Optimal Weaning from an Evolutionary Perspective:

The evolution of our brains, meat eating, and a reliance on ketogenic metabolism

I recently had the privilege of presenting a talk, with the same title as this post, at the Ancestral Health Symposium.
I am posting the video here, with a transcript, some references, and related material.


This is what I said for each slide, with comments / clarifications in square brackets.
Times are approximate.

Optimal Weaning from an Evolutionary Perspective

My talk is called Optimal Weaning from an Evolutionary Perspective and I’d like to break down that title a little bit.
‘Optimal’ implies best for something, and here that something is going to be brain development.
The word ‘weaning’ can also benefit from clarification,
because we often use it to mean the end of breastfeeding,
but I use the convention meaning the beginning of the end,
with the introduction of first foods.
For ‘evolutionary perspective’, I just want to point out that what we know about our past can inform our understanding of physiology,
but our physiology can also constrain the possibilities of the past.


I’ve concluded that weaning infants onto an animal based diet best meets their nutritional needs,
and the rest of this talk will be about why.
Primarily I’ll be talking about the unique properties that resulted from the evolution of our brains.
I’ll also give a bit of evidence from modern health studies and trials,
and then finally I’ll give a little bit of the how,
based on my own experience in weaning one of my children onto animal based foods.

Human brains are unique

Human brains are unique in many ways, but one of the most striking things is their sheer size, especially relative to our bodies.
In particular, when you take into account that we are primates, it’s really quite extraordinary.
Primates already have brains that are about three times as large as most other mammals, at least relative to their size [1],
and then humans have again about two and a half to three times as large brains as other primates do.
And we didn’t always have that large a brain,
that three times expansion occurred
over the course of a few million years.
And a second related way that our brains are unique, is that our individual human brains do most of their growth after birth [2].

Altricial vs. Precocial

It’s helpful to think about this in context of the distinction between altricial and precocial animals,
which is based on their degree of development at birth.
Altricial animals are underdeveloped.
They tend to have a short gestation, compared to precocial animals, who have a long gestation.
They’re poorly developed, so they may be missing hair.
They usually have underdeveloped sense organs, for example unopen eyes.
They’re usually born in litters, as opposed to singletons,
and they have less adult-like proportions,
whereas precocial animals are essentially adult-like in their proportions.
They have underdeveloped limbs,
which means that they can’t do what precocial animals do,
which is move like the adults that they’re born from,
and they tend to be smaller at birth,
and their parents are younger when they reproduce.

Humans appear altricial but are precocial

Humans don’t really fit into this paradigm very well
when you look at it at first glance,
because they appear to be altricial,
but they’re actually better understood as being precocial.
Primates in general are highly precocial,
and humans, when they fit that,
are to the extreme,
for example, we have enormous newborns, and we reproduce relatively late.
Our babies appear altricial, though, because they’re born helpless,
they don’t have adult proportions at all,
and they can’t walk or have the motor skills that you would expect them to have.
But it’s helpful to think of them as actually precocial, but born early.
And one reason to think that is because of fetal brain growth rates.
We have our brains growing at the same rate as fetuses do persisting for up to a year [ should say at least ]
after birth,
and if you then look at our babies when they are a year old
they look a lot more like you would expect them to look if they were born precocial:
they have motor skills that you would expect them to have,
and teeth, for example.

Human bains continue to grow postnatally

Here’s [sic] a couple of graphs from the Smithsonian.
There’s one for chimpanzee brain growth and one for human brain growth.
As you can see with the chimpanzee brain growth,
they complete about half of their brain growth in gestation, and the rest over the course of a couple of years.
Note that chimpanzees, like many primates wean quite late compared to us [3];
they wean at about four years of age,
which is well after all their brain growth is completed.
Humans, on the other hand, have a very steep rate of growth before birth,
and it continues into the second year [4], [5],
and then the rate slows down some,
although it’s still pretty significant,
and then it’s followed by what looks on this graph like a levelling off,
but this graph does end at age 10
and we know that there are growth spurts after that, too.

Rapid brain growth sustained beyond weaning

What I want to draw attention to with that is that
the fetal-like brain growth doesn’t just extend beyond birth,
but it also extends beyond the end of weaning.
[This is a mistake. I meant to say that the rapid brain growth continues past the end of weaning,
but it is “fetal-like” only past the
beginning of weaning.]
So, we have this fetal-like growth in the first year,
continued rapid growth to 5 years [ Or is it 4? ] [6],
continued slower growth through childhood,
and then, if you combine that with the fact that we wean early [3],
we realise we need to support that kind of rate of growth even beyond weaning.
[ I’m also wondering whether weight is the best measure. Volume, density, cholesterol levels are all other measures to consider, but I won’t get into that here and now. ]
Our brains are really vulnerable, and they have many critical periods,
each of which builds on the one before,
so if you haven’t completed one of your stages of brain growth,
you may not be able to complete the next stage successfully,
and that means that you need continuous support through a long period of time [7].

Brain growth requirements

What kind of support do we need to give growing brains?
Well there are at least three kinds of ways that we need to support a growing
One is that they need specific micro-nutrients.
Even adult brains can suffer if they don’t get enough of certain kinds of micronutrients and
certainly developing brains that are missing these nutrients, if they’re
missing them at critical times sometimes they can’t even recover from the detriment.
Secondly brains require an enormous amount of energy.
At least 20% of the energy that we consume as adults goes to our brain
and that’s even more extreme in a newborn who has about three quarters of the energy that they consume go[ing] right to
the brain [8], [9].
And then thirdly, of course we need material for the structural
components, and brains are made mostly of cholesterol and fat.

Brain evolution requirements

In parallel to that,
the evolving of the brain has similar requirements.
We needed those micronutrients and the energy and the structural components.
We needed them to be available over a period of years for each individual and then that needed to
be compounded more or less continuously for millions of years for us to be able
to make that three times expansion.

Brain requirements: co-adaptations

While our brains were expanding over this long
evolutionary period,
there were co-adaptations that allowed them to expand,
particularly contributing to the extraordinarily high energy requirements.
These co-adaptations I would like to talk about in more specifics:
a high quality diet (by which I mean high in animal foods),
shrinking intestines, a reliance on the ketogenic metabolism,
and increased body fat particularly in babies.

Co-adaptation: eating meat

First of all, meat eating.
The plants that were available to us at the time that we were expanding
our brains were simply too fibrous, too low in protein, too seasonal, and too low
in calories to provide the needed energy.
So significant fatty meat eating was necessary for the protein and the energy as well as the micro-nutrients for
developing our brains to our current form.
[ See the post, Meat is best for growing brains for more detail about the implausibility of plants as a sufficient food source.]

Brain requirements: micronutrients

I’m going to just zoom in on a few
of those particularly critical micronutrients.
We have the minerals
iodine [10] , iron [11], and zinc [12];
the fatty acid DHA [13], which is in all your brain cells in the phospholipids.
It’s particularly important in vision (retinal cells) in the
and vitamins A and D.
If you don’t get enough
of these vitamins and minerals and fatty acids as your brain
is developing you can suffer developmental delay, disability.
There is a tendency to emotional fragility and susceptibility to
psychiatric disorders and it’s often not recoverable.

Micronutrient sources

For these micronutrients, animal foods are either the only, the best, or the most bioavailable source.
For DHA it’s almost exclusively found in animals.
It’s true that there is some in microalgae,
but it’s not very plausible but that’s where we were getting it while we were evolving.
Vitamin D is only available in animal sources.
It’s true you can get it from sunshine, but again if you take into account the
seasonality and the various geological periods we went through,
It’s — we would need more.
Iron is available in plants, but it’s three times more bio-available in animal sources [14].
Similarly with vitamin A, which is 12 to 24 times more bioavailable in animal sources [15], [16].
If you think about the sheer amount of plant food that you would have
to eat to try to make up for that,
it’s just not plausible at all.
For zinc it’s simply — animal sources are simply the best.
And then I’d also like to note that some plants actually interfere with the absorption of those minerals,
so it might not just be not a benefit to try to get them from plants but it could actually
be a detriment.
[ I refer the interested reader to the blog of Dr. Georgia Ede, and in particular, her post on vegetables ]

Co-adaptation: shrinking intestines

A second co-aptation is shrinking intestines.
In 1995 Aiello and Wheeler came up with a hypothesis to try to explain how
it could be that these brains that we’re growing which requires so much energy
could have gotten that energy without giving up something else,
and they noticed that we did give up something else.
We gave up a drastic amount of the size of our intestines.
Intestines are also really energy-intensive,
so that smaller size freed up energy for the brain
But there’s also a feedback loop,
because having less intestines reduced our ability to consume fibre.
A lot of other primates get a lot of their energy by consuming fibre and
putting them through the factory of bacteria that turns that fibre into fat.
We no longer have much of that ability at all and
so that also increased our need to get our fat directly from an animal based diet.
[ See the post, Meat is best for growing brains for more detail about the the Expensive Tissue Hypothesis, and shrinking intestines. ]

Brain requirements: structural components

Going back to brain requirements,
I wanted to re-emphasize the structural components
I’d said that brains are mostly fat and cholesterol.
By dry weight it’s about 60% lipids [17],
about 40% of that which are cholesterol [18],
but there’s a problem because fatty acids don’t cross
the blood-brain barrier very easily [19],
[ That is, DHA and AA enter the brain easily, but not the long chain fatty acids that white matter, gray matter, and myelin are mainly composed of. ] [20], [21]
cholesterol almost not at all [22].
So all of that fat and cholesterol is reconstructed in the brain and it’s
reconstructed we know, out of ketone bodies [ See next two slides ].

Ketone body fates

[ This slide I inadvertently omitted! It shows the biochemical pathways of ketone bodies being made in the liver,
and what is relevant for this talk, being transformed into fuel, as is familiar to many,
but also into fat and cholesterol, which may be new to many in audience. ]

Co-adaptation: reliance on ketogenic metabolism

That brings me to the third co-adaptation,
which is using fat for energy and for substrates in the brain
with ketone bodies.
Ketone bodies are directly usable by the brain for energy,
unlike fatty acids.
They are used to create most of the fat and all the cholesterol.
[ Correction! Most of the fat and all of the cholesterol is synthesised in the brain,
and preferentially by ketone bodies, but some is also made from glucose (which, of course, can be made on demand from protein. ] [23], [24], [25]
and most importantly, they can easily and abundantly cross the blood-brain barrier.
There are other benefits to being in a ketogenic metabolism,
for example, it increases the density of mitochondria in brain cells which allows more energy to flow
and it also decreases the vulnerability of the growing brain to stress and trauma.
You may be aware of the extreme neuroprotective properties
of the ketogenic diet.
For example, it mitigates drastically the damage that you would incur if you had a traumatic brain injury or stroke, so that’s
obviously adaptive.
[ See the post The medical-grade diet, for more on neuroprotective properties of ketogenic diets. ]

Co-adaptation: reliance on ketogenic metabolism

The fact that we use ketone bodies for brain energy and material,
which we and some other species also do in gestation,
explains why newborns are in mild ketosis all the time [26].
Infants use ketones three to four times more efficiently than adults
[ Correction! four to five times. (Three to four is in newborn rats.) ] [27],
so mild ketonemia for a baby is more like a deeper ketosis for an adult.
Even children as old as 12 and probably older
can become ketogenic much more quickly and easily than you might expect.
We’re talking about a matter of hours of fasting to develop the kind of ketosis
that would take adults several days [28].
But even human adults become ketogenic more easily than other species and they do it without calorie restriction.
This is really significant.
I know of no other species that sustains ketosis without either starvation or semi-starvation,
and it has implications for animal models of ketogenic diets therapies,
because there may be cases where an animal requires caloric restriction for the therapy to be
effective, whereas in humans it probably doesn’t,
and would be a detriment to compliance and to health outcomes.
So I wanted to emphasize that humans have co-opted this trait
that was previously an adaptation to cope with periods of starvation, and it
still is in other species, but we have co-opted it into a default metabolism at
least for the period of childhood to support the brain growth in particular,
but also to meet the brain’s ongoing energy requirements.

Co-adaptation: increased body fat

Finally, the last co-adaptation I want to talk about is increased body fat,
because it goes along with all the others
It’s striking, again, when you compare humans with other primates,
how fat they are.
Even adults are fat compared to other primates.
Other primates and most terrestrial animals
actually have less than 5% body fat,
and humans have easily somewhere between 15 and 20%, even very lean ones.
Human babies take that to the extreme.
They start out at about 15%.
That’s doubled in a couple of months and it continues to increase over the first
Baby fat is different in character from the kind of fat you’d see in obese
It’s subcutaneous, not visceral [29], and it’s very low in polyunsaturated fatty acids
even if their mother is eating a lot of polyunsaturated fatty acids,
whereas obese adults tend to have a kind of roughly corresponding level and
quality of fatty acids to what they’re eating.
So there’s obviously a lot of filtering going on.
And what polyunsaturated fatty acids are there are almost all DHA and arachidonic acid,
which is another important brain fat,
so it seems that this extreme body fat in babies is there to provide a
continuous supply of fat that can be used by the brain both for energy and
for materials via the ketogenic metabolism that we are relying on [30].

Summary of Evolutionary Evidence for Meat

[ This is the other slide I missed.]
I seem to be missing a slide.
I just wanted to quickly summarize what what I’ve said about evolution of the brain.
The first is that we needed to evolve — we needed to eat meat to allow us to evolve
the brains that we did.
That’s for energy and for micronutrients.
And I also wanted to emphasize the ketogenic metabolism part,
because not only is it a natural normal default state for children but it shows that it’s not detrimental,
it’s actually a benefit.
It’s actually critical.
It’s actually part of the mechanism of how we build our brains.
And so I’m bringing that up because someone who’s thinking
about weaning their baby onto animal-based foods might worry:
Wouldn’t this make them ketogenic and could that be a problem?
And I just want to emphasize that not only is it not a problem,
it’s the way it’s supposed to be
and you could hardly stop if you wanted to because even when they sleep they’re
going to go into ketosis.

Weaning onto meat: clinical trials

OK, so onto clinical trials.
I know of two clinical trials that compared eating — weaning an infant onto the fortified cereals
that we mostly recommend now, versus weaning them onto exclusively meat.
The first one compared or took some measurements comparing them and the meat
weaned children had a higher zinc status,
which we know is very important.
They had adequate iron without the benefit of supplementation that the cereal arm had.
They had increased head growth which in children is a good index of brain growth,
and it’s also correlated with higher intelligence and that’s not
even taking into account the size of your head at birth so it’s
not just the size of their head,
it’s the amount of growth that happened between birth
and the later time that’s correlated with the higher intelligence.
And the second study just showed better general growth without increased adiposity
That was what the researchers were worried about was that if you wean babies onto
meat they would get fat in a way that would increase the risk for modern
diseases and that of course didn’t happen.

Slide with refs

And I just have those references
there for your reference.
This kind of study is what I think has led to certain
agencies like the Canadian government and the La Leche League to include meat as a
recommended first food.

How? It’s easy.

Finally I’m going to talk a little bit about how to
do that just based on my experience from doing that with my third child.
I was very influenced by Baby-Led Weaning.
The core understanding from them is that
you don’t — you can basically give a baby
the same food that an adult eats.
The risk of choking has been greatly exaggerated.
You don’t need to buy into this whole, you know, factory-made baby food stuff.
You can give them what you eat for the most part.
So what I have done, for example:
I was in the habit of making bone broths that had some meat in the
broth and I started by giving him broth on a spoon and increasingly
over time added some fragments of meat.
I also gave him bones to teethe on from my
steaks and chops, and again I increasingly left meat and fat on it,
which he enjoyed a lot.
I fed him a lot of egg yolks and beef and chicken liver,
which have a nice soft, silky texture.
They’re extremely nutrient dense and to
this day — this child is almost seven and liver is one of his favourite foods which
pleases me to no end.
I’m really grateful to Aaron for being the first to bring up the word pre-masticate in this conference yesterday,
so I didn’t have to be,
and I also know from being in the audience that several people besides me did prechew their
food for their babies and it’s certainly plausible —
I would expect that a lot of people in the past did that and I
did that.
I also often made plain unseasoned beef jerky which is really
good for teething — sort of reminds me of a dog with rawhide he would gum down on
it and pull and then he’d suck on it for a long time and it would basically just
Also still one of his favorite foods.

(Photo slide)

And I’ll just leave you
with a couple of photos of that baby who is almost 7.
On the left here we have him at six months with a lamb bone that he was teething on.
At the bottom: when he was two I discovered that he had liberated a stick of butter from the
fridge, because that’s so delicious,
and by two-and-a-half he was scrambling his
own eggs.
This child basically had almost no plant matter in his diet for
the first two years of his life and even now his diet is primarily animal-based.
Please give me your questions. Thank you.


I’ve included the names of the questioners that I knew.
If you are one I left out, introduce yourself!
Again, my clarifications or further comments in brackets.

Question 1 (Christopher Kelly)

C: I fully(?) subscribe to your ideas presented here and I have a very healthy two and a half year old daughter
that’s eaten much the same way.
But I thinks there’s an important point missing from your talk that is:
the ketones come from medium chain triglycerides,
that come from mom’s milk from eating carbohydrates.
So the carbohydrates are synthesised in the breast tissue
that make MCTs.
Those MCTs are put in the breast milk,
and that’s a really important ketogenic substrate, so I think that mom should be in ketosis,
You see what I’m saying? The ketones should be synthesised by the baby.
A: I understand what you’re saying, yes.
So I just want to give a couple of counter-examples.
I didn’t eat any carbohydrate while I was making breast milk,
and although there are medium chain
triglycerides in the breast milk,
that’s certainly not the only reason that
babies are in ketosis.
Even the babies postweaning that i mentioned earlier get
into ketosis very rapidly, because it’s just the natural state.
You can make it — that’s why what I’m positing here,
and I’m not — it’s not my idea — but what
I’m saying here is that the baby fat that is there is being turned into
ketones just from the fat that’s stored on the body,
just the same way that I make them
C: Right
A: And I forgot to mention that,
I talked about how fat babies are and how
fat adults are compared to other primates,
and I think it’s quite significant.
It would be unusual to see an animal that’s that fat if you
thought that we weren’t naturally ketogenic animals.
C: Yeah and I’ve actually measured ketones, blood ketones, in my
daughter when she was still an infant, breastfed only, and it was 1.6 mmol.
But I can actually send you the studies that show that the the MCTs in milk,
they go down and there’s studies where they’ve looked at giving MCTS to mom
and they don’t go anywhere. Mom metabolizes them all.
None of them appear in the breast milk, so I think like the carbohydrates for mom,
It’s not my opinion, I can send you the studies that show that that might be
A: I’d like to see that. I guess what I’m trying to say is that the ketones that
are in the baby’s blood don’t only come for a medium chain triglycerides…
C: Right, right, I understand that.
Okay, yeah. I work with a doctor, he’s just finishing his PhD in neonatal
neuroprotection so he’s done quite a lot of research in this area so I’ll send you
some studies.
A: That’s fantastic. I would love that.
C: Okay, thank you.

Question 2

Q: Hey, that was great talk. Thank you. Can you say something about the
timeframe and you’re, you know after three children and all of your research
and interest in this, your thoughts on the timeframe for beginning
the weaning process and then also how large that window of transition looks
A: Sure. There’s a lot I don’t know but I know that the recommendation currently
is to start weaning at around four to six months and I think that the reason
for that is because the amount of breast milk that children get, the caloric input
just can’t provide much more than what they need by the time they’re that
large and so I would say to start giving your baby food as soon as they start to
express interest in it.
Just, you know, let them be the ones who say “I’m ready to
start eating. Give me that.”
And then how long it goes: Humans tend to wean a lot
younger than other primates and I don’t know to what degree that’s enculturated
and to what degree that’s natural.
With my experience, my first
child, I, he stopped breastfeeding at about two years and then each one after
that was earlier and earlier with the last one, he stopped at nine months.
So, I’m sorry I don’t know more about that.
Q: No, no, it’s okay. I just kind of wanted to
see what your thoughts are.
I suppose there’s some, aside from nutritional implications
of how soon or early or late you you move away from breastfeeding
I’m sure there’s other implications as well but it’s just it’s hard to understand.
I just have a newborn, so I was just interested.
A: Congratulations!
Q: Yeah. Thank you so much!

Question 3 (Georgia Ede)

G: Amber, thank you for an exceptionally good talk.
I just had a curiosity question as a psychiatrist.
You having raised three
children on this unique diet, which I wish were more common,
[ Clarification: Unfortunately only my third child was weaning onto meat, though our household was always generally a low carb one. ]
can you comment at all
about how your children fared emotionally and physically compared to
their peers? As a mother I would be very curious to hear.
A: Well there’s so much
individuality I don’t want to necessarily claim too much.
I know that my youngest
child does have a very even temperament, especially compared to one of his
brothers, but then on the other hand his oldest brother has perhaps the most even
temperament of all, so don’t I don’t know what to conclude about that.
One interesting thing that has been commented on to me many, many times is
that my youngest child was never — he never missed a single day of daycare
throughout — when he started at two and, so the entire three-year period, many
of his peers,
all of his peers missed significant time to many illnesses and he missed
not a single day, so I like to attribute that to his diet.
G: Thank you very much. It was fascinating.
A: Thank you.

Question 4 (Ben Sima)

B: Has it been difficult to maintain
his diet of high-fat from a social perspective, for example, they go over to
someone else’s house and they have candy or something with other parents?
A: It is a challenge and the older they get the more of a challenge it is.
My other
children also at the time that I was weaning him, they were also
transitioning to a more meat-based diet and yes it’s
— I mean for example there,
the number of special occasions that you have when you’re at school seem to be
almost as numerous as the number of days
Like, it’s always somebody’s birthday or
some occasion and that’s always being celebrated with some kind of gluteny,
sugary snack and yeah, it’s a struggle.
B: So do you find that he has a sweet tooth or does he kind of shun that
A: He loves sweet things when he gets his hands on them, but he doesn’t seem to be obsessed
with them.

Question 5

Q: I just wanted to offer the cross cultural perspective that the worldwide
age of breastfeeding cessation is about four to five years.
[ But see footnote 3 below, which argues that the natural age is about 2.5 and for important, persuasive reasons. ]
It’s only in the United States that it’s young, around a year, but if you look cross-culturally it is
actually four years in most cultures.
A: Thank you for that.
So that’s for the very end of breastfeeding?
Q: Yeah. So that’s kind of our biological norm.
It’s more of a cultural thing here.
The other thing that’s interesting is around four to six months —
infants get a big bolus of iron from the placenta especially if we allow for delayed cord
clamping —
and then around four to six months that initial iron starts to go
down which is another reason why, like you’re saying,
meats are such a good first food,
but that’s why that four to six months seems to be a good time to
start foods is because that —
not that breast milk is lacking in iron and zinc,
but that that’s not where they’re supposed to get it from.
You get for placentally and
then it starts to go down around four to six months which is why,
traditionally the idea of “ok let’s put iron in rice cereal”
which we know — not a good idea but yeah that’s another reason why that four to six-month window seems
to be a good time for getting those iron and zinc rich foods in.

Question 6 (Nick Mailer)

Q6: Thanks for the talk, it was very good.
Something that hasn’t been discussed so much in this community
is that weaning and continued breastfeeding is not merely about
nutrition but it’s also about keeping the bond between the mother and the
and that’s something that’s often overlooked.
I know that there are
people who I know who have generally weaned but, you know,
when the child is a bit ill
or is feeling a little bit insecure the child will revert for a little while to
getting a little bit of breast milk or maybe once at night just to say goodnight.
It becomes part of a ritual and part of a bonding process rather than as an
essential continuing of nutrition,
which is why as long as you’re
comfortable with it there’s no harm in weaning in that extent, finally later,
and that sometimes people feel the pressure — okay it’s four to six months I better stop
by six months or something will happen — and people do feel that pressure which
is why I think in the US and the UK people kind of feel that it’s a race
to the final cessation of weaning and it doesn’t have to be as far as I’ve heard.
A: Right. Excellent point. Thank you.

Question 7

Hi. Thanks for the talk.
So I have three children also.
My youngest is 15 months.
We thought a very similar, you know baby led weaning
process, as your youngest.
My question is, so my oldest is 11 too — quite a gap in
between them,
and you mentioned that vitamin D is one of the critical elements for brain
development and prior to my son being born I had never seen like my
pediatrician recommending vitamin D supplementation.
So i guess my question
is what are your thoughts on supplementing, like, drops as a newborn,
and also what are some of the better animal sources other than I think fatty
fish to get vitamin D from.
A: Yes, liver fatty fish… I’m surprised that you
didn’t, weren’t recommended vitamin D drops because I remember that from even 15
years ago when my first son was born.
Q: Yeah I don’t remember if it’s possible. Five years between each of them.
So, I think that’s weird you know.
A: Right.
Q: Did you do those?
A: I did. I did do those with the first two children.
Actually I did it with all of them, come to think of it.
Q: Thanks.
A: I figured there’s — the amount you would
have to get to overdose is high enough that it wasn’t going to hurt.
Q: Yeah. We did it too.
I just wasn’t sure. I hadn’t heard it before him, and you mentioned it, so
thanks. Alright.
A: Thank you.

Question 8

Q: Hi. I missed the first part your talk which I’m bummed about, but
I have a four-year-old who regularly steals butter out of the fridge, and her first
foods were I think egg yolk, and
I don’t think I did liver right away because I wasn’t doing
that much liver but now she loves liver too.
It’s like her favorite food.
A: Isn’t it good!
Q: Yeah, I mean I don’t particularly like it, but I eat it.
But she like — she loves it.
I just wanted to add, too, maybe this will be covered in the next talk,
about breastmilk and the microbiome, but one of the things that I found interesting about
breastfeeding and the importance of it for the longer term is that it actually,
the way that children remove milk from the breast actually
helps to form the jaw and the palate,
and so we see a lot today where women have to
go back to work, you know six weeks, 12 weeks after giving birth and so they’re
pumping a lot and because we’re getting bottles
and that’s really changing the
way that our mouths are structured, I mean as are our nutrients in
the womb and the palate formation.
I mean, anyone familiar with Weston Price’s work knows that, right,
but I just think it’s an interesting piece, too,
and I don’t think that there’s this —
once kids start food they have to stop breast milk.
In fact those things go
together quite well for a long time because of the emotional factors and
because of the palate formation
and the muscle strength and the jaw formation.
A: Right.
Q: So, that I think is an interesting interesting piece, too,
and yeah I’ve seen the same sort of statistics that hunter-gatherers usually
breastfed three to four years,
but they actually had a lower body fat,
and so that would suppress ovulation for longer,
which is why their children were
spaced 4-5 years apart.
And there was no dairy.
People weren’t eating dairy, so only dairy that was available was
breast milk and the way that that dairy produces certain vitamins…
A: Lactose in particular is broken down into glucose and galactose
and galactose is used to build some the brain material as well.
Q: There’s a question, so I have anoher question I’ll ask you later.

Question 9 (Kevin Boyd)

Q: Okay that was interesting.
Who are you? That’s, it’s interesting that you’d, she’s — that’s my whole
talk this afternoon.
Please come.
Nutrition is concerned with nutrients, but not mechanical aspects of food
processing and what she brought up was what I was gonna talk about a little bit,
but how did you learn about baby led weaning, because, that is,
for people who might not
know could you explain a little bit about what it is and how you learned
about it and how you are executing it with your own children?
A: Well, I’m not sure where I first heard of it, but the thing that I said that
was the core important idea from it is what I’ve taken mostly from it,
and that’s that babies don’t necessarily need you too mush everything up you can,
you can give them a chicken drumstick and they’ll deal with it.
Q: Yeah. I’m going to really elaborate and so many wonderful points you made today,
at one-thirty today.
A: Ok. Well, I won’t steal your thunder, then!
Q: It was a great talk.
A: Thank you.

Question 10

Q: Hi, I’m the token pre-mastication question.
So you know, it goes:
You know, you have your first baby and you sterilize everything before
it touches her mouth and by the third baby you’re picking up a pacifier and
you’re popping it in your own mouth before you pop it in theirs,
and there was some concern about that in terms of, I guess, oral hygiene and what I
had heard was, you know, it’s not such a wonderful thing to introduce your mouth
germs to your baby, but if your pre-masticating their food perhaps you
disagree with that.
A: Yes. Yes. I suppose if you had something unhealthy going on your mouth, that would
be a problem, but I — I don’t really think that there’s anything unhygienic about
the mouth, if you’re healthy.
Q: OK.
OK, well, thank you.


I’ve never given a talk to an audience of this size and calibre before.
I particularly want to thank Sean Baker, Zooko Wilcox, and Jeff Pedelty for their support and encouragement in making it happen.
I’m grateful also to the patient organisers of AHS for welcoming me and helping me through the process, particularly Katherine Morrison, Grace Liu, and Ben Sima.


[1] Using EQ (encephalisation quotient), that is: a measure of relative brain size for mammals that takes into account some physical characteristics that affect the brain-body ratio.
[2] Evidence type: experimental

Martin, Robert D.
Fifty-second James Arthur lecture on the evolution of the human brain 1982


[3] Evidence type: review of data collection

Kennedy GE1.
J Hum Evol. 2005 Feb;48(2):123-45. Epub 2005 Jan 18.

“Although humans have a longer period of infant dependency than other hominoids, human infants, in natural fertility societies, are weaned far earlier than any of the great apes: chimps and orangutans wean, on average, at about 5 and 7.7 years, respectively, while humans wean, on average, at about 2.5 years. Assuming that living great apes demonstrate the ancestral weaning pattern, modern humans display a derived pattern that requires explanation, particularly since earlier weaning may result in significant hazards for a child. Clearly, if selection had favored the survival of the child, humans would wean later like other hominoids; selection, then, favored some trait other than the child’s survival. It is argued here that our unique pattern of prolonged, early brain growth — the neurological basis for human intellectual ability — cannot be sustained much beyond one year by a human mother’s milk alone, and thus early weaning, when accompanied by supplementation with more nutritious adult foods, is vital to the ontogeny of our larger brain, despite the associated dangers.”

[On the data set:]
“Weaning is a process, not an event that can be placed at a specific point in time; therefore, it is not subject, in any meaningful way, to precise mathematical or statistical analyses or even to exact determination. Sellen’s (2001) recent paper has, perhaps, done as much as possible to overcome the inherent problems of determining human weaning time. An ‘‘average’’ age of weaning can only suggest the age at which most young in a particular group cease nursing; moreover, in humans, as the Amele demonstrate, it is not uncommon for a mother to continue to nurse an older youngster even though she has an infant as well. Data reported in Table 1 were taken from field studies, individual ethnographic reports, and from the Human Relations Area Files (HRAF: category 862, on-line edition); data points were included only when a definite age or clear range was expressed. All were pre-industrial, ‘‘natural fertility’’ populations practicing a range of subsistence economies from agriculture to foraging, and many were mixed economies.”

“Although a mean weaning age can be calculated from the human data in Table 1 (30.1 months; n = 46), it seems more accurate to conclude that the ‘‘natural’’ weaning age for humans is between 2-3 years and generally occurs about midway in that range. The minimum reported weaning age was one year (Fiji, Kogicol) and the maximum was about 4 years (several native American groups); several entries, however, reported that individual children may nurse as long as 6 years. Goodall (1986) also reported that a few Gombe chimps also nursed far longer than the population average. Sellen (2001), using a slightly larger sample (n = 113) also taken from the HRAF (microfiche edition), reported a very similar mean (29 months +/- 10 months), and a very similar peak weaning period between 2 and 3 years.”

“As noted below, stable nitrogen isotope analysis on bone tissue from several prehistoric societies suggests a somewhat wider range of ‘‘natural’’ weaning ages. For example, since nursing infants occupy a different (higher) trophic level than do their mothers, the isotopic composition of nursing infants’ bones and teeth should, in theory, differ from that of the adults in their group. Weaning time, therefore, should correspond to the point at which infant and adult tissues reach a similar isotopic composition ( Herring et al., 1998 ). Following Fogel et al. (1989), several authors have found an elevated level of δ15 N in infant osteological remains (relative to adults of the same group), which, they argued, constitutes a ‘‘nursing signal’’ ( Katzen- berg, 1992; Katzenberg et al., 1993, 1996; Schurr, 1994; Tuross and Fogel, 1994; White and Schwarcz, 1994 ). For example, at the Sully site in North Dakota and at the Angel site in the Ohio Valley, δ15 N reached adult levels at about 24 months (Tuross and Fogel, 1994; Schurr, 1997), suggesting rather early weaning. In Nubia, on the other hand, there was a gradual decline up to about age 6, indicating a slow introduction of adult foods ( White and Schwarcz, 1994 ). Others have used stable carbon and oxygen isotopes in dental enamel to track dietary changes in young children. Stable carbon (δ13 C), for example, may be used to detect the introduction of solid foods, and hence the beginning of the weaning period, while oxygen isotopes (δ18 O) may track the decreasing consumption of human milk (Wright and Schwarcz, 1998). Using this approach, it was found that, among the Preclassic and Postclassic Maya, solid foods were first introduced probably late in the first year, but that the weaning process was not concluded until 5 or 6 years ( Wright and Schwarcz, 1998).”

“[E]xtensive field data, collected in modern traditional societies, ancient textual references, and biochemical evidence from prehistoric societies, all suggest that in humans, the ‘‘natural’’ weaning age is generally between 2 and 3 years, although it may continue longer in some groups.”

[4] Evidence type experiment

John Dobbing and Jean Sands
Arch Dis Child. 1973 Oct; 48(10): 757–767.

“One hundred and thirty-nine complete human brains ranging in age from 10 weeks’ gestation to 7 postnatal years, together with 9 adult brains, have been analysed in order to describe the human brain growth spurt quantitatively… The growth spurt period is much more postnatal than has formerly been supposed.”
“The postnatal cut-off point of the sigmoid curve of weight accumulation seems to be between 18 postnatal months and 2 years for whole brain.”

[5] Evidence Type: review of experiments

Martin, Robert D.
Fifty-second James Arthur lecture on the evolution of the human brain 1982

[Emphasis ours]
“The foregoing comparisons have demonstrated that Homo sapiens shares a number of general features of brain size and its development with the other primates, most notably in producing precocial off-spring and in the shift to a distinctive relationship between brain size and body size during foetal development (fig. 8). But human beings also exhibit a number of special features which set them apart from other primates, or at least from their closest relatives the great apes. These may be listed as follows:

  1. The remarkably large size of the adult brain relative to body size.
  2. The rapid development of both brain and body during foetal development, resulting in a distinctively large brain and body size at birth, compared to great apes.
  3. The greater degree of postnatal growth of the brain, accomplished by continuation of foetal brain : body relationships for at least one year after birth and associated with the “secondary altricial condition.

[This shows pattern of brain to body weight ratio, not just brain weight]

[6] Evidence type: experiment

Changes in brain weights during the span of human life: relation of brain weights to body heights and body weights.
Dekaban AS.

“More than 20,000 autopsy reports from several general hospitals were surveyed for the purpose of selecting brains without a pathological lesion that had been weighed in the fresh condition. From this number, 2,773 males and 1,963 females were chosen for whom body weight, body height, and cause of death had been recorded. The data were segregated into 23 age groups ranging from birth to 86+ years and subjected to statistical evaluation. Overall, the brain weights in males were greater than in females by 9.8%. The largest increases in brain weights in both sexes occurred during the first 3 years of life, when the value quadruples over that at birth, while during the subsequent 15 years the brain weight barely quintuples over that at birth.”
“[T]he largest increases in brain weight occur during the first year of life, when the weight more than doubles that at birth (see Tables 2, 3; Figs 2A, 5). Further increases in brain weight also occur quite rapidly, although the increments from the preceding age groups are smaller. At about 3 years of age in males and between 3 and 4 years in females, the brain weight reaches four times the value at birth. Further growth of the brain is considerably slower, as it takes the brain 15 years (between ages 4 and 18) to nearly quintuple its birth weight and reach its mean highest value in young adults.”

[7] Evidence Type: review of human and non-human animal experiments

CIBA Foundation Symposium
John Wiley & Sons, Sep 16, 2009 – Science – 192 pages

“The human growth spurt appears to extend throughout the last trimester of pregnancy and well into the 2nd year of postnatal life, and by analogy similar harm would be expected in the brains of humans growth-retarded during this time [as rats in reported nutrient deficiency experiment]
“There is no question but that the transient period of brain growth, known as the brain growth spurt, is more vulnerable to growth restriction than the periods both before and afterwards. Vulnerability in this sense means that quite mild restriction leads in experimental animals to permanent, irrecoverable reduction in the trajectory of bodily growth and to easily detectable distortions and deficits in the adult brain… In the present case the ‘damage’ consists of permanent but non-uniform reduction in the extent of brain growth. There is accumulating evidence that it has functional importance. An important feature of this type of vulnerability is that it is highly dependent on the timing of the insult, although not as finely so as the earlier teratology.”

[8] Evidence type: review of experiments

Siegel GJ, Agranoff BW, Albers RW, et al., editors.
Philadelphia: Lippincott-Raven; 1999.

“The brain consumes about one-fifth of total body oxygen utilization
“The brain is metabolically one of the most active of all organs in the body. This consumption of O2 provides the energy required for its intense physicochemical activity. The most reliable data on cerebral metabolic rate have been obtained in humans. Cerebral O2 consumption in normal, conscious, young men is approximately 3.5 ml/100 g brain/min (Table 31-1); the rate is similar in young women. The rate of O2 consumption by an entire brain of average weight (1,400 g) is then about 49 ml O2/min. The magnitude of this rate can be appreciated more fully when it is compared with the metabolic rate of the whole body. An average man weighs 70 kg and consumes about 250 ml O2/min in the basal state. Therefore, the brain, which represents only about 2% of total body weight, accounts for 20% of the resting total body O2 consumption. In children, the brain takes up an even larger fraction, as much as 50% in the middle of the first decade of life [15].”

[9] Evidence type: review

Stephen Cunnane (Editor), Kathlyn Stewart (Editor)
ISBN: 978-0-470-45268-4
June 2010, Wiley-Blackwell


[10] Evidence type: review

Delange F.
Proc Nutr Soc. 2000 Feb;59(1):75-9.

“I is required for the synthesis of thyroid hormones. These hormones, in turn, are required for brain development, which occurs during fetal and early postnatal life. The present paper reviews the impact of I deficiency (1) on thyroid function during pregnancy and in the neonate, and (2) on the intellectual development of infants and children. All extents of I deficiency (based on I intake (microgram/d); mild 50-99, moderate 20-49, severe > 20) affect the thyroid function of the mother and neonate, and the mental development of the child. The damage increases with the extent of the deficiency, with overt endemic cretinism as the severest consequence. This syndrome combines irreversible mental retardation, neurological damage and thyroid failure. Maternal hypothyroxinaemia during early pregnancy is a key factor in the development of the neurological damage in the cretin. Se deficiency superimposed on I deficiency partly prevents the neurological damage, but precipitates severe hypothyroidism in cretins. I deficiency results in a global loss of 10-15 intellectual quotient points at a population level, and constitutes the world’s greatest single cause of preventable brain damage and mental retardation.”

[11] Evidence type: review

Micronutrient Deficiencies in the First Months of Life
edited by F. Delange, Keith P. West

“Iron plays a critical role in brain development, including its postnatal stages. Youdim et al., Youdim, Rouault and Beard reviewed the biological mechanisms whereby iron deficiency could possibly affect brain structure and functioning. The accumulation and distribution of iron in various regions of the brain depend on the stage of its development. This might indicate that brain regions vary in their vulnerability to iron deprivation, and suggests that the effect of iron deficiency on brain iron content could depend on the timing of the exposure. Animal studies indicate that low dietary intake of iron in the neonatal or preweaning period (before postnatal days 14-21 [ this must be rodents? ] may reduce whole-brain iron content that is not reversible by dietary repletion and produce irreversible effects. In rats, such effects occur before completion of brain organization and myelination and establishment of dopaminergic tracts. By contrast, dietary depletion in the postweaning period can also reduce brain iron content but this might be reversible upon dietary repletion. This illustrates that the timing of exposure to iron deficiency must be carefully considered when examining possible effects of iron deficiency on mental performance.
“Iron is not only required for brain growth and differentiation of neuronal cells, but also for protein synthesis, hormone production and other aspects of cellular enrgy metabolism and functioning. When sufficiently severe to reduce hemoglobin concentrations or cause anemia, iron deficiency might adversely affect oxygen delivery, thereby leading to reduced functioning of the central nervous system. Such deletrious effects of iron deficiency might be partially or completely reverese by iron repletion.
“Effects of iron deficiency might also be determined by other mechanisms. For example, it has been hypothesized that anemic children experience delayed acquisition of skills because they explore and interact less with their environment than nonanemic children, and they induce less stimulating behavior in their caretakers. Additionally, several studies have indicated that anemic children tend to be more fearful, withdrawn and tense, have reduced ability to focus their attention [25, 26], and are therefore less exposed to environmental stimuli that may promote mental and motor development.”

[12] Evidence type: review (mostly non-human animal experiments)

Bhatnagar S, Taneja S.
Br J Nutr. 2001 May;85 Suppl 2:S139-45.

“Cognition is a field of thought processes by which an individual processes information through skills of perception, thinking, memory, learning and attention. Zinc deficiency may affect cognitive development by alterations in attention, activity, neuropsychological behavior and motor development. The exact mechanisms are not clear but it appears that zinc is essential for neurogenesis, neuronal migration, synaptogenesis and its deficiency could interfere with neurotransmission and subsequent neuropsychological behavior. Studies in animals show that zinc deficiency during the time of rapid brain growth, or during the juvenile and adolescent period affects cognitive development by decreasing activity, increasing emotional behavior, impairing memory and the capacity to learn. Evidence from human studies is limited. Low maternal intakes of zinc during pregnancy and lactation were found to be associated with less focused attention in neonates and decreased motor functions at 6 months of age. Zinc supplementation resulted in better motor development and more playfulness in low birth weight infants and increased vigorous and functional activity in infants and toddlers. In older school going children the data is controversial but there is some evidence of improved neuropsychological functions with zinc supplementation. Additional research is required to determine the exact biological mechanisms, the critical periods, the threshold of severity and the long-term effects of zinc deprivation on cognitive development.”

[13] Evidence type: review

McNamara RK, Carlson SE.
Prostaglandins Leukot Essent Fatty Acids. 2006 Oct-Nov;75(4-5):329-49. Epub 2006 Sep 1.

“There is now good evidence suggesting that DHA is accrued in rodent, primate, and human brain during active periods of perinatal cortical maturation, and that DHA plays an important role in neuronal differentiation, synaptogenesis, and synaptic function. In animal studies, prenatal deficits in brain DHA accrual that are not corrected via postnatal dietary fortification are associated with enduring deficits in neuronal arborization, multiple indices of synaptic pathology, deficits in mesocorticolimbic dopamine neurotransmission, deficits in hippocampal serotonin and acetylcholine neurotransmission, neurocognitive deficits on hippocampus and frontal cortex-dependent learning tasks, and elevated behavioral indices of anxiety, aggression, and depression. Human and primate infants born preterm or fed diets without DHA postnatally exhibit lower cortical DHA accrual compared to infants born at term or fed human milk postnatally. Children/adolescents born preterm exhibit deficits in cortical gray matter expansion, neurocognitive deficits, and are at increased risk for attention-deficit/hyperactivity disorder (ADHD) and schizophrenia. Individuals diagnosed with ADHD or schizophrenia exhibit peripheral indices of lower DHA status and exhibit deficits in cortical gray matter expansion and deficits in cortical dopamine neurotransmission. Based on this body of evidence, it is hypothesized that perinatal deficits in brain DHA accrual represents a modifiable neurodevelopmental risk factor for the emergence of neurocognitive deficits and subsequent psychopathology. Evaluation of this hypothesis is currently feasible.”

[14] Evidence type: review

J D Cook
Am J Clin Nutr February 1990 vol. 51 no. 2 301-308

[ Emphasis mine ]
“Dietary iron supply encompasses both the total amount of ingested iron and its bioavailability. Before 1950, nutritionists emphasized only total iron intake as a measure of dietary adequacy. Wider application of isotopic techniques during the l9SOs and l960s led to the realization that the bioavailability of ingested iron may be more important than total intake. There are two separate pathways of iron entry into the mucosal cell. The largest fraction of dietary iron is in the form of inorganic or nonheme iron, the absorption of which is determined largely by the nature of the meal. Nonheme-iron absorption occurs mainly from the duodenum because of the greater solubility of luminal iron in the proximal, more acid, region of the small intestine. Isotopic studies with extrinsic labeling demonstrated that all dietary forms of nonheme iron ingested in the same meal form a common pool within the intestinal lumen. Absorption from this pool is determined not by the type of the iron ingested but by enhancers, which promote absorption by maintaining iron in a reduced soluble form, and inhibitors, which bind iron or make iron insoluble and prevent its uptake by the brush border (29-32). The bioavailability of nonheme iron is enhanced by ascorbic acid and various tissue foods, such as meat, fish, and poultry, but not dairy products (33). A large number of dietary constituents impair iron absorption and these factors have been the major focus of absorption studies during the past decade. The most important inhibitors include tea, coffee, bran, calcium phosphate, egg yolk, polyphenols, and certain forms of dietary fiber. The extremes in bioavailability of nonheme iron as measured from isotopically labeled single meals served in a laboratory setting is nearly 15-fold (Fig 2). If tea is eliminated, absorption will increase about threefold. If meat is added, absorption will again increase 2-3 times. Maximal enhancement absorption occurs when a large quantity of ascorbic acid (eg, 2g) is taken with the meal.
“The second dietary iron fraction is heme, which is absorbed into the intestinal cell as an intact porphyrin complex. Specific receptors for heme iron have been identified in laboratory animals (34) but not in humans. After heme iron enters the cell it is rapidly degraded by heme oxygenase (35), and the released iron then enters the common intracellular iron pool. Subse- quent mucosal handling ofthis iron appears to be identical to that of inorganic iron. Because heme iron remains protected within the porphyrin complex before its uptake by the mucosa, it does not interact with dietary ligands and is therefore unaffected by the nature of the meal. Percentage absorption of heme iron is 5-10-fold higher than from nonheme iron. Although heme represents only 10-15% of dietary iron in meat-eating populations, it may account for nearly one-third of absorbed iron (36). Because absorption of heme iron is constant and independent of meal composition, the contribution of heme iron can be readily calculated from dietary records. This is in distinction to marked differences in the availability of non-heme iron.”

[15] Evidence type: review

Clive E. West*,†,2, Ans Eilander*, and Machteld van Lieshout*
J. Nutr. September 1, 2002 vol. 132 no. 9 2920S-2926S

“The bioefficacy of β-carotene in plant foods is much less than was previously thought. Intervention studies enrolled schoolchildren in Indonesia (10) and breast-feeding women in Vietnam (11) (Table 1). In each study there were four dietary groups: low-retinol, low-carotenoid diet (negative control); dark-green leafy vegetables (as well as carrots in the Indonesian study); yellow and orange fruits; and a retinol-containing diet (positive control). For dark-green leafy vegetables, the bioefficacy was 1:26 and 1:28; while for fruit, the bioefficacy was 1:12. This suggests that, with a mixture of vegetables and fruits in a ratio of 4:1, which is typical for both developing and developed countries, the bioefficacy of β-carotene from a mixed diet is 1:21. Chinese children aged 5–6.5 y yielded similar results for green and yellow vegetables (1:27) (14). Van Lieshout et al. (15), using the plateau isotopic enrichment method, also found relatively poor bioefficacy of β-carotene in dark-green leafy vegetables. β-Carotene in pumpkin was 1.7 times as potent as that in spinach (Table 1).”

[16] See also the extensive review in the Vitamin A chapter of Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc Panel on Micronutrients, Subcommittees on Upper Reference Levels of Nutrients and of Interpretation and Use of Dietary Reference Intakes, and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, which is accessible and would take a lot of space to include here.
[17] Evidence type: review

Crawford MA.
Am J Clin Nutr. 1993 May;57(5 Suppl):703S-709S; discussion 709S-710S.

“The brain is 60% structural lipid, which universally uses arachidonic acid (AA; 20:4n6) and docosahexaenoic acid (DHA; 22:6n-3) for growth, function, and integrity. Both acids are consistent components of human milk. Experimental evidence in animals has demonstrated that the effect of essential fatty acid deficiency during early brain development is deleterious and permanent. The risk of neurodevelopmental disorder is highest in the very-low-birth-weight babies. Babies born of low birth weight or prematurely are most likely to have been born to mothers who were inadequately nourished, and the babies tend to be born with AA and DHA deficits. Because disorders of brain development can be permanent, proper provision should be made to protect the AA and DHA status of both term and preterm infants to ensure optimum conditions for the development of membrane-rich systems such as the brain, nervous, and vascular systems.”

[18] Evidence type: experiment

O’Brien JS, Sampson EL.
J Lipid Res. 1965 Oct;6(4):537-44.


[19] Evidence type: review

William M. Pardridge
Chapter in Fuel Homeostasis and the Nervous System, Volume 291 of the series Advances in Experimental Medicine and Biology pp 43-53

[ Emphasis mine ]
“Although free fatty acids are an important carbon source for cellular combustion in tissues such as skeletal muscle, fat, or liver in the postabsorptive state, brain does not significantly combust circulating free fatty acid, even after several weeks of prolonged starvation.(32) This failure to oxidize circulating free fatty acids is not due to a deficiency of the relevant free fatty acid oxidizing enzymes in brain since labeled free fatty acids are readily converted to CO 2 following the intracerebral administration of [14Cj-labeled free fatty acid,(33) and small amounts of circulating free fatty acids are converted to Krebs cycle intermediates (34). Rather, the failure of brain to utilize circulating free fatty acids as an important source of combustible carbon is due, in part, to a slow transport through the BBB. In the absence of plasma proteins, both medium chain and long chain free fatty acids are rapidly transported through the BBB. (35) However, free fatty acids are more than 99% bound by high affinity binding sites on circulating albumin, and only approximately 5% of plasma free fatty acid is unidirectionally extracted by brain on a single pass through the cerebral microcirculation .(36) Moreover, there is a prominent enzymatic barrier to the utilization of the circulating free fatty acids,3 as depicted in Figure 5. There is rapid esterification into membrane-bound triglyceride of circulating free fatty acid at either the endothelial membrane or the brain cell membrane. Thus, in the steady state, an equal amount of free fatty acid taken up by brain and esterified in the endothelial or brain cell membranes is released to blood via hydrolysis of membrane-bound triglyceride via brain microvascular lipoprotein lipase. 3 This enzymatic barrier protecting brain intracellular space from circulating free fatty acids is very well developed and breaks down only under pathologic conditions in brain.
[ As far as I can tell, it has only recently been discovered that there are some mechanisms for transporting fatty acids across the blood brain barrier, but how much and under what circumstances is poorly understood. This statement expresses that candidly: ]

Murphy EJ.
J Neurochem. 2015 Dec;135(5):845-8. doi: 10.1111/jnc.13289. Epub 2015 Sep 17.

“How do fatty acids enter the brain and what role, if any, do membrane and cytosolic fatty acid binding proteins have on facilitating this process? This is a fundamental question that many lipid neurochemists will freely admit they cannot answer in any kind of definitive manner.”

[20] Evidence type: experiment

O’Brien JS, Sampson EL.
J Lipid Res. 1965 Oct;6(4):537-44.

[ palimitic = 16:0, stearic = 18:0, oleic = 18:1 ]

[21] Evidence type: non-human animal experiment

Fatty acid transport and utilization for the developing brain.
Edmond J, Higa TA, Korsak RA, Bergner EA, Lee WN.
J Neurochem. 1998 Mar;70(3):1227-34.

[ Emphasis mine ]
“To determine the transport and utilization of dietary saturated, monounsaturated, and n-6 and n-3 polyunsaturated fatty acids for the developing brain and other organs, artificially reared rat pups were fed a rat milk substitute containing the perdeuterated (each 97 atom% deuterium) fatty acids, i.e., palmitic, stearic, oleic, linoleic, and linolenic, from day 7 after birth to day 14 as previously described. Fatty acids in lipid extracts of the liver, lung, kidney, and brain were analyzed by gas chromatography-mass spectrometry to determine their content of each of the deuterated fatty acids. The uptake and metabolism of perdeuterated fatty acid lead to the appearance of three distinct groups of isotopomers: the intact perdeuterated, the newly synthesized (with recycled deuterium), and the natural unlabeled fatty acid. The quantification of these isotopomers permits the estimation of uptake and de novo synthesis of these fatty acids. Intact perdeuterated palmitic, stearic, and oleic acids from the diet were found in liver, lung, and kidney, but not in brain. By contrast, perdeuterated linoleic acid was found in all these organs. Isotopomers of fatty acid from de novo synthesis were observed in palmitic, oleic, and stearic acids in all tissues. The highest enrichment of isotopomers with recycled deuterium was found in the brain. The data indicate that, during the brain growth spurt and the prelude to myelination, the major saturated and monounsaturated fatty acids in brain lipids are exclusively produced locally by de novo biosynthesis. Consequently, the n-6 and n-3 polyunsaturated fatty acids must be transported and delivered to the brain by highly specific mechanisms.”

[22] Evidence type: review

Brain Cholesterol: Long Secret Life Behind a Barrier
Ingemar Björkhem, Steve Meaney
Arteriosclerosis, Thrombosis, and Vascular Biology. 2004; 24: 806-815

“Although an immense knowledge has accumulated concerning regulation of cholesterol homeostasis in the body, this does not include the brain, where details are just emerging. Approximately 25% of the total amount of the cholesterol present in humans is localized to this organ, most of it present in myelin. Almost all brain cholesterol is a product of local synthesis, with the blood-brain barrier efficiently protecting it from exchange with lipoprotein cholesterol in the circulation. Thus, there is a highly efficient apolipoprotein-dependent recycling of cholesterol in the brain, with minimal losses to the circulation.Although an immense knowledge has accumulated concerning regulation of cholesterol homeostasis in the body, this does not include the brain, where details are just emerging. Approximately 25% of the total amount of the cholesterol present in humans is localized to this organ, most of it present in myelin. Almost all brain cholesterol is a product of local synthesis, with the blood-brain barrier efficiently protecting it from exchange with lipoprotein cholesterol in the circulation. Thus, there is a highly efficient apolipoprotein-dependent recycling of cholesterol in the brain, with minimal losses to the circulation.”

[23] Evidence type: review

Morris AA
J Inherit Metab Dis. 2005;28(2):109-21.

“The second function of KBs in the brain is to provide substrates for the synthesis of various molecules. KBs are particularly important for the synthesis of lipids, such as cholesterol in myelin. Studies in 18-day-old rats found that KBs are incorporated into brain cholesterol and fatty acids much more readily than glucose is incorporated (Webber and Edmond 1977). Studies of cultured mouse astrocytes and neurons gave similar results (Lopes-Cardozo et al 1986). The preferential use of KBs for lipid synthesis probably occurs because they can be converted directly to acetoacetyl-CoA in the cytoplasm by acetoacetyl-CoA synthetase (EC, see Figure 1). Cytosolic acetoacetyl-CoA thiolase can then convert acetoacetyl-CoA to acetyl-CoA. Cytosolic acetyl-CoA can be generated from glucose (via the tricarboxylic acid cycle and ATP-citrate lyase, Figure 1) but this is a less direct pathway due to the inability of acetyl-CoA to cross the mitochondrial inner membrane. KBs are incorporated into fatty acids in the brain but they are primarily used for cholesterol synthesis (Koper et al 1981). Acetoacetyl-CoA synthetase expression in human brain parallels that of HMG-CoA reductase (EC, providing further evidence for the importance of this pathway in sterol synthesis (Ohgami et al 2003). Although KBs are the preferred substrates for brain lipogenesis, they appear not to be essential. Thus, rats fed a hypoketogenic diet develop normally (Auestad et al 1990). Development is also normal in most human patients with defects of ketogenesis (Morris et al 1998; van der Knaap et al 1998), though imaging sometimes shows white-matter abnormalities (see Clinical Considerations below).”

[24] Evidence type: review

Yeh YY, Sheehan PM.
Fed Proc. 1985 Apr;44(7):2352-8.

[ Emphasis mine ]
“Persistent mild hyperketonemia is a common finding in neonatal rats and human newborns, but the physiological significance of elevated plasma ketone concentrations remains poorly understood. Recent advances in ketone metabolism clearly indicate that these compounds serve as an indispensable source of energy for extrahepatic tissues, especially the brain and lung of developing rats. Another important function of ketone bodies is to provide acetoacetyl-CoA and acetyl-CoA for synthesis of cholesterol, fatty acids, and complex lipids. During the early postnatal period, acetoacetate (AcAc) and beta-hydroxybutyrate are preferred over glucose as substrates for synthesis of phospholipids and sphingolipids in accord with requirements for brain growth and myelination. Thus, during the first 2 wk of postnatal development, when the accumulation of cholesterol and phospholipids accelerates, the proportion of ketone bodies incorporated into these lipids increases. On the other hand, an increased proportion of ketone bodies is utilized for cerebroside synthesis during the period of active myelination. In the lung, AcAc serves better than glucose as a precursor forbiddingly the synthesis of lung phospholipids. The synthesized lipids, particularly dipalmityl phosphatidylcholine, are incorporated into surfactant, and thus have a potential role in supplying adequate surfactant lipids to maintain lung function during the early days of life. Our studies further demonstrate that ketone bodies and glucose could play complementary roles in the synthesis of lung lipids by providing fatty acid and glycerol moieties of phospholipids, respectively. The preferential selection of AcAc for lipid synthesis in brain, as well as lung, stems in part from the active cytoplasmic pathway for generation of acetyl-CoA and acetoacetyl-CoA from the ketone via the actions of cytoplasmic acetoacetyl-CoA synthetase and thiolase.”

[25] Evidence type: non-human animal experiment

Koper JW, Zeinstra EC, Lopes-Cardozo M, van Golde LM.
Biochim Biophys Acta. 1984 Oct 24;796(1):20-6.

“We have compared glucose and acetoacetate as precursors for lipogenesis and cholesterogenesis by oligodendrocytes and astrocytes, using mixed glial cultures enriched in oligodendrocytes. In order to differentiate between metabolic processes in oligodendrocytes and those in astrocytes, the other major cell type present in the mixed culture, we carried out parallel incubations with cultures from which the oligodendrocytes had been removed by treatment with anti-galactocerebroside serum and guinea-pig complement. The following results were obtained: 1. Both oligodendrocytes and astrocytes in culture actively utilize acetoacetate as a precursor for lipogenesis and cholesterogenesis. 2. In both cell types, the incorporation of acetoacetate into fatty acids and cholesterol exceeds that of glucose by a factor of 5-10 when the precursors are present at concentrations of 1 mM and higher. 3. Glucose stimulates acetoacetate incorporation into fatty acids and cholesterol, whereas acetoacetate reduces the entry of glucose into these lipids. This suggests that glucose is necessary for NADPH generation, but that otherwise the two precursors contribute to the same acetyl-CoA pool. 4. Both with acetoacetate and with glucose as precursor, oligodendrocytes are more active in cholesterol synthesis than astrocytes. 5. Using incorporation of 3H2O as an indicator for total lipid synthesis, we estimated that acetoacetate contributes one third of the acetyl groups and glucose one twentieth when saturating concentrations of both substrates are present.”

[26] Evidence type: experiment

“A total of 272 venous blood samples was obtained from umbilical cord and from children of varying ages from birth to 8 years. All were analysed for blood glucose and either FFA, glycerol or ketone bodies.”
[ Fasted overnight ]

[27] Evidence type: experiment

Kraus H, Schlenker S, Schwedesky D.
Hoppe Seylers Z Physiol Chem. 1974 Feb;355(2):164-70.

“Removal of circulating ketone bodies by the brain is greater in newborns than in infants. Both values are higher than those reported in adults [14]. This is demonstrated by the differences in the slopes of the’regression lines. From these data, however, the conclusion cannot be drawn that there is a specific enhancement of ketone body metabolism in the brains of young individuals. The total metabolic rate could be increased in the infant brain due to denser arrangement of blood capillaries, shorter diffusion distances and a higher cerebral blood flow. In order to avoid objections arising from these differences the contribution of ketone bodies to the total oxidative metabolism of the brain was calculated (last row of Table 1). Hence it follows that the brain’s capacity to utilize ketone bodies is specifically increased in newborns in comparison with infants. These values in turn are five and four times higher respectively than those reported in adults [14]. This conclusion is also justified by the finding that the contribution of glucose is not significantly altered throughout the different age groups. Corresponding relative values in newborns, infants and adults are 0.26, 0.27, and 0.33. The results of the present paper are confirmed by the report that the estimated cerebral uptake of ketone bodies in a group of older children (aged up to 14 years) was about three to four times higher than values observed in adults [19]. As cited above it was shown in different animals that the capacity to utilize ketone bodies is higher in the infant than in the adult brain [2, 20]. The increased ketone utilization by the animal brain during the neonatal period resulted from higher activities of the enzymes of ketone body utilization. Whether this also applies to the human infant brain remains to be tested.

[28] Evidence type: experiment

P F Bougneres, C Lemmel, P Ferré, and D M Bier
J Clin Invest. 1986 Jan; 77(1): 42–48.

[ Emphasis ours ]
“Using a continuous intravenous infusion of D-(-)-3-hydroxy[4,4,4-2H3]butyrate tracer, we measured total ketone body transport in 12 infants: six newborns, four 1-6-mo-olds, one diabetic, and one hyperinsulinemic infant. Ketone body inflow-outflow transport (flux) averaged 17.3 +/- 1.4 mumol kg-1 min-1 in the neonates, a value not different from that of 20.6 +/- 0.9 mumol kg-1 min-1 measured in the older infants. This rate was accelerated to 32.2 mumol kg-1 min-1 in the diabetic and slowed to 5.0 mumol kg-1 min-1 in the hyperinsulinemic child. As in the adult, ketone turnover was directly proportional to free fatty acid and ketone body concentrations, while ketone clearance declined as the circulatory content of ketone bodies increased. Compared with the adult, however, ketone body turnover rates of 12.8-21.9 mumol kg-1 min-1 in newborns fasted for less than 8 h, and rates of 17.9-26.0 mumol kg-1 min-1 in older infants fasted for less than 10 h, were in a range found in adults only after several days of total fasting. If the bulk of transported ketone body fuels are oxidized in the infant as they are in the adult, ketone bodies could account for as much as 25% of the neonate’s basal energy requirements in the first several days of life. These studies demonstrate active ketogenesis and quantitatively important ketone body fuel transport in the human infant. Furthermore, the qualitatively similar relationships between the newborn and the adult relative to free fatty acid concentration and ketone inflow, and with regard to ketone concentration and clearance rate, suggest that intrahepatic and extrahepatic regulatory systems controlling ketone body metabolism are well established by early postnatal life in humans.”

[29] Evidence type: experiment

Harrington TA, Thomas EL, Modi N, Frost G, Coutts GA, Bell JD.
Lipids. 2002 Jan;37(1):95-100.

“The role of body fat content and distribution in infants is becoming an area of increasing interest, especially as perception of its function appears to be rapidly evolving. Although a number of methods are available to estimate body fat content in adults, many are of limited use in infants, especially in the context of regional distribution and internal depots. In this study we developed and implemented a whole-body magnetic resonance imaging (MRI)-based protocol that allows fast and reproducible measurements of adipose tissue content in newborn infants, with an intra-observer variability of <2.4% and an inter-observed variability of <7%. The percentage total body fat for this cohort of infants ranged from 13.3-22.6% (mean and standard deviation: 16.6 +/- 2.9%), which agrees closely with published data. Subcutaneous fat accounted for just over 89% of the total body fat, whereas internal fat corresponded to almost 11%, most of which was nonabdominal fat. There were no gender differences in total or regional body fat content. These results show that whole-body MRI can be readily applied to the study of adipose tissue content and distribution in newborn infants. Furthermore, its noninvasive nature makes it an ideal method for longitudinal and interventional studies in newborn infants.”

[30] Evidence type: review

[ Emphasis ours ]
“The likelihood that the composition of fatty acids delivered to the fetus can affect the quality of fetal development is more compelling. The concentration of DHA in the brain of neonates is dependent on the intake of pre-formed DHA (Farquharson et al., 1993; Jamieson et al., 1999; Makrides et al., 1994) and many workers have reported beneficial effects of LCPUFA intake in early post-natal life in particular (Birch et al., 1992 ; Hoffman et al., 1993; Horwood, Darlow and Mogridge, 2001; Lucas et al., 1992, 1998). In this context, much has been made of the relatively high concentration of DHA in the fetal brain at term and the importance of in utero DHA supply but this is not specifically a fetal/placental issue as the human brain, including that of the pregnant mother, maintains a high concentration of DHA throughout life. Furthermore the total amount of DHA present in the fetal brain at term is not much greater than that in the placenta itself. An issue that is much more clearly specific to the fetus and placenta is the very high concentration of DHA and AA achieved in the fetal adipose tissue and the fact that 16 times more DHA is stored in the adipose tissue than is deposited in the fetal brain during in utero life. Within a few hours of birth there is a dramatic rise in plasma TG and NEFA indicating mobilization of adipose tissue stores ( Van Duyne & Havel, 1959 ) such that the concentration of DHA in the adipose tissue is undetectable after two months of post-natal life on a diet devoid of pre-formed DHA ( Farquharson et al., 1993). Thus the importance of this adipose store of LCPUFA may be to protect processes such as brain and retinal development against a poor dietary supply of LCPUFA during the critical first months of post-natal life. The fact that most of the LCPUFA such as DHA which is accrued by the fetus is actually stored in fetal adipose tissue also implies that there is normally an excess availability in utero for development of the fetal organs and tissues and that it is only in low birth weight babies, where the body fat content may be very low (Sparks et al., 1980), that the supply of LCPUA may become limiting for fetal requirements during in utero life.”

similarities between germ-free mice and ketogenic humans

similarities between germ-free mice and ketogenic humans

tracing a chain of ideas

Sometimes the assumptions that scientists start with about what is “good”, “healthy”, or “normal”
can cause them to interpret results in a completely different way than someone starting with different assumptions would have.
Then, the resulting conclusions become the assumptions in the next round of interpretation,
leading to a chain of logic in which one questionable assumption leads to another.
We recently read a paper in which the authors made a series of logical steps,
and it became almost comical to us how at each step we would have interpreted
their results in an opposite way than they did.
When the results of their experiment are looked at from our perspective, it
suggests an intriguing hypothesis:
Maybe some of the health benefits a ketogenic diet are due, not just to the
diet being low in digestible carbohydrate and thus leading to ketosis, but
also to being low in indigestible fiber and thus starving certain gut

Or, to phrase the same hypothesis differently, maybe one mechanism by which a
glycolytic or high-fiber diet causes health problems is that it feeds harmful gut bacteria,
and the presence of those bacteria causes the health problems.
If that hypothesis were true, it would imply that if you are eating a
low-carb diet, then including a lot of low-carb vegetables would feed these
hypothesized harmful gut bacteria and reduce some of the potential health benefits of
a low-carb diet.

in brief

The purpose of this article is two-fold:

  • First, to compare the authors’ interpretations of the observations to ours, given what we know about the metabolic effects of ketogenic
    We draw attention to the fact that the metabolism of germ-free mice is strikingly similar to that of ketogenic dieters.
    This similarity holds at the whole-body level in terms of behaviour and physical characteristics, as well as the level of mitochondrial
    We show that these characteristics appear to be beneficial.
  • Second, to raise the following questions:
    Are some of the benefits of a ketogenic diet mediated by starving gut bacteria, and if so,
    does eating fiber (i.e. low-carb vegetables) reduce some of the health benefits of a keto diet?
    Would eating a carbohydrate- and fiber- free diet confer some keto-like benefits even in the absence of ketosis?

the end of the chain

It all started when we saw the following statement on the Wikipedia page about butyrate :

"Butyrates are important as food for cells lining the mammalian colon
(colonocytes). Without butyrates for energy, colon cells undergo
autophagy (self digestion) and die.[1] Short-chain fatty acids, which
include butyrate, are produced by beneficial colonic bacteria
(probiotics) that feed on, or ferment prebiotics, which are plant
products that contain adequate amounts of dietary fiber."

The topic of butyrate is exciting to some scientists, because they have the idea that eating indigestible fiber is good for human health.
Epidemiological studies have found correlations between high fiber intake and relatively less disease.
However, randomised controlled trials have repeatedly failed to confirm the hypotheses that the fiber intake was actually protective. [1].
Therefore when a new idea comes up that might explain how eating fiber would be good for human health, scientists still hoping for such evidence latch onto it.
Butyrate is an example of such a candidate mechanism for how eating fiber would be good for human health.
To us, since we think that eating fiber is useless (at best) for health,
the statement above poses a challenge and a mystery.
Almost the only source of butyrate in the human body is, as the wikipedia page explains in the excerpt above,
from gut bacteria digesting fiber that you ate.
(There’s also some butyrate in butter, presumably made the same way in cows.)
If butyrate is necessary for the health and even the survival of colon cells,
wouldn’t that mean that a low-fiber diet — such as an all-meat diet — would
be very unhealthy?
Amber hasn’t eaten any significant amount of indigestible fiber in more than four years;
does this mean that her colon cells have died off?
So we set out to investigate what led to that statement on wikipedia.
Our investigation ultimately led to an intriguing hypothesis about a candidate mechanism to explain some of the health benefits of a keto diet.
The paper referenced as "[1]" on the wikipedia page is Donohoe-2011-“The Microbiome and Butyrate Regulate Energy Metabolism and Autophagy in the Mammalian Colon”. We read it with interest.
The authors of this paper performed a good experiment, made precise measurements, got interesting results, and clearly reported their results.
But when it came to interpretation, they started with some assumptions we don’t think are warranted,
and therefore produced a chain of reasoning that eventually led them and their readers, such as the authors of the wikipedia page, to conclusions that are opposite from ours.

similarities between germ-free mice and ketogenic dieters

If you have followed the debates about low-carb diets conferring a metabolic advantage (demonstrated by their superior performance as weight loss diets [2], [3])
then the above description of germ-free mice should sound familiar.
Compared to low-fat dieters, ketogenic dieters tend to be leaner (i.e. have a higher ratio of muscle to body fat), and have lower insulin and blood glucose levels.
This can happen despite similar caloric intake.
Their liver glycogen levels are also lower; ketogenesis may depend on low glycogen levels [4].
However, the germ-free mice are not ketogenic, presumably because they are consuming regular, glucose-plentiful diets.
In fact they are less ketogenic than the conventional mice, as measured by beta-hydroxybutyrate in the blood.
So what is the cause of the similarity in metabolism between germ-free mice and ketogenic humans?

There is one other important way in which the germ-free mice were different from the conventional mice.
They had lower NADH/NAD+ ratios and ATP levels (per mitochondrion) in their colon cells, but not in the liver, heart, or kidneys.
Note that the heart, liver and kidneys favour fat metabolism, even in glycolytic (non-ketogenic) dieters [5].
The authors took this to be further evidence that the mice were in a state of energy deprivation,
even though by all accounts they appeared to be using substantially more energy.
They even previously mentioned this in connection with the reduced fatness:

"[Germ-free] mice exhibit increased locomotor activity. Therefore, the increased food consumption and decreased body fat of germ-free mice may simply be due to increased energy expenditure." — from Donohoe-2011

However, it is a mistake to assume that lower NADH/NAD+ ratios and ATP levels per mitochondrion corresponds to less cellular energy.
In fact, it is likely to be the opposite.

mitochondrial energetics is the commonality

There are three other conditions we know of that reduce the NADH/NAD+ ratio: calorie restriction [6], ketogenic diets [7], and the diabetes drug metformin [8].
Ketogenic diets share mechanisms with caloric restriction.
Indeed, it seems likely that benefits of calorie restriction come from the activation of ketone bodies [9].
When you use fat and ketones for fuel instead of glucose, you produce fewer free radicals through reducing the NADH/NAD+ ratio [6].
This is probably the main mechanism by which it achieves the neuroprotection we mentioned in a recent post.
Similarly, the reduction of the NADH/NAD+ ratio is probably one of the mechanisms by which calorie restriction can increase lifespan [5].
Calorie restriction also preserves ATP production, but it does this by increasing the number of mitochondria to match or exceed the lower ATP yield per mitochondrion [10], [11].
There is preliminary evidence that a ketogenic diet also increases mitochondrial number [12], [13].
So the idea of Donohoe et al. — that total ATP production is compromised because the NADH/NAD+ ratio in the individual mitochondrion has lowered ATP output per mitochondrion — seems unwarranted.
Instead, there is likely to be a compensatory increase in mitochondrial number.
That would be consistent with the fact that the mice appear to have more energy, not less.
Ketogenic dieters have also been measured to have more energy expenditure than low-fat dieters [14].
So, a reduction of NADH/NAD+ ratio is associated with health benefits, and proposed longevity mechanisms.
As you might now suspect, previous studies have shown that germ-free animals have increased lifespans [15].
(They also show decreased anxiety [16] and increased bone mass [17]. Once again, to us this sounds like a better kind of mouse to be!)

fiber-free for better health?

Given this observation — that some of the benefits of ketogenic diets are present in mice that don’t have gut bacteria which process dietary fiber, even though the mice are not in ketosis — it raises the following questions:

  1. Could the starvation of gut bacteria be a part of the mechanism of the benefits of ketogenic diets?
  2. Since butyrate restores the mitochondrial working of the cells to be like the conventional controls (which, from our perspective, is a worse physiological state), could fiber be actually counter-productive to a ketogenic diet?
  3. In analogy to the way the putative benefits of fiber may simply be that they displace refined carbohydrates in the diet, could the reason probiotics can lead to improved health be not because they are beneficial, but because they push out more harmful strains [18]?
  4. Could a diet free of carb and fiber (i.e. one extremely low in plants) have benefits independent of its tendency to be ketogenic?

We don’t have enough evidence to settle these questions, but they are interesting hypotheses that come directly from the results of this study.

in sum

  • Contrary to the conclusions of the authors and Wikipedia editors that butyrate is necessary for cell energy, we interpret the results as showing improved cellular energy in the absence of butyrate.
  • We now have another source for making hypotheses about potentially important cellular metabolism. Before we learned about germ-free mice, we could already use mechanisms discovered from caloric restriction and compare them to mechanisms of ketogenic diets. Now we can compare and contrast mechanisms from caloric restriction, ketogenic diets, and germ-free animals.
  • This raises some interesting (perhaps even provocative) questions about the health effects of dietary fiber and gut flora on human health.


[1] Evidence type: review

Carla S Coffin, MD FRCPC and Eldon A Shaffer, MD FRCPC
Can J Gastroenterol. 2006 April; 20(4): 255–256.

(emphasis ours)
"A recent pooled analysis of 13 prospective cohort studies (6) found that dietary fibre was not associated with a reduced risk of colorectal cancer after adjusting for other dietary risk factors. The Cochrane collaboration (7) systematically reviewed five studies of over 4000 subjects for the effect of dietary fibre on the incidence or recurrence of colorectal adenomas and incidence of colorectal cancer over a two-to four-year period. The population included all subjects that had adenomatous polyps but no history of colorectal cancer or a documented ‘clean colon’ at baseline with follow-up colonoscopy. Study interventions included soluble and insoluble dietary fibre or a comprehensive dietary intervention with high fibre whole food sources. The combined data showed no outcome difference between the intervention and control groups in the number of subjects with at least one adenoma or a new diagnosis of colorectal cancer. The Cochrane reviewers (7) concluded that there was no evidence from randomized controlled trials to suggest that increased dietary fibre intake would reduce the incidence or recurrence of adenomatous polyps.
"Widespread popular media advertisements have purported the benefits of soluble fibre in lowering the risk of atherosclerotic coronary artery disease, mainly by modifying the main coronary artery disease risk factors (ie, dyslipidemia, diabetes and obesity). As for diabetes, high fibre diets slow the postprandial rise in blood glucose and thus, improve glycemic control (8). In dyslipidemic patients, pundits have proposed that psyllium lowers serum cholesterol by binding bile acids in the intestinal lumen resulting in decreased absorption and increased fecal excretion. The ensuing bile acid depletion increases hepatic demand for the de novo synthesis of bile acids from cholesterol. Investigating this mechanism, Van Rosendaal et al (9) found that fibre administration had no effect and certainly did not lower serum cholesterol. Similarly, an earlier study (10) comparing the effect of wheat bran on serum cholesterol of hyperlipidemic and normolipidemic controls showed no change in total cholesterol or ratio of low density lipoprotein to high density lipoprotein cholesterol. Another trial (11) of intensive dietary advice regarding fat, cereal fibre and fish intake on diet and mortality of men with a recent history of myocardial infarction did not find any substantial long-term benefit. The authors admitted to limitations of dietary data in the study (ie, only short-term period of advice and limited number of questions), but there was no evidence to guide decisions about value of dietary advice to increase fish or cereal fibre by people with coronary disease. We await the results of three Cochrane protocols undertaken to review the evidence of dietary fibre in fruits and vegetables, wholegrain cereals or high-fat, low fibre dietary intervention in the prevention of coronary heart disease (12–14). Any conclusions regarding the effectiveness of fibre for the prevention of heart disease appear premature."
"In one of the first randomized, placebo-controlled trials of the role of bran in patients with [diverticular disease] (17), the authors concluded that dietary fibre supplements do nothing more than relieve constipation, and the impression that fibre helps [diverticular disease] is “simply a manifestation of western civilization’s obsession with the need for frequent defecation”. Recent systematic reviews (18,19) of the role of dietary fibre and [diverticular disease] (both asymptomatic diverticulosis and symptomatic diverticulitis) conclude that most of the positive evidence of the effects of fibre supplementation in treating or preventing disease is from retrospective analyses with inherent limitations and high risk of bias."
"Systematic reviews have shown that the treatment of IBS patients with fibre is controversial. One recent meta-analysis of 17 randomized controlled trials (20) quantified the effectiveness of different types of fibre. The reviewers found that fibre was only marginally effective in terms of global symptom improvement or constipation and there was no effect in IBS related abdominal pain. Fibre has a role in treating constipation but its value for IBS, pain and diarrhea is controversial. Any effectivenss of fibre in the long-term management of IBS remains questionable. Clinically, bran is no better than placebo in the relief of the overall symptoms of IBS, and is possibly worse than a normal diet for some symptoms."

[2] Evidence type: review of randomised controlled trials in humans.

Hession M, Rolland C, Kulkarni U, Wise A, Broom J.
Obes Rev. 2009 Jan;10(1):36-50. doi: 10.1111/j.1467-789X.2008.00518.x. Epub 2008 Aug 11.

There are few studies comparing the effects of low-carbohydrate/high-protein diets with low-fat/high-carbohydrate diets for obesity and cardiovascular disease risk. This systematic review focuses on randomized controlled trials of low-carbohydrate diets compared with low-fat/low-calorie diets. Studies conducted in adult populations with mean or median body mass index of > or =28 kg m(-2) were included. Thirteen electronic databases were searched and randomized controlled trials from January 2000 to March 2007 were evaluated. Trials were included if they lasted at least 6 months and assessed the weight-loss effects of low-carbohydrate diets against low-fat/low-calorie diets. For each study, data were abstracted and checked by two researchers prior to electronic data entry. The computer program Review Manager 4.2.2 was used for the data analysis. Thirteen articles met the inclusion criteria. There were significant differences between the groups for weight, high-density lipoprotein cholesterol, triacylglycerols and systolic blood pressure, favouring the low-carbohydrate diet. There was a higher attrition rate in the low-fat compared with the low-carbohydrate groups suggesting a patient preference for a low-carbohydrate/high-protein approach as opposed to the Public Health preference of a low-fat/high-carbohydrate diet. Evidence from this systematic review demonstrates that low-carbohydrate/high-protein diets are more effective at 6 months and are as effective, if not more, as low-fat diets in reducing weight and cardiovascular disease risk up to 1 year. More evidence and longer-term studies are needed to assess the long-term cardiovascular benefits from the weight loss achieved using these diets."

[3] Evidence type: review of randomised controlled trials in humans.

Although this analysis is not peer-reveiwed, it is thorough, appears to be accurate, and does not omit any counter-evidence as far as we are aware.
Kris Gunnars
October 15, 2013
Authority Nutrition

(emphasis ours)
"In this article, I have analyzed the data from 23 of these studies comparing low-carb and low-fat diets.
"All of the studies are randomized controlled trials, the gold standard of science. All are published in respected, peer-reviewed journals.

"The majority of studies achieved statistically significant differences in weight loss (always in favor of low-carb). There are several other factors that are worth noting:

  • The low-carb groups often lost 2-3 times as much weight as the low-fat groups. In a few instances there was no significant difference.
  • In most cases, calories were restricted in the low-fat groups, while the low-carb groups could eat as much as they wanted.
  • When both groups restricted calories, the low-carb dieters still lost more weight (7, 13, 19), although it was not always significant (8, 18, 20).
  • There was only one study where the low-fat group lost more weight (23) although the difference was small (0.5 kg – 1.1 lb) and not statistically significant.
  • In several of the studies, weight loss was greatest in the beginning. Then people start regaining the weight over time as they abandon the diet.
  • When the researchers looked at abdominal fat (the unhealthy visceral fat) directly, low-carb diets had a clear advantage (5, 7, 19).
[4] Evidence type: review of experiments

McGarry JD, Foster DW.
Arch Intern Med. 1977 Apr;137(4):495-501.

A two-site, bihormonal concept for the control of ketone body production is proposed. Thus, ketosis is viewed as the result of increased mobilization of free fatty acids from adipose tissue (site 1) to the liver (site 2), coupled with simultaneous enhancement of the liver’s capacity to convert these substrates into acetoacetic and beta-hydroxybutyric acids. The former event is believed to be triggered by a fall in plasma insulin levels while the latter is considered to be effected primarily by the concomitant glucagon excess characteristic of the ketotic state. Although the precise mechanism whereby elevation of the circulating [glucagon]:[insulin] ratio stimulates hepatic ketogenic potential is not known, activation of the carnitine acyltransferase reaction, the first step in the oxidation of fatty acids, is an essential feature. Two prerequisites for this metabolic adaptation in liver appear to be an elevation in its carnitine content and depletion of its glycogen stores. Despite present limitations the model (evolved mainly from rat studies) provides a framework for the description of various types of clinical ketosis in biochemical terms and may be useful for future studies."

[5] Evidence type: authority

El Bacha, T., Luz, M. & Da Poian, A. (2010)
Nature Education 3(9):8

"[M]any different cells do oxidize fatty acids for ATP production. Between meals, cardiac muscle cells meet 90% of their ATP demands by oxidizing fatty acids. Although these proportions may fall to about 60% depending on the nutritional status and the intensity of contractions, fatty acids may be considered the major fuel consumed by cardiac muscle.

Other organs that use primarily fatty acid oxidation are the kidney and the liver."

[6] Evidence type: controlled non-human animal experiments

Su-Ju Lin, Ethan Ford, Marcia Haigis, Greg Liszt, and Leonard Guarente.
Genes Dev. 2004 January 1; 18(1): 12–16.

"Our studies show that a switch to oxidative metabolism during CR increases the NAD/NADH ratio by decreasing NADH levels. NADH is a competitive inhibitor of Sir2, implying that a reduction in this dinucleotide activates Sir2 to extend the life span in CR. Indeed, overexpression of the NADH dehydrogenase specifically lowers NADH levels and extends the life span, providing strong support for this hypothesis. Regulation of the life span by NADH is also consistent with the earlier finding that electron transport is required for longevity during CR (Lin et al. 2002). The NAD/NADH ratio reflects the intracellular redox state and is a readout of metabolic activity. Our findings suggest that this ratio can serve a critical regulatory function, namely, the determination of the life span of yeast mother cells. It remains to be seen whether this ratio will serve related regulatory functions in higher organisms."

[7] Evidence type: controlled non-human animal experiments

Marwan Maalouf, Patrick G. Sullivan, Laurie Davis, Do Young Kim, and Jong M. Rho Neuroscience.
2007 March 2; 145(1): 256–264.

"[W]e demonstrate that ketones reduce glutamate-induced free radical formation by increasing the NAD+/NADH ratio and enhancing mitochondrial respiration in neocortical neurons. This mechanism may, in part, contribute to the neuroprotective activity of ketones by restoring normal bioenergetic function in the face of oxidative stress."

[8] Evidence type: controlled non-human animal experiment

Paul W Caton, Nanda K Nayuni, Julius Kieswich, Noorafza Q Khan, Muhammed M Yaqoob and Roger Corder
J Endocrinol April 1, 2010 205 97-106

(emphasis ours)
Metformin increases SIRT1 in db/db mice
Systemic activation of SIRT1 with the activator SRT1720 is reported to lower blood glucose and improve insulin sensitivity in Zucker rats and diet-induced obese mice in part through inhibition of hepatic gluconeogenesis (Milne et al. 2007). Therefore, we investigated whether metformin inhibited gluconeogenesis through changes in hepatic SIRT1. Eight-week-old db/db or control (db/m) mice were administered metformin (250 mg/kg per day; 7 days). Levels of SIRT1 protein, activity and NAD+/NADH ratio were significantly increased in metformin-treated db/db mice compared with the controls and untreated db/db mice (Fig. 1A, C and D). Despite increased protein levels, Sirt1 mRNA levels were unchanged following metformin treatment (Fig. 1B). Levels of SIRT1 protein and activity as well as NAD+/NADH levels were unchanged between the control and untreated mice (Fig. 1A–C). Metformin had no effect on SIRT1 in control mice (data not shown). Furthermore, incubation of HepG2 cells with metformin (2 mM) also resulted in increased levels of SIRT1 protein and activity and NAD+/NADH ratio (Fig. 1E–G). This indicates that increasing SIRT1 protein and activity could be a key mechanism by which metformin inhibits gluconeogenic gene expression."

[9] Evidence type: review of experiments

Marwan A. Maalouf, Jong M. Rho, and Mark P. Mattson
Brain Res Rev. 2009 March; 59(2): 293–315.

"Calorie restriction and the ketogenic diet share two characteristics: reduced carbohydrate intake and a compensatory rise in ketone bodies. The neuroprotective effects of reduced carbohydrate per se are being investigated by several research groups (Mattson et al. 2003; Ingram et al. 2006). We have evaluated the possibility that ketone bodies might mediate the neuroprotective effects of calorie restriction and of the ketogenic diet. An expanding body of evidence indicates that ketone bodies are indeed neuroprotective and that the underlying mechanisms are similar to those associated with calorie restriction – specifically at the mitochondrial level."

[10] Evidence type: review of clinical reports

G. López-Lluch, N. Hunt, B. Jones, M. Zhu, H. Jamieson, S. Hilmer, M. V. Cascajo, J. Allard, D. K. Ingram, P. Navas, and R. de Cabo
Proc Natl Acad Sci U S A. 2006 February 7; 103(6): 1768–1773.

"[M]itochondria under CR conditions show less oxygen consumption, reduce membrane potential, and generate less reactive oxygen species than controls, but remarkably they are able to maintain their critical ATP production. In effect, CR can induce a peroxisome proliferation-activated receptor coactivator 1α-dependent increase in mitochondria capable of efficient and balanced bioenergetics to reduce oxidative stress and attenuate age-dependent endogenous oxidative damage."

[11] Evidence type: review of controlled experiments

Marwan A. Maalouf, Jong M. Rho, and Mark P. Mattson
Brain Res Rev. 2009 March; 59(2): 293–315.

(emphasis ours)
"Slowing of brain aging in calorie-restricted animals was originally believed to result from reduced metabolic activity and, hence, decreased production of reactive oxygen species, a natural byproduct of oxidative metabolism (Wolf 2006). Several studies revealed that calorie restriction was associated with energy conservation (Gonzales-Pacheco et al. 1993; Santos-Pintos et al. 2001) and that mitochondria isolated from calorie-restricted animals produced less ATP than those from controls fed ad libitum, a finding compatible with increased UCP activity (Sreekumar et al. 2002; Drew et al. 2003). However, separate investigations in rodents have suggested that, when adjusted for body weight, metabolic rate does not decrease with calorie restriction (Masoro et al. 1982; McCarter et al. 1985; Masoro 1993). More importantly, calorie restriction prevents the age-related decline in oxidative metabolism in muscle (Hepple et al. 2005; Baker et al. 2006). These data are supported by recent studies indicating that, in contrast to isolated mitochondria, ATP synthesis in intact myocytes and in vivo does not decrease following calorie restriction (Lopez-Lluch et al. 2006; Zangarelli et al. 2006). Additional support is provided by the finding that, in yeast, oxidative metabolism increases with calorie restriction (Lin et al. 2002). […] Although the effects of calorie restriction on ATP generation might appear to contradict those on uncoupling proteins, this discrepancy can be explained by the fact that calorie restriction also promotes mitochondrial biogenesis, thereby enhancing total metabolic output per cell while decreasing mitochondrial production of reactive oxygen species (Diano et al. 2003; Nisoli et al. 2005; Civitarese et al. 2007)."

[12] Evidence type: in vitro non-human animal experiment

Bough KJ, Wetherington J, Hassel B, Pare JF, Gawryluk JW, Greene JG, Shaw R, Smith Y, Geiger JD, Dingledine RJ.
Ann Neurol. 2006 Aug;60(2):223-35.

The full anticonvulsant effect of the ketogenic diet (KD) can require weeks to develop in rats, suggesting that altered gene expression is involved. The KD typically is used in pediatric epilepsies, but is effective also in adolescents and adults. Our goal was to use microarray and complementary technologies in adolescent rats to understand its anticonvulsant effect.
Microarrays were used to define patterns of gene expression in the hippocampus of rats fed a KD or control diet for 3 weeks. Hippocampi from control- and KD-fed rats were also compared for the number of mitochondrial profiles in electron micrographs, the levels of selected energy metabolites and enzyme activities, and the effect of low glucose on synaptic transmission.
Most striking was a coordinated upregulation of all (n = 34) differentially regulated transcripts encoding energy metabolism enzymes and 39 of 42 transcripts encoding mitochondrial proteins, which was accompanied by an increased number of mitochondrial profiles, a higher phosphocreatine/creatine ratio, elevated glutamate levels, and decreased glycogen levels. Consistent with increased energy reserves, synaptic transmission in hippocampal slices from KD-fed animals was resistant to low glucose.
These data show that a calorie-restricted KD enhances brain metabolism. We propose an anticonvulsant mechanism of the KD involving mitochondrial biogenesis leading to enhanced alternative energy stores."

[13] Evidence type: controlled non-human animal experiments

Srivastava S, Kashiwaya Y, King MT, Baxa U, Tam J, Niu G, Chen X, Clarke K, Veech RL.
FASEB J. 2012 June; 26(6): 2351–2362.

(Emphasis ours)
"We measured the effects of a diet in which d-β-hydroxybutyrate-(R)-1,3 butanediol monoester [ketone ester (KE)] replaced equicaloric amounts of carbohydrate on 8-wk-old male C57BL/6J mice. Diets contained equal amounts of fat, protein, and micronutrients. The KE group was fed ad libitum, whereas the control (Ctrl) mice were pair-fed to the KE group. Blood d-β-hydroxybutyrate levels in the KE group were 3-5 times those reported with high-fat ketogenic diets. Voluntary food intake was reduced dose dependently with the KE diet. Feeding the KE diet for up to 1 mo increased the number of mitochondria and doubled the electron transport chain proteins, uncoupling protein 1, and mitochondrial biogenesis-regulating proteins in the interscapular brown adipose tissue (IBAT). [18F]-Fluorodeoxyglucose uptake in IBAT of the KE group was twice that in IBAT of the Ctrl group. Plasma leptin levels of the KE group were more than 2-fold those of the Ctrl group and were associated with increased sympathetic nervous system activity to IBAT. The KE group exhibited 14% greater resting energy expenditure, but the total energy expenditure measured over a 24-h period or body weights was not different. The quantitative insulin-sensitivity check index was 73% higher in the KE group. These results identify KE as a potential antiobesity supplement."

[14] Evidence type: randomised controlled clinical trial

Cara B. Ebbeling, PhD; Janis F. Swain, MS, RD; Henry A. Feldman, PhD; William W. Wong, PhD; David L. Hachey, PhD; Erica Garcia-Lago, BA; David S. Ludwig, MD, PhD
JAMA. 2012;307(24):2627-2634. doi:10.1001/jama.2012.6607.

"The results of our study challenge the notion that a calorie is a calorie from a metabolic perspective. During isocaloric feeding following weight loss, REE was 67 kcal/d higher with the very low-carbohydrate diet compared with the low-fat diet. TEE differed by approximately 300 kcal/d between these 2 diets, an effect corresponding with the amount of energy typically expended in 1 hour of moderate-intensity physical activity."

[15] Evidence type: review of non-human animal experiments

H A Gordon and L Pesti.
Bacteriol Rev. 1971 December; 35(4): 390–429.

"Two attempts have been made to construct life tables and to determine lesions at natural death in germ-free and conventional animals. One study (105) was conducted in genetically closely linked Swiss Webster mice and included over 300 germ-free and the same number of conventional controls which were introduced into the colony at the age of 12 months (to eliminate the effect of early losses). At natural death, the ages of the mice were (means and standard errors in days 19; females, are given): germ-free males, 723 681 i 12; conventional males, 480 i 10; females, 516 i 10. This pattern of survival rates seemed to continue throughout the course of the experi- ment. In the second study (335), approximately 50 germ-free and the same number of conven- tional ICR mice were introduced into the colony after weaning. At natural death, the age of the mice was (using the same mode of expression): germ-free males, 556 i 43; females, 535 + 46; 41; females, 547 ± conventional males, 536 45. In the first trimester of life, the survival rate was essentially the same in the germ-free and conventional control groups. In the middle third, the germ-free mice displayed an increased survival rate (e.g., 40% cumulative mortality was reached for the combined group of germ-free males and females only at the age of approximately 580 days, whereas for the conventional controls this value was approximately 410 days). Increased mortality of the germ-free group at more advanced age resulted in the similarity of mean ages between the opposing animal groups when all animals participating in the study were considered."

[16] Evidence type: controlled non-human animal experiment

Rochellys Diaz Heijtz, Shugui Wang, Farhana Anuar, Yu Qian, Britta Björkholm, Annika Samuelsson, Martin L. Hibberd, Hans Forssberg, and Sven Pettersson
Proc Natl Acad Sci U S A. 2011 February 15; 108(7): 3047–3052.

"Microbial colonization of mammals is an evolution-driven process that modulate host physiology, many of which are associated with immunity and nutrient intake. Here, we report that colonization by gut microbiota impacts mammalian brain development and subsequent adult behavior. Using measures of motor activity and anxiety-like behavior, we demonstrate that germ free (GF) mice display increased motor activity and reduced anxiety, compared with specific pathogen free (SPF) mice with a normal gut microbiota. This behavioral phenotype is associated with altered expression of genes known to be involved in second messenger pathways and synaptic long-term potentiation in brain regions implicated in motor control and anxiety-like behavior. GF mice exposed to gut microbiota early in life display similar characteristics as SPF mice, including reduced expression of PSD-95 and synaptophysin in the striatum. Hence, our results suggest that the microbial colonization process initiates signaling mechanisms that affect neuronal circuits involved in motor control and anxiety behavior."

[17] Evidence type: controlled non-human animal experiment

Sjögren K, Engdahl C, Henning P, Lerner UH, Tremaroli V, Lagerquist MK, Bäckhed F, Ohlsson C.
J Bone Miner Res. 2012 Jun;27(6):1357-67. doi: 10.1002/jbmr.1588.

The gut microbiota modulates host metabolism and development of immune status. Here we show that the gut microbiota is also a major regulator of bone mass in mice. Germ-free (GF) mice exhibit increased bone mass associated with reduced number of osteoclasts per bone surface compared with conventionally raised (CONV-R) mice. Colonization of GF mice with a normal gut microbiota normalizes bone mass. Furthermore, GF mice have decreased frequency of CD4(+) T cells and CD11b(+) /GR 1 osteoclast precursor cells in bone marrow, which could be normalized by colonization. GF mice exhibited reduced expression of inflammatory cytokines in bone and bone marrow compared with CONV-R mice. In summary, the gut microbiota regulates bone mass in mice, and we provide evidence for a mechanism involving altered immune status in bone and thereby affected osteoclast-mediated bone resorption. Further studies are required to evaluate the gut microbiota as a novel therapeutic target for osteoporosis."

[18] Evidence type: review of experiments and hypotheses

Parvez S, Malik KA, Ah Kang S, Kim HY.
J Appl Microbiol. 2006 Jun;100(6):1171-85.

(emphasis ours)
Probiotics are usually defined as microbial food supplements with beneficial effects on the consumers. Most probiotics fall into the group of organisms’ known as lactic acid-producing bacteria and are normally consumed in the form of yogurt, fermented milks or other fermented foods. Some of the beneficial effect of lactic acid bacteria consumption include: (i) improving intestinal tract health; (ii) enhancing the immune system, synthesizing and enhancing the bioavailability of nutrients; (iii) reducing symptoms of lactose intolerance, decreasing the prevalence of allergy in susceptible individuals; and (iv) reducing risk of certain cancers. The mechanisms by which probiotics exert their effects are largely unknown, but may involve modifying gut pH, antagonizing pathogens through production of antimicrobial compounds, competing for pathogen binding and receptor sites as well as for available nutrients and growth factors, stimulating immunomodulatory cells, and producing lactase. Selection criteria, efficacy, food and supplement sources and safety issues around probiotics are reviewed. Recent scientific investigation has supported the important role of probiotics as a part of a healthy diet for human as well as for animals and may be an avenue to provide a safe, cost effective, and ‘natural’ approach that adds a barrier against microbial infection. This paper presents a review of probiotics in health maintenance and disease prevention."

We were talking about gluconeogenesis, not ketogenesis.

Our last post described the evidence that the rate of gluconeogenesis (GNG) is stable under a variety of metabolic conditions.
We also described several experiments in which large amounts of protein were ingested or infused and did not increase the rate.
We concluded that eating more protein than your body needs probably doesn’t increase GNG.

Many of our readers expressed confusion about the implications of this finding, and our purpose in posting it.

The reason we investigated this was to address the following concern. One of the reasons keto dieters want to minimize the amount of carbohydrate they eat is so that their bodies don’t have to deal with excess glucose in the blood.
Whenever we ingest carbohydrate, it becomes sugar in the blood&nbsp¹.
Since blood sugar must be kept within a narrow range for safety&nbsp², eating carbs then causes the body to release insulin in order to draw sugar quickly and safely out of the blood and into storage (as fat tissue)&nbsp³.

In our opinion, the ideal situation is to introduce no significant amount of sugar into the blood by eating, and instead allow the body to supply the blood with just the amount of glucose it needs by producing it at a slow and steady rate through GNG.
This is achieved by keto dieters who carefully count any carbohydrates they eat, with the goal of keeping them below a certain level, for example, 25g per day.

Because some people have said that when you eat protein above basic requirements it turns into sugar, the question some dieters have is whether they need to count excess protein toward their carb counts&nbsp.
They want to know if eating an extra 30 grams of protein means that they have added some 20 grams of sugar into their bloodstreams that now has to be dealt with just as if they had eaten 20 more grams of carbohydrate.
This is the conclusion we were setting out to deny.
Protein you eat in excess of your needs does not become extra blood sugar, unless you are severely diabetic.

However, this does not mean that eating too much protein has no adverse effects, or that keto dieters should be unconcerned about excess protein intake!
In particular, there is another important reason that keto dieters minimize the carbohydrate they eat — to increase the levels of ketones in the blood.
So a second question, and one that we did not address in the last post, is whether excess protein inhibits ketogenesis, the production of ketone bodies.
In contrast to the situation with gluconeogenesis, we suspect protein does inhibit ketogenesis.
If so, that’s a valid reason for not eating more than you need.


¹ Evidence type: authority

Marks’ Basic Medical Biochemistry: A Clinical Approach. Michael
A. Lieberman, Allan Marks. Lippincott Williams & Wilkins, Apr 21, 2008.
p. 479

The major carbohydrates of the diet (starch, lactose, and sucrose) are digested to produce monosaccharides (glucose, fructose, and galactose), which enter the blood.

² Evidence type: authority

Marks’ Basic Medical Biochemistry: A Clinical Approach. Michael
A. Lieberman, Allan Marks. Lippincott Williams & Wilkins, Apr 21, 2008.
p. 483

(Emphasis in original)

[I]nsulin and glucagon maintain blood glucose levels near 80 to 100 mg/dL, (90 mg/dL is the same as 5mM), despite the fact that carbohydrate intake varies considerably over the course of the day.

³ Evidence type: authority

Human Biochemistry and Disease. Gerald Litwack. Academic Press, Jan 4,
2008. p. 583

The anabolic effects of released insulin, after glucose is sensed by glucoreceptors of beta cells, are to cause the uptake of glucose and amino acids from the blood into muscle, and the uptake of glucose from the blood to form triglycerides in fat cells.

Evidence type: observation

Protein turns into glucose if you eat too much?!!

So I am trying to research a bit over the interwebs about just how much protein is to much and at what point your body will convert protein into glucose but there are so many different opinions on this… *pulls her hair out* This is where i think Calories in vs. calories out makes more sense… what yall think?

Is there a rule of thumb to what the bodies tipping point is for when it will convert protein into glucose?

How much protein can you eat before it turns to glucose?

muffin_maiden: I’ve read before that eating too much protein at once can cause it to turn to glucose, but how much protein can you eat before that happens?
I tend to eat two larger meals (or one big one) during the day with between 10 and 16 ounces of protein at a time.
Would that amount turn to glucose or are we talking that you’d have to eat a LOT of meat before that happens?


redtoile: Thanks for this post. I worry about this all the time.


CarolynF: According to Dr. Atkins, it is around 52 percent of protein gets converted to glucose.

So, if you overeat protein at each meal, it will act like carbs.