Dr. Brianna Stubbs – Role of Ketone Supplements

Dr. Brianna Stubbs – Role of Ketone Supplements

November 3, 2019 3 By William Morgan


– Okay, so I’m gonna start
off with my disclosure.
I’m the research director at Human,
and we sell an exogenous ketone ester.
I’m not a clinician,
but perhaps a bit more relevant
right now is I’m an athlete,
a recovering athlete.
I spent four years of my life
spending three hours a day
sitting down, going backwards in a circle
around a rowing lake
in a ditch in the U.K.
I was a member of the British
international rowing team.
So a number of speakers have
touched on the potential role
for exogenous ketones in
a variety of different applications.
So I’m gonna try and bring
some of this all together
and give you a framework
so that you really appraise
how exogenous ketones can be used
for health and performance,
and how does this fit in with how we know
that the ketogenic diet works.
Now, really when we’re
looking at this field
the devil is in the details.
There are a lot of differences between
exogenous ketosis and endogenous ketosis.
There are differences between
different ketone compounds
in terms of what they
do in our physiology,
but also considerations
such as price and taste,
all of these things are gonna affect
their application as we go forwards.
That’s the pointer.
Which one?
Green button, okay.
Having two is confusing.
Could I just see a show of hands
who’s ever tried an exogenous ketone?
Loads of people, excellent.
So I’m gonna define
exogenous ketones for today
as a substance that you consume
that contains ketones
that are bio-identical
to the ones that our bodies produce,
and after consuming them, you end up
in a state of mild, acute ketosis.
Now, this brings me to my first detail
we need to be cognizant of.
Ketosis up until now has really be used
to refer to the state of ketogenesis.
The state of having high
ketones in the blood.
And also the state of
increased ketone oxidation,
but now with exogenous ketones,
we can have hyperketonemia,
and increased ketone
oxidation without ketogenesis.
So that really leads to a
number of key differences
between exogenous and endogenous ketosis,
which we’ll run through quickly now.
With exogenous ketones, the
time of onset is very rapid.
Peak ketone levels are often reached
between 30 to 90 minutes after
consuming a ketone supplement.
But that’s not maintained
for all that long,
so within three to four hours,
levels of ketones have returned
to whatever your baseline was before.
So it requires top ups
to maintain ketosis.
With exogenous ketosis, you do not need
to restrict carbohydrates to
have ketones in the blood,
and this, as many of our
speakers have alluded to,
has interesting applications
where the settings,
where levels of ketones are important,
and adherence can be difficult,
such as in a pediatric population
or an elderly population,
or perhaps in certain physical situations
like with the military of elite athletes
where carbohydrate restriction may be
less easy to implement.
One key difference is lypolysis.
With endogenous ketosis, you
have a high rate of lypolysis,
and that’s what’s driving
ketone production,
and that’s why ketogenic diets
are successful for weight loss,
However with exogenous ketones,
they actually are anti-lypolytic
because ketones antagonize
the nicotinic acid receptor
and thus decrease plasma free fatty acids,
so don’t pay any attention
to any headlines you read
in trashy magazines
saying that ketone drinks
are the next miracle weight
loss pill in a bottle.
That’s definitely not true.
And then to speak to
really to what a lot of
what Jeff and Steve were just saying,
long term adaptations occur
during endogenous ketosis
that we really don’t know
if any adaptations occur
to exogenous ketosis,
so this is at the moment
our understanding of it
is as a short term strategy
to provide ketones as a fuel.
But to echo a theme again said by many,
talked about by many of our speakers,
BHB the molecule itself is interesting
in terms of its role in,
not only fuel metabolism,
but neuroprotection,
inflammation, oxidative stress.
So there may be some
overlap in the benefits
between endogenous ketosis
and exogenous ketosis
whilst there are clearly still settings
where the hot state of whole
body carbohydrate restriction
is important and on the flip side,
settings where having both
ketones and carbohydrate
present in abundance is of advantage.
So we’re just gonna
give a quick run through
of the different types of
exogenous ketones that are out there.
Medium chain triglycerides,
now according to my definition,
these wouldn’t technically be considered
as an exogenous ketone
as they’re actually a fat
that our body metabolizes into ketones.
Typically after consuming
a standard dose of MCT,
as Steven Kunane showed earlier,
levels of blood ketones
are anywhere between
0.5 to one millimolar.
Next up, ketone salts.
Now these are the most widely available
exogenous ketones right now.
Typically ketone salts
use beta hydroxybutyrate
as its more stable and easier
to formulate than acetoacetate.
The ketone is bound by a
mineral, to a mineral ion.
Typically sodium, potassium, calcium.
Then I do think in the future,
it’ll be interesting to see whether
we get more sophisticated ketone salts.
Perhaps using a charged amino acid
such as lycine or arginine.
Now this brings me onto a second detail,
and this is talking about the difference
between different types
of ketone compounds.
So in ketone land, there’s this property
called optical isomerism.
So I like to describe it to people as
we have a left hand and a right hand,
four fingers and a thumb.
They don’t overlay on one another,
and beta hydroxybutyrate
has the same property.
These two isoforms exist,
and our body generally, or exclusively,
produces and metabolizes
D-beta hydroxybutyrate.
That said, L-beta hydroxybutyrate
is present in trace
amounts intracellularly,
and some early work in animal models
has shown that it can be
used in beta oxidation.
It can be used in lipid synthesis,
and sterile synthesis,
and under certain conditions,
slowly can undergo
conversion to other
physiological ketone bodies.
However, it doesn’t
appear to be as meaningful
an oxidative fuel as
D-beta hydroxybutyrate.
So what you’re looking at
here is a blood ketone levels
after consumption of 24 grams
of a racemic ketone salt.
And the white squares at the top are
L-beta hydroxybutyrate levels,
so you can see that after
the drink, they rise,
and they stay elevated, indicating that
it’s being metabolized
slowly in comparison to D
which rises to a lesser
extent and then falls back
to basal levels after about three hours.
And if we take this out even longer,
you’re seeing here the data from
four hours, eight hours and 24 hours.
L-BHB is still significantly
elevated after eight hours,
so it doesn’t look like
it’s contributing as much
to oxidative metabolism as D.
However, that is interesting if it is able
to signal equivalently to
D-beta hydroxybutyrate,
and some, it’s very, very
early stages research,
and not at all clear at this stage,
but it is possible that
L-beta hydroxybutyrate
could scavenge reactive
oxygen species similarly
to D-beta hydroxybutyrate
and may also bind with
a similar affinity to the
nicotinic acid receptor.
So, really, we need to
characterize what happens
to the body with the physiological isoform
and understand the thresholds,
and then we’ll really be able to compare
what happens when we give
just say L in isolation.
But I can certainly see a role for these
as a longer acting form of
exogenous ketones in the future
because they’re not being metabolized.
And finally, ketone esters, and now,
these are perhaps been surrounded by
a little bit of mystique because
they used to cost a ridiculous
amount for a tiny amount.
They taste like jet fuel
according to most people.
But actually just talking
about ketone esters again
is a little bit misleading because
there’s many different types of ways that
we can glue ketones to other
things using ester bonds.
Different ketone esters behave
differently in the body,
so we really need to be
specific when we talk about
which ketone ester is being studied.
So there are two kind of being discussed
in the literature right now.
The acetoacetate diester
that’s being worked on
by Dr. D’Agostino and Dr. Poff
as they discussed it earlier,
and the beta hydroxybutyrate
ketone monoester.
Now the acetoacetate diester is made up of
two parts of acetoacetate
bound to 1-3 butanediol.
And actually as Dr.
D’Agostino and Dr. Poff
were mentioning, it’s actually
showing a lot of promise
in central nervous system, CNS,
oxygen toxicity and cancer.
And actually, in those settings,
it out performs supplementing
with beta hydroxybutyrate.
Which I think is really interesting
cause it really highlights that
there are differences
between these compounds.
They’re not just the same.
There is only one human study to date,
and that was kind of hobbled
by poor tolerability issues,
but I think it’s really interesting to see
where this ester goes in the
future with the research.
Next up is the beta
hydroxybutyrate monoester
that was developed out of a collaboration
between the NIH and the
University of Oxford.
This compound is made up of one part of
D-beta hydroxybutyrate bound
to one part butane diol.
And it’s been fairly
widely studied in humans
as around about 250 human participants
in the studies to date.
A lot of these are focused
in on exercise physiology
but there’s also data
around the regulation
of blood glucose, lipids, appetite
in a few early clinical studies as well.
And this compound is classified as
generally recognized as
safe by the U.S. FDA,
so it’s available now
as a commercial product.
So I just want to wrap
up this little section
by talking about the
differences we need to consider
between the ketone
supplements that are available
focusing in on the racemic BHB salt and
the D-beta hydroxybutyrate ketone ester.
First up, in terms of the level,
the ability to raise ketone levels,
I would caveat this by saying that for
a number of different endpoints,
we don’t know the
therapeutic level required,
or the effective level required.
So I guess what I would say at this point
is that the beta
hydroxybutyrate ketone ester
allows a very flexible range of ketosis
anywhere between 0.5
up to seven millimolar.
We can titrate up and down with the doses.
Whereas salts tend to be stuck
around one millimolar increase.
What you’re looking at
here is consumption of
24 grams of beta hydroxybutyrate
as either a ketone ester or a ketone salt.
And you can see that the ester reaches
a peak beta hydroxybutyrate
of around three,
and the salt around one,
although some of that
is obviously L-beta hydroxybutyrate,
as you saw earlier.
And on the right you can see, I pulled out
the peak beta hydroxybutyrate
levels reported
in all of the studies
of ketone salts to date.
So those really range between
0.4 and one millimolar.
So it’s fairly standard
that with a racemic salt,
I think that’s probably the limit
of the technology right now,
but still, obviously some
development happened there.
Next up, what about
practical considerations?
So the ketone salts come with
quite a high mineral load,
and the L-BHB and the ketone
esters are still costly
and still taste–we like to
say it tastes like it works,
but some people like
it, some people don’t.
You’ll have to try some one time,
and tell me what you think.
But then the issue I wanna address
within a little more detail is the issue
of G.I. tolerability
because I actually think
that broadly speaking, exogenous ketones
get a pretty bad rap.
So what I was doing in
my studies at Oxford,
at every time point that I
collected a blood ketone reading,
I asked people how they felt.
And they had twelve symptoms
that they could rank
between zero and eight,
so at any one time point,
if they were at death’s door,
they could have given it a score
of 96 in terms of severity.
And so I average this out over all of
the participants in my studies.
On the left, you can see
symptoms after 12 grams
of ketone ester and ketone salt,
and on the right, after 24 grams
of ketone ester and ketone salt.
And you can see that the
maximum on this axis is three,
so all the supplements are
really quite well tolerated
that’s between mild and moderate.
On the left you can see
there’s very little difference
between the esters and salts
and the symptoms are highest
directly after the drink,
but really they go down,
and it’s not that much to speak of.
When you increase the dose,
symptoms increase with both compounds,
increases by more with ketone salt,
and I would say we saw
more, lower G.I. issues
potentially because of the mineral load,
but I do think that these compounds
have been demonized a little,
and to further emphasize that point,
this is data collected during
a three hour exercise study
with ketone ester compared with
a multiple transportable carb drink.
And the black square is the carb drink,
so people are having more
symptoms with the carbs
than with the ketone, but it’s still mild.
The maximum on this axis is 1.8,
so I think that with proper dosing,
and proper formulation,
we can really work around
these and make these
quite a practical
intervention for athletes
and for the broader community.
So be careful how you
use the word ketosis,
endogenous, exogenous.
It matters now that people are
out there using exogenous ketones.
And also pay attention when
we read the literature,
was it a D-L salt?
Was it D or L?
What type of ketone ester was used?
And also pay attention to tolerability,
and let’s work as a community to refine
that and make this practical
strategy going forwards.
So I’m now just going to finish
up my section of the talk
by talking about the exercise
studies I was involved with
at the University of Oxford using the
D-beta hydroxybutyrate ketone ester,
and I wanna say at this point that
I’m really, really standing on
the shoulders of giants here.
I was involved–I’ve been
involved for eight years
but a lot of the work
was done before I arrived
by Dr. Richard Veech and
Professor Kieran Clarke
who developed the ester,
and then Dr. Pete Cox
who pretty much single
handedly conceptualized
and ran the series of studies
I’m about to talk to you about.
So we published in Cell
Metabolism in 2016,
and as I said this was five studies
of athletes that were
following a mixed diet,
so they were not on a ketogenic diet.
It was a randomized control trial,
so they completed both conditions,
and the either consumed ketone
ester with carbohydrate,
or carbohydrate alone, so
this isn’t just a straight up
ketone versus carbs consumption.
This is how does ketones add
to the current gold standard?
The exercise protocols vary
slightly study to study,
but generally, they exercise intensity
was between 70 to 75%,
which is typically regarded
as being quite heavily
dependent on carbohydrate,
and all of these athletes
were just sub-elite,
very well trained athletes.
So the first finding is
that ketones can provide
quite a substantial energy source
and be oxidized during exercise.
The red line at the top
is ketone levels at rest,
and then if you have the same drink and
start exercising at 40% or 75%,
ketone levels fall in an
intensity dependent manner.
And we calculated out that we believe that
ketone oxidation was
accounting for somewhere
between 16 to 18% of energy expenditure
during these conditions.
And we actually calculated that we believe
that we were oxidizing about
0.5 of a gram per minute of ketones,
so it’s contributing as
an oxidative substrate.
But I think probably what’s more profound
is the effect on other aspects
of substrate metabolism,
specifically carbohydrates,
fats, and proteins,
all of them, but carbohydrates first.
Let’s start there.
So this is muscle glycogen
pre and post exercise.
You can see that typically
when you exercise
with carbohydrates, you
burn through glycogen.
That’s the gray bars.
As where as if you have
ketones plus carbohydrates,
you get a profound glycogen
sparing effect during exercise.
This picture of carbohydrate
sparing continues
when you look at the levels of
blood lactate during exercise.
Consistently, we were seeing
two to three millimoles
less blood lactate when
ketone ester and carbohydrate
was consumed compared to
just carbohydrate alone.
And when we looked in
detail in the muscle,
we did metabolomics and looked at
all the intermediates of glycolysis,
and it wasn’t just inhibition
at the level of PDH,
there wasn’t like a back-up.
The whole glycolytic pathway was down,
but they were actually
completing the same workload
through a completely
different metabolic pathway.
What about muscle branch
chain amino acids?
Now, sometimes proteins are
deaminated during exercise
to provide a substrate for metabolism,
and actually taking
ketones before exercise
attenuated this rise, suggesting
that perhaps using ketones
before exercise could
help to spare muscle mass.
And finally, what about fat?
This is a little bit like how Jeff
was talking about earlier,
we saw this effect, and we
couldn’t really explain it.
We saw a very, very big increase
in interim muscular lipid oxidation,
and to me it’s a little odd because
ketones inhibit lypolysis but increase
intramuscular fat oxidation.
This is a graph on the left here,
you can see change from baseline.
So ketone, taking ketone before exercise
increased the amount
of intramuscular lipid
you burn by about 25%,
and we’re not really sure why that was.
Mechanism is still unclear,
but it’s certainly interesting,
and potentially have disease implications.
And so as I said, up until here,
this is, all of the
data up until this point
has been showing you how we’re completing
the same metabolic output,
the 70% max intensity cycling
with a completely different
metabolic phenotype,
so what happens when
we take the breaks off
and these let these athletes
go full pelt down the track?
So we did a study where you did 60 minutes
of pre-fatigue and then a 30
minute time trial for distance,
and we saw that athletes improved
by about 400 meters, 2.3%,
and just to really contextualize that,
I worked out that distance
would be the difference
between first and eighth
position in Olympic road race.
The Nike two hour marathon project,
they were one second a mile
short of breaking two hours,
so at elite levels of
sport this kind of thing
is certainly interesting and
could really move the needle.
This isn’t an isolated result,
and in 2016, Dr. Andrew Murray,
who was previously at the Oxford group,
now is at the University of Cambridge,
published a study in FASEB that looked
at treadmill endurance of rats running
each day for seven days fed ketone ester,
a high carbohydrate diet,
or a western diet high
in carbohydrate and fat,
and he found that each
day the rats were running
around 33% further with the treadmills.
So obviously more of an
extreme result there,
but it’s more of a signal to
this effect is to be believed.
And then finally, there is a study of
British elite rowers of which I was one,
doing a 30 minute time
trial for distance again.
This is available online in
one of our patent applications.
It’s not yet published,
but again there was at
one point 3% improvement
in endurance performance.
So we’re still a little
way from really knowing
exactly how best to use these,
but the physiological shift
is very, very profound.
And I’m very excited to
see where this field goes,
and we’re trying to answer
some of these questions now,
so I’m gonna hand over
at this point to Dawn,
who is going to talk to you about
some of our current research efforts.
(clapping)