Hey everyone, welcome to the Drive

Podcast. I'm your host, Peter Aia.

Hey Dom, thank you for making the trip

out to Austin. It's uh boy, it has been

a long time since we've been in person.

I I'm I'm afraid to uh to hazard a guess

as to when, but I know you and my

brother see each other a lot more, and

I'm always getting pictures of you

visiting him and him visiting you.

>> Yeah. Yeah. Paul's amazing. Yeah, he uh

he's a mentor to me and as you are in

through the health and Paul's like an

amazing you know entrepreneurial mentor

and a life mentor in many different

ways. So but great to see you both and

uh you guys are such you know uber high

achievers in different domains and I

think it's great to see you know it's

great to see you in person for one thing

but it's great to see both of you thrive

in doing what you do. Well, the same can

be said for you. Um, Dom, you've been on

this podcast a couple of times, but I I

know that in podcast land, uh, it's a

we've probably got, you know, hundreds

of thousands of listeners today that

weren't listeners, you know, the first

and second time you were on the podcast.

Um, and frankly, those that were, I

think it would be understandable that

they've forgotten most of what we've

spoken about. Um, and maybe just by way

of background, I'll I'll let folks

understand how how you and I connected.

I believe Ken Ford connected us back in

2011ish

thereabouts. Um, at the time I had was

about a year into experimenting with a

ketogenic diet. Um, having all sorts of

interesting success with it for the most

part once I once I got over the hump of

figuring out how to do it. Um, and I

think we must have connected at uh at

his institute and then the rest is kind

of history. We we then through our

friendship became very uh deeply

involved in the testing of the earliest

generations of um various forms of

synthetic ketones. A topic we will

undoubtedly get to today because it's

impossible to imagine how much

proliferation there has been of these

things that were I mean literally you're

sending me like dirty plastic bottles

with stuff in my kitchen that I'm

experimenting with and and it's like now

look at what you've done. Um so maybe

let's just talk a little bit about how

your interest in this space came to be.

So um for for even for my recollection I

don't recall your PhD was in

neuroscience if I'm not mistaken.

>> Yeah. Uh nutrition and then at the time

studying nutrition and biology I started

doing u a undergraduate thesis project

in neuroscience and the neural control

of autonomic regulation. So specifically

the brain network the rostal vententral

lateral medela. So they are the brain

stem network that controls respiration

uh so inspiratory neurons expatory

neurons and how they respond to oxygen

and uh CO2 and that led me down the path

of oxygen hypoxia hyperoxia hypercapneia

extreme environments and what what

happens to the brain under oxygen

deprivation and nutrient deprivation. At

the time I was interested in alpha L

polyactate because it was in cytoax

which was something I used because I

race mountain bikes. So I was testing

some things uh lactate and then I got

steered onto the ketogenic diet. uh

after getting a fellowship a a post-doal

fellowship by the office of navy

research which is part of the department

of defense to understand the cellular

and molecular mechanisms of central

nervous system oxygen toxicity which

manifested seizures. So I was mostly

interested in drugs but then I pivoted

and went back to the ketogenic diet

because the ketogenic diet works for

many different seizure disorders when

drugs fail. So I was like, "Oh, I can

get nutrition back." Although I was

gravitating towards a tenure track

position and everybody told me this is

like the dumbest thing to do to like you

can't get NIH funding with, you know,

ketogenic. Nobody heard of the ketogenic

diet.

>> What year was this? Uh this was around

200 uh five I started tinkering with

ketones but 2007 I started writing

grants and then I hit on a grant in 2008

like post-doal uh grant and I was I had

a weird position from posttock to

something called a research assistant

professor which is like an intermediate

position before you get into a tenure

track and the university was just kind

of gauging to see my productivity and uh

as my post-docctoral grant was very

sizable it was above like an NIH level

grant which I was getting and it paid

full indirects for that and we can talk

about you know

>> and that came from the military.

>> Yeah. Office of Navy research as part of

the department of defense and then uh

and then I got good data on hyperbaric

atomic force microscopy very mechanistic

research. I also did patch clamp

electrophysiology and conffocal

microscopy.

uh my work was really focused on redux

mechanisms and looking at super oxide

production undergraded levels of oxygen

and different different metabolites.

So in the process of doing all that I

had no interest in cancer but we had

some glyobblastoma cells and we threw

them into the hyperbaric chamber and

under uh under conffocal microscopy we

could see the mitochondria were lighting

up and then kind of exploding or

disappearing uh in the cancer cells and

that was kind of unique and uh and that

led me on a side tangent thing to study

cancer but my central thing that I

studied was neuroscience and I've always

I've been in neuroscience department and

just mainly focused on that.

>> Let's go back to something you said at

the outset just because folks might not

understand why the Navy would be

interested in the effects of too much

oxygen, right? When you think of the

Navy, you think of being underwater.

When you think of being underwater, you

think of oxygen deprivation. So, what is

it about certain types of diving that

actually bring about the opposite

problem?

>> Yeah, good question. Uh so hyperaric

oxygen you experience that with

hyperbaric oxygen therapy right and

there's 14 different FDA approved

applications and that you in that

context you only go to about a maximum

of 2.5 to three atmospheres of pure

oxygen in the context of military diving

like a Navy Seal use a closed circuit

rebreather because there's no bubbles so

there's a stealth component to that and

you're breathing uh high concentrations

of oxygen And at at 50 feet of seawater,

the potential for oxygen toxicity

exists.

>> And just explain tools. Sorry, Don.

Explain to folks exactly what that is.

So, how does a rebreather work? What's

the concentration of oxygen that they're

breathing in?

>> Yep. So, uh a closed circuit rebreather

for example, like a drager rebreather

like the original ones, uh those early

rebreathers and even now it's high

concentration. It's like a essentially

100% oxygen, right? You're breathing

100% oxygen. So there's no nitrogen.

There's 80% nitrogen air we're breathing

right now, right? Uh there's no

nitrogen. So you avert the potential for

nitrogen narcosis. So nitrogen's not

narcotic at one atmosphere, but there

you get something called the martini

effect. And as you go down lower,

nitrogen becomes narcotic. So that's

something else that we study. But uh so

you're breathing 100% oxygen and uh and

then there's a CO2 scrubber. So you're

blowing out the exhaled carbon dioxide

is scrubbed out from the breather and uh

and that keep it's a closed circuit. So

there's no offging associated with uh

scuba diving or even other types of uh

technical diving where you have some

offging, right?

>> And the reason that they can do that is

because you're not wasting gas on the

80% nitrogen. You basically you're you

basically just have to store the CO2

that's coming out once you've scrubbed

it. you've got pure O2 coming in. So

your title your your volume of air

needed is much lower cuz you're just

solving for the oxygen.

>> That's part of it because the oxygen

tanks are are pretty small, right, with

a rebreather. But uh it's analogous to

uh we have a couple ponds on our

property, right? And I I uh when I go in

the pond and uh and I see bubbles coming

across the pond, I know an alligator is

coming towards me, right? So that's how

I when your brother was there, we were

like we were looking at the alligators

and and just uh getting them to come to

us by throwing pebbles in there when

they hear something. So if I go to the

lawn to the pond with a weed whacker, I

see bubbles coming across. So analogous

situation would be a Navy Seal coming

across a body of water that's still you

can clearly see the bubble trail coming

to you. So with a a closed circuit

rebreather that completely averts that

the bubble trail and then there's also

the noise that the bubbles make, right?

So you don't have that. The problem is

if you're wearing a closer and you dive

down to a 100 like 100 feet of seawater

because someone starts shooting at you

or you have to go down deep to put a

mine on the bottom of a bridge or

something like that, you're going to

have a seizure within like 5 minutes. So

oxygen is a stimulant. It stimulates a

massive amount of uh glutamate release

that activates amperceptors, NMDA

receptors. uh it stimulates the neural

network um in ways. It also sort of

deactivates or inhibits an enzyme

glutamic acid decarbox which converts

more glutamate to GABA. So there's like

uh a and there's a big burst in reactive

oxygen species. So you have a

constellation of things going on in your

brain. So I study the negative effects

of high high oxygen which kind of has

some people who study hyperbaric oxygen

a little bit standoffish towards me

because I study the but in the context

of lower oxygen oxygen uh hyperbaric

oxygen therapy can be very therapeutic

and

>> I do want to talk about that. So um

there's a lot I want to ask you about

hyperbaric oxygen but I want to finish

the swing on this particular

application. When was it clear to the

Navy the problem that you described,

which is when we have um closed circuit

rebreathers with 100% oxygen, we're

running into problems with our divers.

And it these problems are dramatic. I

mean, if you have a seizure at 100 feet,

you're going to die pretty quickly. So,

when when did they come to realize this?

And and how is this was this a

relatively recent discovery?

>> No, it's not. And my mentor, Dr. J.

Dean, our lab is like a museum. So we

have all the historic pictures on there

and there's a guy that wrote a book and

his name was Fred Bear and uh he was a a

French physiologist and uh he did a lot

of seinal studies back you know over

well over a hundred years ago in the

1800s showing that like you could give

animals uh they called it like uh

quesons disease too. So that could when

you go down in like chambers when you're

building a bridge you're under high

pressure oxygen or high atmospheric uh

effects. So yeah, I would say about 150

years ago, we realized that oxygen was a

stimulant. We didn't know why. And uh

and then with military diving, then you

have the problem of, you know, averting

oxygen seizures. And there's a number of

people in the Navy. Frank Butler comes

to mind, Claude Pianadosi, Richard Moon.

There's there's a network at Duke

University which did a lot of the

seminal studies and uh and that of and

they established the dive tables for

preventing oxygen toxicity, seizures,

nitrogen narosis, high pressure nervous

syndrome. So these are all things that

you have to avert like when you're

diving depending on what kind of diving

you're doing. Was the Navy coming to you

to say, "Look, we know this is

happening. Can you help us push the

envelope?"

>> Yeah. Well, I kind of went to them or

they came to me because I'd like

specialized knowledge, but I wrote

grants uh to to really delve into it.

It's unknown why these seizures occur,

but it gives us a lot of insight into

the brain to understand it, right? From

a redux effect, from a neuropharmacology

effect. So the grants that I had were

literally called you know uh

investigating the cellular and molecular

mechanisms of CNOS oxygen toxicity and

they kind of gave me unlike the NIH they

gave me like I had a lot of tools to

play with that were really expensive

that we got through what's called a a

DoD Durup grant and that bought chambers

and microscopes and electrophysiology

equipment and I was it allowed me to

tinker in the lab and in the process of

tinkering we just had some serendipitous

discoveries, you know, with the cancer

things and then just fundamental effects

that happen in cells under high

pressure, oxygen, you know, nitrogen,

helium, different gases and just very

basic uh so the office of navy research

has a 6.1 program and that's like basic

science and then 6.2 2 6.3 and as we as

I progressed in my career I started

working up from you know a cellbased

system to animal models to then it went

to a pig model system and now now

essentially we're doing the rat studies

at Duke with human subjects that get

inside a chamber and there we get

diaphragmatic we get EEG we have a line

going into their arm that goes to like a

mass spec to get like blood gases to do

metabolomics

uh they're working a simulator a flight

simulator they're exercising thing

they're it's water out immersion so

their body's underwater but you get the

the hypovalmic effect of the fluid shift

and things like that to simulate that

dive and then we push them to a seizure

believe it or not so this got approved

through an IRB which is even more

amazing than the Khill study uh but we

push them to an EEG seizure to where we

can see the se and then we decompress so

we look at latency to seizure under

ketosis dietary ketosis or supplemental

ketosis or the combination. So those

those clinical trials, I'm

co-investigator on it because it's being

done at Duke. Uh they're registered

clinical trials on clinical trial.gov.

So you can look at look at that.

>> And these are being funded by the DoD.

>> Uh Department of Defense has Office of

Navy research. They have the CDMRP which

is congressionally directed medical

research program and also NAVC. So this

is uh an ONR project that got spun into

a NAVC project. So naval, you know, uh,

sea command project. So NAVC is more

human studies and then ON&R is basic

science and then some human research.

>> All right. Well, I want to come back and

talk about a lot of these things, but I

feel like we should now kind of get

people up to speed on

>> what ketones are. Again, we we can sit

here and talk about this and take this

stuff for granted all day. You obviously

threw around the term nutritional

ketosis. You've also talked about

supplemental ketosis, sometimes referred

to as exogenous ketones. Let's start

with nutritional ketosis and just give

people um some definitions of um how you

achieve it, how much variability there

can be in a diet to get there, what the

thresholds are, and a little bit about

what's happening physiologically.

>> Yeah. Uh before I before I begin, I want

to direct people to your early blogs,

which I assume are still up on

nutritional ketosis.

>> I'm sure they are somewhere.

>> Yeah. on the delta G, there's one with

exogenous ketones, you know, and our

study we kind of did with the ketone

salts, which increased your uh

efficiency, oxygen utilization. So,

nutritional ketosis, uh the key to well,

let's take a little bit of a step back.

Ketosis, uh I like to start with

fasting. So, when you stop eating,

right, you suppress the hormone insulin,

you mobilize fatty acids for fuel. The

brain's not a good, it can't use the

longchain fatty acids that are stored in

your atapost tissue. So through beta

oxidation of fatty acids in the liver uh

beta o accelerated beta oxidation in the

context of insulin suppression generates

these molecules beta hydroxybutyrate and

acettoacetate and then they spill into

circulation and uh they become largely

responsible for preserving brain energy

metabolism in the context of

uh energy deprivation or carbohydrate

restriction. So and the elevation of

beta hydroxybutyrate or acettoacetate in

the blood in the urine or the breath

becomes a biioarker. So uh for ketosis

so you can achieve ketosis through

fasting through diet through supplements

or uh alcoholic keto acidosis right

that's another thing or diabetic keto

acidosis and we could talk about that in

context and then you have nutritional

ketosis which is eating carbohydrate

restricted ketogenic diet that's

primarily high in fat. The original diet

was 90% fat. modified versions of the

diet are about 60 to 70% uh fat with

higher protein. Now, we know especially

in kids, you restrict protein too much,

you could stunt their growth and have

some issues there. So, clinically, a

modified version of the ketogenic diet

is actually being kind of gravitated

more towards even in pediatric epilepsy.

So, we're learning that protein is

really important and it was

underappreciated, I guess, in the early

ketogenic diets. In the context of

sports, it's extremely important and we

can talk about that. So but still it

remains that uh the ketogenic diet is

the most scientifically researched diet

that has an objective biioarker that

defines the physiological state of being

in the diet and that's beta

hydroxybutyrate above 0.5 mill moles per

liter. So that's clinical ketosis and in

the context of ketosis it has um uh

there are remarkable changes in our

metabolic physiology and the

neuropharmacology of our brain and also

beta hydroxybutyrate has very unique

effects uh epigenetic effects which is

kind of a new buzzword that people are

talking about and we we my student just

finished a project on that um and I

think there's uh it's pleotropic so

ketogenic diets have pleotrop ropic

effects and uh

>> tell folks what that means.

>> Yeah, plyotropic is kind of like a fancy

somewhat nebulous word that basically

means there are multiple mechanisms that

are activated uh biochemically,

physiologically, neuropharmacologically

uh that have beneficial effects. So um

and I can go through the explosion of

research that has occurred on PubMed and

clinical trials.gov, gov. But the

important thing is that uh nutritional

ketosis or therapeutic ketosis uh or

let's take a step back. The ketogenic

diet, some people say the ketogenic diet

is not magical. The kid does nothing

magical in the context of body

composition alterations or fat loss.

That could be there's truth to that.

However, I I I say there's a hard stop

there. The ketogenic diet is indeed a

magical diet in the way that uh it

remarkably changes our physiology and

there's no other diet uh that exists

that can for example manage drug

resistant seizures and it does that

because it profoundly changes our fuel

system, our physiology, our biochemistry

and our neuropharmacology.

>> Let's talk a little bit about that.

You've mentioned it a few times now. Um

so let's help folks understand what's

going on here. So this was first um

identified in kids and if I'm not

mistaken um

>> well adults actually if you go back to

yeah like the Mayo Clinic in 1920s

because there was no drugs for epilepsy

so we

>> so what gave them the idea

>> that hey we've got these people that are

experiencing this awful thing now they

had EEGs back then but they really

didn't know much

>> true yeah they actually did some really

good physiology back in the 1930s4s

underappreciated uh well we knew that

fasting controlled seizures Right. I

mean like that was the first

observation.

>> Yeah. I mean gospel of Mark talks about

yeah fasting I mean there's it's all

over like in the literature fasting

could control seizures. So a ketogenic

diet by virtue of elevating these ketone

bodies which were showing up in the

blood and the urine and even in the

breath. Uh they just understood that

these ketone bodies were somehow

associated with seizure control and we

did not have anti-seizure drugs back

then.

>> And when were these first identified? So

you've got Banting and Best identify

insulin or at least isolate insulin in

the 1920s. So that's really the in my

mind I think of that as kind of the

golden era of metabolism.

>> Um when were ketones first isolated BHB

specifically?

>> Yeah, just uh within a decade around

that time. So yeah, so around with

Banting and Best uh kind of discovered

it in the context of diabetic keto

acidosis and then work at the Mayo

Clinic by Wilder and a few other people

were helping uh sort of established the

framework for what would be ultimately

the first ketogenic diet kind of kind of

therapies. And the thing was just eating

like all fat. And then we realized we

got to titrate in the protein to prevent

protein malnutrition. And then there was

a tiny in 1921

there in a clinical it was just like a a

a side note on a on a clinical journal

there was the first observation or

clinical report of a ketogenic diet you

know used in epilepsy and the remarkable

effects and we didn't have anything to

we didn't have

>> and they didn't understand why

>> uh they mechanistically I mean we could

go you know a hundred years later and we

don't fully grasp and understand all the

mechanisms involved and that's why it's

such a fruitful robust area of research

right now with drug companies scrambling

to mimic the keto if we had a drug that

would mim mimic the ketogenic diet it

would be a blockbuster drug

>> because if I understand correctly Dom

>> if you take patients if you took a

hundred patients who are drugresistant

so they're having non-stop seizures

despite all the best available

pharmarmacology my recollection this

could be incorrect And you can update

this

>> is that a ketogenic diet will completely

cure onethird of them will cause about a

50% reduction in seizure activity for

another third of them while onethird of

them will still be unresponsive. Is that

still directionally correct?

>> Yeah. In the context of pediatric

epilepsy about twothirds will be so it's

that high

>> two-thirds will be

>> twothirds will be uh therapeutic

therapeutically responsive uh to a

ketogenic diet therapy for managing

seizures are are highly efficacious for

managing seizures. Twothirds of people

who have failed drug therapy and not

we're not just talking about one drug

we're talking about polyfarm pharmacy

adding multiple drugs like you know uh

the list goes on.

>> And what about adults? Uh so in adults

it's more about closer to

post-adolescence about 30 to 40%. Uh but

then it's thought that at adherence and

compliance right with adolescence with

kids the the parents feed you know

usually a ketogenic formula and

calculated out.

>> Uh but there's also something about the

pediatric brain that's probably more

responsive. And then of that 2/3 about

onethird have like uh complete like

seizure control like more than you know

95 to 100% seizure control and then like

10 to 15% and this really interested me

uh when I went to the first conferences

back maybe 15 years ago were super

responders meaning that they could get

on a ketogenic diet follow it for a year

or two transition off and never get

seizures again.

>> Wow. So that so they talked about the

ketogenic diet being curative and that

was really interesting to me. Of course

the brain is changing as you go through

development but it was shifting brain

networks and network stability uh you

know suppressing inflammation and

changing neurotransmitters in a way that

was there's the kindling effect with

seizures. So seizures beget seizures. So

once you have a seizure uh you're more

likely to have another seizure. So if

you control seizures and you do it

through a protracted time frame, even if

you had it's going to lessen the chance

of you, it's going to decrease that

kindling effect. So um so there's

something going on there and we've

replicated that just throwing you know

sodium beta hydroxybutyrate into a

hypocample brain slice preparation under

different levels of you know things that

stimulate seizures like measuring

seizures in a in a slice with like the

orthodromeic population. uh you can

stimulate and measure the orthodic

population spike of the neurons like uh

firing back and then you can decrease

the amplitude of that over time and

essentially just silence seizures in a

slice and at the same time you're making

that hippocample brain slice more

metabolically resilient. You could throw

different agents at it that would be

neuro degenerative or you know uh

hyperexitable and it will protect it

under the context of various

neurotoxins.

So uh so that I think that that really

interested me. So the early observations

and then I was completely unaware of all

this literature in my posttock and then

when I started delving into it I was

like I have to change the trajectory of

my career to do you know to to just but

I'm going to do it in an innovative way.

I'm going to study the ketogenic diet,

but also in parallel or in tandem or

maybe in some cases exclusively just

delve into what is the most efficacious

form of exogenous ketone we can use and

how can we can it augment the

therapeutic efficacy of a ketogenic

diet? Like there's a lot to unpack here

and nobody was doing it at the time.

>> You've obviously experimented a lot with

a ketogenic diet yourself. I mean when

did you first try a ketogenic diet? like

the clinical ketogenic diet where I got

the little cardio check meter which was

super expensive at the time. I would say

2009 I started actually checking ketones

and uh and the cardio they still had

this cardio.

>> I was using the Abbott one.

>> Yeah.

>> Precision the precision. I got that

later. I don't even think that might

have been out yet, but I got that soon

after because the cardio check actually

did like your HDL and like triglycerides

and things. It was a little bit. We

compared it to uh we also had like an a

lab assay like an Eliza assay. Yeah. We

were comparing it to it. Uh yeah. And

then we got uh the the precision extra

by Abbott. And then I remember I bought

something like $10,000 of strips.

>> I was about to say the strips were $5 to

$10 each.

>> Yes.

>> At the time

>> I found uh I bought them in bulk and I

think

>> Yeah. You hooked me up at one point and

we were able to get them for like a

$1.50 or something. I was going through

three a day. Yeah.

>> Yeah. So, uh that price point has come

down, but now we have the Keto Mojo

which is actually uh aligns more with

our assays and and it does the glucose

ketone index that we can talk about. Uh

yeah, so I started doing that and I have

to when I started it within I guess 5

years after starting the ketogenic diet,

I probably rapidly lost 10 to 15 pounds

and then my my exercise and my lifts

tank too. Like I lost strength on bench

press and not so much deadlift and

squat. But I saw that but I didn't

really care that much at the time. But I

also learned the lesson that protein was

really important. I was thinking ketones

would be basically save you know muscle

and but they don't they have an

anti-catabolic effect that we can talk

about but there's nothing you know if

your protein goes from like 250 grams a

day to like you know 70 to 80 grams a

day you're going to lose a lot of muscle

and the ketones have

>> just don't tell the USDA that or you

know the the RDA they still want you to

believe that 08 grams per kilogram uh is

all you need

>> it's very context dependent right to I

was kind of in the gym and I was even

training with legally facitious. I mean

these these guys are out to lunch and

they just can't seem to they just want

to cling on to this idea that protein is

bad.

>> Yeah. I they're avoiding like uh work

from Donald Layman and Stu Phillips and

guys I think you might have had on the

podcast, right? So uh yeah, I learned a

lot of lessons. I learned that uh uh

clinical ketogenic diet skyrockets my

LDL and APOB and that's an I've learned

how to manage that pharmacologically. I

have a mutation for the MPC1L1 receptor.

So, a tiny dose of a zettoide brings

that down. But most importantly, I

realized that titrating the protein in

to meet whatever to to meet, you know,

your your needs for protein. And if

you're an athlete, if you have a high

metabolic rate, if uh you're trying to

gain muscle, you know, you do have to

leverage protein and that becomes the

key factor. I think the key variable in

getting the ketogenic diet to work for

you and also tracking your lipids is

really important.

>> What do you think are the most common

mistakes people make when they're trying

to um uh enter nutritional ketosis? What

what would be the top three or four

mistakes that people are making?

>> Yeah. Not tracking. I mean, people do

it. They're just like, "Oh, I'm just

going to eat, you know, this or that and

not try." It's like, uh, no, you need to

like just write. You don't have to do it

every day, day in and day out, but you

know, use a good tracking metric. Uh,

Carbon app is great. I know you've had

Lean on. I've used that.

>> And there's other apps out there. The

>> app tracking because you want people to

be able to correlate the blood levels

they're seeing with what they're eating.

>> Yeah. So, the macronutrient uh ratios

and the composition, but also the total

amount of calories, which at the time

when I get into this, no, everybody was

said, you know, if you do ketogenic

diet, you don't have to try calories.

Calories don't matter. But we know

that's like I just knew that was BS to

begin with because there are some people

who can easily overeat on a ketogenic

diet. You know, I could sit down with a

bag of of macadamia nuts and polish the

bag off or sour cream or heavy cream or

whatever. So, it's easy to do. So, yeah.

Uh track total calories, macronutrients,

track your blood ketone levels. Uh you

could do urine or breath, too.

>> Are there what what is the

state-of-the-art on urine and breath

meters these days? Yeah, I I you know,

with the breath meter, I do think that's

pretty legitimate because breath acetone

correlates with seizure control. There

was the Biosense device, but uh they've

kind of fallen out of favor. There's a

device called Keto Air that's pretty

good. It's a small, it's like the size

of a pen,

>> and that actually correlates really well

uh with some of the blood ketone

measurements. I do notice that if I'm in

a calorie deficit, my blood uh ketones

are can be very low, but my breath

ketones are high. And I think your

ketone production that you're measuring

is a consequence of ketone production

and ketone utilization. And in the

context of uh an energy deficit, your

tissues are sucking up ketones out of

your blood fast, but you're blowing off

more uh acetone. So your your blood

ketones are and I think you maybe made

some observations of that too with with

differenti you know under

>> also under high utiliz under high

exercise low like normal exercise

supernormal exercise fasting etc.

>> Yeah.

>> Um and then urine uh people I I mean do

>> people still use it.

>> Yeah. But but you know my my view back

at the time was I was never going to get

better precision than using blood.

>> Yeah. blood's still the gold standard

and there's a lot of uh uh and then you

have interstitial right so I just

switched out I was wearing a continuous

ketone monitor and

>> how many companies make those now

>> well Abbott makes one I can't use it

because they use test flight software

and I have an Android I'm the guy that

has the Android uh so I can't use that

but uh I've sort of done you know uh I

been involved with the company a little

bit and just you know had some calls

with them I know I think you have maybe

two involved with them. Uh, but there's

a company

>> I have no involvement.

>> Okay. Uh, yes, but just disclosed, I

don't get paid by them or anything, but

there's a company that's in China and I

think now they have a footprint in the

US. They're called Sai Bio.

>> And I am very impressed with Sy Bio. So,

the first week the ketone measurements

are very accurate, but the last week

they tend to measure about only half of

what you measure in blood.

>> So, it's a it's a device. Is it micro

needles or is it a long filament? looks

exactly like a CGM device. Uh, uses

essentially the same technology, just a

different enzyme. And, uh, you know, I

could swim all day in salt water. I can,

you know, do stuff on the farm. I don't

knock it off. I It's like probably as

reliable as a CGM device now. It's

remarkably reliable. Uh, the specificity

is good and

>> and it's BHB.

>> It's beta hydroxybutyrate. Yeah. It's

important to uh acknowledge that it's

the D anantimer or the R anantimer of

BHB because there's supplements out

there that are recemic. So you can uh

but yeah I've tested it you know uh

pressure tested it if you will with high

doses of ketones and it it performs well

and so there's emerging technologies. So

the continuous ketone monitor continuous

lactate monitor which is I think it's

going to be lactates and ankome

metabolite.

>> Does anybody have one of those

commercially ready yet?

>> Not commercially ready yet. There's

programs, but I don't think monetarily I

don't think the companies are motivated

to bring it to market. And I think

there's some more testing that needs to

be done. But for example, my colleagues

at the Moffett Cancer Center, you know,

they're like salivating over the the

opportunity to do glucose, ketone, and

uh lactate monitoring especially, you

know, I mean, we see that tumor burden

is tightly correlated with blood lactate

levels. So we use lactate monitoring and

that and if you have an expanding mass

of like metastatic cancer like it just

correlates very nicely and lactate an

metabolite that should be measured.

>> So if mistake number one is you're not

measuring your actual ketone levels and

you're not tracking what you're eating

so you can see the association of hey

when I ate this it went down when I ate

this it went up. Um what are some other

mistakes people make with their diet

formulation? Is it too is is that they

typically airing on the side of too much

protein, not enough protein? Are they

not realizing where carbs are sneaking

into their diet? And and what kind of

guidance do you give people? How many

grams of carbs a day do you tell

somebody? Or do you vary that based on

their activity level?

>> Yeah, taking a step back. So, I view

unlike many people out there, I view a

ketogenic diet as a prescription

metabolic therapy. So that's the world

that I come from, you know, and then

there's like, you know, there's clinical

keto and then there's like internet

keto. So a a and which a lot of people

are following a low carb diet which has

a plethora of metabolic benefits. You

know, you just have to be up on your

blood work and you have to be very

vigilant with tracking, you know, your

biomarkers. Uh but a clinical ketogenic

diet is typically done uh with

consulting or advice or even following

the framework of for example a lot of

books out there by Eric Kasoff uh if you

have cancer Miriam Calamian has a guide

ketogenic diet for cancer. Uh so books

that are out there that tell you step by

step on how to do it. And from a

practical or logistical point of view we

had a small study we ran with Dr.

Allison Hall uh that looked at people

that were just uh they didn't have any

overt pathology but they were just like

take normal people put them on a low

carb ketogenic diet and over the

practitioners tell me that if you

transition a person over four to six

weeks they adhere to it better and you

actually get more favorable health

responses. You don't have a lot of funky

blood work that come back. You know, it

could be the electrolytes with people

that have certain mutations with fatty

acid oxidation disorders. Even ApoE4

carriers tend to like you'll see their

LDL go up and you'll see things like HDL

go down and you'll see they start the

diet and their triglycerides go up. Like

I, you know, I've seen that a lot in

quite a few people and I think there's

some genetics that need to be unpacked

there. Uh in several cases it was people

that were APOE E4 carriers like they're

homozygous. So I think there's something

to unpack there. they just don't uh

metabolize their lipid metabolism is a

little bit different. So I think it's

really important to get blood work,

track triglycerides, track HDL, APOB,

LDL, hemoglobin A1C, insulin levels. I

think I've seen people's insulins go up,

but generally speaking, 90% or 80% or

more insulin goes down. Uh but really

just to um to use there's so many

different guides out there and if you're

doing it to manage a clinical condition,

you should be working with a registered

dietitian that's savvy and the people I

recommend there's advanced ketogenic

therapies and it's a team of people and

it's kind of spearheaded by uh Denise

Potter. She's a registered dietitian,

but she was came from the world of

epilepsy and worked as a conventional

registered dietitian and then

transitioned to ketogenic and now has a

team of a half dozen or more people.

>> But if someone just says, look, I just

want to do this on my own just like any

other diet I might follow. What would be

sort of the guidance you'd give them?

>> Yeah, it depends, you know, why they

want to use it. Uh many

>> Well, I think the most common reason

would be weight loss, right?

>> Yeah, weight loss. Uh so I would say

calories are super important. So just uh

gravitate towards a high protein

ketogenic diet. And if it's just purely

weight loss, I would say high protein,

moderate fat, and then high fiber. So

the carbohydrates that you're getting uh

should be just fibrous carbohydrates. So

you can get 50 to even 100 grams of

carbs per day if onethird of those

carbohydrates are fiber. So that

excludes all ultrarocessed food, even

processed food. Like broccoli is about

1/3 fiber. So, if you go down the list,

there's about I think I have a list of

about 30 or 40 forms of carbohydrates

that are about like one/ird uh a quarter

to 1/3 fiber. So, if you're pulling from

that list, uh you're

>> so you've got you've got all your leafy

vegetables. You mentioned broccoli.

Would carrots be in there?

>> No. No. Broccoli, cauliflower, uh

carrots, no, especially if they're

cooked, they're high they can be highly

glycemic. Uh but avocado,

>> bell peppers. Yeah, bell peppers are a

little bit too high in sugar. They're at

the cut off point. Maybe like a green

pepper or something like that. But

generally things that you'd find in

like, you know,

>> cucumber.

>> Cucumber, yes. Um, you know, uh,

asparagus tomato is tomato. No, tomato

is like a fruit, pretty high in sugar.

>> So, these are things that you need to be

kind of vigilant and there's a lot of,

you know, go-to guides. And that's why I

think it's important to use like a

tracking app, right? And you don't have

to do it like I would never use Oh, I

use it now time to time if I want to

make adjustments. So, um, and and be

very v cuz one thing I noticed

especially using the carbon app or other

apps is that I was like I'm getting

about 3 3200 grams of of or 3200

calories per day, but when I put it into

these tracking apps, it's more like

4,000 calories per day. I,

>> you know, meaning you think you're at

32. Yeah. I always always underestimate

it. Uh probably because just fat is so

calorically dense, right? So the amount

of egg yolks and a lot of fatty fish.

This morning I had like three cans of

sardines. Each can is 20 grams of fat

and 15 grams of protein. And that's so

20 that's 60 grams of fat just from

sardines and extravirgin olive oil, you

know, and that's it adds up. It just

seems like oh this is like nothing. This

is like, you know, it's less than I

would have if I'm eating at home. But uh

it adds up. And I think that people that

are not losing weight or managing

whatever they're trying to manage with a

ketogenic diet, they need to track

calories and simple caloric restriction

or creating even like a 10 or 20% energy

deficit will be the big lever that's

going to cure 90% of what most people

are seeking the ketogenic diet for. And

you could do that.

>> So what's the efficacy then? So what why

do you think a ketogenic diet works? Uh,

do you think it works because under

conditions of caloric restriction, it's

more satiating than diets that are high

in carbohydrates?

>> Yeah, I mean, uh, three, just off the

top of my head, it's, uh, hyper

satiating, especially a high protein

ketogenic diet. It's hypo palatable.

Some people may argue that, but you're

not going to overeat a ketogenic diet

just because it doesn't have the hyper

palatability of a standard American

diet, you know. And I think it

fundamentally is changing metabolic

physiology and brain neuropharmacology

in a way that decreases appetite

regulation. So you know with a higher

protein diet, you're getting higher

GLP1, you're reversing insulin

resistance, you're improving uh fatty

acid oxidation and I think you're

fundamentally weaning your brain off

glucose. So your your brain has is

dependent on glucose with a standard

American and as you're decreasing

glucose availability your brain has a

counterregulatory

dysphoric reaction to that and as it

transitions into ketosis

uh you could avert a lot of this simply

by using ketone electrolytes right so uh

like the stuff that I gave you right so

the key to start so that's you know

electrolytes similar blend as element

but bound to beta hydroxybutyrate

consume that when you start the diet And

that'll largely mitigate two things.

It'll mitigate the electrolytes uh which

you dump a ketogenic diet has a

naturetic effect which means you dump uh

sodium and a diuretic effect. So you

have when you

>> let's talk about let's talk about why

those occur

>> and that's important because these are

the things that kind of really throw a

monkey wrench into some of the clinical

trials when people become you know their

electrolytes and they get dehydrated. So

it's important topic.

>> So when I stop eating carbohydrates and

ramp up my fat. By the way, I do want to

go back to sorry one other point. You

keep saying high protein. Can you define

high protein in this context? You talk I

mean are you talking high by the

standards of the RDA or are you just

saying like you know are you saying like

one gram per pound of body weight? Is

that sort of your guidance?

>> Yeah I mean historically you know 8 to

10 to 12% was used with ketogenic diets.

So, I'm talking about a ketogenic diet

that's 20 to 30% protein. So, that's

considered high,

>> but that's hard for people, I think,

sometimes. I mean, you can obviously

back calculate into that by the

calories, but do you find it easier to

just say, look,

>> keep your carbs at 50 gram and try to

get them from high fiber carbs, get your

protein to x grams, and then limit your

total calories to whatever 3,000 with

fat filling the rest. Um, in other

words, what is it typically working out

to in terms of grams per pound of body

weight in term in protein?

>> Yeah, in protein uh if me for example,

right? So, uh would be upwards of I'm

about 220 pounds. So, that would be uh I

know it sounds crazy, but you know, from

the average RD registered dietitian, but

220 grams of protein. Yeah. So, that

would be the upper end if I'm very

active. I mean today maybe I won't get

that or when I'm traveling

>> but that amount of protein I think uh is

the upper end. I don't think there's any

benefits to go above and be beyond that.

>> And at that level of protein you're not

undergoing so much glucanogenesis that

you're making too much glucose that's

offsetting the ketone process.

>> Yeah. Everybody's a unique uh metabolic

entity. So they're going to have a

different response. But for me

personally, uh especially having eaten 4

or 500 grams of protein, and that's not

I'm not exaggerating there. When I was

in my late teens and 20s, uh that works

for me. That level of protein works for

me. Uh for some people, especially if

they're going to jump from 50 grams a

day or the RDA recommendations to uh and

you want to do that to ideal body

weight. So if you have some

>> because the RDA for you is 80 gram.

>> Yeah.

>> Exactly. 80 grams. You're you're 100

kilos. Yeah.

>> The RDA recommends you have 80 g of

protein, not 220 g.

>> At 80 g, you would not be able to

maintain your muscle.

>> No, not not in my context. No,

definitely not. Uh the more muscle you

have, the more protein, they just have

much higher protein turnover. So, you're

breaking down protein, building protein.

That whole cascade is amped up probably

several times higher in the especially

if you're working out and breaking down

protein, you have a fast metabolism. uh

my recent uh you know resting metabolic

rate showed it was 34% higher. So I

don't you know I don't know give I I'd

have to do further studies but they

thought it was they wanted to redo it

and then they

>> that's even when adjusted for your lean

mass.

>> Yeah. Am I resting? Yep. So uh and I

don't know you know I'm I'm going to

redo it in about two weeks. I was also

off creatine and some other things. So

I'm reloading on creatine just started

and uh and gonna redo that again. But

yeah, my my lean mass is kind of I'm

pretty heavier. So I don't want to throw

that's the upper limit. And I think if

people you can gradually increase your

protein but I'm pro I've been very

vigilant now with my protein especially

after turning 50 that this is important

because things start to your sarcopenia

and the loss of lean body mass is almost

considerably higher you know as you know

like in your 50s and there's different

reasons for that but activity is the

main mitigator for that. So, if you're

providing a stimulus for your body to

grow and maintain muscle, you need uh

protein that's double the recommended

daily allowance. I think if you're

really going to be proactive about it,

>> any other kind of quick dos and don'ts

around things like fruit, berries, uh

artificial sweeteners, how do you think

about all of those things as they factor

into a ketogenic diet?

>> Yeah. Uh, I think fat and I tend to like

I guess carb backload at the end of the

day. I eat no carbs all day and at

dinner I'll have like a salad or

vegetables and then in the evening I

have wild blueberries which have like a

third of the the sugar of regular uh

raspberries, blueberries, wild ones. And

then I have like uh a keto mousse which

is just cocoa powder, chocolate ketone

powder and uh and some stevia or monk

fruit and cinnamon in that and it's has

no effect on my CGM. It actually goes

down. So uh I I found out what works for

me and as long as I am eating you know

fiber if the if the carbohydrates are

delivered with fiber there's really no

uh no glycemic you know counter effect

to that no spiking uh I have a short

list of foods so it's basically you know

berries broccoli

asparagus

dark chocolate like these are things

that I eat every day you know maybe not

the asparagus, but broccoli, berries,

dark chocolate, uh, and salads. And, you

know, that's enough. I'm kind of simple

and I keep things, you know, pretty

simple. I don't like even have, in the

past, I had a desire to have more

different kinds of foods. Uh, I enjoy

that. I mean, we were traveling in

Greece and I'm not going to, you know,

pass up all the great food like when I'm

traveling. Uh, and I ate as much

carbohydrates, you know, as whatever

they were serving me. and I came back

six lbs lighter because, you know, I'm

in and out of the water every day. I'm

walking out in the sun and things like

that. So, actually increasing tripling

or quadrupling my carbohydrate made me

lose six pounds when I come back. And I

was I thought for sure I was eating. I

know.

>> But how did you feel? Did you feel

different?

>> I felt I felt great. Yeah, I'm pretty

metabolically flexible. So I think

that's also a consideration

that if you really delve to into

carbohydrate restriction and your body

is completely fat adapted and it's like

carbohydrates are a foreign substance

and glucose spikes or you're going to

have uh sort of a a pretty big

counterregulatory effect once you start

getting bolining carbohydrates again. So

because you're changing your physiology,

you're changing enzyme. So your gut for

one thing is not going to tolerate that.

You know, just from like fitness

competitors when they diet and then they

finish competition and then they go out

and have, you know, like a cheat meal,

then they're up all night with gas and

bloating because simply if you start

with I mean I could go through all the

different systems, but the GI system

takes a big hit. The liver takes a big

hit. The glucose hitting the peripheral

system can't absorb it. So your CGM goes

off the charts and that can trigger

inflammation. That can alter like gut

microbiome. it's going to affect your

mood. Like these are wild swings that

yo-yo dieters go through. So if you're

low carb, you achieve your goals like

your weight and you want and you miss

carbohydrates, you can slightly just

titrate them back in and just uh just do

fibrous vegetables, just start with

that. And some people can't tolerate

that. But, you know, low fruits, most

people who have like an aversion to

plants or some immune reaction to them

usually can tolerate fruits. So before

we go to the exogenous or synthetic

ketones, I want to now ask you about an

even more uh extreme form of diet, which

I'm sure you get asked a lot about. I

know I do, and I have no insight

clinically, nor do I have any personal

experience with this. Let's let's talk

about this carnivore diet.

>> So I I I realize there are different

ways people go about doing this. There

are some versions that are incredibly

strict where you literally are just

eating meat and nothing but meat. And

then there are others where you expand

that into well you can eat other animal

products you can eat eggs you can have

dairy and things like that. Um but let's

start with just the meat only version of

that diet. Now

first of all what do you think is

happening metabolically? How does one

achieve ketosis with just meat? Because

even the fattest serving of meat, even

if you were eating just ribe eyes, I

don't imagine Well, I I suppose it's

possible that you could get 30% of your

calories from protein and 70% from fat.

So, does it does it produce a ketoic

state as well? Typically,

>> I had a ribeye the other night I think

would hit the keto macros because it was

a lot of fat and I was kind of annoyed

because, you know, there was like less

meat and more fat. But uh yeah, I I

think you can achieve ketosis with a

fatty carnivore diet, especially if

calories are restricted,

>> but you couldn't do it if it was a New

York strip or a fillet. You just don't

have enough fat in it relative to the

protein, right?

>> Uh you could if you were in a caloric

deficit. So if you're in an energy

deficit, right? So your insulin is going

to get like everything is going to get

kind of go in the right direction. So

and that's the issue. Uh I I'm a firm

believer that uh carnivore diets can be

therapeutic for people who have

autoimmune disorders. So that's pretty

clear. There's some people who

>> uh they could also follow a path and do

an elimination diet, but the carnivore

diet is the ultimate elimination diet.

So you're meeting your protein

requirements.

>> You're have enough protein to build

muscle. uh protein has pretty much or

you know um steak and an animal-based

protein diet has pretty much all the

micronutrients. I mean you could argue

you could argue maybe uh vitamin C and

magnesium but you do not see vitamin C

deficiency in people that are on

carnivore diets surprisingly. So there's

some vitamin C in like liver and stuff

too. So if you're eating nose totail

that's not something you have to worry

about. I've seen magnesium trending low

although we don't have the best

magnesium you know measurements but uh

or the blood work for but I've seen uh

magnesium being beneficial for people

because magnesium is something it's you

we get it from chlorophyll right it's

like the central molecule of the of

chlorophyll right magnesium uh and we're

not getting any of that really with a

ketogenic diet or very little

>> I mean you're getting a lot cuz you're I

mean I got a ton I mean I would I had

two salads a day when I was on a

ketogenic diet

>> I'm talking pure carnivore.

>> Yeah, I see. I see.

>> Like they I mean like we're talking

steak and water, right? Like not even

coffee, not even putting pepper on the

steak. Like there are a group of people

who believe that and it's working for

them and they have

>> they have a lot of anecdotal data, you

know, to support that. And I get I get

an inbox full of people that say, "Hey,

look, I had this condition or that

condition. I follow carnivore and here's

my blood work." And I can't argue with

that.

>> Yeah. No, I I I I would I find that

stuff pretty compelling from an

elimination diet perspective. And and I'

I've certainly met a number of folks who

who feel that way. And um yeah, I mean I

I think again it's quite binary. It

either it works or it doesn't. And for

many of these people, they're so

debilitated on any other form of diet

that it's a no-brainer. You're going to

stick with that type of restriction.

>> Yeah. The influencer voice is also

amplified. like Joe Rogan for example uh

had vitilgo and you know that's an

autoimmune disorder and I know people

who have that and uh saying it's the

only thing going on a carnivore diet you

know cured my vitilgo like so I have you

know people that are interested in that

so there's a wide variety of things you

know that it can be therapeutic for

there's a group in uh Budapest Hungary

called Paleo Medicina and I went to

their clinic and they pulled their files

and I saw everything from type 1

diabetes to cancer to different uh

different neurological disorders,

>> you know, and these are all but they're

showing me blood work longitudinally

over time and um could be cherrypicked

the cases, but it was pretty convincing

and they probably have a dozen or more

publications out case series and things

like that. So, uh so there's it's but

it's a form of a ketogenic diet. So I

think that's important to understand

like a carnivore diet is fundamentally

uh if practiced the way they do with

paleomicina where you just focus on

super fatty cuts, fatty fish, fatty, you

know, fatty meats and uh it's a version

of a ketogenic diet and I think that's

why it works.

>> All right, let's go back to

now talk about this world of exogenous

ketones, these supplemental ketones.

Now, you alluded to them already through

the lens of kickstarting a ketogenic

diet, but before we talk about

application, I want to kind of orient

people to the journey you've been on.

>> Um, I was once on that journey with you

being a a regular consumer of all sorts

of these things. Um, I will say lately,

and I when I mean lately, I mean only in

the past 3 months, I recently uh tried a

product uh that I like. I put it in my

coffee in the morning and I believe it

is a

disaster of 13 butane dial.

>> So it doesn't come with sort of the

liver toxicity that I think we should

talk about with respect to 13 butane

dial which unfortunately seems to be

running rampant right now.

>> Um but it's a white powder and what's

blows my mind about it is when you mix

it in water and drink it it's palatable.

It's not delicious, like you wouldn't go

out of your way to drink it, but it is

not horrible the way that most of these

synthetic ketones used to taste. So, you

can just make a shot glass of it and

it's totally reasonable. Alternatively,

it's the creamer in my coffee and it's

fantastic. Um, but let's go way back to

the beginning.

>> Yeah. Yeah.

>> So, circa 2011

>> Mhm. You had

basically only two products you could

consume, right? You had a beta

hydroxybutyrate monoester.

Actually, there were more than that.

There was a ketone salt, which we should

talk about. And you had an accetoacetate

diester. Is that correct?

>> Yep. BHB monoester and and 13butane

dial. Acceto acetate diester. Two

accetoates on 13 butane dial. So, there

are two esters.

>> So, just explain to people. Well, I mean

I unfortunately we have to get into a

little biochemistry here for you to

explain the difference between esters

and salts. And so to everybody

listening, apologies, but if you want to

if you want to understand these things,

and you have to if you want to be a

consumer of them, because everybody is

talking about these things as though

they're the same, and they're

categorically not the same. Um, and most

people have no idea what they're talking

about, and most people who are selling

these things are not being transparent

about what it is you're buying. They

just call everything a ketone.

>> Yeah.

>> So, let's do a little bit of

biochemistry, Dom.

>> Sure. Yeah. Glad to do that. Uh I think

it's maybe even good to step back a

little bit. Uh because if you go to

clinicaltrials.gov and you search ketone

supplement, MCT. So that that's a that's

a 8 to 10 carbon fatty acid that can

convert to ketones. So that's that

that'll come into the conversation, but

I want to throw it. But one of the

original kind of ketogenic substances

was 13b butane dial and I have uh I

think compliments of Ken Ford some of

the MIT reports of you know testing this

compound that from the 1960s and then

there was a report written uh by people

at NASA where they were basically

looking at this as a longduration

spaceflight food 13 butane dial which is

an alcohol it's a dalcohol or a glycol.

So uh it is remarkably ketogenic which

means you consume it and you elevate

beta hydroxybutyrate and uh it's

incredibly stable. So hence you know for

long duration space flight it was reject

oh also it it preserves food. So in the

report they basically soaked they put it

into some biscuits and the biscuits were

like extremely shelf stable. So it's a

hctant which means it keeps uh food

moist and it is it's actually grass

approved to be uh like they put it in

sausage casings and things like that

right so that existed that was 13 butane

dial and I think you know I would say

Dr. there was two people who really I'd

like to credit Dr. Henri Bruningraber

from Case Western and Dr. Richard Vichch

the late Dr. Richard Vch who passed away

a mentor of mine. Yeah. He passed away

like two or three years ago I think.

>> Uh and I remember Dr. Vch saying uh

because I was trying to acquire his

ketoneester for some studies and uh I

ultimately you know used the 13 butane

dial or the monoester beta

hydroxybutyrate for seizures but it

didn't work. And I will I'll pivot and

talk about that. So you have 13 butane

dial was the original kind of ketogenic

molecule and then you have two people

who spearheaded ketone esters. Sorry,

just before we leave that one, you said

13b butane dial elevates beta

hydroxybutyrate. Let's explain how and

why.

>> Yeah, good, good. Okay, so you can

consume 13b butane dial and it's a

precursor to beta hydroxybuterrate. When

you consume it, it goes through the

alcohol dehydrogenase pathway and

produces much like alcohol and you can

elevate BHB with this precursor, but it

needs to be metabolized by the liver.

And when it's metabolized by the liver,

the liver does have to work a bit. If

you consume enough to like jack up your

ketones to three or five millolar for

two or three weeks, you're going to see

your liver enzymes jump up. So, I've

done that with 13. And you have to take

a lot of it. You're talking about 150 to

200 milliliters per day for someone like

me to be in therapeutic ketosis. So,

when you do that, you also you're

generating an aldahhide. So you're

generating

>> and do we think that that's what's

driving up because because let let's

take a step back here.

>> If I asked you to consume

100 grams of ethanol a day y

>> for two weeks your transaminas would go

up.

>> Yeah. Yeah. You see Yeah. I've done that

before.

>> Yeah. So let's let's talk about that. So

So a standard drink is about 15 g of

ethanol. So now I'm going to ask you to

maybe more, right?

>> Yeah. Call 20. We round up 20. So now

I'm asking you to have five alcoholic

beverages a day. And by the way, you

could space that out over the course of

the day and not even get a buzz, right?

But I'm going to give you say five

alcoholic beverages a day

>> for two weeks. You are metabolizing

ethanol with alcohol

>> dehydrogenase

>> and you're going to create all of the

various metabolites. Um and the reason

your trans aminases are elevating is

those enzymes are leaking out of

hpatocytes because the hpatocytes are

injured due to the inflammation that

results from that metabolic pathway. Is

that at all analogous to what's

happening with a comparable dose of 13

butane dial?

>> Yeah, it is. There's a couple things

going on. You drink alcohol, you're

deenergizing the redux state of the

liver and you're generating acetal

aldahhide, an aldahhide molecule which

you know aldahhide damages DNA. It's got

oxidative stress issues that baggage

that comes with it. You're also

generating acetate. When you drink

alcohol, you're generating acetate. And

the brain acetate is actually something

I looked into. It's a remarkable

alternative fuel for the brain. So, uh,

so that's like a lot maybe a lot of

people don't know that, but when you

drink alcohol, you're giving your brain

acetate, and that's we can come back to

that. It's analogous to drinking 13

butane dial is analogous to drinking

alcohol. Instead of generating acetate,

you're generating beta hydroxybutyrate,

another alternative fuel for the brain.

Uh in the intermediary,

>> but do you generate the same amount of

aldahhide?

>> Uh you are generating a beta

hydroxybutyrate aldahhide that is

relatively short-lived, but you can

overwhelm the ADH enzyme. So by if you

drink too much of it you can cause uh

you can overwhelm the enzyatic

degradation and Henry Bruningraber did

some seminal studies on this that he

shared with me some of it's published

they had a they had a ketogenic dog

model that they gave 13b butane dial is

a hypoglycemic agent. So it's a

hypoglycemic agent because it

deenergizes the liver and prevents uh

glycogenolyis and gluconioenesis because

those path those uh mechanisms in the

liver are highly highly energy

dependent. So so that's analogous to

alcoholic keto acidosis. When you have

an alcoholic that's fasting and he

overconumes alcohol, he goes to the ER

because he experiences alcoholic keto

acidosis, which is basically it's, you

know, you have runaway ketogenesis

because you have you're inhibiting

glucanogenesis. Uh, but

>> why can't that patient make enough

insulin in response to the beta

hydroxybutyrate to bring the acidosis

under control?

because the liver cannot uh if you

increase insulin right that insulin is

going to only like you know facilitate

glucose disposal so the main thing is

the liver the liver is like

>> you're saying the liver doesn't respond

to the insulin signal to make less BHB

in that situation

>> and alcoholic keto acidosis

>> it does it doesn't so why does it in the

rest of us

>> like when you and I used to do our

ridiculous 10day fasts and all Do you

still do those by the way?

>> Uh I do like a sardine fast, right? So

I'll do like five day Yeah. two or three

cans of sardines a day and that I get

the same benefits and it mitigates a lot

of the negative effects.

>> Yeah. Yeah. Yeah. So but when we used to

do these 10 and 14 day water only fasts,

um

>> our ketones would actually plateau.

>> Yeah. And even when George Cahill did

the, you know, the seinal studies of

40-day water only fasts, their plat

their ketones plateaued at 7 to 10 days.

And a big part of that was that insulin

is now keeping them in check, right? Any

more elevation in the key the reason the

ketones aren't going to produce a level

of acettosis. Acidosis is is that and

that's why of course kids primarily with

type 1 diabetes can develop keto

acidosis. they don't have the beta cell

uh capacity to offset that rise in

ketones. So this is this this case of

the alcoholic is very interesting to me.

I actually was never aware of this.

>> Yeah. I mean it's you have uh you

deenergize the liver so the liver can't

undergo glucanogenesis and some extent

glycogenolyis. Then you have the

electrolyte balance. You get

dehydration. So it's a constellation of

things. But you know in getting back to

13 butane dial if you consume it and you

consume large amounts of it uh like some

of the early work that was done by you

can overwhelm that enzyatic cascade and

you can start generating you know a lot

of these aldahhide intermediates and

that's maybe not a good thing. So uh so

with 13 butane dial I see like two

problems I think people should be aware

of especially people like maybe that are

elderly or using it for cognitive

enhancement is that you get buzzed on it

and I've I've I know I've probably

consumed 13b butane dial than anybody. I

mean we have we had it in like you know

big 20 liter vials of it and I was

drinking

>> I used to buy it at Sigma Chemicals like

the stuff was dirt cheap.

>> Yeah. Yeah. Uh so I've done experimented

with the recemic and then also with the

um with the RN antimer and kind of the

same thing. Uh it's great and actually I

think it has applications for cancer

because it does have a glucose lowering

effect. We mixed it in with a standard

diet and gave it to animals with

metastic cancer and it suppressed cancer

growth and and put them into keto. So it

has some applications there. Uh but

getting back to the ideal ketone, it's

like it's like it's it's analogous

drinking

13b butane dial to elevate BHB is

somewhat analogous to drinking alcohol

to generate acetone or or acetate which

is a great molecule. I mean

>> Right. But it's a very indirect way to

do it that comes with toxicity.

>> Yeah. So what Dr. Vich and Henry

Burningber did and and there was some

others too involved in in the research.

uh Sammy Hasham developed a glycerol uh

beta hydroxybutyrate esther but they

take uh you can take 13b butane dial and

do a transestrification reaction and add

beta hydroxybutyrate to it or you can

add accetoacetate

to the molecule and when you consume it

you quickly liberate the ketones. So you

get a quick uh elevation of ketones,

beta hydroxybutyrate or accetoacetate

and then the 13 butane dial then goes to

the liver and the pharmacocinetics are

as much as you and we mimicked it

exactly in our lab. You go up you have

an initial peak and then like an hour or

two later you have a second peak from

the 13 butane dial and so it's it's a

nice molecule. I mean it's a nice uh and

I think it's it's dose dependently

potentially problematic. And with the

13b butane dial there's two issues would

be the potential for liver toxicity in

people do that do not have healthy

livers like my liver is pretty healthy I

think and it doubled my liver enzymes if

I take a large dose for two weeks and

then the other thing is if you take a

large dose of 13b butane dial the

narcotic effect in someone who doesn't

have good who is frail who doesn't have

good stability it's going to you know in

Dr. beach's word, it's going to make you

drunk stupid because I was trying to

acquire some of his Esther for something

and I was like, well, I'm just going to

use 13 and he kind of talked me out of

it, you know, and the whole reason for

developing the monoester was to avert

the problem.

>> So, the monoester is beta

hydroxybutyrate with a monoester bond to

13b butane dial.

>> Uh, yeah. Or yeah, 13 butane dial that's

Yeah. bounded to beta hydroxybuterrate,

but you said it in Yeah. So, you could

say it either way. Yep. And why is it

that you don't experience the same

negative issue with that molecule? Is it

because you just consume less of it

because you're getting the one uh you're

you're getting the BHB directly?

>> Yeah, you could take, you know, half the

amount and and get and then the kinetics

are a little bit slower too because you

have to hydrayze the BHB from that and

the liver.

>> And why can't you just consume BHB? Why

is is that not stable enough by its own

other than in a salt?

>> Uh you can. Yeah. So, there's a free

acid and that I tinkered with that

originally with the free acid because

you could buy it and it's super acidic

and it's not very stable in solution and

>> for a variety of different reasons

although you could put free acid needs

to be liquid into like an electrolyte

formulation. So we gravitated towards uh

at the time I was using in my

electrophysi electrophysiology

experiments you can't put a ketoneester

in the bath right because uh it doesn't

it needs to be metabolized by the liver

so you can't put it onto neurons so you

have to use a salt so you mimic you know

the pharmacocinetics of what you get

with the esester so we were putting

sodium beta hydroxybutyrate in

>> and I was thinking okay I'll give this

to the animals but then it was like okay

I'll I have to I was very concerned

concerned with the sodium overload like

you know you know uh hypertension all

the negative effects about salt

>> but all the negative effects about salt

and your listeners may not know this but

most physiologists kind of do that study

it

>> the salt sensitive people or the the

problem with salts and people maybe even

think ketone salts is that when you

consume salt you get hypertension and

some people salt sensitive but that's

specific to sodium chloride so sodium

bicarb sodium citrate sodium beta

hydroxy Butyrate is what I'm talking

about. If you consume large doses, gram

molecules of that, you're not that

doesn't have the same hypertensive.

Something about chloride. So, sodium

chloride. So, you could use potassium

chloride, you know, instead of sodium

chloride for salt. But I but I think

that's an important thing to consider uh

because a lot of people shy away from

ketone salts because it's sodium. But

the salt sensitive sort of hypertension

that you get was pretty much is

associated with sodium chloride. Uh so I

and I was communicating with Patrick

Arnold at the time and we were I kind of

have I was like if I have sodium

chloride but I wanted to get potassium

chloride but I looked I couldn't buy it

from Sigma. It wasn't in the cast

database and nobody had thought about

this. I could like how could nobody have

thought about putting ketones on

different electrolytes? It just wasn't

out there. So, um, so I kind of had the

idea of like sodium, calcium, potassium,

uh, magnesium, you know, so there's

different things that you can combine.

>> So, you just needed a positive cation.

>> Yeah. And I wanted to balance the

potassium uh, the sodium with potassium.

So, that was my original thing. I was

like, I was going to create a ketone

salt and just balance the sodium with

potassium.

>> And are those covealently bound or not?

You don't bound. Yeah.

>> Ionically bound. Okay.

sodium's trying to get everybody back to

high school chemistry. Y

>> you can either take this highly highly

acidic BHB molecule and you can

covealently bind it through an esther to

13 butane dol

>> or you can say let's be done with that

baggage of the 13 butane dol and let's

have um uh let's have a non-coovvealent

an ionic bound to a salt and I just need

a positive charge to offset the negative

charge. Y

>> so then you were saying okay I want to

do sodium cuz I can do a lot with it and

then tell me where the potassium comes

in cuz you want sodium and potassium two

both of them are two positive charges

instead of one calcium or one magnesium

which have two positive charges.

>> Yeah. So the idea is to have monovalent

and dvalent cations ions and you can

spread the beta hydroxybutyrate out to

create like a quad salt was the idea

that back in 2011. So reaching out to

Patrick you know is like it wasn't in

the cast database no one had thought

about it. it wasn't you couldn't buy it

so we had to make it right and then we

made the calcium and the magnesium and

through time basically we settled on a

ratio of sodium potassium to calcium

similar to element so they're kind of

ahead of but element is you know sodium

chloride so uh uh keto start or from

audacious nutrition is sodium beta

hydroxybutyrate it's got you know and

the calcium and it's got a spread of

electrolytes that are similar so you're

giving electrolytes and also giving

ketones and that's really important when

you start a ketogenic diet because

you're replenishing

the the electrolytes that you are

spilling out more through a naturic

effect especially the sodium and also

there's an energetic gap in the brain

when you start a ketogenic diet where

you have you know u uh an energetic need

for the increase in ketones so that had

that becomes

>> that's important for people we should we

should go back to that Don because I

think a lot of people

>> have lived bad experience and they don't

understand why, right? Which is in the