Dr. Dominic D’Agostino – KetoNutrition: From Science to Application

Dr. Dominic D’Agostino – KetoNutrition: From Science to Application

August 5, 2019 6 By William Morgan


– So today I’m gonna talk about
sort of the history of what I do
and why I do what I do starting
with the basic science.
So I was trained as a neuroscientist
from a fundamental perspective
looking at basic cellular mechanisms
and my career,
and that was back in 1995
when Dr. Bullock was already
doing ketogenic diet research.
I was actually studying metabolism
in in-vitro cell cultures.
And that led me over 10 years
to looking at ketones as a
neuroprotective strategy.
And over the years we validated the effect
of nutritional ketosis
and exogenous ketone supplementation
in a variety of model systems
and that has more recently led
to a human research that I will
fill you in on a little bit
as much as I can.
So before I begin always
like to thank our sponsors
because they really do make
this research possible.
It’s not always easy to get funding
for this kind of research
especially at the federal level.
The office of Navy Research
has been sponsoring me
for 12 years now.
The Department of Defense actually funded
a lot of the equipment that
I’ll be showing you in my talk.
NASA actually supports us logistically
to do various missions.
One I’ll be talking
about, the NEEMO mission.
And NAVSEA recently funded a project
at Duke University to look at
the ketogenic diet in divers.
So we have funding from
various private industries.
My university is
supporting us with an SBIR
to develop our company,
Ketone Technologies.
And we work with a
variety of organizations,
501(c)(3) foundations,
that can also benefit from this research
on nutritional ketosis.
So my university, you know,
says that I need to really disclose that
the information I’m presenting
today is not medical advice.
I’ll be presenting some information
on new strategies to
implement therapeutic ketosis
that you may or may not have heard of.
And this presentation includes data
on ketone technologies that some of it
is patented by the
University of South Florida,
some of it’s commercialized
and royalties go back and
actually support our research.
So the primary focus of my research
over the last 10 years or so
and for the next three years
’cause I just got funding,
additional funding was
to understand and prevent
what’s known as central nervous system
oxygen toxicity seizures.
So these are a limitation
for our Navy Seal divers
using a closed-circuit rebreather.
Oxygen toxicity seizures
are also a limitation
of hyperbaric oxygen therapy
which is used for 14 different
FDA-approved applications
including things like
decompression sickness
and ischemic wounds.
So I was a part of a NASA mission
called NASA Extreme
Environment Mission Operations.
And I think we have
actually two NEEMO aquanauts
will attending this event
which is pretty unusual.
In this mission we actually maintain
living in an extreme environment
of saturation of pressure.
And at the end of that mission
the NASA Extreme Environment
Mission Operations, NEEMO,
is a Mars or sort of a deep
space analog that NASA does.
There’s 14 different analogs,
and it’s the only one that
actually has astronauts
participating in it.
And prior to coming up to the surface,
you breathe oxygen to decompress,
to denitrogenate.
And when you do that
you breathe 100% oxygen
at about an hour time frame to decompress
and that’s really pushing the limits
of CNS oxygen toxicity.
A Navy seal diver just
at 50 feet of seawater
can only stay there for about 10 minutes
before they have the potential
for oxygen toxicity seizures.
And we were breathing
100% oxygen at 60 minutes
in that environment.
So in that particular mission,
I actually stayed in a state
of nutritional ketosis.
So we use a variety of tools really
to understand fundamentally,
mechanistically,
and from a physiological perspective
what these extreme environments do.
Elevated oxygen, elevated nitrogen,
and also elevated CO2.
We’re becoming more
interested in the effects
of hypercapnia, elevated
CO2 in the context
of elevated oxygen levels.
And we use a wide variety of tools
including things like
atomic force microscopy,
scanning confocal laser microscopy,
electrophysiology, and radio telemetry.
And we’ve adapted these tools for use
inside of hyperbaric chambers
like the one shown here
where we have atomic force microscopy
and confocal microscopy.
And this allows us to
look at things really
at the basic fundamental level
to where we can look at the cell membrane,
the viscoelastic properties
of the cell membrane.
We can quantify for example,
oxidative stress as a function of oxygen
and how that changes lipid aggregates
or the actual composition
or surface of the membrane.
And with confocal we can
look at the mitochondria.
We can optically section the cell
and look at mitochondrial
reactive oxygen species production
as a function of oxygen over time.
On the other end of the spectrum
we do whole animal research
using radio telemetry
where we do EEG measurements,
ECG, and diaphragmatic EMG
to look at respiration.
Using this equipment,
it kinda allows us to vet out
various neuroprotective strategies
to find out what works from
like a top-down approach.
And then we can go back
at this point in time,
go back mechanistically to determine
how particular ketogenic
agents are functioning
from a mechanistic perspective.
So we have the ability to do EEG studies
so we can detect in very high resolution
the occurrence of a seizure
almost before it happens
because there’s some
cardiorespiratory biomarkers
that we think can predict
an impending seizure
that might be useful.
And now we’re actually
looking at vetting out
different detection strategies
and mitigation strategies.
So in 1995 my primary focus
and kinda still is today is neuroscience.
I was investigating the
effects of high pressure,
of low-pressure oxygen
and high-pressure oxygen
using in-vitro cell culture preparations
and also brain slice
preparations as shown here.
And it was really in an effort
to understand fundamentally
as my Ph.D. work transitioned
to my postdoctoral fellowship work,
my postdoctoral fellowship work was to
really understand fundamentally why cells
overproduce oxygen-free radicals
and why this may be contributing
to metabolic dysregulation
that contributes to these
tonic-clonic seizures
that are a limitation of NAVY SEAL diving.
So to do this we use a
variety of preparations
and one was the hippocampal
brain preparation,
brain slice preparation,
so where we essentially
can cut a living brain
into a tissue slice like a piece of bread
and that has the intact site architecture
so we can measure the
electrical activity in the brain
under different parameters.
And in this study we measured the effect
of different levels of oxygen
from 20, 40 to 60 to 95% oxygen.
And in the middle picture is a snapshot
of the hippocampal brain slice preparation
of the CA1 region.
The fluorescence that you see there
is a dye we used dihydroethidium
and that detects the
formation of superoxide anion
which is a precursor free radical
for other reactive intermediates
that we think disrupt neuronal function
and start to disrupt
also glucose metabolism.
So,
this preparation also allows
us to look at seizures.
So in this image here
we can detect the
orthodromic population spike
which are all these
neurons firing together
after being stimulated.
So we stimulate one time
and that the amplitude of this
orthodromic population spike
measured under hyperbaric
oxygen conditions,
you could see relative
to control conditions,
there’s a greater number of neurons
that are hyper-excitable and firing.
When we increase the level of oxygen
not only do we get a big amplitude
in the orthodromic population spike,
we get these secondary spikes that occur
from a single stimulus.
So these secondary spikes are analogous
to a seizure in a slice.
And as you may know, the
ketogenic diet really evolved
as an anti-seizure strategy.
So at this time I started
becoming more interested
in the ability to administer
a ketogenic therapy
to prevent oxygen toxicity seizures.
And in my early work back in the mid-90s
I was actually interested in a molecule
called alpha-L-polylactate.
So I was mostly interested in lactate,
but it didn’t really have an
effective in our preparation.
So as a continuation of this work
going from cellular
studies to animal studies
we started doing these
telemetry experiments
to vet out different agents
that could potentially mitigate,
be a countermeasure to
oxygen toxicity seizures.
And as that work evolved,
and I’ll get to more this later,
we started collaborating
with organizations
or facilities like Duke University
where they have a hyperbaric chamber
and they can do a wide
variety of experiments
to also fundamentally understand
what is contributing to
oxygen toxicity seizures.
They study things like nitrogen narcosis
and also decompression sickness.
So in this experiment
or in this setup here
they don’t actually push
the divers to a seizure,
but there are a variety of
physiological biomarkers,
cardiorespiratory biomarkers,
that can actually detect
an impending seizure
before it happens.
And we’re doing a study right now.
It’s double-blind,
it’s a placebo-controlled study
looking at the effects
of nutritional ketosis.
So and also, we as part of
the NASA Extreme Environment
Mission Operations,
we did a variety of
cognitive function tests.
Here’s me using an iPad underwater
at about three atmospheres,
breathing hyperbaric air
and doing things like out
looking at reaction time,
looking at decision-making,
so under these extreme environments.
We’re at the point now
where we’re collecting data.
We wanna collect data from two,
at a minimum of two or three missions,
and then that data sort of becomes
the baseline data to compare
a ketogenic intervention.
Although in this particular mission,
I actually stayed ketogenic
because that was my baseline.
So there are a variety
of things that we can do
to prevent oxygen toxicity seizures.
Not all of them are feasible.
For example, you know
according to the dive tables,
the NAVY dive tables,
if we adhere to strict exposure time
that will decrease our
chances for oxygen toxicity.
So at 30 feet of seawater
our length of exposure
is roughly 80 minutes.
But at just 50 feet of seawater
our length of exposure is just 10 minutes.
And after 10 minutes we have the potential
for oxygen toxicity seizures.
And this varies considerably
between different people.
And it can also vary considerably
between the same person.
If one person, the same person,
is sleep deprived or on
high levels of decongestants
like ephedrine, pseudoephedrine,
that can actually increase
our predisposition
for oxygen toxicity seizures.
So there’s a wide variety
of things that could augment
or initiate oxygen toxicity seizures.
During my initial studies,
I became mostly interested
in antioxidant compounds,
things that can prevent the formation
of reactive oxygen species
which I thought was disrupting
normal brain metabolism
and the neural pharmacology of the brain.
So antioxidants tend to work very well
in in-vitro cell cultures and
in brain slice preparations,
but they don’t work very well in in-vivo,
in whole animal studies.
So the go-to drug really
for oxygen toxicity
as it pertains to sort of
like a disabled sub-scenario
where you need to get
the guys denitrogenated
and up to the surface would
be anticonvulsant drugs
like by vigabatrin and other drugs
at very high concentrations or doses
that could impair war fighter
performance and capabilities.
So I became increasingly interested
in alternative strategies for this.
One of the things that caught my attention
was the observation
and this was documented
by two independent labs
that fasting could actually delay
the latency to seizure up to 250%.
And this was above and beyond
any anticonvulsant drugs that I saw.
There were a few experiment compounds
that reached that level.
But this idea of,
I didn’t know how it worked at the time
because,
and fasting didn’t seem very feasible,
but mechanistically I
became interested in it.
So,
if I can get this to advance,
so the question was how does fasting
change brain energy metabolism?
So the work that was referenced before
by Dr. George Cahill
really inspired me to
go in this direction.
And when I first read this study
I actually had to call him.
He was alive at the time,
This is prior to about 2008 or nine,
and I asked him for some of
the details of this study
which was pretty remarkable.
And there were some
other things that he did,
maybe some of it not published,
but it was something that could probably
not be reproduced today
where they fasted subjects for 40 days.
And prior to 1967 when this was published,
it was,
most people were under the impression
that glucose was the
exclusive fuel for the brain.
There was some people looking
at lactate and amino acids,
but as a primary brain fuel,
it was thought that largely
100% of your energy metabolism
needed to be derived from glucose.
And that’s true in a fed state.
If you’re eating a normal diet,
roughly 100% of your
brain energy metabolism
is coming from glucose.
So but after about a week to 10 days
you could see that the level
of beta-hydroxybutyrate
and another ketones like
acetoacetate are also elevated.
After about 10 days, ketone,
the body beta-hydroxybutyrate
becomes the primary substrate
for brain energy metabolism.
And he looked at the AB
difference in these subjects
over the 40-minute time point.
And you could see glucose does not go into
severe hypoglycemic ranges, right,
because we have very powerful
homeostatic mechanisms
that maintain our blood glucose.
There’s gluconeogenesis
from gluconeogenetic acids.
The glycerol backbone of triglycerides
becomes a source for glucose over time.
So in an extension of this study
that was not actually
published in the original work,
but is found elsewhere,
they injected these fasting
subjects with 20 IUs of insulin
which if you’re on a normal diet
and your glucose is suppressed
with an insulin administration down to
hypoglycemic levels,
severe hypoglycemic levels,
so I teach the medical students
and we teach that if you’re
under two millimolar,
you typically go into
a coma, and you’re not,
and one, you’re basically
approaching death.
So these subjects experienced
severe hypoglycemia
in a fasting state with insulin.
And so just as reference
that would be around down here,
the level of glucose.
And they were asymptomatic
for hypoglycemia.
So,
after reading this and
talking with Dr. Cahill,
I realized that this had
profound implications
for safety and also for performance.
We know when your blood glucose dips,
your cognitive and physical
performance also dips.
So I became increasingly fascinated
with how to employ this
approach in my studies.
So historically there
are really about two ways
that we can sort of induce
therapeutic ketosis.
There’s starvation.
No one wants to do that.
There’s calorie restriction
and you can only maintain that
over a certain period of time.
And there’s things like
intermittent fasting too
that have been more popular recently.
There’s also the ketogenic diet.
And there’s a lot of discussion as to
what is the optimal ketogenic diet
to maximize the therapeutic
effects of nutritional ketosis.
So the diet that we pretty much employ,
that I use myself and that
we use in our studies,
is about 20% protein and 70% fat.
And a lot of people
ask me, it’s like well,
will this kick me out of ketosis
if my macros are this or that?
And you know, my response is just measure.
You know, use a
commercially-available tool
to determine if your particular,
so a ketogenic diet is defined,
it’s the only diet that’s defined
by an objective biomarker
that we can measure,
our urine or blood ketones.
And that makes it kinda unique thing
from a scientific perspective.
So the ketogenic diet
is maybe not difficult
for you all to adhere to.
But for the large majority
of the population,
it is difficult to sustain
day in and day out.
You need to consistently decrease
liver glycogen and maintain
that decrease in liver glycogen,
and suppression of insulin signaling
to drive hepatic gluconeogenesis.
A small carbohydrate meal can quickly
kick you out of nutritional ketosis.
And if you are trying to mitigate
or prevent seizures,
that can trigger a seizure.
So more recently,
over the last 10 years or so,
there are various things
that can be employed
that can induce nutritional ketosis
and circumvent the dietary restriction
that’s typically associated with
getting into therapeutic ketosis.
And we know that ketones are viewed
as an alternative form of energy.
So when it comes to, you know,
the most potent ketogenic agents,
I would say ketone esters
can put your ketone levels
pretty much wherever you want them to be.
And that could be different depending
on whether you’re using it for seizures,
performance enhancement,
or whatever your approach would be.
So we know that ketones
are an alternative fuel
for the brain and the
heart and other tissues
like the muscles.
And more recently,
over the last five to 10 years,
we understand that they’re very powerful
signaling molecules from the perspective
of a neuroscientist.
This is one of the graphs
that I frequently show
and kinda walk through it.
In the interest of time,
I’m not gonna walk you through this,
but we are interested in things like
adenosine as functioning.
Adenosine way up with a ketogenic diet
in tissues and in the blood.
And also the GABA to
glutamate ratio is increased.
So glutamate’s a hyper-excitatory
neurotransmitter,
and GABA is more of an
inhibitory neurotransmitter,
and glutamic acid
decarboxylase is an enzyme
that converts that,
that makes that conversion.
So the ketogenic diet and more recently
exogenous ketones have
been shown to increase
the enzymatic conversion
of glutamate to GABA.
So that’s an area that
we’re focusing on now.
And we heard recently that,
in the last talks, that
beta-hydroxybutyrate
is a histone deacetylase inhibitor.
So through protein,
through acetylation of proteins,
that can have tremendous
epigenetic effects.
Now we’re studying a disorder
called Kabuki syndrome
and we think there was some
work done at Johns Hopkins
and we’re transferring
the Kabuki syndrome mouse.
And their observations demonstrated
that the epigenetic therapy
of beta-hydroxybutyrate
employed with a diet
or a ketone supplement
actually saved the Kabuki phenotype
in regards to it prevented
the neuronal degeneration
in the hippocampus.
So we want to validate sort of some
of the exogenous ketones
that we’re studying in the lab right now.
We know that the NLRP3 inflammasone
is suppressed by beta-hydroxybutyrate.
So that has wide-ranging implications
on a wide variety of diseases.
And there’s a number of ketogenic,
or ketone receptors to
beta-hydroxybutyrate.
And more recently, acetoacetate
has been shown to be a receptor to that.
So as you can imagine,
there is an emerging
number of applications
to therapeutic or nutritional ketosis.
Nutritional ketosis can be
employed in different ways
through dietary means
and through exogenous ketone supplements
in the form of ketone salts,
ketone esters or
medium-chain triglycerides.
When I first started studying
the ketogenic diet in 2008 or nine,
2008 I believe,
the only therapy that it
was really validated for
was pediatric epilepsy.
And over last 10 years
you can just look at
PubMed and see the explosion of research
on nutritional ketosis and ketones.
So I put, you know, two categories here
of strong evidence and emerging evidence.
We know we’ve had historic data that
low-carb diets, ketogenic diets
can promote weight loss
and the maintenance of that weight loss.
And I think that’s the most,
that’s the key factor, right?
It’s pretty easy to lose weight,
but it’s more difficult to
maintain that weight loss.
At least the people here, you know,
are under the impression
through their research
that you can maintain that weight loss.
Type II diabetes did not really,
there wasn’t a whole
lot of research on this
about 10 years ago.
Over the last 10 years,
through a number of studies,
some of them funded by Virta Health,
very compelling data that type II diabetes
and I know we’ll hear more about that
in the upcoming talks are very,
people with type II
diabetes are very responsive
to low-carbohydrate diets
and ketogenic diets.
And inborn errors of metabolism,
including pyruvate dehydrogenase
deficiency complex,
the ketogenic diet is actually
the frontline of therapy for that.
For epilepsy, it’s sort of
the fallback therapy for drug-refractory
or drug-resistant epilepsy.
It’s not to the point now
where it’s frontline therapy.
But for things like pyruvate
hydrogenase deficiency syndrome
it is the frontline therapy.
So for type I diabetes,
I know my student, Andrew
Koutnik, may argue.
He has a poster on the use of
carbohydrate-restricted
diet for type I diabetes
that you might wanna go to.
There’s emerging evidence
and maybe strong evidence
that type I diabetes can be managed.
There’s far, far less variability
in your glucose and a far,
a huge decrease in the
dependence of insulin
to manage type I diabetes
with nutritional ketosis.
Nonalcoholic fatty liver disease,
things like polycystic ovary syndrome,
brain tumors in cancer,
my research associate, Dr. Angela Poff,
will be presenting on that tomorrow.
There’s a number of applications.
And when it comes to
neurological applications,
we study glucose transporter
type I deficiency syndrome.
Again, this is a neurological disorder
that is highly responsive
to the ketogenic diet.
If a kid has glucose transporter
type I deficiency syndrome,
they really need to be on a ketogenic diet
for quality of life and to just maintain,
to be able to function.
So it’s a very powerful approach.
And in some cases it’s very
difficult for that child
to employ the ketogenic
diet and to stay with it.
So that’s why it’s some of
the things that we’re doing,
developing technologies that can induce
therapeutic ketosis and circumvent
that dietary restriction
that not all people can follow
is important for that community.
Dravet syndrome, Lennox-Gastaut syndrome,
of course, epilepsy,
adult epilepsy,
the ketogenic diet was really only
sort of embraced for adult epilepsy
not until about 2008 or 10.
And they use a modified
ketogenic diet approach.
So when it comes to emerging
evidence and applications,
we’re gonna hear about
Alzheimer’s disease, autism.
Angelman syndrome is
something that we study.
We study the Angelman syndrome mouse model
and have moved to
actually a clinical trial
for Angelman syndrome right now
using ketogenic supplements.
Kabuki syndrome is another project
that we are just starting up right now.
Because of lack of space,
I put anxiety on there,
but anxiety is also something
that adults with Kabuki
syndrome experience anxiety.
We have a number of publications to show
that anxiety behavior goes down
in a state of nutritional ketosis.
So that’s another emerging application.
I don’t really have time
to talk about it today,
but,
and that may be due to a lowering
of glutamate and an elevation of GABA
which is more of an inhibitory
brain-stabilizing hormone.
Neurotrauma, traumatic brain injury.
With traumatic brain injury
you have glucose impairment
or impairment of glucose utilization
that can be detected by an
FDG-PET scan for example.
And about 80 to 90% of people
with penetrating traumatic brain injury
have a seizure.
So it makes sense that if
you’ve had a concussion
and if you’ve had,
if our war fighters are coming home
with traumatic brain injury,
we think it’s very important for them
to employ nutritional
ketosis at the very least
to prevent the seizures
that are very common
with penetrating traumatic brain injury.
So the last two things I wanna focus on
and they relate more from
an operational standpoint
from the war fighter or
maybe even the astronaut,
we’re gonna look at anesthesia resistance
and the employment of nutritional ketosis
or therapeutic ketosis for
oxygen toxicity seizures.
And this is work that we did back,
it was published back in 2013.
We started these studies in 2009 or 10
and it took a while to sort of vet out
and find the ketogenic agent
that was most neuroprotective
in this regard.
And we tested a number of different things
when we did this.
But under normal baseline conditions,
if we expose a rat to five
atmospheres of oxygen,
which is equivalent to
132 feet of seawater,
that produces these tonic-clonic seizures
within about five to 10 minutes.
And the therapeutic range of ketosis
that we need to get to is anywhere
between two to five millimolar
at least with a ketone ester.
And there needs to be an elevation
of not only beta-hydroxybutyrate,
but also an elevation of acetoacetate.
So we used agents that elevate
beta-hydroxybutyrate exclusively,
and we did not have anti-seizure effects
of these agents.
So we used a ketone ester that elevates
beta-hydroxybutyrate more or less
in a one-to-one ratio.
So after about 10 minutes,
rodent models usually have a seizure,
mice and rats in about five to 10 minutes
at five atmospheres of oxygen.
If they are given,
acutely given a ketone ester,
meaning they’re eating a high-carbohydrate
standard rodent chow,
and we administer a ketone ester orally,
and then we dive the rat
in the hyperbaric chamber,
we typically see resistance
up to 60 minutes.
So in our study that we published
there was a 575% increase
in the latency to seizure.
And that’s above and
beyond any anticonvulsant
that I know of.
By GABA training at very high levels
gives you about 400%
anticonvulsant effect.
So we’re giving a metabolic substrate
that has a greater anti-seizure
neuroprotective effect
than any anticonvulsant experimental
or FDA-approved that we know of.
So this was sort of our
first study that we did.
And now we’re doing a
number of studies looking at
a half dozen different agents
and combinations of things
and looking at specifically
CNS oxygen toxicity.
More recently we made the observation
that in studying the glucose
transporter deficiency mice
these mice go down very
fast with anesthesia
because their brains are very,
they’re kind of on the edge, right?
Because they’re already,
they’re very hypoglycemic,
The CSF of glucose
transporter deficiency mice
is about two, maybe
2.5 millimolar glucose.
So their brains are kind of
starved for energy as is.
And we noticed that they go down
very fast with anesthesia.
But if they’re in a state
of nutritional ketosis
with either the ketogenic diet,
a ketone ester or a ketone salt,
that the latency to their
anesthetic induction
which is the point where they fall over
and they’re immobile
was greatly increased.
So our lab was doing,
my wife was doing a lot
of these experiments,
and members of our lab
really observed that
these mice were much more
resilient to anesthesia.
So it became,
this weird observation actually became
a study in and of itself
in a recent publication.
So we validated this.
It made sense in the glucose
transporter deficiency mice,
but we also did studies
using normal healthy
Sprague Dawley rats and we observed that
a ketogenic diet and to a
lesser extent ketone supplements
delayed the anesthetic
effect of isoflurane
which is an anesthesia
that we use very commonly
in our rodent models.
And also a rat model,
the WAG/Rij rat model,
that our collaborator uses in Budapest,
is a rat model for absence seizures.
We observed also a pretty profound
delay in the latency of
seizure with a ketone ester.
So one of the big projects we’re sort of
spearheading right now is to look
at the effects of nitrogen
narcosis and CO2 narcosis.
So if you work with animals,
CO2 anesthesia or CO2 narcosis
is what you use to put the animal down
before you kind of study him.
And also nitrogen narcosis
is experienced by divers.
If you’re breathing air, for example,
with standard scuba and
you go down to 150 feet,
you will experience what’s
called the Martini effect.
So you’ll basically be
drunk from nitrogen.
So the anesthetic potency of a gas
is proportional to its lipid solubility.
Halothane or isoflurane
is very lipid soluble.
So it has a very potent anesthetic effect.
Nitrogen’s not very lipid soluble.
But at high-pressure,
it becomes a pretty potent narcotic agent.
And CO2 is also a very
potent narcotic agent.
So this is relevant to
an operational setting
also because CO2 is a big problem.
It’s a big operational
problem we could say.
So outdoor right now,
we’re breathing anywhere between,
depending on if you’re inside a car
without the ventilation on
or you have a motorcycle helmet on,
the levels can get higher,
but typically it’s about
350 to 400 parts per million
or 450 parts per million of CO2.
So the OSHA limits
is about 1,000 parts per minute.
So that’s,
they determine that’s sort
of like the safety limit.
And then if you’re above that,
then you start to experience
general drowsiness.
And if you’re above say
2,500 parts per million,
you start to get adverse health effects.
So I’ve been, you know,
involved in a number of animal studies
where we look at things
like the immune system.
We look at the brain activity.
We look at the gut,
the tight junctions of the gut.
If you’re above 3,000 parts per million,
it starts to break the
tight junctions of the gut
and makes you have a leaky gut.
So these are some of things
that sort of caught my interest
to put more attention into CO2.
And also from,
if I can get this slide to advance,
so in the context of
an operational setting,
World War II subs really approach levels
in some cases up the 4%.
And that could be 10 or
20,000 parts per million.
So they were exposed.
Today’s submarines are actually
somewhere around 3,000 parts per million
and they’re trying to bring that down.
In the case of a disabled submarine,
the levels of CO2 can get very high
and that can have a very potent narcotic
and even deadly effects.
So many of the scenarios where people die
in these operational environments
whether it’s a spaceship,
you know, Apollo 13,
they had the CO2 problem,
or in a submarine setting,
CO2 really is one the biggest problems.
So it’s really important to understand it,
and also to mitigate it.
So on the International Space Station
they experience a level of CO2
that’s about 10 to 20 times higher
than the level of CO2
we’re breathing right now.
And that’s also very
similar to the NASA analog
that I was involved in,
the NEEMO mission.
So during the NEEMO mission,
I periodically took pictures of the CO2
monitoring system.
At one point it was 1.27
and actually got up to 2% oxygen
which was about 20,000 parts per million.
So this is way above the safety levels.
You know it on ISS they’re
living there for months.
But in this space analog
we were there for 10 days.
I measured it myself, you know,
a lot of urine, blood,
and saliva measurements
to look at how this was
affecting my physiology.
We also measured things like sleep
and heart rate variability
that we still have to analyze.
So we think that this
is an important problem.
It’s important to
employ, we believe,
studying it first at
a basic science level,
and also a whole animal model level
to determine practical implementation
of counter measures,
and also monitoring.
So when it comes to the ketogenic diet
here’s an example of a meal that I ate.
You know on the NEEMO mission
actually this meal,
I would either put coconut oil or MCT Oil
and a can of chicken and
I had macadamia nuts.
So the idea you can’t really get a lot of
fresh fruits or vegetables
in this environment,
so you have to kind of,
your strategy needs to be
pretty much canned food.
And this is a meal that I had last week
and it was a pizza
that’s on the market now.
I see an explosion of different foods
that are low-carb foods
or even ketogenic foods.
And a salad and cookies that my actual,
one of my students made
that are ketogenic.
So a variety of new
technologies are helping us
to prepare foods that are
thought of as comfort foods,
but they can have the macronutrient ratios
or even ingredients in them
that make them ketogenic.
So on the NEEMO mission I was actually
after an EVA where we
go outside the habitat
and work in the water,
I became mildly hypothermic.
And I experienced that because
I was shaking when I got back.
We were out in the water
for about six hours.
My blood glucose measured
when I came in 2.3,
and my ketone levels were 6.9.
So my ketones were then
at that point in time,
you know by far,
the primary fuel for my
brain and functioning.
During that time I actually took
a number of cognitive tests
outside in the habitat
looking at reaction time
and things like that
and there was no impairment at that level.
Eating on a day-to-day basis,
a modified, what I call
modified ketogenic diet,
which was described by
Dr. Finney and Dr. Bullock
it brings me to at the end of the day
a level of glucose of
3.3 and 3.3 ketone levels
which gives you a glucose
ketone index of 1.0.
And we use that glucose ketone index
sort of therapeutically because
we know a wide variety of
diseases will respond to that
from an anti-seizure perspective
and also from an anticancer perspective.
So there’s a number of
monitoring technologies
that are out there from
urine to breath to blood,
and also future devices
that are being developed
that can measure continuously
like the glucose
measurement, like the Dexcom,
potentially beta-hydroxybutyrate,
acetoacetate, and lactate.
I’m communicating with a few companies
who think this technology
will be available
in the next two or three years.
And that could be very useful
if you’re using the ketogenic
diet therapeutically
or also from a performance standpoint.
So in summary,
and I want to kinda go through
each one these very fast and to determine
or just mention the key questions
that each of these things,
each of these projects are looking at.
So the recent grant that I got funded
through the Office of Naval Research
is focused on optimizing
ketogenic metabolic therapy
looking at various ketone technologies
whether it be an ester or a salt,
or even medium-chain triglycerides
to mitigate oxygen toxicity seizures.
And we’re also looking
at various predictors
of oxygen toxicity seizures.
We’re looking at
CNS oxygen toxicity in the
context of hypercapnia.
We know high levels of CO2
increase brain blood flow
and oxidative stress.
So we wanna understand that.
There’s a mouse study
we’re doing right now
on Kabuki syndrome.
And we’re looking at
the epigenetic effects
of beta-hydroxybutyrate.
And also more recently we
started the human studies
which include the study at Duke University
funded by NAVSEA to look at the effects
of the ketogenic diet on early biomarkers
of oxygen toxicity seizures.
And we’re collecting a lot of data,
five IRBs worth of data on
the NASA NEEMO missions,
including 22, which I was on 23,
is coming up and next month
it’s going to be SEALAB
or SEATEST V mission.
In each of those missions
we’ll have six people.
And as we collect data,
we’ll understand what this
extreme environment does
to a wide variety of biomarkers
and potentially how a
ketogenic intervention
can help enhance our safety and resilience
in those environments.
So I wanna thank you for your attention.
And I’ll be here for questions after.
Although I don’t really have time,
one last slide that I
wanted to quickly show
because I get this a lot,
how do exogenous ketones
impact the glucose levels?
So we’ve shown in mice, rats, and humans
that acute administration
of exogenous ketones
in the form of ketone
salts, ketone esters,
and even medium-chain triglycerides
lower blood glucose profoundly.
And I think that may be,
I didn’t get to talk about it,
but that may be one of the most important
sort of therapeutic effects
of exogenous ketones.
Thank you.
(audience applauds)