratio of oxaloacetate to acetyl-CoA.

So how would increasing that ratio, by supplying oxaloacetate, still give people the benefits of ketogenic diets.? The idea is that by supplementing more of the ‘flame’ (oxaloacetate) that promotes fat burning (use of acetyl-CoA) this lowers the need to do so by drawing on your own amino acids stored in muscle tissue, a precious resource. You would still have to keep dietary carbohydrates very low, since carbs raise insulin the most compared to the 2 other available macronutrients protein and fat. Keeping a low insulin level this way is crucial to tipping the scales in favor of more acetyl-CoA relative to oxaloacetate.

The reason given for why supplementing oxaloacetate wouldn’t kick you out of ketosis is because you’d still keep insulin low enough to draw enough fat out of your body fat stores and thus end up with an ‘excess’ of acetyl-CoA relative to oxaloacetate. The caveat being that you must keep dietary carbohydrates very low, since carbs raise insulin the most compared to the 2 other macronutrients protein and fat.

Some people on a ketogenic diet who fancy themselves as biohackers have gambled on an oxaloacetate supplement to test whether or not it can help maintain muscle mass or even pack on some muscle. More commonly perhaps, some hope it will improve their insulin sensitivity, as reflected in their at-home glucose monitor or lab fasting blood glucose values.

The word gamble is used advisedly given the lack of research on this supplement, a fact that’s a bit disappointing given the important role the actual molecules plays inside our human metabolism.

Nevertheless, oxaloacetate appears relatively safe and could be a worthwhile supplement to try for a short time, so if you do use it we’d be curious to see what it did for you or didn’t do.

Remember that it can change blood sugar levels and many people out there do have blood sugar control issues, so please be smart about this and ask your physician before starting such an experiment.

 

Takeaways

#1 Oxaloacetate is a crucial molecule in your metabolism

#2 Oxaloacetate has been studied as life-extension molecule and to treat metabolic disorders with promising (but early) results

#3 Maybe oxaloacetate can helping ketogenic dieters spare protein

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