Dr. Dominic D’Agostino: Emerging Applications of Nutritional Ketosis

can you all hear me okay
yeah okay so just as a show of hands how many people here follow a carbohydrate
restricted diet okay and how many follow what you would call a high carb diet for
your training or lifestyle or whatever okay so it's good to know I I didn't
know coming into a CrossFit community because you know you hear about the
athletes and they don't care yeah yeah that's I think a good point
well yeah yeah well before I begin I'd like to thank Greg and Karen for the
invitation it's great to be here to be among a community that's very passionate
about what they do I at the Medical College medical students and I want to
kind of direct them towards this event next year
– and the organizers – I want to thank the organizers not all conferences have
such great logistics and great people behind it and I can tell the people
behind it doing the logistics are very passionate about this event and it
really shows with the organization so today I'm going to be talking about
emerging applications of nutritional ketosis and and I'm gonna focus you know
talk about the original application of the ketogenic diet which was to control
epilepsy and before drugs sort of came on the scene the ketogenic diet was
really the standard of care for epilepsy and then later on as drugs emerged it
then became used for drug refractory or drug-resistant epilepsy and that led me
down the path of using nutritional ketosis with the observation that
fasting ketosis can manage seizures I became interested in the ketogenic diet
and ketone supplementation which I'll be talking about and using that for a very
specific application which is central nervous system oxygen toxicity seizures
which limits Navy SEAL safety and operational activities based upon the
closed circuit rebreathers that they use and in the process of studying
nutritional ketosis for oxygen toxicity seizures we had developed a number of
technologies funded by the Department of Defense that allowed us to look at a
range of different cell types one of those cell types with the cancer cell
type and and made some observations that led me down a path that looking at the
Warburg effect and cancer as a metabolic disease and that connected me with Tom
Seaford back ten ten years ago and it led to several students doing PhD
dissertations on the topic of cancer so I'm going to touch on sort of what we do
from an operational perspective supporting the Navy and also our work
with NASA and also touch upon I know they'd seem very dissimilar but touch
upon our cancer research – before I begin because I don't want to forget and
I'd like to acknowledge the people who have supported the research that I'm
going to show you today and even the idea of using nutritional ketosis the
ketogenic diet and ketones implementation the office of Navy
research which is part of the Department of Defense really they were generous
enough to buy into my idea that nutritional ketosis could delay or
mitigate oxygen toxicity seizures so it was about 15 years ago and it took about
a couple years to convince them to fund the work so about 12 years ago they
started funding this work and we also partner with with NASA on various
missions extreme environment missions I'll talk about NAVSEA which is funding
a ketogenic diet study at Duke University
diving research subjects on a ketogenic diet while they're exercising and doing
cognitive function tasks and we do EEG measurements and we actually push them
to the edge of a seizure so that's funded by NAVSEA so the animal work that
I do in the lab actually is transitioning to human lab work and also
operational stuff and and we have funding from DARPA for our next NASA
project and we have NIH funding with my collaborator looking at Alzheimer's
disease looking at ketone supplementation in various models of
Alzheimer's so we have an industry support – in some cases internal support
from the University of South Florida and we also partner with a lot of
foundations 501c3 foundations for things like kabuki syndrome or glucose
transporter or type 1 deficiency syndrome maybe things you haven't heard
about but they're there diseases that are very responsive to the therapeutic
effects of nutritional ketosis and and my University asked that I do a
disclaimer disclosure and my conflicts of interest so this information is not
medical or nutrition advice I'm not a registered dietician of a PhD scientists
the presentation includes data on ketone technologies that are patented and those
patents are held by the University of South Florida and we have licensing
partners that have commercialized some of the patents royalties from those
commercialized products go back to the University of South Florida
I also get royalties which I donate back to the university to fund some of the
research that I'll be showing you today and I'm also co-owner of a company
ketone Technologies LLC I don't have any ketone supplements I don't I don't have
any supplements of my own but the university has licensing partners our
company does partner with NASA and we do some other things so we support
education and also research activities so before when I got into this before I
started studying ketones we needed to develop tools to understand the
fundamental changes that occur in the brain and then the muscles of people
astronauts and and Navy SEAL war fighters that are in these extreme
environments so environments where the oxygen partial pressure is high or the
total pressure of a gas is high or low so we created a number of environmental
chambers and here's one of them this was my postdoctoral fellowship project was
to create a hyperbaric atomic force microscopy and an AFM actually has a
scanning resolution of an electron microscope but you can image living
tissue with it and you can get down into looking at proteins on the membranes and
assess memory and lipid peroxidation I also got another Department of Defense
grant to put a confocal microscope in there that would allow us to look at to
measure simultaneously membrane changes in response to graded levels of oxygen
and pressure and simultaneously measure the production of oxygen free radicals
as a function of oxygen levels in the cells and in tissue and this allows us
to understand fundamentally how these extreme environments affect cells
tissues and organs and we we also have adapted these technologies for use
inside a hyperbaric chamber where we actually do physiological measurements
and we implant a radio telemetry device inside rats where we can measure EEG
diaphragmatic EMG to look at respiration an ECG to look at heart rate things like
heart rate variability and we create an environment inside these environmental
chambers that simulates military dive operations or an operational setting and
then we collect in this case telemetry 14 channels of data and then what we're
looking is we're we're administering a drug or most of my work has been on
ketones and we want to enhance or delay as a countermeasure to delay the
deleterious effects low oxygen or high oxygen that causes oxygen toxicity
seizures and I started looking at and and still do we look at cells and one of
the cell types that I was looking at was a u-87 glioblastoma cell and these were
first originally derived from a 44 year old brain tumor patient so I was looking
at fibroblast smooth muscle cells various types of primary neuronal
cultures from the hippocampus and the cortex and I observed that as you
increase the level of oxygen over time there was a proportional increase this
is time on the x-axis here and the level of superoxide production and the slope
of the line will indicate the level of superoxide production which is the
primary free radical produced by primarily the mitochondria in response
to high levels of oxygen or stress or mitochondrial damage and we saw that
neurons and basically metabolically active cells have a pretty high slope
but these cancer cells here were really off the charts and I didn't understand I
was looking at all the different cell types and going looking at the data and
saw that cancer cell mitochondria and the mitochondria are these punctate
staining things here these little balls this is a nucleus of the cell and the
mitochondria we're over producing oxygen free radicals in the presence of high
oxygen and and this was very a very interesting phenomenon to me
and as the level of oxygen got higher and higher with hyperbaric oxygen
I saw the mitochondria starting to disappear and then the cells would
explode so I never saw neurons explode or I never saw muscle cells explode in
the presence of high oxygen but I saw these cancer cells exploding under
hyperbaric oxygen conditions and I didn't know why it was happening and
that led me to looking at the the Warburg effect which is essentially and
I'll talk about it a little bit damaged mitochondrial function or oxidative
phosphorylation with a gradual sort of compensatory fermentation and the
energetic processes are switched away from the mitochondria and more towards
glycolytic effects and I'll talk about that shortly so we also observed that in
colleagues basically observed that if you fast a rat for 24 or 36 hours they
could withstand the effects of high pressure oxygen up to 5 atmospheres of
oxygen that typically produce a seizure in five minutes they could go about 15
minutes or 20 minutes so this motivated us to develop various strategies to
induce therapeutic ketosis and I'll talk about the ketogenic diet and talk about
ketone esters and also ketone salts and they different supplemental forms of
ketones that are on the market so the work that I did in cells and tissues and
also in whole animal studies over the last couple years transition to work
that I personally have done as a crew member in NASA extreme environment
Mission Operations where I lived underwater for 10 days in a hyperbaric
environment and I measured blood urine and saliva and tissues I measures my
skin microbiome gut microbiome all these things we collected a lot of data on
this mission and it's fantastic because we can work with astronauts and it helps
NASA understand how living in these extreme environments can how we can
develop countermeasures for deep deep space operations and we also have work
that we're doing as I mentioned at Duke University where we put subjects inside
a hyperbaric chamber we have them pedal a bike we measure EEG and you see a
couple you see all the lines coming in there we have blood coming from the
person directly to a mass spec where we look at blood gases and blood
metabolites and it's a very advanced set up and it allows us to really push
people to the limits and simultaneously they are doing cognitive function tests
and piloting basically an airplane and a simulation so we look at their
performance on various tests and and my wife is a cognitive neuroscientist so
she's very interested in behavioral studies so when I was on the NASA
mission and she was a crew member in in the last NASA Nemo mission mission 23
but on my mission she started experiments looking at cognitive
function using the NIH toolbox like reaction time decision-making all these
things so everything I'm showing here from the cells to the the mission to the
work at Duke we're basically understanding what these extreme
environments do at baseline and what these extreme environments do to our
safety and performance in the context of nutritional ketosis or therapeutic
ketosis and that can be achieved with a diet that can be achieved with
intermittent fasting or ketone supplementation and we're sort of
looking at all these different ways to induce therapeutic ketosis but I'm going
to take a little bit of a step back and talk about some of the work and some of
the people that inspired me to go down this path when I was trying to explain
the observation that was made from some Navy research scientists demonstrating
that fasting could prolong an animal's exposure to high-pressure oxygen and
delay a seizure by up to 200 250 percent before even I started studying this so I
connected early on when he was still alive dr.

George Cahill
and was asking him about this study here prior to 1967 and even now people some
people believe that glucose is the primary fuel the only fuel that the
brain can use for energy and for so prior to 1967 this was sort of in the
textbooks work that George Cahill did on subjects that were fasted for 40 days
and these were primarily overweight obese subjects demonstrated that brain
energy metabolism changed significantly and what the brain was using for fuel
changed significantly so after about a week to ten days as you'll see on the
graph over here brain energy metabolism is derived primarily about 60% or more
from the ketone bodies beta-hydroxybutyrate and a co acetate
and these are elevated only after fairly extreme starvation
they called it starvation or prolonged fasting so starvation would be a
situation where their health was declining fast these subjects appeared
lucid they did well in various psychological tests and their blood
measurements indicated that they're relatively healthy even after 40 days of
fasting in an extension of the study that could never be approved by IRB
today they they injected these fasted subjects with twenty I use of insulin to
push their blood glucose down into a range that I teach is basically fatal
hypoglycemia so the you know and some of the lectures that I teach to the
first-year medical students we teach about when your blood glucose gets down
below to about thirty you go into a coma a little bit lower you go into a seizure
and then you die so these subjects experienced severe
hypoglycemia in the range of 1 to 2 milli molar so down to a level where the
meter probably wouldn't even read it like I've pushed my level down there and
the meter just flashes low so it doesn't even measure at these low levels and
they had no harmful effects were observed in this extreme hypoglycemia
because for zuly the ketones were functioning to
preserve brain energy metabolism and cognitive function and so they had no
symptoms of hypoglycemia which was amazing and you know I I teach in my
lecture and I always sort of add you know this study in there that in the
context of a normal diet yes it this level of hypoglycemia would be fatal if
your ketone levels are not elevated so to me this was really remarkable
observations that elevating your blood ketones could sort of make you Bock
proof and in the event that you go hypoglycemic from insulin shock or you
know peripheral glucose utilization is exceeding the capacity to maintain blood
glucose levels the ketones are sort of like insurance to prevent any
hypoglycemic episodes and I see this in my student and I'll show you some of his
data later and ruku t'nuk who's a PhD student soon to defend he studies cancer
cachexia but he's type 1 diabetic and uses low-carb and the ketogenic diet to
manage his type 1 diabetes when I first started giving these talks I said if you
have type 1 diabetes don't ever even think about carb restriction or the
ketogenic diet so I've changed my tune about that there are now publication
authored by David Ludwig from Harvard to show that carbohydrate restricted diets
may be optimal for those even with type 1 diabetes so a little bit about ketones
in general ketones we know our energy substrates and now more recently in the
last four or five years we come to understand them as a powerful signaling
molecule that functions almost like a hormone there's a ketone receptor there
are several ketone receptors ketones function as histone deacetylase
inhibitors ketones function to suppress inflammatory pathways that in a way
that's completely independent of their metabolic function so they have
important signaling properties clinical ketosis is defined as a blood level of
ketones that's above 0.5 milli molar so that takes about if you stopped
eating now if you're not on a ketogenic diet regular if you stopped eating now
it takes about 24 hours or your blood ketones to really get up into the
clinical ketosis range so you could achieve it with with fasting and if
you're low carb you would get into ketosis faster if you were if you're
doing intermittent fasting some people do urine ketones that's okay
it's not optimal but a urine ketone level of 15 milligrams per deciliter on
the keto stick that you could buy any CVS or Walgreens will correlate to about
0.5 million mol or ketone level nutritional ketosis I define it as a
dietary strategy to elevate ketones into into this range and that typically
involves a carbohydrate consumption fibrous carbohydrates non starch
non sugar of less than 10% of the total diet and generally speaking 25 to 50
grams of carbohydrates that is the level where you start to get into nutritional
ketosis and start to get some of the benefits of deuterostome ketosis
ketoacidosis and this comes up a lot with the medical students or if I teach
at a clinical conference all the hands go up well what about ketoacidosis
ketoacidosis is a very specific metabolic derangement associated
primarily with the absence or insufficient amount of insulin in the
body so without insulin when our ketones level rise that actually releases a
small amount of insulin which helps your body fine-tune ketogenesis in the liver
so without insulin we have runaway ketogenesis
and in the context of high glucose high ketones can be very detrimental to
health and create an acidotic situation that if it's not corrected with fluid
electrolytes and insulin injection will lead to coma and death so you know so
even I was going to say even people with type 1 diabetes can successfully do the
ketogenic diet if they manage their insulin correctly keto adaptation is a
time-dependent physiological adaptation to using Fatiha
and ketones for energy so we know that the more you do the ketogenic diet or
carbohydrate restriction the more you adapt the easier it gets and the more
benefits you derive from it from those adaptations so part of what we're doing
in the lab is actually measuring those adaptations looking at the gene
transcription looking at the presence of the mono carboxylic acid transporters
which are up regulated about 50 percent after about two weeks in rodent models
after being in nutritional ketosis the glucose transporters are also changing
and it seems to be a tissue specific changes in the brain and the muscle and
we haven't reported on that yet but we're putting that together for
publication and the last thing I want to highlight is exogenous ketones because
this term did really not exist years ago like 10 years ago and now they're on the
market I get a lot of questions about it and there are a lot of research a lot of
research being done I think there's at least a half dozen registered clinical
trials on clinical trials.gov right now looking at exogenous ketones and there
are many forms of exogenous ketones there are electrolyte mineral salts
there are at least three to four different types of ketone esters or as a
mono ester a diaster and at raster and so there's various forms and we are
investigating how these different forms of different applications of these forms
and how they can be formulated and what therapeutic applications they may have
so there are different strategies that one can use to get into a state of
nutritional therapy to ketosis there is starvation that's not fun but there's
caloric restriction there is intermittent fasting
there's the ketogenic diet which is a specific macronutrient ratio the
classical ketogenic diet the four to one was about 87 percent fat so now we know
I'm just coming from an epilepsy conference that the modified ketogenic
diet which is what what you see here or at least the ratio is about 75 percent
fat 20% protein and a minimal amount of carbohydrates like 5% seems to have
similar seizure protection in adults and maybe in PD in some PD
Jurek populations too depending on the disorder so these things basically
starvation and the ketogenic diet and intermittent fasting mobilize fats the
fats go to the liver and it stimulates beta oxidation of fats with the
continuous suppression of insulin so only in the context of mildly depleted
liver glycogen and continual suppression of the hormone insulin and blood glucose
drops a little bit too but the homeostatic mechanisms that maintain
blood glucose are very powerful so blood glucose really does not bottom out it'll
might stay in the the 70 to 80 milligram per deciliter range even with no
carbohydrate consumption for many people so these ketone bodies are produced
beta-hydroxybutyrate acetoacetate acetyl acetate can spontaneously decarboxylate
to acetone interestingly acetone has some interesting functions on various
ion channels which can affect brain function and this is difficult for
patients to achieve so we developed various forms of exogenous ketones and
also acknowledged that fats ketogenic fats like medium chain triglycerides
which go directly to the liver via hepatic portal circulation and are
oxidized very fast to ketone bodies they're not packaged into chylomicrons
like the long-chain fats and then ketone salts and ketone esters are metabolized
partially in the liver but mostly spill into the blood and then rapidly elevate
ketone levels like a ketone ester if a person consumed it right now on stage by
the time I get off stage it'll look like I fasted for 10 days so you can achieve
a level of ketosis in the 5 to 6 million molar range go from zero to 5 to 6
within 30 minutes so there are very powerful agents that we're studying but
as the science sort of advanced we understand these molecules not only as
energetic substrates for the brain the heart and even skeletal muscle but they
have powerful signaling properties in the brain and in other tissues so I'm
not going to go through all the all the signaling pathways here but you
could see in this panel below that there are many different signaling pathways
that are impacted by nutritional ketosis so changing our metabolic physiology
significantly changes brain energy metabolism and also the
neuropharmacology of the brain so one of the studies that we did in Angelman
syndrome we take brain tissue out and we look at
all the different neurotransmitters and the ratio of glutamate to gaba changes
significantly it activates glutamic acid decarboxylase which makes a very an
excitatory amino acid transporter and inhibitory or brain stabilizing
neurotransmitter known as gaba so gaba also has anti-seizure effects so
it's one of a dozen different mechanisms and that's what's really fascinating
about the ketogenic diet it doesn't just work through one mechanism it works
through many different mechanisms in synergy and that's why there are no
drugs that really can mimic to get the ketogenic diet because it works through
so many different mechanisms so I've given talks at pharmaceutical companies
where they want me to give a talk on the mechanism of the ketogenic diet so they
can sort of reverse engineer some drug to target a mechanism and when I throw
up you know that panel there that shows all the mechanisms I think they get
depressed because they realize a drugs really not possible there is a compound
called two deoxy glucose and it inhibits by inhibiting glycolysis you can
stimulate some of these pathways and now there is a clinical trial as a ketogenic
diet in a drug so it's basically a glucose antagonist so that there are and
we are doing cancer research with that compound – so here's the biogenic or
bioenergetic effects of ketones and in this case it's just the brain so the
liver is the site of ketone production so under situations of suppressed
glucose gluconeogenesis in the liver and also suppressed insulin signaling and
mild glycogen depletion the liver produces these ketone bodies as acetyl
co a from beta oxidation of fatty acids accumulates and the acetyl co a
condenses together to form acetyl acetate and then beta hydroxy butyrate
beta hydroxy butyrate is the primary ketone body in circulation because it's
more resistant to degradation whereas acetyl acetate can be
spontaneously decarboxylated but beta hydroxy butyrate needs to be broken down
to acetyl acetate to be used as fuel so keep that in mind but co acetate is
essentially the oxidized form of beta hydroxy butyrate not to get to like
technical here but I just want to highlight that that in the context of so
the point is the liver makes ketones but does not use ketones as an energy source
it lacks succinylcholine sprays and that's very interesting because cancer
cells also lack this enzyme many most cancer cells lack this enzyme that
allows the cancer cells to use the ketone bodies for fuel so the liver
lacks sucks Neil Cody transferase and that's sort of like an evolutionary sort
of advantage because the liver is a very greedy organ if you're hungry and you
eat something the liver will take what it wants amino acids and glucose and
things and then you know put back in the circulation you know what you can use
but the liver is very greedy but in the case of ketones the liver doesn't really
use ketones as fuel it produces it so these ketone bodies spill into
circulation and they bypass many of the regulatory steps associated with the
glucose being able to support bioenergetic functions so in the case of
impaired glut one glucose transporter one deficiency or glut 3 deficiency
that's the transporter on the membrane of neurons in the case of those being
deficient or not functioning or in the case of Alzheimer's disease or traumatic
brain injury the glut 3 transporter gets internalized inside the cell and then
the glucose can't can't get into the cell but ketones bypass that process it
even bypasses pyruvate dehydrogenase complex so if you have peopIe Roubaix
dehydrogenase complex deficiency syndrome is treated with the ketogenic
diet so for kids that had this they need to be on the ketogenic diet
pdh is also impaired in Alzheimer's disease and also traumatic brain injury
so then by virtue of bypassing these regulatory sites ketones can preserve
brain energy metabolism and that's a very important thing for a number of
different disease states that we study including gland deficiency we're also
looking at yeah a number of different neuro metabolic disease states where the
ketogenic diet is very therapeutic so in Alzheimer's disease so we know
Alzheimer's disease is characterized as glucose hypometabolism and the hallmark
characteristic of Alzheimer's disease is a decrease in intensity of a
fluorodeoxyglucose PET scan so there's less of an intensity showing radioactive
glucose present in the liver there's less uptake of glucose it's also
interesting to observe that a number of studies showing that cerebral blood flow
increases about 30 percent during acute hyper ketone emia so even in a very
short order if I consume ketones right here within about 15 to 20 minutes you
can measure with Doppler blood flow measurements that blood flow is
increasing in the brain and some people that actually gives them a headache
if they consume a large dose of like a ketone ester it's increasing blood flow
too much so with that kind of metabolic effect on the brain and some of the
things signaling things I was talking about you can imagine that there's
emerging applications at the ketogenic diet and I saw this early on that when I
started studying this it was really only pediatric epilepsy but I just saw you
know so many different opportunities I at the time that I've started talking
with George Cahill and Richard Veatch and theodoor van Italy all the icons
people I consider icons they encouraged me to go down this path and I was a
young untenured professor and I realized that you know I was gonna really delve
into this to make this my career so so this these are the applications for kid
and I didn't even there are many applications that I didn't even put on
here like the ketogenic diet for acne or polycystic ovary syndrome or we said
various psychological effects of ketones – and we're getting into that so I am
just going to focus primarily on cancer and some of the work that we do in an
operational setting from the NASA NEEMO missions but just look at the emerging
applications and on the left here are really things that have strong evidence
in the literature and weight loss and weight management type 2 diabetes I
think we can say there's strong evidence for that obviously inborn errors of
metabolism the last prior to coming here I was in Chicago meeting with the
doctors who actually give ketones intravenously through with all these
different neuro metabolic disorders and they can bring children to life by
giving them ketones when they have specific metabolic disorders and things
like Lennox gusto syndrome it's been used for decades for that disorder in
epilepsy and you know I have it in the emerging applications but I think type 1
diabetes – there's emerging data from people out there using it like the group
type 1 grit on Facebook my student my PhD student is part of that group and it
was there was a publication that essentially resulted from from that
group so there's more data emerging and in cancer ten years ago I think there
was one or two studies on clinical trials.gov
and now I look this week there's over 30 clinical trials on using the ketogenic
diet in cancer studies so this is a very emerging field and I think you're gonna
see with the clinical trials now a lot more studies results from this study is
hitting pubmed so it was observations that we made in the cell types that we
studied under hyperbaric oxygen therapy and also with supplemental ketones we
observed that ketones decreased proliferation in these cancer cell types
that led me down a path I wasn't supposed to be studying it I was
supposed to be studying oxygen toxicity seizures because we had a contract with
the Navy and I was full-time on that contract but I was obsessed with these
observations that we made in cancer cells and the only thing that really
explained the observations that we saw especially the damaged mitochondria and
the overproduction of oxygen free radicals as we increased oxygen
concentration and no one had saw that before because no one has a microscope
inside a hyperbaric chamber so these are some novel observations and
I needed to explain them and it led me it connected me with several people
including Tom Seifert at Boston College and I read his review shortly after
connecting with him cancer as a metabolic disease which he published in
nutrition and metabolism and then he's got a book by the same name cancer as a
metabolic disease I have published at least seven articles or studies with Tom
Seaford and we work together in different capacities but he explained to
me the Warburg effect which I had taken cancer biology in college and I had
never heard of it before that cancer mitochondria or cancer metabolism is
fundamentally different from metabolism of healthy cells so essentially the
Warburg effect in one sentence is damaged mitochondrial respiration and
there's compensatory fermentation so the basic energy processes that allow a cell
to maintain its bioenergetic potential would be oxidative phosphorylation the
mitochondria is making about 88 to 90% of the ATP the energy currency in the
cell in neurons and heart and skeletal muscle – and as the as a person or the
cells are exposed to a number of different agents they could be chemicals
radiation inflammation hypoxia insulin resistance and hyperglycemia produces a
very ripe ripe environment for the mitochondria to be damaged and the
mitochondria DNA to be damaged the nucleus has very robust DNA repair
mechanisms the mitochondria does not have as robust DNA repair mechanisms so
if a cell is bombarded with things like radiation or carcinogenic agents the
capacity for the mitochondria to repair itself is not as as high as
not as robust as the the nucleus ability to repair DNA so the mitochondria take a
big hit and as mitochondrial function is impaired by progressive damage to
environmental agents viruses for example can cause cancer and the viruses that
cause cancer impair mitochondrial function so mitochondrial function goes
down cellular ATP levels go down and the nucleus of the cell essentially can
sense the bioenergetic potential of the cell can sense the ATP levels and it
senses that the cells in an energetic crisis and when it's in when it gets to
this threshold I would say you know when you and every cell is different every
person is different I mean there's a lot of variables here but there becomes a
threshold where progressive damage to mitochondrial function causes a cascade
of events to activate a number of genomic pathways that stimulate the cell
to increase glycolysis and various eco genes are associated with increased
glucose metabolism so a normal cell then transforms and understanding to that
embryonic cells that are proliferating and growing fast also have a glycolytic
phenotype but normal cells that are not proliferating primarily get their energy
from mitochondrial oxidative phosphorylation when the mitochondria
are damaged by a number of different agents I believe that hyperglycemia
hyperinsulinemia mitochondrial syndrome is a major driver for this mitochondrial
damage when the cell transitions from an oxidative phosphorylation energy pathway
to a more glycolytic pathway through medic and real damage then there's a
point of no return it transitions from a normal cell to a healthy cell and it's
it's debated but it's not fully understood if a tumor cell can
transition back to a healthy cell generally we don't believe that that can
happen maybe in some cases it can but when a normal
when it's activated and an aquagenic program and drivers are kicked on it
becomes a tumor cell and there are a number of factors that can drive the
Warburg effect and actually make that tumour and expanding biomass to a large
solid tumor and drivers of the Warburg effect can kick on invasiveness and
metastasis where those tumor cells get in circulation and then metastasize and
then it becomes sort of an irreversible process so these are the drivers of the
Warburg effect and maybe I guess Tom Seaford would say the initiators of the
Warburg effect so the the metabolic theory of cancer sort of posits that
it's the initial damage to the mitochondria that's the enabling factor
that essentially transitions a normal cell to a cancer cell there are genes
involved no doubt but the metabolic control of those genes is likely sort of
the root cause and now the geneticists you know in years past it was really
just linked to genetic alterations but now we have an appreciation and an
understanding and NIH directed research to understand how metabolism is
directing those gene pathways to actually initiate carcinogenesis and and
the factors associated with cancer progression to so damaged mitochondria I
believe in the theory of metabolic theory of cancer is the initial cause
and also a major driver there's a derangement of tumor metabolism tumor
hypoxia as a tumor expands as the biomass expands the core of that tumor
becomes hypoxic damages the mitochondria more there's more genetic mutations and
that the the inside of the tumor takes on a more aggressive Warburg phenotype
so it's literally fermenting sugar you know as as it grows and and really
people with advanced tumors if they look at the actual tumor the mitochondria are
defficient are structurally and biochemically abnormal and according to
Tom and some of the colleagues that I've connected with when it comes to
aggressive tumors they have never found a tumor that has what we would call
normal mitochondria so really the medic damaged mitochondria are really a major
driver of cancer if your mitochondria are healthy they call the shots healthy
mitochondria will keep a high bio energetic state of the cell high ATP
levels will enhance the fidelity of the nuclear genome such that DNA repair
processes will happen and preserve that genomic stability so that's a really
important point I think that Tom Seaford tries to make is that the ultimate tumor
suppressors are healthy mitochondria and there are different ways exercise
CrossFit ketogenic diet low carb nutrition intermittent fasting all these
things we know periodic caloric restriction enhance mitochondrial
function things like elevated insulin glucose lactate increased pi3 a KTM tor
pathway is a major driver for cancer there are drugs being developed that
target this pathway by Lou cantly for example one of our collaborators and
these drugs interestingly do not work in the context of a normal diet they need
to be used in the context of a diet that suppresses insulin signaling so the
ketogenic diet dramatically enhances the effect of these metabolically targeted
drugs to pi3 kinase inhibitors elevated Ross and inflammation so reactive oxygen
species overproduction kicks on inflammatory pathways which can damaged
mitochondria and really stimulate this you know carcinogenesis suppress anti
and tumor immunity so as the tumor pumps out lactate and and lowers the pH that
actually changes the micro environment to prevent your body from recognizing
that you have a tumor and the ketogenic diet increases cancer associated
immunity so it helps increase the vigilance of your immune
system to recognize cancer and to attack it through a number of mechanisms and my
colleague Adrian check at formerly at Barrow Neurological Institute had
studied that and and published on that so in getting back to how we can change
this idea of changing metabolic physiology to not only change brain
energy metabolism but to target the Warburg effect and there are there's a
seminal paper called the hallmarks of cancer and there are particular there's
eight things that sort of characterize the hallmarks of cancer and I'm going to
talk about that in the next slide but keep that in mind as I go through the
things that are associated with the ketogenic diet so we know that about
when we give exhaustion escy tones we can lower blood glucose by 50% there was
also a paper and exercise science study showing that the ketone ester beta
hydroxy butyrate mono ester can cause a 50% reduction in lactate we know that
glucose and lactate are major drivers for cancer growth and proliferation we
know that there's a reduced proliferation and glycolytic ATP levels
in the presence of ketones actually dr.

Fineman here published an article
showing that acetyl acetate or in the ketone bodies could decrease reduce
proliferation and reduce glycolytic ATP production and there is a reduction in
glutamine ce mec and various pathways associated with cancer cachexia so
ketones directly affect a number of pathways associated with muscle wasting
and that's a that's the project of my PhD student and Rakuten ik is really
studying sarcopenia and cancer cachexia so and this is the diet so this is a
diet and this is administration of a metabolite that your body makes is
really changing these pathways there's a reduction in proliferation and
metastasis and a reduction in a number of different inflammatory pathways and
drivers in as I mentioned my colleague Adrian check
looked at enhanced tumor associated immunity and the ketogenic diet caused a
dramatic increase in the body's ability to recognize cancer and this is this is
an animal models that particular study but they're studying in humans now and
it also has an anti a pop tonic effect and a anti-angiogenic and a pro
apoptotic effect so that's the ketogenic diet especially in the context of
caloric restriction or periodic caloric restriction kicks on pathways again that
associated with the body's ability to recognize and attack cancer and some of
the to the more interesting things have emerged in the last five years is this
the effect of ketone bodies working through epigenetic mechanisms so there's
epigenetic enhancement of cellular defenses that are associated with
preserving healthy mitochondria and perhaps extending longevity or health
span over time and and there was a study that I was involved in he was actually
published in Nature Medicine looking at the effect of beta hydroxy butyrate on
suppressing an inflammatory pathway associated with driving cancer growth
and that's the nlrp3 inflammasome so when that when that protein complex gets
activated it kicks on and elevates many different inflammatory cytokines
including things like aisle 6 and aisle 1 beta so ketone body specifically
without metabolic regulation specifically regulates and suppresses
that that pathway so again you can achieve this physiological state through
time restricted eating ketogenic diet the food that makes up the ketogenic
diet is very important in years past epilepsy clinics would give hydrogenated
fats in the form of a supplement called keto cow and just you know it was just
not it they would give Crisco so now there's a much greater appreciation for
the types of fats and how these diets are formulated it's also acknowledged
that the ketogenic diet does not have be as strict 90% fat as we once thought
so modified forms at the ketogenic diet I'm actually a form that I follow which
is about 75% fat is being used clinically now and there's a number of
drugs that I mentioned before mimic many aspects of nutritional ketosis and that
would be to deoxy glucose perhaps three bromo pyruvate the jury's kind of still
out on the utility of that drugs like Luna de mean that inhibit hexa kinase 2
metformin has a mild calorie restriction sort of effect metabolic effect and
we're studying that too and we've published some research on that
so we also published a paper with our colleagues in neuro-oncology at Moffitt
Cancer Center and the sort of the gist of this review this publication was that
the ketogenic diet could target the Warburg effect and then that it could be
a very powerful at least an adjuvant to the current standard of care for high
grade glioma and we're focusing on low-grade glioma probably only because
the the glioblastoma patients are taken up by the pharmaceutical companies
because they want to use their drugs so the only patients that really could we
could apply to do an NIH sponsored research would be low-grade glioma
patients that also gives us a bigger window to assess the efficacy of this
therapy because with high-grade glioma you know you got about a year but with
low-grade glioma you have more time to work with the patient and to work out
the kinks of the diet and maintaining that nutritional ketosis so so the the
message that we wanted to convey in this review which was you know co-authored
with with just conventional neuro oncologists and people who really didn't
even study the ketogenic diet but our research and some of those studies that
have been out there convinced them that this was a very viable approach
especially for brain tumor patients that have epilepsy they have seizures too so
they have two things that the ketogenic diet can work very effective for they
have seizures caused by the brain tumor and a rapidly expanding highly
glycolytic tumor so it just makes sense that brain
two more patients not all cancers are as responsive to ketogenic diet therapies
there are cancers like liquid cancers like leukemia lymphoma
testicular cancer these things are very responsive to the standard of care not
that they you shouldn't use the ketogenic diet but they should consider
the standard of care of the frontline approach but anyway with high-grade
glioma there is no effective therapy so we believe that a metabolic based
therapy should be the frontline approach and only under certain situations really
the standard of care be used but the slide that I showed you previously
really went through all the different mechanisms and clearly demonstrates by
published literature some of its animal model studies some of it some of it's
inhuman that nutritional ketosis or therapeutic Ito gets ketosis targets all
the hallmarks of cancer so when a drug company is developing a drug to target
cancer they're usually targeting you know invasiveness or angiogenesis
they're really looking to target a very specific thing like Avastin for example
of Aston just targets angiogenesis the ketogenic diet especially if it's
calorie restricted targets all these things so that's an important thing and
the last sort of slide that I have is a coming to the end is this sort of
scenario and this is research that my student who published in cell the cell
journal or review on the anti catabolic effects of ketone bodies and ruku t'nuk
whose type one diabetic uses nutritional ketosis to manage his type 1 diabetes
has did this review and is studying the effects of ketones and the lab and a
number of different animal model systems animal models of cancer cachexia but
also using something called lipopolysaccharide or LPS where we give
LPS create massive systemic inflammation and then we try to mitigate that with a
number of things including ketone bodies that using a ketone ester
so ketone bodies we know decrease nitrogen excretion it reduces alanine
mobilization so the major gluconeogenic amino acid would be alanine so alanine
goes down quite remarkably if you infuse
ketones and that was a human study where they IV infuse ketones and showed Ionian
goes down significantly in ancient one of the most interesting effects of
exogenous ketones is that it caused a dramatic effect at lowering your blood
glucose levels so in animal models in in rats for example that have a blood
glucose of a hundred and twenty to a hundred and fifty if you give ketone
esters to their maximum tolerable dose the blood glucose goes down to 30 or 40
milligrams per deciliter that's not changing their diet
that's just a ketone induced lowering of blood glucose so this has not been
published in humans yet this level this dose level I mean I've studied it my
I've consumed it myself and can show and can demonstrate that you know you ki can
get glucose levels down to the range where it just doesn't even read on the
meter with certain ketone esters so I think that's an important therapeutic
application and I know people are studying this now looking at insulin
resistance and diabetes but it stimulates muscle protein synthesis and
increases muscle regeneration and proliferation we know a co acetate does
the ketogenic diet has been reported to have anti kick x'q effects at reducing
pancreatic colon lung cancer and skeletal muscle catabolism in rodent
models so we're interested in partnering with the Moffitt Cancer Center to get a
clinical trial in humans putting patients on the ketogenic diet can be
difficult so they're very interested in supplementation I am interested in both
the ketogenic diet and then supplements essentially as an adjuvant to the
ketogenic diet but they're kind of resistant against using the ketogenic
diet so for future directions what we're really kind of this idea that we've
talked about and Tom safer and my colleague we've written and co-authored
a review on this talking about this idea of a pressed pulse approach where a
press therapeutic you know program would be a daily routine of maintaining a
therapeutic ketosis range of and Tom Seaford uses the glucose ketone
index if your glucose level is 3 milli molar and your ketone level is 3 milli
molar you would have a glucose ketone index of 1 if your ketones were if your
glucose was 4 and your ketones were 2 you would have a glucose ketone index of
2 we feel that keeping in to that 1 to 2 range if you look at all the animal
model studies especially for seizures it's extremely therapeutic and it knocks
down it hits all those pathways that I just showed you that target cancer
metabolism the drug metformin conceivably could be used continuously I
think Tom's severs a little bit resistant against metformin it may have
some side effects but exercise meditation these things can help you get
an ideal glucose ketone index which we know we talked about the metabolic zone
so you bring glucose down to the level of ketones and ketones up if you stay
within that zone we know experimentally in animal models and I think the human
data will show this and some of it points in that direction that you are at
the very least slowing taking the foot off the gas pedal of cancer growth for
the cancers that are responsive to that have the Warburg effect or have a
Warburg phenotype we say but that sets the stage for other other treatment
options to be used and our idea is to use them in an on and off fashion three
weeks on three weeks off the stand I am a proponent of standard of care chemo
radiation and immune therapy I think for many cancers these can be highly
effective and well-tolerated I've communicated with enough patients that
they get a much better response if they're on the ketogenic diet and and
the side effects are much less – if they're on the ketogenic diet hyperbaric
oxygen therapy we're just an animal model studies now but it's like the
studies that I showed you what I was doing 10 years ago when I was looking at
brain tumors and the cells and the mitochondria were exploding and the
normal healthy brain cells were not I mean that was sort of very convincing to
me that high pressure oxygen was far more toxic the cancer cells than they
were to normal healthy cells and we published that
observation neuroscience but really didn't package it as an anti-cancer
effect it was just like an interesting observation IV vitamin C and David
diamond turned me on to this that vitamin C is a glucose antagonist
vitamin C at high levels and millimolar concentration can be a pro-oxidant and
can actually drive redox chemistry it can drive the Hebert Weiss reaction and
Fenton chemistry and it redox biochemistry in a way that actually
stimulates reactive oxygen species production and oxidative stress so it
could be used as a pro-oxidant therapy with or without hyperbaric oxygen
therapy but I think it would work better with hyperbaric oxygen therapy and a
whole toolbox of metabolic drugs so we're doing these studies now in
preclinical animal models and we're looking at breast cancer brain tumors
and lung cancer we're looking at a variety of different things so here are
ongoing and future projects we have oxygen toxicity studies in rats and in
humans we actually have a registered clinical trial it's being conducted at
Duke preclinical animal model work looking at press post therapies
preclinical cancer cachexia studies the low-grade glioma clinical trial that I
talked about is a future goal so we're repackaging in our o1 NIH proposal and
hope to get that that funded we have we're studying a syndrome called kabuki
syndrome which is a rare genetic disorder and in the context a kabuki
syndrome we believe that beta-hydroxybutyrate
is an epigenetic therapy so it's actually stimulating a set elation and
it's modifying the histones ability to activate various DNA components to
therapeutic ly treat kabuki syndrome and this was a we got the mouse model from
Johns Hopkins and we have some encouraging studies going on now we have
a clinical trial with Angelman syndrome with Vanderbilt and I didn't have much
time to talk about it today but the NASA extreme environment Mission Operations
is sort of the big project that I'm sort of
moving towards and allocating more effort into basically moving our
research or laboratory research out into an operational setting where we look at
the gut microbiome we look at strength we look at body composition we do
metabolic measurements psychological measurements we look at sleep heart rate
variability stress all these different things so I'm really excited about that
we recently got DARPA funding for the next mission to study that and I really
have to give a big thank I mean I I'm here presenting it but it's really the
students the postdocs and the research associates that are in the trench doing
the work allowing me to be here today and and that includes a long list of
growing people including Christy who's here today in the audience she helps out
in the lab many different projects and helps to maintain our website – and my
wife she has another lab in psychology and she's not at the College of Medicine
anymore but she's on main campus and she's actually she has resulted she has
done a lot of publications over the last couple couple days I think more than
half of my publications over the last year are primarily result of her efforts
I have all the different references here to point to different the research the
science that I talked about a number of different books I want to highlight
tripping over the truth Tom Seaford's book cancer as a metabolic
disease it's really heavy reading so if you want a little bit lighter reading
with a narrative if you really want the science cancer as a metabolic disease is
an amazing book that really is a tremendous effort
I mean Tompa is heart and soul into that book and it really encompasses a lot of
cancer biology and cancer metabolism tripping over the truth I had the honour
of writing the foreword to that book and that Travis Kristofferson he has another
book coming out in the next month called curable so start looking for his other
book coming out and my last slide I'd just like to thank everyone for your
attention and it's the last talk of the day
and like to thank my assistant Christy for maintaining keto Nutrition RG it's a
website where a lot of the stuff that we do is there she maintains a blog we have
nutrition consultations and we blog about a lot of different subjects
different publications that we like to to basically take recent articles and
package them in more layman's terms to make it accessible to the public so they
have more information easy to digest information about nutritional ketosis
and thank you for your attention

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