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Dr. Volek & Dr. Phinney – Translating the Basic Science of Nutritional Ketosis & Keto-Adaptation

– So, I am dual mode in this next session. I'm gonna to introduce the
first of a pair of speakers who have been working together
for the last 15 years or so, and that's Jeff Volek and myself; and just to give you a 30 second sense of how we met, our first meeting occurred when
Jeff crashed a CME course in San Diego; he'd managed to sneak in and sat down next to a guy
in the back row and said, "Do you know who Steve Phinney is," "since he's supposed to speak soon?" and I said, "Yeah, that's me." (audience laughs) I don't remember that that was Jeff; I just remember the incident
because after I gave my talk, he and another guy, who both
of them at that point were competitive power lifters,
got me in a corner and asked me a bunch of questions, and that was 1996, I think.

But in 2003, Jeff and I
reconnected at a nutrition conference in San Francisco. I walked by a poster that had
work on the ketogenic diet and body composition in males with metabolic syndrome; and I looked at that and
said, "Wow, that's amazing," and then I noticed that it
referenced a couple of my papers from back when the
dinosaurs walked the earth, and I met the co-author, and the relationship for
the last 15 years has been, for me, kind of a career resuscitation, and just a true gift. So, what I want to do is
introduce Jeff at this point. As you know, he's a professor
here at Ohio State University, and an international expert in the topic; and we will be talking about the emerging science of nutritional ketosis. (audience applause) – Okay, that was just really
an excellent talk, John, and it kind of struck me that this tool of a ketogenic diet, from a therapeutic perspective,
it's really the opposite of how you think of drugs
being developed where you start with the chemistry, you
know what the formula is, and you know what the target
is, and you do animal studies, and you take it into various
phases of human trials, and we're kind of doing the
opposite here ketogenic diets.

I mean we know they work in humans. We've known for a long time
they work to treat seizures and even diabetes, and now
we're back-filling that with some of the molecular mechanisms,
so it's just fantastic work you're doing. It's a lot of still important questions to address related to
how we wield this tool, and how it works, but we
know it works in many ways. So, I put this historic slide together just to emphasize the
point that in many ways, from my perspective anyway, we've been living in the dark
ages when it comes to our diet policy and nutrition, and we're ignoring a
lot of relevant science; but in particular, if we
look at the metabolite, ketones as a metabolite,
they've been maligned more than any other metabolite
that I can think of, and this is really unfortunate.

If you go back, and on
the top here I've kind of got a lot of the negative
factors that have contributed to this connotation of
ketones being negative; it really started with their discovery. They were discovered back in the middle of the 19th century in the
urine of uncontrolled diabetics, and that negative connotation has really stuck as labeling these as a harbinger for metabolic problems. And then, you know, you
kind of fast-forward. Insulin was discovered in 1920s by Frederick Banting, and prior to that time ketogenic
diets were actually used to treat diabetics; but with
the discovery of insulin, and this was a life-saving
discovery, it's super important, but it also allowed us to
continue what at the time was we started to embrace
agricultural carbohydrates, and then of course you have
Ancel Keys coming on the scene with a diet-heart
hypothesis further promoting low fat, high carbohydrate diets which led to the first US
Dietary Guidelines in 1980, followed by the surge
in obesity and diabetes, and we're still fighting this
negative perception around ketones, which are
fat-derived metabolites.

But what's going on in
the bottom of this slide are a lot of positive things. So, you can go back pretty
far in history and read about the use of ketogenic diets. You have William Banting,
a different Banting, writing Letter of Corpulence
back around the same time the ketones were discovered,
and you do have ketogenic diets being successfully used by a
lot of physicians to manage both diabetes and epilepsy back in the early part of the 20th century.

You have Stefansson's work,
which I think Steve's gonna to talk a little bit more about;
he literally locked himself up and consumed a ketogenic diet to prove that it wasn't harmful. But notably, you have George
Cahill's pioneering studies at Harvard throughout the
'60s and the '70s really documenting the underlying
metabolism and physiology of ketones during starvation. I still go back and read
these papers in the '60s; they were just elegant
experiments documenting how starvation ketosis plays
out physiologically. And you've got Dr. Atkins
coming on the scene in the '70s who popularized the Atkins Diet, which is still very prominent
today, and we're fortunate to have Atkins as a sponsor here. So, if you look throughout most
of the '70s, '80s and '90s, there's very little research
done on ketogenic diets; it was a toxic topic to be involved with, with one notable exception, and that's Steven Phinney's work. So, he published some really
seminal work on keto adaptation and ketogenic diets in the '80s; and I think these, for me, these were just like reading word out of the gospel.

I mean these were studies that existed when no other people were doing studies; and so that really inspired me to think that I was thinking along
the right direction, and I started to do work in the late '90s, and I think several other people
started to do work as well, including Eric Westman, and it's just grown from that time to now. Over the last 15 years, I
would say we're entering the golden age of ketones
where we have all these new discoveries, which
we'll hear about today, on mechanisms of ketones, oN applications of ketogenic diets.

So, welcome to the golden age of ketones. (audience applause) I just want to mention briefly what my team does here at OSU. I'm really fortunate to
have an incredible group of doctoral students, master's
students, undergraduates and other team players
that contribute to a really exciting environment where
we're trying to advance the knowledge and application
of ketogenic diets. Fundamental to what we
do is feeding studies, so we've established
infrastructure for doing controlled feeding studies, ketogenic
studies, and trying to apply that in as many different populations, ranging from clinical work, a big focus on cancer, and you'll hear Parker
Hyde talk Friday morning; but we're also studying, at
the other end of the spectrum, military performance, and how
we can enhance the soldiers' health and readiness and
resilience and performance; and a lot of underlying
physiology, including muscle adapatations, cardiac adaptations, etc. So, we have I think about
a half a dozen posters on display that my students
will be standing next to, this afternoon or this
evening at our poster session, that'll give you a little
snapshot of some of the work that we're currently involved with.

So, I wanted to just
introduce a couple terms; and you've heard these before, but I think it's worth emphasizing. When we talk about ketosis,
understanding concentration is really fundamental. If you're eating a normal mixed diet, your ketones are suppressed. So, your concentration of
ketones in your circulating blood is for most people under .2 millimolar. When you restrict
carbohydrates for most people, under 50 grams a day, you normalize ketones into the range of nutritional ketosis, which
we've sort of arbitrarily defined as between .5 and up to 3-4; occasionally, you can transiently get a little higher than that. So, that's an entire order
of magnitude higher than you would have in the carb
fed state, but an entire order of magnitude lower than
what you see in ketoacidosis. So, you've got, really …
you could suppress ketones down to .01 millimolar, all the way up to 10
millimolar in ketoacidosis: that's three orders of
magnitude different in this particular metabolite;
and when we're eating a ketogenic diet that's well formulated, you're simply normalizing
ketones into this range of nutritional ketosis where
we're increasingly learning we have broad-spectrum health benefits; and when you do that over
a sustained period of time, that really encompasses what the term "keto-adaptation" means,
and we're just scratching the surface on understanding
the various ways in which tissues and organs adapt to
being in sustained ketosis; but fundamentally,
you're enhancing reliance on fatty acid oxidation and ketosis, and we've documented this
in different populations.

You basically double your
rate of fat oxidation when you're in ketosis. It's true if you're a type
2 diabetic with insulin resistance, or if you're an
elite ultra-endurance athlete: the absolute numbers are
different, but relatively speaking you double your rate of fat
burning, and that I think is important for a variety of reasons. So, keto-adaptation is really
a perfectly natural process that, as humans, we have evolved to have this very elegant sophisticated system of being
able to not just survive, but thrive, in the context
of very little carbohydrate; and you could argue, from
an evolutionary perspective, at least intermittent ketosis was the normal state before the agricultural revolution, which started maybe 10,000 years ago, and that's less than 2% of human history. So, I just very briefly want
to show you a little bit of data from experiments
we've done over the years, and we've done a lot
of perspective studies; this is just one in particular
in people with metabolic syndrome or prediabetes.

So, these were individuals
randomized to either a low carbohydrate or a ketogenic diet; and right off the bat,
we see people randomized to a ketogenic diet lose more
weight without specifically instructing them to restrict
calories, so these are ad libbed on ketogenic diets; and we see this time and
time again that obese people, that follow a well-formulated
ketogenic diet, don't need to count calories, that they
naturally restrict energy. You can see the individual
responses on the right where the average weight loss in
the ketogenic group is higher than any individual
person on a low fat diet.

And we've done a lot
of work characterizing the insulin-resistant
phenotype, if you will, around responses to ketogenic
diets, especially around dyslipidemia, and we see that
cholesterol profiles improve. There's nothing more potent
than a ketogenic diet to lower triglycerides, and
it also consistently raises HDL cholesterol and improves
the particle distribution, you'll hear from Ron Krauss later today, but it does have a variable
response on the LDL cholesterol concentration;
but independent of that, you consistently see decreases
in the small LDL particles, and there's increasing evidence that they are the most atherogenic
particles circulating.

We see improvements in glucose and insulin and measures of insulin sensitivity, as well as improvements
in hormone sensitivity. So, we see improvements in
greater decreases in leptin. We've also done similar
work with thyroid hormones, yet we see no change in the
function of these hormones; so no signs or symptoms of
hypothyroidism, for example, even though T3 is dropping, so that leads us to believe that we're enhancing
sensitivity to these hormones perhaps at the receptor
level and signaling level.

We've also measured saturated fat levels in many studies now, not just
this study, and a consistent finding is that despite
consuming two to three, sometimes even four times
as much saturated fat on a ketogenic diet, that
levels in the blood actually go down or stay the same; and this has led us to the concept that you are not what you eat, you are what you save from what you eat, and this kind of piggy-backs off on enhanced fat oxidation. When you're eating saturated
fat on a ketogenic diet, you're promptly oxidizing
that incoming saturated fat and converting it to C02 and water. Saturated fat is, in fact,
a preferred fuel when you're in ketosis, and this is very
important because elevated levels of saturated fat in the
circulation and in membranes is consistently associated
with higher risk for heart disease, diabetes,
even some types of cancer.

And you heard from John that there were some anti-inflammatory effects in animals who had ketogenic diets; we see the same consistent
effect in humans trials. So, half the inflammatory
markers we measured in this experiment were significantly
decreased in a group fed a ketogenic diet
compared to a low-fat diet, and we're seeing this in
some of our ongoing trials, including patients with type
2 diabetes, that there's a potent inflammatory mechanism,
and you'll hear from Dom D'Agostino after this talk
about some of the mechanisms that may be at play here. So, what we've learned over
many studies now over many years is that a ketogenic diet essentially reverses all the signs and symptoms of
metabolic syndrome in this insulin-resistant phenotype,
and it's led me to kind of view this on a continuum
where the more carbs you eat, the more you have a higher
likelihood of developing the insulin-resistant phenotype; and if that progresses, type 2 diabetes.

The more you restrict
carbohydrates, especially down to levels that induce ketosis,
the more you express this keto-adaptive phenotype, which
is a non-diabetic phenotype, and it's driven by carbs in the diet. Everybody has a slightly
different carb tolerance, and it changes over the lifespan, and perhaps other other
environmental factors, but this relationship between
carbs and manifestation of insulin-resistant phenotype versus keto-adaptive phenotype holds true. So, I thought it would be
important, because I'm not sure it will be addressed by other speakers, to talk about the idea of a well-formulated ketogenic diet. I really appreciate John mentioning some of the nuances around optimizing the diet for the animals, and it's certainly very
relevant for the human as well, and we have some understanding of how to best formulate and implement the diet to
maximize safety, effectiveness, pleasure and satisfaction with the diet, and most importantly sustainability; and so on that note I will just say the diet's anything from a burden or sacrifice,
from my perspective, and I think many of you in the
room would concur that it's, in fact, a very pleasurable
way to eat and enjoy food.

But I'm gonna to invite Steve to the stage to expand on that a bit, and talk to you about some
of the characteristics of a well-formulated ketogenic diet. – So, one of the concepts that
Jeff and I wanted to do was mix in not just the elegant
basic science and mechanisms here and pathways, but also
to provide some guidance into how this translates into something
useful in the real world, and you'll hear a number of
presentations on different disease states and such; but
what I wanted to deal with is something I struggled
with for a number of decades, and that is, okay, we
can do this in the lab, we can do it in the metabolic ward: what happens when we take
this out in the real world? And one of the first places is to define. We use this term,
"well-formulated ketogenic diet," but what is that? What are the confines of that? And probably the best
visual representation we've come up with is to
differentiate this from the standard American diet,
what the average American and most people in the developed
world eat, but a better rendition of that health-wise
is moving to a Mediterranean diet with less carbs, a
different mix of fats; and then there is the paleo diet based on our understanding of what our distant ancestors
ate, and so that takes the evolutionary perspective of
what our genes over the last two million years exposed
to, and that's thought to be higher in protein, lower in
carbohydrate, and it's typically called low-carb, but it's
still in the 20-30% range.

So, I really thank Professor
Ramsay to put some of his mice onto a mouse paleo diet and
look of the effects on that, and there are some benefits; but at least in the mouse model,
there is a very significant distinction between a higher
protein and significant carb level, which will keep ketones under .3, fasting ketones under .3
millimolar, in most humans unless they're doing high-intensity,
high-volume exercise.

So, to achieve nutritional ketosis really provides this narrow island; we think of it as an island of safety. Typically, it's under 10%
of daily energy intake relative to one's daily expenditure. So, here we're not talking
about macros in terms of what's on your plate; but if you're
burning 2000 calories a day, you have to get under,
typically under, 10% of that, which would be about 50 grams of carbs to be on this island of safety. And again, if you take your
protein intake too high, that protein intake begins
to suppress ketogenesis. So, it has to be a moderate protein, very low but not zero carbohydrate intake. Then, if you do the math on
that, if it's 10% or less carbs, and it's 20% or less
protein, it's oh my gosh; what your body has to burn each day is more than 80% of this energy as fat, and that's really daunting.

How do we do that? Jeff showed you some pictures,
and that's compatible with a well-formulated ketogenic diet. So, how does one do that? Thinking again in terms of about a 2000 calorie per day intake, and again we don't specify
calories; it's just that the fat is eaten to satiety, we'll
let the natural highly evolved human instincts, is
when you take the carbs down, get that insulin signaling down, let natural instincts drive fat intake; but if we restrict carbs to anywhere from the 25 or 30 grams
per day total intake, up to 50 or so, what can you have? And you can see that, recognize, that there is some
carbohydrate in protein foods. You know, when an animal is slaughtered, there's glycogen in the muscle, and that's bioavailable carbohydrate, but it's a small amount. So, if you're eating a
moderate protein intake, that protein-based carbs
might be 5-10 grams per day; and if you eat 3-5 servings of non-starchy vegetables per
day, depending on your choices that puts you in the 10-15 gram range.

If you give people 1-2 ounces
of nuts and seeds per day, that's again 5-10 grams. At the higher end, from
20 up to 50 grams per day, if you give people 4 ounces
of berry fruit per day, that's again a 5-10 gram
of carbohydrate intake. Then, there's things in
sauces, and such as that. So, you can see that one can
stay in the 30-50 gram range and have a range of choices; and again, from the pictures
here, realize that there are quite a bit of protein-containing
foods here and there, and cheeses, but the vast
majority of the calories here are coming from fat. It doesn't mean that the
person has to eat all their daily energy need as fat,
because we again let their instincts dictate what their intake is, and they can choose from a wide range of luscious foods and condiments. So, when we say, "Well, we take
away more of your starches," "and we take away much of the
sweets that we typically eat," "but we give you savory
and we give you unctuous," it's a trade-off.

We also give people who have
severe metabolic impairments, such as type 2 diabetes,
metabolic syndrome, and other inflammatory-based
diseases, we also give them not just a technical
improvement in metabolic health, but we give them a subjective response. Again, when somebody's
with type 2 diabetes who's taking 100 units of insulin a day, gets off 100 of insulin during the day, that's a very tangible
perceived benefit, and we can do that when we get the composition right and we individualize it
to the metabolic needs of each person, rather than
having a single formula cookie-cutter approach. So, this is variable, individualized; but again, the key here is
keeping protein moderate and carbohydrate restricted. So, one of the questions
that I'm frequently asked is, "So, what macro should I be
eating?" and I always push back and say, "Well, we don't do macros." We define carbohydrate on an
individual tolerance basis; and the best way to
determine your carbohydrate tolerance, if you want to
be in nutritional ketosis, is you get a finger stick
glucometer with a ketone testing and measure your ketones,
and that is now a very robust and accurate technology, and
now we have multiple vendors who are coming out with
provenly accurate devices.

So, as Jeff showed you
when he did the study with Cassandra Forsythe, and took
people with metabolic syndrome and put them non a
well-formulated ketogenic diet and they ate to satiety, initially they under-ate calories. So, in this what we
call "induction phase," if they're eating 90 grams
of protein and 30 grams of carbohydrates, that would
be 120 calories of carb and 360 calories of protein;
and then when they ate that to satiety, they were
under-eating total calories, and so the difference
between their expenditure and their intake was basically unseen "dietary fat," but the dietary fat was
coming from internal reserves; and as people typically
follow this over many months, the weight loss continues, but it tapers, and eventually people will
naturally come to a new steady state, and that is a combination of increasing dietary fat, so their need to meet satiety goes up; and also if somebody loses
40 pounds, their resting metabolism is gonna come down somewhat, and that's a reality, and that's a normal physiological response;
that's not a toxic effect from the diet, it's just
coming from carrying an extra burden of fat, which has
metabolic requirements both at rest and during exercise, and people reach a new steady state.

So, the key here again is
we don't dictate calories and we don't count calories. We basically rely … and this is not in
everyone, but in most people their natural instincts
are to under-consume through a period of time to
weight loss, and then they reach what is a new steady state, and the important point here
is that across these phases our dietary instruction doesn't change from day one 'til the end; they may increase their
carbohydrate slightly, if they can maintain ketosis with a little bit greater
intake of carbohydrate, which gives them a broader
range of food choices, in which they can have a
caprese salad with four ounces of tomato and maybe some
berries at breakfast in the same day and maintain that
metabolic beneficial state. So, I want to begin to wrap
up with what Jeff and I have, working with Dr.

Brooke
Bailey who's in the audience, have come up with. How do we define a
well-formulated ketogenic diet? And we came up with
basically 10 principles, and these are posted on a blog
post that we put up recently at our blog at Virta Health;
and the most obvious one is that, until proven otherwise,
sustained nutritional ketosis, in humans at least, appears
to have better clinical response than intermittent
ketosis in terms of degree of weight loss and improvement in manifestations of insulin resistance. So, you know, it seems like
a no brainer, but it's still a point of contention,
and there's still a lot of work to be done, whether
intermittent ketosis or continuous ketosis is the most beneficial; but the greater the degree
of insulin resistance, our experience is the
better the response will be if somebody sustains nutritional ketosis. Next is that it needs to
maintain lean body mass and function; and again,
you've seen that elegantly in the mouse model that Professor
Ramsay presented to you, and Jeff has shown that in his research: that we can take people
on a well-formulated ketogenic diet, eating to
satiety, not overeating protein, and yet they either maintain
or increase lean body mass.

So, again, this idea
that it's a muscle waste, it has to be a very high protein diet or you'll waste muscle, is inaccurate. Probably the most difficult
one to convince people that it is important is electrolyte
and mineral management. We assume that people will
just naturally eat enough minerals and electrolytes
to maintain their needs; but when someone enters a
state of nutritional ketosis, it changes the kidney's
functioning of sodium, and that's been known since the 1950s, and it's called the
natriuresis of fasting, natrium being the Latin term for sodium, that renal sodium excretion increases when one is in nutritional ketosis.

But to put it as simply as I can: if you combine a ketogenic
diet with a sodium restricted diet in somebody who doesn't
have obvious need for sodium restriction, that is
hypertension or congestive heart failure, you'll cause a
decrease circulating volume, and that leads to a
whole panoply of symptoms and side effects that aren't
necessary, and those oftentimes called "the keto flu,"
and that's not keto flu; that's the inadequacy of an
essential nutrient called sodium to meet physiological needs. Again, as I've emphasized
in the previous slide, fat needs to provide the majority of dietary calories in all
phases, and we can discuss, "What about in the early phase?
Can we cut the fat way back" "and have people lose more
weight?" and I'm going to address that in the next slide.

Again, a lot of people
like to count calories, and if they want to they can, but we don't prescribe calories, and we don't tell people to purposefully restrict in those circumstances
because that's not something that humans are designed to do for years and decades, so
most calorie-restricted diets fail within the first six
months or the first year. Again, our predilection
is this should be mostly, or wholly, composed of
whole foods or real foods that manufactured foods may have some roles in some circumstances;
but what people are gonna eat for the duration of
their lifetime is gonna be predominantly real foods that are purchased in the normal pathways of grocery stores,
or you get a box delivered to your door or whatever;
it should be real food. Now, here I want to be a
little bit provocative, but also science-based; and I
will say that in my experience having done short-term very
low calorie ketogenic diets for weight loss, not just in
my research but in outpatient clinical settings, I've been
disappointed in terms of the long-term results; But again, where you
have people restrict fat in an artificial way, they don't eat to satiety, but they can use willpower to use this type of diet to
lose a whole lot of weight; but when you look at the
results of studies where you look at one year or beyond, I
have yet to see a place where a rapid initial very low
calorie ketogenic diet results in lasting effects in a group of people.

We all know individuals
who have done this, but show me a group of people. So, we tried to pull together data from five published studies, and the yellow one at the bottom, the purple
one, and the green one are all studies that used
formula weight-loss diets under 1000 calories per
day for roughly the first 3-5 months, and then were
followed up from anywhere for a year to two years;
and you can see that in all of these cases, by the
end of the first year weight regain is beginning; and then the blue line in there … I apologize to Dr. Sarah
Hallberg who will be presenting data from the study she's
heading up working with us at Virta Health on reversing
type 2 diabetes … and this is a case where people
are eating fat to satiety from day one, that the
weight loss is slower, but it's more progressive,
and at the end of year one we don't see rebound and weight regain.

So, because a chronic condition,
such as type 2 diabetes, isn't going to be cured in
one year, or isn't going to be cured in six months, from a
philosophical point-of-view as a physician, why would
I want to use something which is only going to
provide transient benefit to the patient, and then
have them begin to lose control and gain that weight back? And so I would say that any .. if it's a well-formulated ketogenic diet, you have
to have demonstrated, for that condition, that it
will have a lasting benefit for the average person
for whom it is prescribed. Again, we picked type 2
diabetes as our primary target, and we picked it in part because it's the hardest one to deal with because when people have
high insulin levels, so secondary insulin
resistance, administered insulin or secretogogs, or insulin
secretogogs, those are the people who have the hardest
time in achieving the metabolic changes, and
so we think we are making progress in meeting
this characteristic of a well-formulated ketogenic diet.

Then, the last two are when
people are on medications for hypertension or type 2 diabetes,
many of those have to be taken away promptly when
the diet is started, and you have to have real-time medication management through the physician and pharmacist, or nurse and office
staff, in order to avoid the side effects of too much
medication in the context of too little carbohydrate
coming in from the outside and dramatically improving
insulin sensitivity through metabolic pathways
we have yet to define. And then the last one, and I
thank Dr. Volek here because when we came up with this list he said, "You've gotta put it on
number 10," and that is a well-formulated ketogenic
diet does not necessarily adhere to traditional dietary guidelines. (audience laughs) Yeah. You get into conflicts
with a number of guidelines when you try to maintain
people's well-being and function on this type of diet.

So, my next little slide is, if I can hit the right button here, the first is, "Do these
provide adequate sodium?" and as I said, with the
exception of hypertension or congestive heart failure, or the other not all
that common conditions where people have to restrict sodium, our experience clinically
is we need to provide them with 5 grams of sodium intake
per day, which is double our current guidelines
of 2.3 grams per day. And we have a speaker, Dr.
Andrew Mente, who has published seminal data in this
obscure journal called, The New England Journal of Medicine.

(audience laughs) From the pure study that demonstrates that for general people, populations around the world
and different cultures, the low point in terms of
mortality for measured sodium excretion, indicating intake,
puts the optimum intake in the range of about 4
grams per day without people being in nutritional ketosis;
add nutritional ketosis and 5 is a modest number. Again, it's horrifying,
but particularly when somebody is in maintenance
for the average, even a person burning 2000
calories a day, they need to eat about 150 grams of fat per day,
and the type of fat matters. That the "healthy" polyunsaturate
fats, which are healthy if you're eating a very low
fat diet when you need those polyunsaturates as essentially fats, isn't the same mix of
fats that you should have when you're on a
well-formulated ketogenic diet where most of your fats
coming in are used for fuel, not for structural
requirement, for membranes, and eicosanoid production,
and things like that.

So, that means avoiding
the high polyunsaturate vegetable oils that are
currently in the marketplace; and the demographics of
that are that are changing. I'm told that there is
now a significant movement in the plant sciences area to move to high monounsaturated
versions of corn and soy, and it already exists for
sunflower and safflower. As Jeff emphasized, that if
you're in nutritional ketosis and you've doubled your
rate of fat oxidation, it appears that some of the
first fats that get into the pathway for oxidation
and saturated fats, in spite of higher intakes,
they don't build-up in the blood, and if anything are reduced.

So, again, worrying about
saturated fats is only associated when you're combining
them with a significant proportion of carbohydrates in your diet. Again, getting adequate
potassium and magnesium as minerals, as those are
important whether you're on a high carb or a low carb
diet; and on a low carb diet, those come predominantly
from leafy green vegetables, and to some degree berry fruits; and if people are so motivated
they can make their own bone broth, which again is a source of not just adding sodium to the diet, but also providing those other nutrients. Finally, the final point is, this is not a high protein
diet; and although we have Bob Atkins to thank for being a pioneer and a bit of a curmudgeon in
terms of persisting out there, selling lots of books and
making this a popular point, he did call it a high-protein diet, and he's forgiven for that.

(audience laughs) But we need to move on. And the last slide, again,
was a slide that Jeff made. Do you want to describe
this slide or should I? So, when I started out in this field, my goal was, "How do we mobilize fat?" "How do we get it to be
burned?" and if you mobilize it in an accelerated rate,
pass it through the liver, make ketones, and use the
ketones to feed the brain, I thought, "That's revolutionary"; but of course George
Cahill figured this all out and published it in the 1960s. What's happened since
then is we now understand that ketones are not just a fuel, and not just for the brain;
they appear to be an optimum fuel for the heart function,
and now there's considerable evidence that, in terms of gut function, that typically if you eat dietary fiber and your microbiome
makes it into butyrate, which is considered to be
an optime fuel for the gut, that's easily supplanted
with beta hydroxybutyrate; and if I make 30 grams of butyrate per day from 30 grams of dietary
fiber, that's a lot; but my liver currently, I'm guessing, I haven't checked my meter, is making between 50-100 grams of beta hydroxybutyrate a day.

So, again, this is a fuel
for multiple organ systems, but now we know it's a signal. So, you've got a molecule
made in one organ, and it goes to other organs,
has multiple effects, and so you have to think
of this as a hormone. This is a very beneficial
regulatory hormone that regulates the body's defense
against oxidant distress and inflammation, which
has an impact on longevity and lifespan, impact on
inflammatory diseases, and cell signaling and
mitochondrial function, including increase in
mitochondrial NAD+ levels. So, this is a potent
signaling molecule that we are just scratching the
surface on what it does, how it functions, and
how do we modulate that, and how do we modulate it to the specific needs of individuals. Thank you very much. (audience applause).

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