Ketones: Not Hippocrates' Food

If you've circulated in the realms of nutritional science or sorcery for any length of time, you've probably heard the phrase ...

Let food be thy medicine

and medicine be thy food

... enough for it to have long past turned to the point of cliché.   Whether or not it was actually said by Hippocrates notwithstanding, you've probably seen it misused as often as it is appropriately applied.   This post is about its misuse in the image below.

Starving cancer:  Dominic D'Agostino at TEDx TampaBay

The interpretation of the quote can certainly be stretched, but in actuality it has a rather simple, inflexible, meaning.   Basically food = medicine.   The contortions begin with redefining food beyond the obvious intent.  We would have to first, I suppose, define food, but one can also be reasonably confident that back in Hippocrates' day, "food" was a pretty straightforward concept.    This post is not a diet wars episode as to what constitutes real, appropriate, safe, proper, perfect, optimal, necessary, toxic, subsistence, preferred etc. food for a human being.  We don't need to answer any of those questions, hopefully anyway, or pick and parse to agree on the spirit of a definition:  food as medicine, medicine found in food.

Fast forward to our modern day, and if you Google this saying you're likely to find yourself on some "nourishing" or "wellness" site hailing the glories of some superfood.   These foods possess magical powers, owed to their miraculum content, but if you look behind the claims you quickly realize that these are often baseless, or at the very least wildly exaggerated truths.   I'm sure you've all seen the memes -- like this one for blueberries!

Even if there is some merit to the claims, the food itself will not contain anywhere near the dose of miraculum used in those worm eye culture studies that might be cited in support.  Rather, you'd have to consume a month's worth in one meal to consume 10% of this dose of miraculum.  Heck, let's use a real example:  resveratrol.  Scientific chicanery aside (I refer to the fraud), even legit claims of this compound's powers involve amounts found in wine that are so small you would end up taking up residence at your local alcohol detox unit should you try to source resveratrol from wine!

Enter concentrates, powders and extracts.  While many such preparations are "natural", and "traditional" or "ancient Chinese secrets" they still do not constitute food.   There's probably some leeway to be had here for teas and such, but work with me on the spirit of this all.  Once we get to the point of popping a pill, can we agree we're out of the realm of Hippocrates' meaning?   At least the consumption of superfoods embraces the spirit.   If we process that in any way so as to be able to consume more than could feasibly be consumed from the whole food, we've traveled down a different path.

Which brings me to the Incestral Health Community, the IHC, what with its heralding of the superior nutrient density of the foods promoted therein and in various factions.  Firstly, despite the food-based mantras, the in-yo-face premise of the IHC and the nutrition camps, is one of elimination.  Fill in the blanks: No _________________, avoid _____________.    It matters not what foods you use to fill the blanks ... grains, dairy, meat, legumes, eggs, nightshades, etc. etc.    Avoiding gluten may well be imperative for the celiac, and the only viable remedy at current time, but technically not eating a food doesn't quite qualify as "medicine".

Then we have ketones ...   

Further complicating the nutritional therapy landscape, we have ketogenic diets and the offshoots of ketone promoting foods and pre-formed exogenous ketones.   These really are three distinct types of nutrition-related types of therapy that  ought to be carefully designated and distinguished when being discussed.  The vast majority of applications involve the compound ß-hydroxybutyrate, often abbreviated as BHB or BOHB.  Briefly:

Ketogenic Diets:

These have been demonstrated to be effective in applications such as epilepsy and GLUT deficiency diseases.  While the exact mechanisms of action in epilepsy remain inconclusive, such diets do appear to work when ketone levels rise to amounts where there is substantial competition and/or substitution for glucose as a fuel source for certain cells, brain cells in particular.  Such diets all restrict carbohydrates, and often restrict, or at least control, protein and calorie intake as well.  Such diets force the body into producing ketones by evoking the starvation metabolism.  These self-made ketones are called endogenous.  
In other therapeutic applications -- e.g. obesity, diabetes and cancer -- there exists much inconsistency in outcomes and controversy over the role of the ketones themselves rather than the concurrent reductions in blood glucose or simple reduction in overall energy input.  
Regardless of the therapeutic mechanism at play, clearly the actual foods constituting the diet are not medicine -- it's more a metabolic trick on the body played by what foods are missing.  In the legit ketogenic diet community, nobody is claiming that cream cheese and mayonnaise are superfoods! And yet, one could make the case that keto diets best embody the spirit of Hippocrates:  cure through diet.

Exogenous Ketones

Within the past few years, the concept of acquiring ketones, specifically BHB, but also acetoacetate, directly has garnered considerable interest.  Whether to help ketosis-resistant folks achieve and maintain elevated ketones, or allow for ketosis in a less restrictive diet, exogenous ketones may be the solution.  
One of the major lines of research for exogenous ketones is not really related to health and medicine at all.   The most well known researcher  in this field within the IHC is probably Dominic D'Agostino, who began his research on exogenous ketones to help Navy SEAL divers using oxygen re-breathers.   While his findings may have relevance to epilepsy and other seizure disorders,  preventing seizures caused by use of equipment that recycles ones oxygen supply (vs. releasing bubbles into the water) is hardly a medical application relevant to everyday life.   In other words, D'Agostino's research  may help elucidate the mechanism(s) by which ketones work for epilepsy, but even then one would need to establish that relevancy to the "unnatural" state being studied.

BHB Salts and Ketone Esters

Consider the following quotes: 
  • The ketone esters are, hands-down, the worst tasting compounds I have ever put in my body. The world’s worst scotch tastes like spring water compared to these things. The first time I tried 50 mL of BHB monoester ... I didn’t stop gagging for 10 minutes. (I did this before an early morning bike ride, and I was gagging so loudly in the kitchen that I woke up my wife, who was still sleeping in our bedroom.)
  • The salts are definitely better, but despite experimenting with them for months, I was unable to consistently ingest them without experiencing GI side-effects; often I was fine, but enough times I was not...
Peter Attia
Founder & President of NuSI

Does this sound like food to you?   Sugar, soybean oil, cornstarch -- I could construct a long list -- these are components of processed foods, but are food nonetheless.  They are simply isolated and concentrated to some degree or another.  So too are the protein powders and products made with them peddled by seemingly every primal, paleo, ancestral marketeer out there.  How about branch-chain amino acids, BCAAs?  Well, we're veering for sure, but while dairy is high in BCAAs, and the whey fraction of dairy is particularly high in BCAAs, isolating them from other amino acids pushes the boundaries.  
But ketones are a step further.  These compounds are not isolated from foods as they are not present in them in any sort of appreciable quantity.  (I've seen claims about consuming ketotic animals, but think about that for just a bit and realize how infinitesimally small even a ketoacidotic animal's ketone concentration would be).  Rather, they are synthesized much like most of the pharmaceuticals and other "chemicals" are.   More on this in a bit.  
1,2 butanediol "jet fuel" -- Food?
Beta hydroxy butyrate salts -- Food?

Ketogenic Foods - Medium Chain Triglycerides

As if discussing ketones weren't "confusing" enough, there's one hybrid way by which one might boost their ketone levels through diet.   This is by consuming foods that promote ketone production irrespective of the carbohydrate content of the diet.  I'm not sure some exact "ketogenic power" has been compared in subjects under differing nutritional circumstances, but the dose-response relationship is far more likely to be related to caloric than carbohydrate nutritional state.  
Medium chain fatty acids (usually abbreviated MCFAs or triglycerides as MCTs) are the  saturated fatty acids of chains 6 to 12 carbons in length.  MCTs came on the nutritional radar for dealing with fat malabsorption issues as these fats sidestep the need for incorporation into chylomicrons.  Thus unlike long chain fatty acids (the vast majority of dietary fats), most MCFAs are retained and metabolized in the liver.  The main exception to this is the 12C lauric acid (which is 45-50% of coconut oil fatty acids) that is often incorporated into chylomicrons (and/or packed up by the liver into VLDL) and is present in higher concentrations in fat tissue of people consuming large amounts of coconut fat (e.g. see Table 6 here).  
The ketogenic MCTs are commonly the caprylic (8C) and capric (10C) fatty acids which are rapidly absorbed.  Since we apparently lack metabolic pathways to elongate these for storage (there appear to be no on ramps to the de novo lipogenesis pathway at these points) the liver must oxidize these and "excess" is not stored but rather converted to ketones for export to other cells to use the energy.  
I call this a hybrid:  Consuming MCTs is not the same as exogenous pre-formed ketones, but since most will be converted to ketones it's a pretty close second.  The conversion to ketones does not seem to depend on the nutritional state of the "Krebs apparatus" induced by carb/protein restriction (see this post for more).  If anyone has come across a study looking at metabolic fate of MCTs I'd be interested.
Bottom line to the point of this post is that MCT oil is more appropriately classed as a metabolic supplement than a food.  Isolating MCTs from coconut oil is hardly a simple processing such as skimming fat off of milk and churning butter fat from the cream, or to use a carbohydrate analogy, it's hardly as simple as boiling down tree sap to make maple syrup.   Keep in mind this is added to the already extensive process of making coconut oil and we've pretty much stretched the limits of qualifying as "food" already.    

So in summary:

  1. Ketogenic diets = Not food
  2. Exogenous ketones = Not food
  3. Ketogenic foods = Food but stretched definition

Before We Go ... 

This post was also prompted by the following quote from Dominic D'Agostino's appearance on Tim Ferriss' podcast (for which yes, there is still a post in progress!) 

At first, the idea of ketones as a macronutrient makes sense -- perhaps a fifth, with alcohol being the fourth.    But they are not.   Nutrients are something we consume as food.  Even if we wish to include some teas, broths, extracts and other processing of foods, we're still talking ingesting external substances to sustain life.  In the field of nutrition, the distinction is drawn between macro and micro.  
  • Macronutrients are classes of substances consumed for calories and structural needs:  fats, proteins, carbohydrates and alcohol.  
  • Micronutrients are pretty anything else qualifying as a nutrient:  vitamins, minerals, various sterols, flavanoids and whatnot.  Generally no or negligible caloric content, often consumed in trace amounts that are nonetheless physiologically important.
A nutrient is something you put in your mouth.  Our cells do not "eat" what we put in our mouths.    Even looking at metabolism of amino acids, fatty acids and glucose doesn't begin to cover it.  There are likely hundreds if not thousands of intermediate molecules that we ingest in small quantities in our foods because they are in all cells.  Like ... say ... pyruvate, or something more obscure like fumarate.   

It is nonsensical to consider the "diet" of your cell as being relevant to the diet you put in your mouth.  This is where you get the ridiculous statements like: "all weight loss diets are high fat because you are consuming your own fat".  No ... we are talking about what you put in your mouth.  Period.   So too, macronutrient refers to the energy molecules in your food.    So speaking of pyruvate, here's a short list of common metabolic intermediaries that I would say are somewhat equivalent to ketones:
  • pyruvate
  • acetyl-CoA
  • lactate
  • glutamine
These may not be equivalent, but there are a whole lot of regulatory loops and whatnot governing levels of these (and no doubt other) intermediates.  We could go to the ultimate cellular energy end -- why not bottle and consume ATP?   This, by the way, is happening already, but it is controversial whether the practice of consuming ATP directly alters the availability of ATP within the cells.   

Ketones (as a class, or the specific ones like BHB) are NOT a macronutrient.  They are not a normal constituent of food.  

Thus even if shown safe (and from a toxicity point of view thus far it looks good for BHB), the FDA is correct in categorizing ketones as a drug (I think it's more that they aren't considered "food" for the purpose of experimentation in animals and especially humans.)  

One more follow-up background-type post on ketones is coming before the -- now past due but gonna blog on it anyway -- post on the Ferriss/D'Agostino podcast.  It discusses the various mechanisms by which "ketones" are proposed to treat cancer.  Briefly we have the diets lowering glucose and/or insulin to starve the cells and/or disrupt growth signalling, and we have the less oft-cited idea that ketones may be toxic to cancer cells.   D'Agostino himself not only follows a ketogenic diet, but consumes both MCT products and exogenous ketones.   We can have the discussion in my post on his podcast as to the ins and outs of this.  But one thing we need to begin doing is distinguish between the nutritional approach (endogenous production via dietary restriction and/or endogenous production via dietary MCTs) or a pharmaceutical one.  

While beta-hydroxybutyrate, its salts or precursors is "natural" and generated in the human body, it is not a food or a macronutrient.  It is not something a human could or would seek out in nature for sustenance (unlike fructose!).  So are we really at a point where medical doctors and scientists are crusading to have sugar removed from lists of generally safe foods to be reclassified as toxic additives, there are some who consider gagtastic shots of synthetic chemicals, totally devoid of anything but calories, as a healthy supplement, food, or even superfood.  

Exogenous ketones show considerable therapeutic potential.  This is good.  Excellent even.  But they are not food, should not be considered food, and should be treated as such.   If they have cancer-cell killing properties, what is that if not "chemotherapy"?    Guess what?  Such therapies are starting to sound a lot like "conventional medicine" ... not food.