Ketosis in an evolutionary context

Humans are unique in their remarkable ability to enter ketosis.  They’re also situated near the top of the food chain.  Coincidence?

During starvation, humans rapidly enter ketosis; they do this better than king penguins, and bears don’t do it at all.

Starvation ketosis

 

Starvation ketosis

Humans maintain a high level of functionality during starvation.  We can still hunt & plan; some would even argue it’s a more finely tuned state, cognitively.  And that’s important, because if we became progressively weaker and slower, chances of acquiring food would rapidly decline.

Perhaps this is why fasting bears just sleep most of the time: no ketones = no bueno..?

Observation: chronic ketosis is relatively rare in nature.  Angelo Coppola interpreted that to mean animals may have evolved a protective mechanism against ketosis (if you were following along, please let me know if this is a misrepresentation).

 

But I think that is misguided.  Animals with a low brain/carcass weight ratio (ie, small brain) don’t need it.  Babies and children have a higher brain/carcass weight ratio, so they develop ketosis more rapidly than adults.  Is this a harmful process?  No!  It’s an evolutionary adaptation which supports the brain.

ketones age

The brain of newborn babies consumes a huge amount of total daily energy, and nearly half comes from ketones.  A week or so later, even after the carbohydrate content of breast milk increases, they still don’t get “kicked out of ketosis” (Bourneres et al., 1986).  If this were a harmful state, why would Nature have done this?  …and all those anecdotes, like babies learn at incredibly rapid rates… coincidence?  Maybe they’re myths.  Maybe not.




 

Ketosis in the animal kingdom

Imagine a hibernating bear: huge adipose tissue but small brain fuel requirement relative to body size and total energy expenditure.  No ketosis, because brain accounts for less than 5% of total metabolism.  In adult humans, this is around 19-23%, and babies are much higher (eg, Cahill and Veech, 2003Hayes et al., 2012).

A possible exception to this is ruminant ketosis, but that’s for a different reason.  They become ketotic because: 1) their gut turns much of what they eat into a ketogenic diet; and 2) this frequently happens during lactation, which combines very high energy expenditure and an enhanced draw on the oxaloacetate pool to make lactose.

Whales?  Nope.  Despite eating for like, 1 month out of the year, they don’t develop ketosis.

Snakes will enter ketosis, not due to high brain needs per se, but likely because even though small brain, total energy expenditure is so low that brain metabolism easily surpasses the [theoretical] 5% threshold (McCue 2006):

snake ketones

Fasting baby elephant seals get ketotic, because they’re babies (Castellini and Costa, 1990):

seals ketones

 

Hypercarnivores (eg, cats) don’t develop ketosis on very low carb diets, like humans would, which seems to be due to their inability to down regulate protein catabolism (urea cycle takes care of the nitrogen; gluconeogenesis the carbon)… but they will do so readily during starvation because of relatively big brains (Blanchard et al., 2002):

hypercarnivore

Similar to cats, dolphins are carnivorous and also exhibit what appears to be a pathological inability to reduce protein catabolism when necessary.  However, unlike cats, dolphins fail to develop ketosis of any sort, whether it’s on their typical low carb diet of fatty fish, or even complete starvation!

Dolphins are the exception to a lot of rules.  I don’t know why.  Most animals with big brains have the ability to enter ketosis, but none do it as well as humans.

 

 

Historically, while intermittent or cyclical ketosis was likely more common than nutritional [chronic] ketosis in humans, this doesn’t mean one form is better than another.  Common =/= optimal.

 

 

Starvation ketosis isn’t nutritional ketosis, but much of what we know about the latter stems from our understanding of the former… this is getting better, with more and more studies of longer and longer durations being published regularly.  And hint: chronic ketosis doesn’t dissolve bones, deteriorate cognitive function, or break your metabolism.

 

Are ketones the brain’s preferred fuel?

Well, let’s just say this: when there are more ketones than glucose, brain uses more ketones than glucose.  This happens in both starvation and nutritional ketosis.

brain fuels

Ketosis proportionately spares glucose utilization in the brain (Zhang et al., 2013)

ketones spare glucose

If ketones were harmful, Nature would’ve surely devised a way to protect the brain!

Disclosure: I’m not keto, not even very low carb in the summer really, so this obviously isn’t some sort of confirmation bias or logic fail or whatever you call it.  I don’t practice what I preach.  Sue me.

Most of the time, I advocate a plant-based low-carb Paleo-like diet for health; keto if obese insulin resistant.  High[ish] protein for all (ymmv).  Seasonal when possible.

 

Impact of ketones on cognition

Would our ability to plan and set traps to acquire food, or quickly devise a strategy to escape predation have been negatively impacted during periods of intermittent or cyclical ketosis?  I think not; more likely the opposite.  And while I [still] believe the physical feats required to do these is not hindered after ketoadaptation, I also [still] believe it’s because we *out-smarted* them, not out-ran them.  Compared to many other species, humans suck at speed.

 

Some evidence:

1. acute: in patients with moderate cognitive impairment or Alzheimer’s disease, given 40 mL MCTs to bolster ketones: cognitive performance improved roughly in parallel with increasing ketones (Reger et al., 2004).

ketones cognition

2. chronic: 20 grams of Axona (purified MCTs) daily for 90 days improved cognition in people with age-associated memory impairment (Constantini et al., 2008).

3. cruel and unusual: expose a group of type 1 diabetic patients to experimental hypoglycemia and give half 40 grams of coconut oil (which is like a longer-chained version of MCTs) (Page et al., 2009).  Result?  Hypoglycemia impairs cognition; however, this is largely offset by increasing ketones with coconut oil.  This group experienced improved: 1) verbal memory; 2) delayed verbal memory; and 3) verbal memory recognition.

4. nutritional ketosis: 6 weeks of a bona fide ketogenic diet in patients with mild cognitive impairment = improved verbal memory performance, and this positively correlated with ketones (Krikorian et al., 2012).

 

Optimal, harmful, or somewhere in between?  You decide (but if you choose harmful, please provide a link! or at least explain why, very clearly…)

Hint: nutritional ketosis isn’t harmful.  FOR. FIVE. YEARS… 1) that’s not cyclical or intermittent ketosis; and 2) five years is probably much longer than the diet you’re following has been tested for “safety.”

 

Ketones in evolution

Without our ability to rapidly enter a robust state of ketosis, we wouldn’t be here, or we’d be some weaker subhuman species.  But ketones have been around for a while… some bacteria store energy in the form of poly-beta-hydroxybutyrate.  Some prokaryotes use ketones instead of triacylglycerols.  Archaea also use ketones; and they’ve been around for billions of years…  it’s estimated that we’ve been doing it for quite a long time, too (from evidence on when our brain would’ve surpassed the [theoretical] threshold).  I’d cite a study by George Cahill here, and maybe you’d read it.  But you should really read all of the studies by George Cahill (it’s not a-whole-lot).  Sorry, I know that sounds ‘preachy.’

Would ketosis have hindered our ability to hunt prey and avoid predation?  My thoughts on our ability to perform high intensity physical activity after ketoadaptation have been thoroughly expressed in the past.  And ketosis clearly doesn’t hinder cognitive functioning.

So, from both a mental and physical perspective, ketosis, chronic or otherwise, did not stop us from becoming who we are.  Indeed, it probably contributed to how we did so.  Well, that and seafood.

calories proper

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  • Tuck

    Great post.
    How are you defining ketosis? Your comment about bears was interesting, I found this paper:

    http://www.bearbiology.com/fileadmin/tpl/Downloads/URSUS/Vol_5/Nelson_Folk_et_al_Vol_5.pdf

    That says:
    “Ketosis does not develop in hibernating black bears. Only slight increases were found in f3-hydroxybutyrate and acetoacetate in blood, increasing from 20+7 and 9+2 /mol/L, respec-tively, before hibernation to 163 +70 and 81+32 A/mol/L during hibernation (Nelson 1980).”
    So their ketone production does increase, but according to that paper if it went too high they’d have to pee, which is a problem when you’re hibernating. 😉
    Dogs (most like us, in many ways) do go into ketosis, but it takes a few days, quite a bit longer than humans. Dogs can also fully recycle lactate into glucose: no drop in glycogen during endurance exercise.

    • Tuck

      Comments widget is wonky!

      Also, Dr. Richard Bernstein, who came up with the modern idea of a low-carb diet for diabetics, has been on a VLC for a few decades, and seems fine.

      I’ve looked high and low for evidence that ketogenesis is harmful in humans, and none of the people who’ve been studying it the longest report anything bad (assuming a reasonably normal diet).

      Richard’s not going to like this post. 😉

      • they are plenty of anecdotes that VLC is safe long-term… but more importantly, there are plenty of clinical studies that confirm this 🙂

    • Dustin Sikstrom

      I’ve read that before about dogs in ketosis but I haven’t been able to find the source in forever! Do you happen to have it available? I’d be very grateful!

    • “How are you defining ketosis?”

      as far as this blog post is concerned, very broadly.

      It’s difficult to make comparisons across species, given the many nuances and differences in study designs… so instead I compared, for example, humans who exhibit something like a 5-6x increase in ketones to penguins’ 3x increase, and I’m not sure about the time frame in the bear study you cited, but they only exhibit a ~2x increase after fasting for 2-4 times longer.

      • Greta

        http://www.ncbi.nlm.nih.gov/pubmed/11409630 says ketones in bears increase 17-fold.

        • baseline value in that study was *very* low, ~0.02 mM… so even after a 17-fold increase, final value was still << 0.5 mM, whereas in humans it'd easily be 10x higher.

          • Greta

            The next question is why so low to begin with. Is this normal for bears or just in this study? I think there’s so little research on animals like this that it’s dangerous to make blanket generalizations. I read one study of ketosis in porpoises in which they determined ketosis by smelling their breath and measuring AcAc, neither of which is very accurate.

          • Good point… I suspect values at the lower end of the spectrum might be less accurate.

            Bears consistently show very low active ( 5 mM.

          • Greta

            Seems to me there would be (at least) 2 possible explanations for low ketonemia. (1) Bears use fat or the products of fat breakdown in other pathways and hence don’t produce many ketones or (2) Bears produce lots of ketones but their brain takes them out of the blood at the same rate as they’re being produced.

            Do you know if anyone has measured levels of monocarboxylate transporter in bears? I read somewhere that in some hibernator (marmot?) the MCT levels increase a lot when they hibernate.

          • I think it’s reason #1. They have a huge amount of triacylglycerols; the fatty acids can provide energy to tissues and the glycerol backbone provides ample gluconeogenic substrate to fuel their [relatively small] brain…

            In humans, ketones spare muscle. In bears, ketones aren’t necessary because they don’t break down muscle for gluconeogenesis.

    • Collectively, we do keto better than dogs & bears, but dogs have a better Cori Cycle, and bears are immune to disuse atrophy. I suspect these things are highly inter-related at the level of intermediary metabolism.

      • Evolutionary trade-off: mind over body..?

        the adaptations in bears & dogs seem more strictly related to physical activity, whereas in humans it is to support brain function…

        • Josh

          “I also [still] believe it’s because we *out-smarted* them, not out-ran them. Compared to many other species, humans suck at speed.” and “Evolutionary trade-off: mind over body..?”

          We do suck at speed, but are great at moving over distances, and evidence is showing that fat adaption rocks for endurance over CHO – (see Ben Greenfield et al.)

          Starvation ketosis was the trade off to keep our brains at working baseline to keep looking for food. (See above point – persistence hunt for days w/o food.)

          As humans became expert hunters our minds, adapted for baseline survival in starvation ketosis, became supercharged in nutritional ketosis – an evolutionary side effect.

          Therefore:

          Starvation ketosis = baseline cognition/life support

          Evolutionary side effect:

          Nutritional ketosis = super charged cognition/life support

          • great summary!
            it’s difficult to pinpoint the timeline of these evolutionary events… eg, which came first? and did that *cause* the next change?
            Also, see Jake Jaglarski’s comment: http://disq.us/8jryrk

          • While I do not doubt some role that cyclical ketosis may have played in the evolution of human cognitive abilities, I’d like to add a few words about persistence hunting.

            A) Humans have the ability to carry food and water during a persistence hunt, and we are adept at finding them along the way, too. The San people, for example, can spot a solitary twig on the desert landscape, which points them to an underground reserve of starch and water in its tuber.

            B) A persistence hunt is more of a long walk than it is a long run. My understanding is that a normal-to-quick walking pace is a predominantly fat-burning activity, regardless of whether a person is in ketosis.

            C) Humans are able to ‘walk down’ prey, due to exceptional tracking abilities.

            Tldr; the major factors in successful persistence hunting are: sweating; the ability to carry and find food and water during the hunt; the ability to track, and the ability to walk great distances. I don’t see ketosis as a major factor, but it is likely a contributing factor. Chronic ketosis, tho, does not appear to be factor at all.

          • “My understanding is that a normal-to-quick walking pace is a predominantly fat-burning activity, regardless of whether a person is in ketosis.”

            This is true.

            At the other end of the spectrum (faster speed, higher intensity, etc.), “ketoadaptation” seems to matter. That is, the body will not (or can not) use fats & ketones unless ketoadapted. Eg, http://bit.ly/10Opopz.

          • “Humans are able to ‘walk down’ prey, due to exceptional tracking abilities”

            “due to exceptional tracking abilities”

            …we out-smarted ’em 🙂

          • Josh

            The point was that this trait (ketosis) was selected before we were smart. Spotting a twig and finding tubers are learned. We are giving early hominids too much credit and comparing them to societies today. They were completely different.

            We weren’t always smart.

            The major factors in successful persistence hunting are:

            sweating – A selected for genetic evolutionary advantage.

            the ability to carry and find food and water during the hunt – Something we learned, not – not genetic

            the ability to track, and the ability to walk great distances. Something we learned – not genetic

            Ketosis – A selected for genetic evolutionary advantage.

            We needed to survive in order to learn. The advantage could have been ketosis + sweat glands.

            The end result is the learned hunt. There was lots of trial and error, and something would have had to keep us alive.

            Tldr;

            Primitive humans needed to sustain life while “learning” to become effective hunters. That learning could have taken a long time and sweat glands and ketosis sustained us until we were smart enough to walk, carry water, and find buried food.

          • “The point was that this trait (ketosis) was selected before we were smart.”

            my gut says this isn’t so clear cut, but my metabolism-bias says you’re absolutely correct.

    • I’ve read bears actually do wake up to pee during hibernation; they either drink it or feed it to their cubs! This is speculated to be one of the reasons why bears lose so little muscle mass & strength during hibernation… possibly due to gut microbial conversion of urinary nitrogen into amino acids… but much speculation here

  • tessmck

    Bill, your writings get better and better as time goes by!

  • Jake Jaglarski

    Great article, Bill! One thing I’d like to point out is that I believe there needs to be more research on the whole idea of a “preferred fuel”. Each organ/tissue has its own preferred fuel, and this is also dynamic – changing with time, environmental cues, etc. (1) There is also a lot of research going on establishing lactate’s role in the nervous system, decreasing excitotoxicity and having some similar effects of BHB, glucose (when it’s actually being used appropriately), and so forth (2).

    From my brief reading of Cahill’s work, along with that of neonatal ketosis and lactate metabolism, and coupling that with this article, it is clear to me that BHB and lactate plays a role in human brain development, probably in addition to thyroid hormones. This is an area of significant interest to me, because I find that the presence of even a little bit of BHB enhances my cognition greatly and decreases my neuro-psychiatric symptoms. Yet, BHB/lactate can easily be increased by exogenous means and without necessarily eating 30 or less g/carb/day. In fact, in terms of ALS, a non-ketogenic diet with ketogenic precursors works better than a ketogenic diet with ketogenic precursors (3).

    BHB is also an HDAC inhibitor (HDACi), and so are short chain fats; medium chain fats increase BHB even in the face of glucose consumption, and medium chain fats, along with BHB, has been shown to decrease DHA in some tissues and organs yet raise it, along with some MUFAs, in the brain (4).

    This is where I part ways with the likes of Kruse, Cunnane, etc. and side with Dr. Kwasniewski and Dr. Peat. Considering that some extensive research has also indicated that heat stress and eating ruminant animals led to a big brain (5), and others have disputed Cunnane’s hypothesis, and that things outside of our consumption of DHA actually increases it’s level in the brain, I think seafood played much less of a role in evolution than some may argue. To me, this indicates that, from an evolutionary perspective, we *may not* have had to eat a long-term, extremely ketogenic diet to grow our brain, and that perhaps neonatal ketosis plus a life time of dietary ketogenic precursors was more than enough. That last part is pure speculation, though, and I want to look into that more.

    Yet once again, great article.

    (1) http://www.ncbi.nlm.nih.gov/books/NBK22436/
    (2) http://onlinelibrary.wiley.com/doi/10.1002/jnr.20336/abstract
    (3)http://www.winningthefight.org/Content/Protocol/Atlanta_Poster_AHS_Conference_Draft_V1.pdf
    (4) http://link.springer.com/article/10.1007%2Fs11064-009-9952-5
    (5) http://www.scribd.com/doc/46048940/The-Hot-Brain-Survival-Temperature-And-the-Human-Body

    • Dustin Sikstrom

      Great thoughts. It is interesting to consider that heat stress + ruminant animals is a possibly more “preferred” fuel compared to seafood. After all, humans are great persistence hunters against ruminant animals (bipeds with and ability to sweat and breathe while running vs animals that overheat and can’t breathe at higher speeds), combined with this specific benefit of ketones, that sort of paradigm may be more likely the adaptation of usefulness compared to hunting seafood, which is more an issue of cunning rather than ability.

      > that things outside of our consumption of DHA actually increases it’s level in the brain,

      Such as? DHA synthesis is quite difficult, isn’t it? So how would the levels increase from “other things”?

      • Jake Jaglarski

        Interesting perspective on hunting, heat, etc.

        The one study I posted above displayed that MCT supplementation increased PUFA in the brain. One could also search up the link between ketones and PUFA in the brain; some researchers have hypothesized that this is one way that ketogenic diets are anti-convulsant in nature, among other things, but I think that delta G ATP hydrolysis increases, anti-hypoxia effects, increased GABA, etc. is more likely than an increase in DHA/PUFA.

        Also, desaturase/elongation enzymes appear to work better when there is less PUFA in the diet. Peter @ HyperLipid has discussed this, largely in the comments section of his blog.

        This shows that despite a very, very low intake of o3 fats, the Masai have “normal” levels of these fats:
        http://www.lipidworld.com/content/10/1/141

        I’m looking for the study, but there is a similar one in vegans and vegetarians. Also, I think that ELOVL3 plays a role in elongating fats. MIT in ’44 also shows that with adequate pyroxidine, we can synthesize PUFA: http://www2.gwu.edu/~nsarchiv/radiation/dir/mstreet/commeet/meet4/brief4.gfr/tab_e/br4e1c.txt

      • “DHA synthesis is quite difficult, isn’t it?”

        yes. Diet is by far the best source of DHA.

        “So how would the levels increase from “other things?”

        Lower rate of DHA depletion?

        Maybe not actually lower levels, but less being more effective for other reasons; eg, same amount insulin gets more done if more insulin sensitive..?

    • “I believe there needs to be more research on the whole idea of a ‘preferred fuel.'”

      did you notice my *very* careful wording around this? 🙂

      “Well, let’s just say this: when there are more ketones than glucose, brain uses more ketones than glucose.”

      it’s very context-dependent, like you said, and almost always a drastic over-simplification of the real question at hand. Ie, if brain uses more of one fuel, does that imply brain functions *better* on that fuel?

      thanks for the links!

      Lastly, it’s even more complicated given all of the different roles of ketones in the brain:
      a “super-fuel” according to Veech et al.;
      a signaling molecule (like you mentioned);
      a source of carbon for lipid remodeling…

      • “from an evolutionary perspective, we *may not* have had to eat a long-term, extremely ketogenic diet to grow our brain”

        I don’t disagree with this at all. I think it’s more our ability to rapidly enter ketosis, regardless of how that happened.

        Seafood DHA may have been involved, and I’d bet that, gram for gram, a little DHA back then was far more effective than it is now for other environmental reasons. Eg, lower demand, less competing n6 oils, etc.

        • Jake Jaglarski

          “did you notice my *very* careful wording around this? :)”

          Yes, I did, haha. I hope you didn’t take my thought on that particular topic as a critique of your writing! More so that in general, we as a community, and for those in an academic/scientific/medical field, should look into this topic more.

          Also, interesting thoughts on ketones, DHA, etc. Do you have any interesting studies/books on ketones and lipid remodeling? Never thought about that one.

          I wonder if our ability, as humans, to rapidly enters ketosis ties back into its role in brain growth and protection as a neonate, and we can harness thus its power for regeneration when the time arises. Nutritional Ketosis with energy restriction, more so than mct-induced or cyclical ketosis, has survival mode written all over it – increasing gluathione, decreasing excitotoxicity, protecting healthy cells from ROS yet selectively making cancer cells more prone to ROS, etc.

          Can’t wait to continue digging through your blogs!

          • “Do you have any interesting studies/books on ketones and lipid remodeling?”

            brain can’t/doesn’t take up very much cholesterol from the blood, so ketones provide carbons for chol synthesis.

            Some quantification, ketone vs. glucose carbon: http://bit.ly/1uXiG4u

            That, and more, in the bible of rat pup brain ketone metabolism: http://bit.ly/VFN8Rl

            And some differences between human babies & rat pups: http://1.usa.gov/1tmbvQj

    • gdubs

      There is no such thing as preference when it comes to chemical influences. Chemistry reacts according to the laws of physics. Change the chemistry of the body and it will only react according to what is available as a reacting agent. There may be a more chemically “optimal” fuel (which would be dependent on required energy demands for a given state) but there is no chemical “preference”.

    • Jack Kruse

      Preferred fuel is tied to the circadian signaling. When it is disordered carbohydrates are preferred. Nora Volkow shows this in her latest research. In most cancers with a redox shifted Q cycle, Warburg found that they also prefer carbs. In an infant its unmyelinated growing brain wants ketones to myelinate and finish neuronal growth. The context is always the back round environmental drivers. Bill has made this point over and over again. Those in the dark during sleep also have a preferred fuel. It is not glucose either.

  • George

    Excellent writing.
    I have some thoughts – food caught by hypercarnivores tends to be high protein to fat, outside keto ratios. Hard to avoid protein if you’re a modern hypercarnivore. Need to conserve some fat, even. Maybe easier to store energy as protein compared to human.
    Dolphins and whales, penguins – there’s a theory that blood sugar is protective against hypothermia.

    • Thanks, George!

      I find the differences between carnivores and humans to be very interesting… including all of the different carnivores (eg, cats and dolphins exhibit different responses to roughly similar dietary protocols, and both differ from humans as well.)

  • Dustin Sikstrom

    Great post! I’ve been interested in the comparison of humans being in ketosis vs. other animals for a while now, for the same reason you talked about (should humans even spend time in ketosis?) I’ve come to the same conclusion as you, it seems humans have a particular adaptation to time in ketosis.

    Concerning cats, it seems there are two large reasons they fail to thrive in ketosis like us. First, you mentioned that lack of ability to downregulate amino pathways. The distinction for humans is that ketones can be burned in place of BCAAs, making our body’s amino sparing (from Volek and Phinney). Second, I’d like to add that a cat is also poor at ketosis because of how amazing they are at gluconeogenesis. Our body is terrible at GNG and simply cannot provide all the energy our brain needs. But the feline body can convert protein at an astounding rate and easily provides it’s brain all the energy it needs via glucose.

    Now on to ruminant ketosis:

    > A possible exception to this is ruminant ketosis, but that’s for a different reason. They become ketotic because: 1) their gut turns much of what they eat into a ketogenic diet; and 2) this frequently happens during lactation, which combines very high energy expenditure and an enhanced draw on the oxaloacetate pool to make lactose.

    Not necessarily so from what I’ve read. There are a few issues here with ketosis being toxic for ruminants. I’ll specifically point out what I’ve learned from cows, because that’s what comes up the easiest in Google.

    “Humans are particularly good at ketosis because of how well we mobilize fatty acids from adipose tissue. Ruminants on the other hand must create fatty acids from blood phosphatidylcholine (lecithin). Healthy animals can be recognized by high levels of milk glycerophosphocholine and low levels of milk phosphocholine.

    […]
    In ruminants, because most glucose in the digestive tract is metabolized by rumen organisms, glucose must be supplied by gluconeogenesis for which propionate (produced by rumen bacteria and absorbed across the rumen wall) is normally the principal substrate in sheep, with other gluconeogenic substrates increasing in importance when glucose demand is high or propionate is limited. Pregnancy toxemia is most likely to occur in late pregnancy because most fetal growth (and hence most glucose demand) occurs in the final weeks of gestation; it may be triggered by insufficient feed energy intake (anorexia due to weather conditions, stress or other causes), necessitating reliance on hydrolysis of stored triglyceride, with the glycerolmoiety being used in gluconeogenesis and the fatty acid moieties being subject to oxidation, producing ketone bodies.”

    http://en.wikipedia.org/wiki/Ketosis#Veterinary_medicine

    In plain English, ruminants should be getting their high fat diet via their fermentation. They also should be getting their glucose via GNG. When a young one goes into ketosis, it’s the lack of glucose available to support their growing structures, generally from not eating, forcing the body to use fat from adipose tissue instead of from fermented grass.

    So it seems absolutely certain that ketosis is toxic to ruminants and for the very reason that it is toxic to them, it points towards ketosis being that much more reasonable for humans (ability to mobilize fatty acids from adipose tissue).

    Thanks again for this write-up!

    • George

      Are you sure ketosis isn’t just one symptom of starvation, rather than the toxicity?
      In peripartal ruminants the ketones are turned to fat in the liver, this probably becomes the accessible depot. But micronutrient deficiency and fungal toxins might compromise this in starvation.
      It seems strange to me than an animal storing so much fat can’t access that energy. Is that a product of selective breeding for fatness?

    • “Our body is terrible at GNG and simply cannot provide all the energy our brain needs.”

      If it did, we wouldn’t survive very long in starvation! Ketosis reduces the need for gluconeogenesis, which in turn spares skeletal muscle. http://caloriesproper.com/?p=2719

    • “Our body is terrible at GNG and simply cannot provide all the energy our brain needs.”
      Quite the opposite, actually. See http://nigeepoo.blogspot.co.uk/2012/04/how-eating-sugar-starch-can-lower-your.html

  • I love it when smart people write clearly and concisely – writing in riddles or in a long incomprehensible rant really shits me to tears.

    Thanks, a pleasure to read.

    • Sky King

      “writing in riddles or in a long incomprehensible rant really shits me to tears.” Wooo are you referring to in particular? Anyone? 😛

  • The question I tweeted that got the Twitter thread started was basically, “Is there any mammal in nature that walks around (or swims) in chronic ketosis?” The answer appears to be a resounding ‘no.’ Not a single mammal. Not a single human population.

    “During starvation, humans rapidly enter ketosis…”

    Starvation itself takes a while. But in any case, humans can far more rapidly exit ketosis than we can enter into ketosis. This can be done by simply eating too much lean meat. Does this seem like a state the body prefers?

    “It’s as if they evolved protection from the ketotic state…”

    I admit this is odd phrasing, even for a tweet. I had carnivorous predators in mind, which rely on sprinting to eat. Perhaps it would have been more accurate to say, “It’s as if efficient gluconeogenesis pathways have helped them to survive.”

    In any case, the initial question was asked merely to enlist the help of Twitter users in finding a mammal that lives in chronic ketosis. Genuine curiosity. If one existed, wouldn’t we all want to take a closer look?

    As I’ve stated elsewhere, I believe ketosis provides many benefits, some of which I’ve learned about here. I’m reasonably sure I enter ketosis daily. However, without a natural example of mammalian chronic ketosis and without sufficient chronic ketosis research…I have strong reservations regarding this approach when it is not medically necessary.

    Cyclical ketosis? Short-term ketosis? Absolutely. But I would never conflate the research on these with long-term chronic ketosis.

    Can you answer the question, “How does long-term chronic ketosis affect blood markers, reproduction and libido, anxiety, depression, bone-density (sans vitamin and mineral supplementation in non-epileptics), relative happiness, and longevity?”

    We don’t know, and again — we lack a natural example of chronic ketosis. We don’t know how long it may take for (potential) adverse events to present themselves. We don’t know what % of the population would react poorly to longterm chronic ketosis. And, there are insufficient gender studies.

    Is ketosis a big part of what makes us (humans) who we are? Of course! So are fingernails, but I keep mine trimmed.

    • I’ve chatted with some people who have been in continual nutritional ketosis for a decade or more.

    • Tuck

      “We don’t know, and again — we lack a natural example of chronic ketosis. We don’t know how long it may take for (potential) adverse events to present themselves. We don’t know what % of the population would react poorly to longterm chronic ketosis. And, there are insufficient gender studies.”

      Johns Hopkins has been studying this since the 1920s. They’ve not found a single negative consequence to long-term ketosis. They initially thought they’d found a few negative effects, but they didn’t pan out in the long term.

      “Current and former patients treated with the high-fat ketogenic diet to control multiple, daily and severe seizures can be reassured by the news that not only is the diet effective, but it also appears to have no long-lasting side effects, say scientists at Johns Hopkins Children’s Center.”

      http://www.hopkinschildrens.org/high-fat-ketogenic-diet-to-control-seizures-is-safe-over-long-term.aspx

      Exactly how much evidence do you require?

      • “Exactly how much evidence do you require?”

        a six-year study? a seven-year study?

        We have a situation here with plenty of positive long-term data and no negative long-term data. If every positive study was matched by a negative one, I’d say the issue is unresolved, but that’s simply not the case.

    • Thanks for the comment, Angelo.

      “…humans can far more rapidly exit ketosis than we can enter into ketosis… Does this seem like a state the body prefers?”

      well, when you put it that way… good point!

      I think this is a means of protecting the body from high levels of both glucose and ketones, which would be pathological. Like mild ketoacidosis; ??? oxidative stress.

      Long time to enter ketosis bc: 1) we’re carb-adapted (? ratio of glycolytic:oxidative enzymes); and 2) glycogen stores can hold you over until mitochondrial proliferation…
      rapidly exit ketosis bc it literally takes minutes for ingested glucose to enter the bloodstream (& don’t want high levels of both fuels)…

      Also, what Jake said about “preferred fuels” http://disq.us/8jrs5a… it’s hard to say, which is why I tip-toed around it:
      “Well, let’s just say this: when there are more ketones than glucose, brain uses more ketones than glucose. This happens in both starvation and nutritional ketosis.”

      “Is ketosis a big part of what makes us (humans) who we are? Of course! So are fingernails, but I keep mine trimmed.” ? Ha! awesome.

      • Martin

        Long time to enter ketosis? “http://rspb.royalsocietypublishing.org/content/119/815/381.full.pdf+html?sid=78537be1-f3b7-4d98-8436-ddddd223d30a” that is less than 3 hours of walk + not high sugar diet “(& don’t want high levels of both fuels)…” high levels of glucose and the liver don’t need to make glucose any more and will use all the excess acetylCoA made from beta oxidation that will no longer be that promotes ketosis into the krebs cycle…

    • You can say the same about sobriety.

      Just because it’s “easy to exit” doesn’t mean we should always be in a non-sober state, though I do enjoy it.

    • Martin

      I don’t know what was your point but:
      “Is there any mammal in nature that walks around (or swims) in chronic ketosis?” Yes! That will be the inuit people, aka eskimo. Look at the Courtice and Douglas paper cited bellow and will notice that ketosis is not far if a diet that contains no large amounts of carbohydrates.

      …humans can far more rapidly exit ketosis… yes! That is because ketones are made mainly in the liver while it is “making” glucose. As a high level of glucose in blood is available, no glucose production is necesary and acetylCoA in the liver can be used by the Krebs cycle (no more lack of oxalacetate). No more ketones!

      • Payotee

        Although many have tried, no scientific study has ever found evidence of ketosis in the Inuit. Not ever!

  • rs711

    Hey Bill, the “FOR. FIVE. YEARS…” hyperlink brings me to NCBI website with ‘no items found’. I’d like to add that one to my library.

    Very succinct post that does not overreach in terms of extrapolating ‘oughts’ to humans. The science is strong in this one! Too many questions floating around my head after the post – I’ll abstain until I can formulate a proper one.

    Just to provide some context via potential mechanisms in the mean time: http://jcn.sagepub.com/content/28/8/1027.abstract “How Does the Ketogenic Diet Work? Four Potential Mechanisms”

    – carbohydrate reduction
    – activation of adenosine triphosphate (ATP)–sensitive potassium channels by mitochondrial metabolism
    – inhibition of the mammalian target of rapamycin pathway
    – inhibition of glutamatergic excitatory synaptic transmission

    • http://www.ncbi.nlm.nih.gov/pubmed/24800673

      Long-term effects of a ketogenic diet on body composition and bone mineralization in GLUT-1 deficiency syndrome: a case series.

      • rs711

        Thanks! (sorry, your link works fine – hadn’t noticed my NCBI search settings were still active)

        • just listened to Kiefer’s podcast where he mentioned the calorie usage study… but the study wasn’t cited 🙁

  • “Is long term ketosis necessary/safe?”

    necessary: in some cases, yes. But definitely [obviously] not for everyone.

    safe: yes.

    • feardorchamacgabhann

      The Inuit used to spend most if not all of their lives in ketosis. It didn’t affect them. I’ve been in ketosis for more than 7 months. I don’t feel any different.

      • While the Inuit data have been debated, I’ve no doubt that long-term low carb (keto or not) is absolutely “safe.”

        If you don’t mind me asking, why did you choose keto? …and why stay on it if you “don’t feel any different?” (just curious)

        • rs711

          The data has been debated and a few interesting ‘addendums’ are worth adding on. The Inuit remain an excellent example of a traditional population relying significantly on ketones – or at the very least on a predominantly fat-derived metabolic fuel.

        • feardorchamacgabhann

          I didn’t. I chose 50g as being a good induction for LCHF. I felt great and got all my weight off on it, dropping to 30g/day for 2 weeks due to circumstances beyond my control.. I’m staying put at 50g now at my desired weight. I could start messing with it, but why would I. ? I’ve had positive sticks after exercise etc.

  • Jane Karlsson

    Bill, I would like to draw your attention to something very interesting. There is a pathway by which beta hydroxybutyrate could prevent age related disease.

    Its HDAC-inhibitor activity leads to transcription of the MnSOD gene. It goes BOHB -> FOXO3A -> MnSOD.
    http://www.ncbi.nlm.nih.gov/pubmed/23223453

    Extra copies of MnSOD make flies and worms live longer. The H2O2 it produces goes to the nucleus and activates transcription of precisely those genes whose activity normally declines with age.

    ‘Transcriptional profiling of MnSOD-mediated lifespan extension in Drosophila reveals a species-general network of aging and metabolic genes’
    http://www.ncbi.nlm.nih.gov/pubmed/18067683

    CONCLUSION: The data suggest that MnSOD up-regulation and a retrograde signal of reactive oxygen species from the mitochondria normally function as an intermediate step in the extension of lifespan caused by reduced insulin-like signaling in various species. The results implicate a species-conserved net of coordinated genes that affect the rate of senescence by modulating energetic efficiency, purine biosynthesis, apoptotic pathways, endocrine signals, and the detoxification and excretion of metabolites.

    • Hi Jane,

      Thanks for the links. Beta-hydroxybutyrate is certainly an interesting lil’ molecule… many “functions” http://disq.us/8jscc4

    • Jack Kruse

      I know Jane is interested in transition metals and SOD2. But how the react in mitochondria with respect to oxygen or lack there of is even more interesting when you consider what betaHB does to delta psi and the reduction of oxygen by ECT. Understanding why solid oxygen and mitochondria have become linked particularly interesting. Oxygen has a very powerful magnetic order. Oxygen contains electrons and is capable of creating very powerful magnetic fields around mitochondria in animals. Oxygen molecules have recently attracted attention because of the relationship between the molecular magnetization and crystal structures, electronic structures (ECT), and superconductivity. Oxygen is the only one of the simple diatomic molecules, and one of the few molecules in general, to carry a magnetic moment. When oxygen is lacking in mitochondria, it can affect other metals used in mitochondrial biology, like Mn, Fe, Cu. These also have interesting magnetic properties. When O2 is low and these metals are more reactive than normal. These inner mitochondrial membranes no longer work well tunneling electrons. They begin to resemble bacteria or archea cell membranes. Hypoxia-tolerant animals naturally have low membrane permeabilities. Humans are not one of those creatures. Cell membrane permeability decreases even more during hypoxic conditions in us. Research in mammals has implicated hypoxia inducible factor (HIF) as a key regulator of gene expression changes in response to hypoxia. Critical Care Medicine 33(12) S423-425, Hypoxia-inducible factor-1 (HIF-1) by Paul T. Schumacker, PhD

  • Do babies learn at incredibly rapid rates when they’re hungry? Somehow, I think not.

    They just cry a lot, like…babies! 😀

    Ah-ha!

  • “nutritional ketosis isn’t harmful. FOR. FIVE. YEARS…”
    Human lifespan >> five years.
    Would you like to comment on http://nigeepoo.blogspot.co.uk/2014/08/ketogenic-diets-and-sudden-cardiac-death.html ?
    “Ketogenic Diets and Sudden Cardiac Death.”

  • “Evolutionarily, metabolism of ketone bodies is conserved among eukarya, bacteria, and archaea…”

    http://bit.ly/1vwehmw

  • The liver of healthy adults is capable of producing up to 185 g of ketones per day… http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3810007/

  • mayhap

    Starvation = burning of essential tissues.
    Fat = non-essential tissue (you don’t need it to be alive).

    Not eating for 72 hours will have you into ketosis without being anywhere near starving. The emphasis on starvation throughout the article is very misleading and simply incorrect. For instance, There’s no such thing as a “starvation ketosis”.

    For more information, please do some research on fasting.

    http://www.allaboutfasting.com/effects-of-fasting-ketosis.html

    • I think the most biologically appropriate way of looking at it is as a continuum. Also, for what it’s worth, Cahill frequently spoke of “phases of starvation,” which began shortly after the fed state…

      “There’s no such thing as a ‘starvation ketosis.'”

      I accept that, to a degree. I meant ketosis that occurs in the absence of food intake, as opposed to ketogenic diets. Wikipedia sets the bar at a ketone level of 3-6 mM in the context of no food intake (http://bit.ly/1ryaCqi).

      “Fat = non-essential tissue (you don’t need it to be alive).”

      “you don’t need it to be alive” …any examples of this? I realize you don’t need *a lot,* and I’m aware of some conditions where there’s very little… but I wouldn’t want to have “none.”

      • mayhap

        Analyzing the statement rationally: if you truly are starving, you will not have any fat. Your body is not so dumb it will burn essential tissue (liver, kidneys etc) before depleting all the fat and muscle reserves.

        That alone should be sufficient to convince anybody. There’s also: http://en.wikipedia.org/wiki/Congenital_generalized_lipodystrophy

        People in this condition are not capable of having fat storage.

        OK, thanks for clarifying your intent. You may want to consider finding a better term to indicate ketosis in the absence of food intake. Perhaps simply “ketosis” vs “nutritional ketosis” although I perhaps “nutritional ketosis” has it’s own issues.

        • “Your body is not so dumb it will burn essential tissue (liver, kidneys etc) before depleting all the fat and muscle reserves.”

          This is true for very few tissues: brain, and maybe adrenal glands. But liver weight declines quite rapidly; heart weight a little slower… I like to think of it as a continuum.

          http://bit.ly/1lwlItA & http://ajpendo.physiology.org/content/239/4/E269

          Lipodystrophics have fat, it’s just not stored in adipose tissue. (also, these people aren’t very healthy)

          • mayhap

            We’re talking about essential vs. non-essential tissue though. Burning essential tissue is destructive. From an evolutionary standpoint, that’s implausible.

            Change in organ weight does not translate to the burning of essential tissue.

  • Louis

    Great article Bill! Love this evolutionary explanation.

    I’m not very knowledgeable with the nutrition stuff, so I have a dumb question. Does a long term ketogenic state tax the liver and possibly cause damage to the system?

    I tried looking it up, but I’m not sure I can comprehend the studies with my background. Here’s one of them http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3679496/

    • Thanks, Louis! 🙂

      The ketogenic diet has been studied quite long-term in humans, and it does not “tax the liver” or “cause damage to the system.”

      Ketogenic rodent diets are usually unhealthy and filled with trans fats, which explains why some rodents studies show a negative effect of keto.

  • As you stated above, comparatively, “humans suck at speed.” On the other hand, it is generally believed that the ability of humans to run down ungulate prey over long distances ie superior endurance running as a hunting tactic might be one of if not the single most significant physiological hunting adaptation of humans. This is still the main hunting tactic in a few remaining primitive African peoples. We are almost unique in this ability, This is another reason for us to be good at keto adaptation besides maintaining our brains high relative energy requirements during starvation and periods of low carbohydrate intake. I doubt primitive man carb loaded before these hunts.

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  • Danny J Albers

    If only ketosis was half as effective for weight loss as the fear campaign against it, we could all be skinny in a week.

  • Jord

    What are some of the main differences between nutritional and starvation ketosis? In one of your other posts you mentioned only starvation ketosis was muscle sparing; and NOT nutritional ketosis.

    How does the body ‘know the difference’?

    • “What are some of the main differences between nutritional and starvation ketosis?”

      food 🙂
      jk, but really, many different enzymatic & metabolic pathways. If you’re interested in this rabbit hole, start with the urea cycle.

      “In one of your other posts you mentioned only starvation ketosis was muscle sparing; and NOT nutritional ketosis.”

      #Context: nutritional ketosis is not more muscle-sparing than non-keto diets (and may even be worse), and ANY diets are more muscle-sparing than starvation.

      As starvation progresses, nitrogen excretion declines [due to ketosis], so it is said that starvation ketosis is muscle-sparing.

  • Mike Berta

    “Most of the time, I advocate a plant-based low-carb Paleo-like diet for health; keto if obese insulin resistant. High[ish] protein for all (ymmv). Seasonal when possible.”

    I’m having trouble understanding what a high-ish protein plant based diet is. Do you get most of your protein from nuts & seeds? Legumes? Basically just curious what your main protein sources are on a paleo plant based diet.