[1] [Rhonda]: Hello, everyone, I'm sitting here with Dr.

Dominic D'Agostino in
Tampa, Florida.
[2] Dominic is an assistant professor at the University of South Florida where his
primary research
[3] focus is on metabolic therapies, particularly nutritional ketosis, ketone
supplementation,
[4] and how they affect a wide variety of pathological conditions ranging from
neurological disorders
[5] like ALS to epilepsy to muscle wasting and cancer.
[6] So very, very interesting stuff that Dominic's doing here in Florida.
[7] He showed me some of his really cool equipment, which is super-exciting and
very interesting.
[8] Some things I hadn't seen before.
[9] So welcome, Dominic.
[10] [Dom]: Thanks for having me.
[11] [Rhonda]: Yeah, thanks for inviting us to your lab.
[12] [Dom]: Great to have you here in my lab, yeah.
[13] [Rhonda]: Super-cool.
[14] [Dom]: Thanks.
[15] [Rhonda]: So tell us a little bit about your...some of your more recent
interests and research
[16] where you're, sort of, been, what have you been looking at.
[17] [Dom]: Okay, so more recently, I'd say within the last three to five years,
and it took
[18] a while to develop them, but as you know we're working on ketone
supplementation.
[19] And the idea is to, kind of, mimic the therapeutic effects and performance-
enhancing effects
[20] of the ketogenic diet.
[21] So nutritional ketosis achieved through a dietary means with a low-
carbohydrate, high-fat
[22] diet has therapeutic effects for a broad range of neurological disorders, in
particular,
[23] seizures.
[24] And you can make the argument that pretty much every neurological disorder is
some way
[25] linked to a metabolic dysregulation.
[26] And we're interested in understanding how nutritional ketosis may help to
preserve and,
[27] sort of, stabilize brain energy metabolism to metabolically manage these
seizure disorders.
[28] So in the process of understanding and studying the ketogenic diet, we are
developing a broad
[29] range of ketone supplements which can include ketone esters and ketone mineral
salts, which
[30] where we combine a ketone body, beta-hydroxybutyrate, to an essential
electrolyte and create a wide
[31] variety of salts.
[32] And we're working...a lot of the work now is focused on formulating these to
make them
[33] tolerable, to make them palatable, and to understand their therapeutic potency
for different
[34] types of disorders.
[35] [Rhonda]: Yeah, so you mentioned that at the root, or at the heart of a lot of
these neurological
[36] disorders is a metabolic dysfunction and how, first of all, when we talk about
nutritional
[37] ketosis, to me, it's so, it's such a broad way of describing.
[38] [Dom]: Very broad.
[39] [Rhonda]: What is nutritional ketosis?
[40] Like, and how do you achieve it?
[41] [Dom]: So nutritional ketosis could be, it's defined...they, kind of, have the
same definition
[42] in my mind.
[43] It's achieving and sustaining a level of blood ketones.
[44] And I think when people say they've done the ketogenic diet, they did that it
didn't work
[45] for them or it did work for them, I would ask the question, "Well, did you
measure blood
[46] ketones?
[47] Did you confirm, in fact, that you were able to achieve a state of ketosis?"
[48] Defined as an elevation of blood ketones above 0.5 millimolar at the very
least.
[49] Ideally, you want to stay between one and three millimolar of ketones.
[50] And when you've achieved that state... [Rhonda]: You're talking about blood
ketones?
[51] [Dom]: I'm talking about blood ketones, yeah, which is, kind of, the gold
standard.
[52] And this can be measured.
[53] There's a number of different devices out there that measure blood ketones.
[54] And when that...the state of nutritional ketosis is achieved, you're also, not
only not only
[55] that biomarker is, kind of, there and we have technologies to measure it, but
it would also
[56] be important to measure your blood glucose and maybe insulin levels, too.
[57] The suppression of the hormone insulin drives hepatic ketogenesis and drives
the body's
[58] ability to make ketones.
[59] And that has therapeutic implications for type 2 diabetes, obviously.
[60] So my definition of nutritional ketosis would be an elevation of blood ketones
and the,
[61] kind of, the difficulty in prescribing that or telling someone to do it is
that the way
[62] to implement that is, kind of, similar with everyone, but everyone responds
differently
[63] depending on where you're coming from.
[64] So if you have an obese subject that's type 2 diabetic, it's going to be
different than
[65] an athlete.
[66] And women, there's some differences between women and men, I think.
[67] So defining nutritional ketosis is relatively easy with an elevation of blood
ketones, but
[68] implementing it and being able to, for the individual to commit to it and have
that,
[69] kind of, ability to control their diet, which is very linked to lifestyle, has
been, sort
[70] of, a difficult thing to do.
[71] And that's where ketone supplementation, kind of, comes in and can allow
someone to rapidly
[72] achieve nutritional ketosis and sustain it and perhaps get many of the
therapeutic benefits
[73] that we're just finding out now.
[74] We know that ketones are more than just a metabolite.
[75] They are more than just an energy metabolite that the brain can use, but they
are metabolites,
[76] especially beta-hydroxybutyrate, are very powerful signaling molecules.
[77] And we're just beginning to understand, sort of, the therapeutic effects of
these metabolites
[78] as signaling molecules and that's a big thrust of our lab right now.
[79] [Rhonda]: Oh, you're interested at looking at this and the effects... [Dom]:
Yes.
[80] [Rhonda]: Interesting, I'm familiar with some of Eric Verdin's work at
Gladstone and how
[81] he's... The science... [Dom]: He's a pioneer in...
[82] [Rhonda]: I'm very interested in beta-hydroxybutyrate as not only as a source
of energy for mitochondria.
[83] So being able to be converted into a thermodynamically favorable source of
energy, but also the fact
[84] that it's able to change cell signaling in the brain and it's able to turn on
genes that
[85] are involved in dealing with stress better, some of these genes are involved
in longevity,
[86] FOXO3 for one.
[87] [Dom]: Absolutely.
[88] [Rhonda]: So it's all very interesting.
[89] But something that I...like, in my mind that I'm not exactly certain about is
that nutritional
[90] ketosis.
[91] So eating a high-fat diet and, of course, there's, okay, what types of fat are
you eating?
[92] Are you eating more polyunsaturated, you're eating more saturated?
[93] You know, how much protein are you eating?
[94] What types of carbohydrates?
[95] Are you getting fiber?
[96] I mean, there's so many diets, very complicated.
[97] But there is no doubt that there are interesting therapeutic effects from
nutritional ketosis.
[98] I am interested in the the actual end product, which is ketone bodies and
these signaling
[99] molecules like beta-hydroxybutyrate being able to get those maybe even without
having
[100] to eat a high-fat diet, you can get them from fasting, from intense exercise,
right?
[101] Also, you can achieve... [Dom]: Post-exercise ketosis.
[102] [Rhonda]: Post exercise.
[103] [Dom]: Absolutely.
[104] [Rhonda]: So, I guess, the, kind of, the question I had for you with
nutritional ketosis besides
[105] having to define it was, what do people eat to obtain that?
[106] How do you get blood ketone levels between one and three millimolar?
[107] Like, what do you have to eat?
[108] What do you not have to eat?
[109] [Dom]: Okay, that is a good question and it varies depending on who you talk
to and what's
[110] optimal.
[111] I think a good way to approach it would to be describe what has been used
classically
[112] and how the diet has evolved over the last two to three decades, I think,
with some of
[113] the work with Eric Kossoff at Johns Hopkins has, kind of, advanced the idea
of using a
[114] modified Atkins diet or modified ketogenic diet.
[115] And I can, kind of, talk a little bit about strategies that I use, I think,
and others
[116] that I know use to achieve that state and sustain it for optimal performance
in health,
[117] I think.
[118] So in taking a step back, the classical ketogenic diet would be like a 4:1 or
3:1 diet, and
[119] that's, kind of, the ratios of the macronutrients.
[120] Four being fat and one being a combination of carbohydrates and protein
together.
[121] So a pretty protein-restricted diet.
[122] And the ketogenic diet is not a high-protein diet.
[123] It's actually moderate to low protein diet.
[124] And most people don't understand that, they think, especially in the fitness
community,
[125] if they go on a ketogenic diet...if they say they've been on a ketogenic
diet, what they
[126] will describe to me would be a very low-carbohydrate, high-protein, moderate-
fat diet, but the ketogenic
[127] diet as it is used classically for drug-resistant epilepsy, the original was,
like, 90% fat,
[128] like 85% to 90% fat and maybe about 10% protein, typically, and 8% to 10%
protein, and a very
[129] minimal amount of carbohydrates, and it was heavily based upon the used of
dairy fat.
[130] So dairy was the primary, kind of, vehicle, yeah, to get calories into you.
[131] And we know that the use of dairy especially in some people, dairy protein in
particular,
[132] but even sometimes dairy fat, too, can have negative consequences for some
people.
[133] So there's a wide variety of, kind of, ketogenic diets out there and they,
the ketogenic diet
[134] has been defined by this ratio of macronutrients.
[135] But what we're learning now is that it's more than just macronutrients to
optimize the diet,
[136] especially for individuals.
[137] The sources of the macronutrients, the fatty acid profile, the type of
protein, it allows
[138] for some amount of carbohydrates, and the types and quality of the
carbohydrates as
[139] it relates to gut health and gut microbiome, I think, is really important.
[140] I think it's really important to optimize the diversity of carbohydrate
sources in the
[141] form of raw vegetables, and I think that it can optimize the diversity of the
gut microbiome,
[142] too.
[143] I think those two are linked, the diversity of the foods in your diet and the
diversity
[144] of your gut microbiome.
[145] I've seen that just through feedback.
[146] It's not really studied, but it's something everyone knows and it should be
studied.
[147] So the classical ketogenic diet is very strict to follow.
[148] There's a few studies showing that it can influence a lipid profile in a
negative way,
[149] meaning a high elevation of LDL.
[150] And in kids, I think, that follow the diet, they had a high level of
triglyceride.
[151] There was one study that's often referenced in regard to the ketogenic diet
being atherogenic
[152] the triglycerides are really high in some of the kids.
[153] [Rhonda]: It's probably a very complex gene-nutrient interaction, as well.
[154] [Dom]: Absolutely, yeah.
[155] [Rhonda]: There's some, I'm not sure if you're familiar with any of this
work.
[156] It's something I'm getting into recently is this nutrigenomic field and
particularly,
[157] there is PPAR-gamma and PPAR-alpha, which is important for ketosis and
polymorphisms
[158] that are associated with not being able to respond well, so it's very likely
that some
[159] of these people that don't respond well or may have that polymorphism.
[160] [Dom]: Yeah, undoubtedly, because there are some people that really have a
negative effect,
[161] but I would it's, kind of, few and far between...maybe as high as 20% in some
circles, but generally
[162] speaking, if you have a dietitian that's pretty savvy and has worked with
enough people, I
[163] really emphasize experience because there's no substitute for experience.
[164] So you could know as much...yeah, you could know the biochemistry behind
nutritional ketosis,
[165] all the pathways, whatever, but working with a dietitian, I always stress
that in people
[166] that want to try the ketogenic diet to start off with a good dietitian.
[167] They can tailor and tweak the diet for your specific needs and I find that,
for me, personally,
[168] a diet that's low in dairy is really essential because I just don't do good
with dairy, and
[169] nuts have been a staple for some people for the ketogenic diet and I have,
like, a mild
[170] nut allergy.
[171] So that's another food that I've, kind of, had to eliminate.
[172] But despite that, I have been following what I call a modified ketogenic diet
and I think
[173] it's pretty similar to the modified Atkins diet that Eric Kossoff has been
using at Johns
[174] Hopkins.
[175] He's at Johns Hopkins, mainly a neurologist, but has a team of dietitians
working with
[176] him and has done an incredible job advancing, sort of, the use of the
ketogenic diet.
[177] You know, he follows in the steps of John Freeman, who was really a pioneer
in getting
[178] the neurology world to recognize a ketogenic diet as a viable metabolic
therapy for drug-resistant
[179] epilepsy.
[180] And he did a lot of work with The Charlie Foundation and worked with them to
help promote
[181] awareness of the diet, education of the diet.
[182] So some work that Eric Kossoff has been doing over the years and publishing
on is showing
[183] that the modified Atkins diet has much of the therapeutic potency of the
strict classical
[184] 4:1 ketogenic diet.
[185] So instead of 90% fat, the modified Atkins diet is roughly 65% to maybe 70%
fat which
[186] is, kind of, what I follow now, and about 20% to 30% protein, with the
balance being
[187] still very low on carbohydrates, like no more than 5% or 10% carbohydrates.
[188] But it's more liberal in the use of protein.
[189] And it's also, advocates the use of medium-chain fatty acids, can be
incorporated into that.
[190] So by following a diet that's more liberal with the protein and less not
restrictive,
[191] and less in of a need of a such a high-fat content, I've been able to
maintain a moderate
[192] state of ketosis as do many of the therapies or many of the patients that are
benefiting
[193] from this therapy for a wide range of disorders.
[194] So I think that makes the diet more accessible to people, and I think the
biggest hurdle
[195] now is just compliance.
[196] So people know the benefits of the diet, some of them are a little concerned
with the side
[197] effects of the diet as far as lipid profiles being altered.
[198] [Rhonda]: What about gut?
[199] [Dom]: The gut, yeah.
[200] [Rhonda]: Have you been looking...how long have you been doing this modified
ketogenic
[201] diet?
[202] [Dom]: It, sort of, evolved from 2008 to '09, I started experimenting with it
because that's
[203] when I got interested in using... [Rhonda]: And you've continued on ever
since then?
[204] [Dom]: Yeah, I've never really gotten out of ketosis.
[205] [Rhonda]: It's quite a long time.
[206] That's quite a long time.
[207] [Dom]: Yeah.
[208] If I did, I may have reverted back to, like, a low-carb Paleo which is maybe
up to 40%
[209] to 50% fat or protein on some days.
[210] So I've been a little more liberal on the protein at times, but yeah, I've
been following
[211] it for a long time.
[212] And I do blood work really consistent.
[213] [Rhonda]: Well, the reason I ask is because, it's the one, like I mentioned,
I'm very interested
[214] in nutritional ketosis, which is why I'm excited to talk to you because you
know so much more
[215] about it.
[216] And I'm trying to, like, get to the bot-,...there's this conflict in my head
with eating a lot
[217] of fat and its effects on the gut because I know a lot of my gut researchers,
a lot
[218] of my friends are, kind of, looking at gut health and one of the main things
that you
[219] do induce endotoxin, which is released from bacterial cell membranes.
[220] I remember it's one of main things needed to induce gut permeability is if
you have
[221] a high-fat diet.
[222] You feed mice, you feed...this is all done in animals, of course, which is...
[223] There's lots of problems with that, but...
[224] [Dom]: What's the typical fat source for that?
[225] Is it lard or is it...?
[226] [Rhonda]: A variety of different fat sources.
[227] There's lard, there's corn oil.
[228] I mean, so there's there's a variety of different fat sources, but fat itself
in order to be
[229] digested, you have make these bile acids like deoxycholic acid, which which
causes endotoxin
[230] release.
[231] It also acts as a surfactant.
[232] I mean, it's like a detergent.
[233] So, I'm not convinced that it's not not healthy, but I'm not...I'm, sort of,
trying to get
[234] to the...there's a disconnect in the literature because there's so much
information out there
[235] showing the benefits of a ketogenic diet, nutritional ketosis.
[236] [Dom]: Let me ask this question real quick.
[237] So when endotoxin is released from these bile acids, so there would be a
predictable, a
[238] characteristic cytokine profile that would reflect that, right?
[239] [Rhonda]: Yes, so there's a cytokine profile and you also measure endotoxin
in the blood,
[240] which is a very tricky thing to do because there's a lot of false positives
and I know
[241] someone who's trying to develop an assay to make it actual-, because he's
very OCD about
[242] it.
[243] It's not out there for clinical use yet because of that reason, and even
doing it in animal
[244] studies, there's a lot of researchers that don't really do it right,
measuring endotoxin.
[245] [Dom]: Is there any benefit to endotoxin?
[246] So when I go exercise right, and you measure my blood and we look at reactive
oxygen species
[247] or inflammatory mediators, you could look at the blood and say, "Don't do
that, this
[248] is not a good thing to do."
[249] Whereas if you have periodic spikes maybe and endotoxin, is it stimulating a
hormetic
[250] effect where it's enhancing my resilience or resistance to toxins, do we know
that?
[251] [Rhonda]: So endotoxin, I would say based on everything that I have known and
researched
[252] and from my interactions with people that have been doing this research.
[253] It's not like reactive oxygen species where there's it's a potent signaling
molecule that
[254] has this hormetic effect, increases mitochondria biogenesis, it increases all
these genes involved
[255] in dealing with stress there's lot of benefits.
[256] You know, endotoxin release from the gut, one, it causes more VLDL production
because
[257] VLDL sucks soaks it up.
[258] So that's part of the reason why inflammation is also correlated with an
increase in LDL
[259] number.
[260] It also binds to ApoB, it binds to the part, it binds to where the LDL
receptors bind so
[261] that LDL can't be recycled as well.
[262] So it, kind of, prevents.
[263] There's a lot of bad things about endotoxin being released.
[264] Now I don't know, maybe there is some, sort of, slight benefit from endotoxin
being released.
[265] You know, I don't want to get too into the endotoxin world.
[266] I'm just saying there is, in my...I'm trying to, like, understand in my mind
how....
[267] [Dom]: So you might be a little biased because some of the high-fat diet work
has endotoxin.
[268] I'm a little bit, I need to get educated, I mean, I understand endotoxin
from, kind
[269] of, like a basic science point of view.
[270] [Rhonda]: Right, like, "sepsis, bad."
[271] [Dom]: Yeah, from "sepsis, bad," but I do know when your body is challenged,
even things
[272] like radiation.
[273] I mean, there are some things...you know, I don't know of any case where an
auto antibody
[274] is a good thing, but I know most of the things that are bad out there do have
some benefits,
[275] it's the level it's the level.
[276] [Rhonda]: Absolutely, dose is very important.
[277] [Dom]: And the phenotype's ability to adapt to that chemical, that stimulus
is really
[278] important.
[279] Like, old people don't adapt to older phenotypes don't adapt to an oxidative
stress stimulus
[280] as robust.
[281] So I would be interested, and there's ways to simulate endotoxin, right?
[282] Experimental models and that's something we can do, challenge, perhaps run an
experiment
[283] where we have animals on different diets where we can challenge them and look
at inflammatory
[284] cytokines.
[285] We're doing a lot of that work now.
[286] [Rhonda]: And gut health in general, gut permeability.
[287] I would love to see some ketogenic research go in that direction because
there's so many
[288] unanswered questions in my mind.
[289] And there's a lot of bad data out there, like so from the high-fat diet and
the effects
[290] on the gut because when you look at controlled diets and the high-fat diet,
well, the controlled
[291] diets have, like, 50% more fiber, and it's like, "Well, that's not really the
same thing
[292] if you're just changing fat."
[293] So there's, you have sift through all sorts of crap, and it's, like, there's
lots of data
[294] you just have to throw out, but still at the end of the day, I'm uncertain
and I'm weary
[295] about me, eating a high-fat diet.
[296] Not not mention the fact that I have certain gene polymorphisms that may not
be as compatible,
[297] but because of that, because of gut health, that's my major, the limiting
factor for me
[298] is gut health and I like to see more research on ketogenic diets and gut
health, like, that's
[299] something that I think is important.
[300] [Dom]: How to optimize it.
[301] [Rhonda]: Yeah, or just what the effects are, like maybe they're for one,
we're starving
[302] out probably a lot of the pathogenic sugar-eating bacteria.
[303] So there's probably some good things going on.
[304] And then there's, well, what effect does medium-chain triglycerides has?
[305] Is it the same as long-chain fats?
[306] Maybe not.
[307] So maybe...so there is different types of fat there's studies that had been
coming out
[308] very recently showing the effects of polyunsaturated fat on the gut biome,
and how it has a positive
[309] effect.
[310] So maybe if you eat certain types of fat, more of these types of fat versus
the others.
[311] There's lot of things out there to be explored.
[312] [Dom]: Undoubtedly shifts it, yeah.
[313] It shifts it.
[314] I mean, your gut microbiome has an appetite for whatever you're feeding it
and that probably
[315] influences profoundly your own appetite.
[316] So I think if you have sugar-eating gut microbes, you're probably going to be
craving sugar
[317] if you go a few hours without having sugar.
[318] And I think I would be very interested in not only, like, shifting someone
from a high-carb
[319] diet to two or three different types of ketogenic diets, I think, would be
important with specific
[320] fatty acid compositions and fiber compositions.
[321] And I think it's the diversity of the fiber that's incorporated.
[322] [Rhonda]: Diversity, yes, it is very important.
[323] There have been there's lots of different types of bacteria and they're
eating different
[324] precursors to generate a lot of these other signaling molecules, short chain
fatty acids
[325] and things like that that are regulating your immune system, that are
regulating literally
[326] hematopoiesis, Tregs, natural killer cells lots of...and this is a whole
blooming field
[327] of research.
[328] That's also another reason I've been a little hesitant to experiment with
this because I'm
[329] so, fiber is so important for me, fiber from vegetables.
[330] You know, I'm not adverse to fiber from fruits, so fiber from fruits,
legumes, beans, like,
[331] I like to get a lot of fiber in my diet, and so I don't know if that, is that
compatible
[332] with it?
[333] [Dom]: I get more fiber on a ketogenic diet.
[334] You know, and we're talking about a well-formulated ketogenic diet, as Jeff
Volek likes to...
[335] And because that is really important because you talk to people that you eat
ketogenic
[336] diets and it's all over the board.
[337] But I think a well-formulated ketogenic diet would have an abundance of fiber
sources,
[338] everything from green vegetables, of course, but would include a salad, and I
think it's
[339] really important from a gut microbiome perspective to get in raw vegetables,
I think, from what
[340] I've known and a half-dozen individuals that I talk to that are, kind of
experts in this
[341] field.
[342] They think that that has a pretty profound effect, and I have always done
that and I
[343] would say my gut health has not... It may be due to what I eliminated in my
diet.
[344] I grew up in an Italian family eating a lot of pasta, bread, so they were the
staple foods,
[345] and I gravitated toward a Paleo diet mid-90s, early 2000s and then the
ketogenic diet, and
[346] I have never had better gut health than when on a ketogenic diet, but my diet
is, like
[347] I said, more of a modified Atkins and has a pretty liberal amount of
vegetables in it.
[348] And I think the benefit to including the vegetables, they're just carriers
for the fat and they
[349] also slow protein digestion, which helps minimize the insulin spike that you
can get from protein
[350] and helps keep me in ketosis.
[351] But, I mean, getting back to your question about the ketogenic diet or high-
fat diet
[352] influencing endotoxin or factors, I would think that would show up in the
literature
[353] that if some, and maybe it does, but it usually, a high-fat diet is in the
context of a high-carbohydrate
[354] diet, too.
[355] So that's what we don't know when we talk about LDL particles being elevated,
like,
[356] even skyrocketed, LDL, little peak.
[357] That is only understood in the context of a high-fat diet, which also
includes also
[358] sugar like a western diet.
[359] So we don't yet understand lipidomics and the shifts in lipid profile of the
ketogenic
[360] diet, LDL(p), specifically, we don't understand it in the context of
ketoadaptation.
[361] [Rhonda]: Okay, what's that?
[362] [Dom]: Ketoadaptation, I would, it's, kind of, a term that Jeff Volek and
Stephen Phinney
[363] coined, but I think it's very descriptive in my mind as a physiological
process when
[364] your body has adapted to using fatty acids and ketones for fuel where you've
biochemically
[365] and physiologically shifted your metabolism from burning glucose as the
primary fuel to
[366] burning glucose and also equal or maybe more, in some cases, ketone bodies
primarily from
[367] your central nervous system.
[368] So when that happens, that's acutely, you get an elevation of blood ketones
and over
[369] time, what you do is get an upregulation of the transport mechanism so your
ability to
[370] make ketones, utilize ketones, and metabolize ketones in the cell is
dramatically increased
[371] as is the oxidative capacity of your cells.
[372] [Rhonda]: After you start making more ketones.
[373] [Dom]: After, yeah.
[374] It's, sort of, driven by being in a state of ketosis enhances fat oxidation
over time.
[375] So when we say ketoadaptation, we should probably say keto and fat
adaptation.
[376] So there's studies out there that show our metabolic physiology changes
pretty profoundly
[377] from eating this.
[378] We basically, we burn what we eat, right?
[379] So with a high-carbohydrate diet, we are pretty much burning that as fuel and
our bodies can
[380] adapt remarkably well to burning a macronutrient profile that's reflective of
the ketogenic
[381] diet.
[382] And when we do that, a lot of really remarkable, beneficial metabolic
processes happen including
[383] mitochondrial biogenesis, reduction of ROS, reduction of inflammation, a
reduction of
[384] specific inflammatory cytokines that may be associated with with age-related
chronic diseases
[385] are reduced.
[386] [Rhonda]: And so reduction of ROS, because I would, no, I guess some of
Richard Veech's,
[387] have put some ideas out there about the...
[388] [Dom]: Ketones, direct effect, yeah, on that, too.
[389] [Rhonda]: Yeah, it's so funny because in my mind I always think about like,
well, if you're
[390] inducing your mitochondria to work more, you're going to make more reactive
oxygen species,
[391] right, and that's, sort of, what I think would be a driver of killing
abnormal cells, cancer
[392] cells that are primed to die.
[393] They're expressing way more pro-apoptotic proteins they've countered it with
anti-apoptotics.
[394] All they need is a little push, a little reactive oxygen species pushed to
death.
[395] [Dom]: And that's increased initially.
[396] [Rhonda]: It is.
[397] [Dom]: So yeah, it actually activates like a Nrf2.
[398] So when someone gets on a ketogenic diet, it's a stress to the body and
you...
[399] [Rhonda]: Yeah, so you are...you aren't making more, because if you are
causing your mitochondria
[400] to only work, right, that's the only way you can make energy, then you'd
think that you
[401] have to be making reactive oxygen species.
[402] At least if you're looking in the context of a cancer cell, which just would
be glycolytic
[403] and not using the mitochondria at all, right?
[404] Then definitely there would be a much more, an increase in ROS.
[405] So ketone, so you're saying that it can suppress ROS.
[406] Is that through some of what Richard Veech has put out there in the semi-
ubiquinone,
[407] how it's like... [Dom]: Oxidize Q, makes it less available.
[408] [Rhonda]: Yeah, right, because that's the most... [Dom]: If Q is oxidized,
yeah, so.
[409] [Rhonda]: So Q being ubiquinone.
[410] [Dom]: Yeah, ubiquinone.
[411] If ubiquinone is oxidized, which is achieved with our beta-hydroxybutyrate
metabolism,
[412] if that's oxidized, then you have less availability for that electron to
react with molecular
[413] oxygen in the metabolic pathway.
[414] So you would produce less superoxide anion, which is your precursor to more
reactive oxygen
[415] species.
[416] And that's been shown elegantly in a number of models including the cardiac
model, which
[417] he did, the Langenhorn [SP] model, the perfused heart preparation showing
that you get a greater
[418] hydrolic efficiency of the heart in the presence of ketones.
[419] You know, with a given amount of oxygen, you can generate proportionally more
ATP, energy
[420] currency.
[421] [Rhonda]: Is there another way that ketones also suppress ROS?
[422] Or is that through the hormetic effect of activating mitochondria, then
increasing Nrf2
[423] and things like that?
[424] [Dom]: Yeah, that would be a secondary effect.
[425] I would say from a acute point of view, as simply as a metabolic fuel through
the mitochondrial
[426] efficiency is greater.
[427] So you have a greater mitochondrial membrane potential, a greater driving
force for ATP
[428] synthase to make ATP.
[429] So it energizes the mitochondria in a way that would be expected from a
metabolic fuel
[430] that's, sort of, superior from a bioenergetic point of view.
[431] So you have a greater capacity to generate ATP for a given amount of oxygen
that's available.
[432] So with that occurring, the metabolic efficiency of the cell would be, sort
of, preserved,
[433] you're using less oxygen to make the same amount of ATP, less reactive oxygen
species.
[434] And, of course, if you're shifting away from glycolysis and shifting towards
oxidative
[435] phosphorylation... [Rhonda]: So in the context of a cancer cell.
[436] [Dom]: In the context of, yeah, any kind of cell, like our tissue, really,
skeletal muscle
[437] or cancer cell, yeah, you are forcing the body in a way and to stress,
initially, to
[438] upregulate mitochondrial machinery, really, and more mitochondria will start
budding off
[439] and creating mitochondrial biogenesis.
[440] [Rhonda]: So it increases mitochondrial biogenesis.
[441] [Dom]: Yeah, the number of mitochondria.
[442] Then, the proteins that are associated with the electron transport chain,
those proteins
[443] are upregulated.
[444] [Rhonda]: That's very interesting.
[445] It acts very similar to lactate.
[446] I don't know if you're familiar with any of, like, the brain work, and George
Brooks, and
[447] lactate.
[448] [Dom]: Yeah.
[449] I...very interested in lactate as a graduate student.
[450] [Rhonda]: Because it does the same thing.
[451] Goes to the same transporter, right?
[452] [Dom]: Yeah, at MCT.
[453] I studied lactate as, sort of, an undergrad and graduate student, like, I am
studying
[454] ketones now as an alternative fuel.
[455] [Rhonda]: Oh, really?
[456] We're you looking at it in the brain?
[457] [Dom]: Yeah, during hypoxia.
[458] So I studied the neural control of autonomic regulation, so brain hypoxia and
what our
[459] brains do under hypoxia.
[460] And lactate is a big player in preserving brain function, viability, health,
and I studied
[461] lactate as an alternative energy source under hypoxia.
[462] And now, I think of ketones as, like, the alternative energy source when your
brain
[463] is under normal physiology.
[464] And I think there are some uses for lactate, too, as a fuel.
[465] I think when we exercise we're creating lactate and we feel good, it's not
really talked about.
[466] It's something that I want to study and maybe talk about a little bit more is
that the lactate...you're
[467] also sending, not only are you sending ketones to your brain, but you're
sending lactate
[468] to your brain, and I think that's maybe not talked about that much, but
there's a potential
[469] out there for lactate supplements.
[470] [Rhonda]: George Brooks in UC Berkeley, he's...I don't know if you're
familiar with any of
[471] his work.
[472] [Dom]: A little bit, yeah, peripherally.
[473] [Rhonda]: He pioneered the whole lactate shuttle theory, but he's been
looking at the effects
[474] of lactate generated during exercise, for example, when you're forcing your
muscle cells
[475] to work harder and you're making more lactate, it gets over, it crosses over
the blood-brain
[476] barrier gets into neurons.
[477] So neurons themselves actually use lactate generated from astrocytes.
[478] So they are using, I mean, neurons actually using lactate.
[479] It's also a thermodynamically and energetically favorable source of energy
much like ketones.
[480] And so neurons like doing that because, one, it's easier, and two, because
glucose can
[481] then be freed up to be shunted into the pentose phosphate pathway, which can
be used to generate
[482] NADPH, which is important for glutathione recycling.
[483] [Dom]: Antioxidant capacity, yeah.
[484] [Rhonda]: Right, which makes sense why...
[485] Probably, I think there's a lot of parallels between ketone bodies and ketone
supplements
[486] and how they're not only being used as a preferential source of energy in the
brain.
[487] Do you know anything about this, about, like, how frees up glucose then to be
used for other...
[488] [Dom]: Glucose sparing.
[489] [Rhonda]: ...metabolic pathways?
[490] Yeah, glucose sparing.
[491] [Dom]: Yeah, it's thought that some of the work by Steven Cunnane, I think,
is shedding
[492] light on this, too.
[493] [Rhonda]: Where is he at?
[494] [Dom]: He's in Canada.
[495] I forget the institute that he's at.
[496] Joe LaManna has done some similar work and he's at Case Western and looked at
the, kind
[497] of, the interaction of what does the brain prefer...what's the preferred fuel
source
[498] for the brain.
[499] I get this question a lot.
[500] I think it depends on, you know...I don't know if it's right to say that the
brain always
[501] prefers ketones.
[502] [Rhonda]: The brain cell we're talking about, for one.
[503] The neuron, astrocytes.
[504] [Dom]: Neurons and astrocytes.
[505] But, yeah, I guess, I mean, maybe we're definitely biased towards
understanding neurons relative
[506] to astrocytes.
[507] [Rhonda]: I think most people that ask me that question are....
[508] [Dom]: Astrocytes are fascinating.
[509] I think we need to study that more.
[510] But I think in the context of, like, aging and a context of traumatic brain
injury or
[511] pathology, I think the brain will really prefer to use ketones because...or
in the context
[512] of some kind of stress hypoglycemia or something like that, I think the brain
will also prefer
[513] to use ketones.
[514] [Rhonda]: Yeah, so why do you think that is?
[515] [Dom]: Well, I think... [Rhonda]: I might have my own reasons why.
[516] [Dom]: There's a whole host of reasons or things that can cause impaired
brain energy,
[517] brain glucose metabolism and that could be internalization of the GLUT3
transporter,
[518] which occurs...it's kind of linked to Alzheimer's pathology.
[519] [Rhonda]: GLUT... [Dom]: GLUT3, yeah.
[520] And there's a couple of key enzymes that are either deficient or not active
like they should
[521] be, pyruvate dehydrogenase complex is deficient.
[522] [Rhonda]: So wait, are these in...are the GLUT3 changes in astrocytes or in
neurons?
[523] [Dom]: Primarily in neurons.
[524] [Rhonda]: Neurons, okay.
[525] [Dom]: So the glucose transporter in neurons.
[526] [Rhonda]: So if neurons are using lactate primarily...the astrocytes are
actually what's...
[527] [Dom]: Shuttling a lot.
[528] [Rhonda]: The astrocytes are using glucose and that's why the brain needs
glucose and
[529] they're producing the lactate.
[530] The neurons are using the lactate because it's getting shunted and converted
into pyruvate.
[531] [Dom]: And the contribution of that is not completely known, but it's pretty
significant
[532] contribution during hypoxia, I would think.
[533] [Rhonda]: There's been studies out there showing that not just during
hypoxia, but actually
[534] just under normal physiology that... [Dom]: It's a key player.
[535] [Rhonda]: It is, yeah, the neurons are getting lactate continually from
astrocytes which
[536] are generating it, but that the astrocytes become aberrant during...for
whatever reason,
[537] it's not known, Alzheimer's leaves traumatic brain injury, so they can't make
that lactate
[538] and neurons have to start using the glucose, which then is, but I mean,
that's just one.
[539] [Dom]: Yeah, I've heard about that, I haven't looked into that.
[540] Yeah, so there's some key enzymes then that people look at not only just the
lactate levels...
[541] [Rhonda]: I think that...I have no idea what they're looking at, but for the
pyruvate dehydrogenase
[542] complex, you're saying that's also aberrant in some of these disease states
because then,
[543] you wouldn't be able to use the lactate because you couldn't convert it into
pyruvate.
[544] So anyways, it's all kind of, I totally interrupted you, though, but you were
talking about...
[545] What were you talking about, the aberrant enzymes, like GLUT3 and pyruvate
dehydrogenase,
[546] and how these are aberrant in different neurological disorders.
[547] [Dom]: Yeah.
[548] So I think, I think, well, maybe the question we're trying to get at is the
contribution
[549] of ketones as a brain energy source and especially in, sort of, in academia
and circles where
[550] I teach, it's not even, still not really known, it's not really accepted or
understood that
[551] much.
[552] But I think the capacity, the metabolic flexibility of the brain to be able
to use ketones, we
[553] can exploit that and we do that with nutritional ketosis, and it's altering
brain energy metabolism
[554] and the neuropharmacology of the brain in ways we don't completely understand
now, meaning
[555] the neurotransmitters in the brain.
[556] So I could draw off GABA.
[557] So you have more GABA, the GABA-to-glutamate ratio is shifted in favor of
higher GABA.
[558] So there's a higher GABA-to-glutamate ratio when one is on the ketogenic
diet.
[559] [Rhonda]: In people that are not having...in normal people, as well?
[560] Just, like, in general?
[561] [Dom]: Yeah.
[562] [Rhonda]: Interesting.
[563] [Dom]: It's thought that, and there's different reasons for that.
[564] There's glutamic acid decarboxylase is an enzyme.
[565] [Rhonda]: Is that how it helps with epilepsy?
[566] [Dom]: That's part of it.
[567] I think there's about 20 or more things going on if you look at all the
signaling pathways
[568] [crosstalk 00:39:37] actually what happens, yeah, with metabolism, but I
think a key player
[569] in that is an elevation of GABA to glutamate.
[570] And we need glutamate to make GABA, right, but the enzyme is elevated and the
pathways
[571] are shift in favor of more glutamate to GABA, which has a stabilizing effect
on your cell
[572] membrane and neural interactivity, in general.
[573] [Rhonda]: How readily do ketones cross the blood-brain barrier?
[574] [Dom]: It's thought up to five millimolar, maybe six, seven millimolar, they
can readily
[575] cross the blood-brain barrier.
[576] [Rhonda]: You have to get that high before they start crossing?
[577] [Dom]: No they start impeding once you get levels up that high.
[578] It hasn't really been studied in-depth.
[579] We did brain metabolomics to show that when we looked at the ketone levels in
brain tissue
[580] and ketone levels in the blood, and there's a high correlation there.
[581] Interestingly, we had a diet, too, that was high in medium-chain fatty acids.
[582] And although I heard the medium-chain fatty acids could readily cross the
blood-brain
[583] barrier long-chain fatty acids typically don't, short-chain fatty acids sort
of do.
[584] But we found very high levels of medium-chain fatty acids indicative of them
and these were
[585] normal, healthy animals.
[586] So when you take medium-chain fatty acids, they are readily from the looks of
our metabolomic
[587] data, just readily crossing the blood-brain barrier and capable of being used
as fuel...
[588] [Rhonda]: That's fascinating, I had no idea.
[589] [Dom]: ...which is very, yeah, it's really interesting.
[590] I heard about that, but when you see the data it's at really high levels.
[591] [Rhonda]: So when they're in the brain, then how are they...so then what
happens?
[592] So they're used...
[593] [Dom]: Yeah, their medium-chain fatty acids can be oxidized just like fatty
acids for
[594] fuel, yeah... [Rhonda]: Wow, interesting.
[595] [Dom]: ..uh-huh... oxidative, but ketones are also very high in the brain and
to really
[596] capture and understand it, you have to, sort of, capture the brain tissue
really quick
[597] and freeze it and then do an analysis because the brain's using it as fuel
after you take
[598] it, your brain's, kind of, still alive.
[599] Sort of, the step that I was showing you in the lab where we can take the
brain out and
[600] cut it like a piece of bread and then record from it.
[601] So that brain is still active.
[602] So it, sort of, uses the metabolites.
[603] So to get a very clear snapshot of the difference in tissue versus blood is a
little tricky
[604] as is getting ATP levels in the brain.
[605] It's a little tricky.
[606] We're working on that to be able to do that.
[607] Another question which I think will involve radio tracers is actually to do,
like, a ketone
[608] PET scan where we can look specifically at the regional distribution of
ketones and figuring
[609] out what areas of the brain may be preferentially shuttling them and using
them as fuel and
[610] how that may change under different pathologies, how that may change under
oxygen deprivation,
[611] glucose deprivation, high oxygen, as I study oxygen toxicity.
[612] [Rhonda]: Please look at genetic states like ApoE4 because that's one
thing...
[613] [Dom]: Yeah, that's a biggie.
[614] [Rhonda]: Yeah, I'm very interested in some of this work you're talking about
in ketone
[615] supplements helping with neurological disorders like Alzheimer's.
[616] It's been shown that that is dependent on ApoE status, and that just, it's
disappointing
[617] to me because I really want to understand why and I just... Do you have any
idea?
[618] [Dom]: Well, so you're referring to the Henderson paper where they looked
at...
[619] [Rhonda]: Both papers.
[620] [Dom]: ...Axona AC-1202?
[621] So the finding was in that study, which is relatively small, that at least
not with the
[622] diet, but using a ketone supplement that was formulated with 20 grams of
medium-chain triglycerides.
[623] So they gave to their patients, I think, just once a day.
[624] And they did show fairly convincingly that the elevation of beta-
hydroxybutyrate correlated
[625] with an improvement in cognitive function, but that correlation was not
observed in the
[626] ApoE4 positive group, which was a little bit...it was kind of surprising.
[627] I would like to see that study done using the ketogenic diet or maybe the
ketogenic
[628] diet formulated with ketone supplementation.
[629] So, the question is...it did not have a negative effect, but the question is
why didn't it
[630] have a positive effect?
[631] [Rhonda]: Was there not another study where they actually did the ketone
supplement, beta-hydroxybutyrate?
[632] I thought there was, but I could be mistaken just from my lack understanding
because that
[633] would shed some more light.
[634] [Dom]: Yeah, well, they used caprylic triglycerides, C8, which kind of makes
a lot of ketones,
[635] relatively speaking.
[636] [Rhonda]: Unless the ApoE is changing the way you're making ketones, right?
[637] [Dom]: With fatty acids, yeah.
[638] [Rhonda]: But they measured, you said they measured beta-hydroxybutyrate in
everyone
[639] and the levels were the same because it's like I want to understand why there
was no
[640] positive benefit in ApoE4 carriers because that's the one thing that...it
seems so promising,
[641] right, that these ketone, potentially ketone supplements or a ketogenic diet
can help modulate
[642] Alzheimer's disease.
[643] [Dom]: Yeah, we...and I think you could do it in different ways.
[644] My student presented yesterday, she presented this week, but she graduated
with her Ph.D.
[645] yesterday and her work showed that there's a remarkable increase in blood
flow, and previous
[646] work has shown that ketone bodies can increase brain blood flow by 30% to
40%.
[647] So that's another, when you have vascular dementia, when you have a
decreased, that
[648] being, staying in a state of nutritional ketogenesis...
[649] [Rhonda]: Or just brain injury in general.
[650] [Dom]: Yeah, it can have a profound effect.
[651] [Rhonda]: Did she understand any of the mechanisms or do you know?
[652] Can you talk about it?
[653] [Dom]: Yeah, we're looking at that.
[654] Well, we did ischemic wounds, which I mean, I guess you could kind of relate
to an aged
[655] brain, right, with clogged arteries.
[656] We did a Doppler blood flow measurement and showed that it spiked up
considerably when
[657] we can elevate ketones.
[658] One of the things, it was not dependent upon VEGF.
[659] So we looked at all the different factors, so VEGF was not increased in the
wound.
[660] We looked at a couple of different other things that we thought would be
increased.
[661] Well, the one thing that stood out in the data was adenosine.
[662] So adenosine levels are significantly elevated.
[663] Now adenosine is sort of thought to make us sleepy.
[664] You know, when we drink coffee, it's like an adenosine receptor antagonist.
[665] [Rhonda]: No way.
[666] [Dom]: There's high levels of ATP, sort of, being used and we think that they
may be causing
[667] an elevation of adenosine, but we really have to delve into the metabolomics
to understand
[668] why that's happening.
[669] Regardless, adenosine is a very powerful vasodilator, and it's in higher
concentrations, significantly,
[670] in the blood and that may be increasing the profusion of tissues, peripheral
tissues,
[671] and I think that was it.
[672] [Rhonda]: That's great.
[673] Did it have any effect on blood-brain barrier at all as you look at that?
[674] [Dom]: We haven't looked at that.
[675] My colleague has been, kind of, looking at that a little bit.
[676] We know with fasting and the ketogenic diet that you can increase
permeability to the
[677] blood-brain barrier.
[678] Things get through faster.
[679] [Rhonda]: You mean ketosis through fasting or both, combining the two?
[680] [Dom]: Well, yeah, sort of, yeah, fasting-induced ketosis or even the
ketogenic diet can help
[681] increase the permeability of the blood-brain barrier to a wide variety of
things.
[682] So if you are, sort of, the implications from his perspective that if you're
getting a chemotherapeutic
[683] drug, if you're getting some kind of drug that needs to cross the blood-brain
barrier
[684] that's impaired in some way, you might be able to get that across faster in a
state
[685] of fasting ketosis or the ketogenic diet.
[686] So maybe if you're fasting maybe there's just less stuff in your blood,
there's competition
[687] of things getting through and your blood's sort of clear and you introduce
the drug and
[688] you get more rapid transport because there's co-transporters and other things
or things
[689] that might be in their diet that may be impeding transport, there's multiple
independent lines
[690] of evidence to suggest that being in a state of ketosis can help better
transport things
[691] across, but when we talk about permeabilizing the blood-brain barrier, that's
like a bad
[692] thing, right, making it more permeable.
[693] In general, though, you get a knockdown of neural inflammation from the diet
and from
[694] therapeutic ketosis, which is something the epilepsy world is very interested
in.
[695] So there's a PET scan technique that allows us to look at neural inflammation
in the brain
[696] and we know that...this is a conference that I recently came from, that maybe
an excellent
[697] predictor of when someone's going to have a seizure.
[698] [Rhonda]: Yeah, that would be really cool to do.
[699] Possibly see if some of those effects remediated through this pentose
phosphate shunt because
[700] glutathione in the brain is one of the major ways of producing inflammation,
right?
[701] [Dom]: Yeah.
[702] [Rhonda]: So let's say you do this in an animal model and then you inhibit
some of the pentose
[703] phosphate enzymes that are using glucose now instead to make NADPH and say,
"Oh, is that
[704] mitigated?"
[705] Do you now not have that same effect?
[706] It'd be interesting to see if that's part of the mechanism because that's...
[707] [Dom]: It's undoubtedly is, yeah.
[708] [Rhonda]: Probably, right?
[709] [Dom]: I mean, it's part of that and, sort of, plays into all that.
[710] [Rhonda]: So I have another question for you.
[711] Thanks for, like, letting me jump all over the place because I'm super-
interested in
[712] this and don't... [Dom]: We need to follow up on the studies.
[713] So one of the studies we, sort of, we want to do, just following back up on
that question,
[714] is where ketones are being metabolized and what their contribution is to
normal brain
[715] energy metabolism and disease states and hypoxia states and traumatic brain
injury.
[716] So that's a lot to do.
[717] [Rhonda]: And those overlap, too, right?
[718] [Dom]: That's the direction of where we're going with that research, is
understanding
[719] that.
[720] [Rhonda]: Just to jump back again before I ask you this other question to
George Brooks'
[721] thing is that he's doing some interesting work working with some physicians
at UCLA,
[722] I believe, with traumatic brain injury.
[723] So these are people that come out with, like, head gunshot wounds.
[724] And they are looking at infusing lactate because he's the lactate guy.
[725] But ketone bodies will work the same way.
[726] [Dom]: I think it would work better from what we know.
[727] [Rhonda]: Maybe even better.
[728] [Dom]: Yeah, I think a cocktail of the two would be...
[729] And I've been debating whether or not to really study lactate sort of the
same way I'm studying
[730] ketones and maybe make lactate esters or lactate and just to see what kind of
results we see
[731] starting with our oxygen toxicity model and working from there, which is an
excellent
[732] model.
[733] [Rhonda]: Obviously, with the lactate, you have to have a intact blood-brain
barrier
[734] because if no oxygen is getting there, you will get the lactic acid build-up,
right?
[735] Because then, I mean, the mitochondria aren't going to be able to use the
lactate, which
[736] is converted to pyruvate as energy, so it builds up, but he has been doing
some work
[737] and looking at this glucose sparing in the brain.
[738] And in this, of course, ketone bodies would work very similarly, in theory.
[739] [Dom]: Do you know how he gets...?
[740] Does he use, like, a lactate?
[741] There's alpha L-polylactate, I think.
[742] That's, like, in a sports supplement and some other thing.
[743] [Rhonda]: He actually designed it... [Dom]: Oh, really?
[744] [Rhonda]: I think he's the one that, yeah, he's got a patent on that.
[745] [Dom]: Oh, wow.
[746] I was using that back in 1991 and -two.
[747] [Rhonda]: Cytomax?
[748] [Dom]: Cytomax, yeah.
[749] [Rhonda]: That's him, that's his.
[750] [Dom]: When I raced mountain bikes, that was, like, my go-to supplement,
alpha-L-polylactate.
[751] [Rhonda]: You should get in touch with George, he's great.
[752] [Dom]: I know, wow.
[753] [Rhonda]: So he... Let's see, what was I just going to say?
[754] I lost my train of thought.
[755] [Dom]: The delivery or the...
[756] [Rhonda]: Oh, yeah, so the delivery that he's doing...in this specific study,
they're doing
[757] it intravenously, so.
[758] But I was mentioning the blood-brain barrier has to be intact, otherwise, it
can go the
[759] opposite way where it's actually bad for you.
[760] But it would be really interesting to see so the question is, one, will this
lactate
[761] or beta-hydroxybutyrate or whatever ketone get into the MCT shuttle better?
[762] So there's questions of which one gets in there?
[763] And can they be used together?
[764] And there's all sorts of interesting things, but I'm sort of interested in
this for my
[765] own personal... [Dom]: Yeah, the neuroprotective capacity seems really
compelling.
[766] I mean, from what we know about lactate approaching it, going to back my old,
like, PhD studies
[767] or whatever during hypoxia, but it would relate to so many traumatic brain
injuries, hypoxia,
[768] so you're mitigating the damage from hypoxia.
[769] [Rhonda]: Yeah, and also traumatic brain injury is inducing damage, and so,
glutathione is
[770] one of the major ways of mitigating that.
[771] There's been studies showing that, early on, it's important.
[772] If you get that early on, it prevents the whole cascade so I think that
ketones and
[773] lactate both seem to have huge potential for glucose sparing, but that, you
know...
[774] [Dom]: I think chilling the body and infusing ketones, lactate with a couple
major few co-factors
[775] that are part of the bioenergetic use of these things would be a home run as
far as...
[776] [Rhonda]: Yeah, get some students on it.
[777] [Dom]: Yeah, these are grants that I'm kind of working on and writing, but
I'm not sure
[778] the funding agencies are ready to fully...they want, like, the magic pill
thing.
[779] [Rhonda]: So to bring it back to the magic pill, I'm kind of interested.
[780] So let's say someone like me that my diet is mostly, I eat a lot of plants, a
lot of
[781] greens, broad spectrum, carrots, I eat a lot of vegetables.
[782] So I get a ton of fiber.
[783] I eat a lot of fish.
[784] And I do eat, like, beans, so I'm not adverse to legumes or even to oats.
[785] I like fiber.
[786] Let's say, I wanted to, I'm, like, super-interested in beta-hydroxybutyrate
because I've been
[787] following a lot of the research from Eric's lab and I want to get some of
those benefits.
[788] I want to increase my FOXO3.
[789] I want to reduce my lipid peroxidation, I want some of that signaling effect.
[790] Plus, I want to beta-hydroxybutyrate to be around to get to the brain, things
like that.
[791] Can I potentially take a beta-hydroxybutyrate, whatever delivery source
powder, pill, whatever
[792] it is, and potentially achieve some of those same benefits that you get from
nutritional
[793] ketosis or ketosis from fasting?
[794] Let's say, but I don't eat a lot of, I don't eat refined carbs, so I'm not
getting a huge
[795] insulin spike for the most part.
[796] So do you know?
[797] [Dom]: So, yeah, you want to have your cake and eat it?
[798] But you don't eat cake, right?
[799] [Rhonda]: But I don't eat cake.
[800] No, I just eat fiber.
[801] [Dom]: You want to have your carbs.
[802] Yeah, that's that's really what we're working on right now and understanding
in a head-to-head
[803] comparison to see if we can derive the same kind of benefits from ketone
supplementation
[804] as we kind of with the ketogenic diet.
[805] We know the first kind of convincing studies of this that we did was with CNS
oxygen toxicity
[806] in our rat model, and in that case, the rats were eating a high-carbohydrate
standard rodent
[807] chow model, and we administered via an oral route a ketone supplement in the
form of a
[808] ketone ester.
[809] That's probably one of the more powerful forms of exogenous ketones that
we've developed.
[810] And that had the ability to prevent CNS oxygen toxicity from happening for
almost, over 500%
[811] delay in that time to CNS oxygen toxicity.
[812] And that could not be achieved with fasting, it could not be achieved with
anti-seizure
[813] drugs.
[814] So when it comes to enhancing and preserving brain energy metabolism in the
face of a tremendous
[815] oxidative stress that breaks down brain energy metabolism, we're able to
enhance that, preserve
[816] that.
[817] So we've also studied in our animal model of cancer, metastatic cancer simply
giving
[818] ketones to the animals on a high-carbohydrate diet, it was almost unexpected
the level of
[819] enhanced survival that we had with ketone supplementation.
[820] [Rhonda]: What kinds of tumor is it?
[821] [Dom]: This is a model of metastatic cancer and the primary tumor, it was
derived from
[822] a glioblastoma, the GBM.
[823] And that tumor cell line is so aggressive that when it's injected or
implanted into
[824] the flank of the animal, there's rapid systemic metastasis to all the organs
and the brain.
[825] And the model that was developed by Professor Tom Seyfried at Boston College.
[826] [Rhonda]: Didn't he publish a paper on...?
[827] [Dom]: It made the cover of the "International Journal of Cancer."
[828] Yeah, when I wanted to this study initially, I wanted to do a brain tumor
model, like with
[829] our diet and our stuff.
[830] He sort of wouldn't let me use the model.
[831] He's like, "Well, use this model of metastatic cancer because it's the most
aggressive thing
[832] out there and no one will..."
[833] He's like, "If you create a cure, something that can cure this animal with
metastatic
[834] cancer, you basically stumbled upon something that has the potential to cure
cancer."
[835] So that, kind of, intrigued me.
[836] So I knew working with his model would be kind of difficult because the tumor
burden...the
[837] animal has died so quick from the tumor burden, but it allowed us to screen a
variety of things
[838] and just using this model understanding that in aggressive metastatic cancer,
the cells
[839] are highly glycolytic, and they're highly in favor of using glucose and
glutamine probably
[840] as an energy source.
[841] We're looking at ways to target glutamine, but have not really, kind of,
implemented
[842] that yet in a combination therapy.
[843] But regardless, the animals are eating a high-carbohydrate diet with ketone
supplementation and it reduced
[844] tumor growth and proliferation.
[845] We think that the ketones may be altering glucose metabolism.
[846] [Rhonda]: They induce cell death?
[847] [Dom]: Well, we think so.
[848] There's more, like, sort of, apoptosis in the tumors that were there, but
just overall,
[849] there's just less tumor growth and less tumor burden and enhanced, most
importantly, a 50%
[850] to 60% increase in survival time in animals that are supplemented with this.
[851] And it wasn't...although the animals tend to eat a little bit less if they're
in ketosis,
[852] naturally, which makes a ketone supplement kind of an attractive thing for
people that
[853] are dieting because when you're sending energy to the brain in the form of
ketones, it has
[854] sort of a satiating effect on your body and it, kind of, shuts off that
hypoglycemic trigger
[855] that makes you want to binge or crave food.
[856] [Rhonda]: So is it changing ghrelin and leptin signaling, or...?
[857] [Dom]: We think so.
[858] Yeah, we think so.
[859] That's the next thing to look at.
[860] It does impact the satiety centers of the brain.
[861] It's not like you don't want to eat, but you have control over your appetite.
[862] [Rhonda]: You know what?
[863] I just thought of it.
[864] Lauric acid, which is C12, suppresses ghrelin in the gut, which is the hunger
hormone...
[865] That's kind of interesting, right?
[866] [Dom]: Is that specific for lauric acid?
[867] [Rhonda]: It's specific.
[868] [Dom]: I knew with certain fats.
[869] Really, lauric acid?
[870] That's interesting.
[871] [Rhonda]: It is.
[872] [Dom]: I'll look that up.
[873] [Rhonda]: Sorry to interrupt.
[874] [crosstalk 00:59:39] Let's continue because this is really cool.
[875] So you fed them a normal high-carbohydrate diet, gave them this ketone ester,
as we were
[876] talking about.
[877] [Dom]: Ketone ester, the same ketone ester, which is.
[878] [Rhonda]: The tumor burden was decreased, survival time increased.
[879] [Dom]: Yep, yep.
[880] And so that was another demonstration, and the data looked very similar to
the ketogenic
[881] diet.
[882] So we did the study.
[883] [Rhonda]: They're eating less, you said, right?
[884] [Dom]: They were eating slightly less, so we went back.
[885] We were thinking, "Well, maybe we're just getting a calorie-restriction
effect," because
[886] if you have a mouse model or any kind of cancer model and you overfeed it the
tumors are going
[887] to grow faster, and if you underfeed it you're going to restrict some of the
tumor growth.
[888] So they were eating a little bit less, but a maybe only 10% drop in body
weight.
[889] So we went back and we did a calorie-restriction control experiment, and
although there was
[890] a decrease in tumor, it was nothing like the ketone supplement.
[891] So ketones we know undoubtedly they have anti-cancer effects, and it could be
maybe through their
[892] expression of their gene expression as a histone deacetylase inhibitor.
[893] We think that they inhibit glycolysis.
[894] We think that they influence a number of pathways associated with cancer
growth.
[895] [Rhonda]: Did you measure mitochondrial respiration?
[896] [Dom]: Of the tumor and the tissue or...?
[897] [Rhonda]: Just, yeah, of, or any tissue, like, so let's say, did you give
them ketones in
[898] this.... [Dom]: We looked at ROS production.
[899] Yeah, it can sort of knock down reactive oxygen species production.
[900] [Rhonda]: In the tumor?
[901] Or in... [Dom]: In normal tissue, yeah.
[902] And now it's kind of interesting, too, that in the tumor tissue in previous
experiments,
[903] I showed that it could knock it down significantly, but I think in the paper
that we published,
[904] there was a slight decrease in ROS production.
[905] [Rhonda]: Yeah, that's interesting.
[906] [Dom]: We don't know, we do...our experiments are sort of like a top-down
approach.
[907] We find out what works and then, we're mechanistically going after it and
we're doing -omics work
[908] metabolomic in particular, and western blots and assays.
[909] So now we're going after the mechanism, and if we understand the mechanism,
we can, kind
[910] of, work backwards and tweak the molecule or adjust the diet in ways that may
enhance
[911] the therapeutic effects.
[912] [Rhonda]: It would be really interesting to do some of...
[913] I don't know if you can radio label these ketone esters and see if, like...
[914] [Dom]: Yeah, that's another thing we'll look at.
[915] [Rhonda]:...are they being used as a carbon source for ATP?
[916] Are they being used for something else, right, like...?
[917] [Dom]: Tracer studies.
[918] That's what we want to do.
[919] Yeah, we're going to partner with a company that has, sort of, the market on
doing these
[920] tracer fate associations.
[921] I think even doing a 13-Carbon glucose tracer fate association study where we
give this,
[922] and we give ketones we look at the fate of glucose in the presence and
absence of ketones
[923] and see how that may be influencing...
[924] [Rhonda]: There you go, is it going to the pentose phosphate?
[925] I mean, this is all stuff I really want to know, so I'm, like, super-excited
someone
[926] is doing it...
[927] [Dom]: And I wanted to do this from the beginning, but I think we want to
find out what works
[928] first and then now that we're identified, sort of, things that work with the
diet and
[929] ketone supplementation, hyperbaric oxygen, I was telling you.
[930] We also study, we do a lot of metformin work.
[931] We have...I have one excellent Ph.D. student and Nate Ward, he's looking at
the effects
[932] of metformin and on survival, tumor growth and doing a lot of the cell-based
assays.
[933] And he's also looking at dichloroacetate, DCA.
[934] So it activates pyruvate dehydrogenase.
[935] So he's looking at each one, individual, and also in combination as a cancer
therapy.
[936] [Rhonda]: Okay, I'll give you some of my ideas.
[937] And so I, just because I want someone to test this.
[938] But with DCA, so I did a lot of work, in my graduate research, I did a lot of
cancer metabolism
[939] I was in contact with Craig Thompson, Ralph DeBerardinis ... all those people
that we
[940] were talking about earlier, and they did a lot of glucose withdrawal studies,
glutamine
[941] withdrawal studies, blah, blah, blah, blah, like all that stuff.
[942] So I've got a lot of interest in it stemming back from years and years ago.
[943] And I also was very active in apoptosis, working with some of the top guys in
the field, Doug
[944] Green.
[945] So I, sort of, like, the way I think about all of this and the intersection
between them
[946] is that, like cancer cells are...
[947] Here's why I think cancer cells are glycolytic.
[948] So I mean, the Warburg effect you've talked about this and you published on
it.
[949] [Dom]: Is it a cause or a consequence?
[950] Yeah, damage respiration.
[951] That's sort of a...
[952] [Rhonda]: Right, so I don't think...and I think even Otto Warburg himself
published
[953] immediately after his original science paper because he originally theorized
damaged mitochondria
[954] were the cause it, but then it's not.
[955] It's not that the mitochondria are damaged enough that they're not respiring.
[956] Even to this day, I don't think we have really shown that or disproven that,
like, thoroughly.
[957] I don't think it's a cause, but the reason I think that cancer cells become
glycolytic,
[958] I don't know what causes it or how, I think the reason is they do is because
they don't
[959] want to use their mitochondria.
[960] And the reason they don't want to use their mitochondria is because
mitochondria produce
[961] ROS, and that will drive...
[962] This is the whole basis of how you kill a cancer cell, chemotherapeutic
drugs, the way
[963] they work is because they induce a little bit of reactive oxygen species
toxicity through
[964] a variety of mechanisms.
[965] [Dom]: Some more than others, but, yeah,
[966] [Rhonda]: Right, through a variety of mechanisms...
[967] [Dom]: Augment oxidative stress, yeah.
[968] [Rhonda]: ...which then pushes the cancer cell to death because normal cells
don't have
[969] boatloads of proapoptotic...
[970] If you look at any cancer cell, they have, like, boatloads of it.
[971] I mean, just tons and tons of proapoptotics, but they have countered it and
they are ready
[972] to die.
[973] They just need a little push, and DCA activates mitochondria, and I think
that's part of how...
[974] [Dom]: Hyperbaric oxygen, too.
[975] [Rhonda]: Hyperbaric oxygen, and we were talking about this earlier.
[976] I think that's also... [Dom]: Naturally stimulate it, yeah.
[977] [Rhonda]: Yeah.
[978] But so I'd like to see someone, sort of, test that because I think that
possibly DCA wouldn't
[979] be as potent at killing cancer cells if you gave it NAC or something that's
going to sequester
[980] the reactive oxygen species.
[981] [Dom]: Yeah, so could you block it, yeah.
[982] That's another interesting, that would be a good control to do, yeah.
[983] [Rhonda]: And studies have shown that giving mice supplemental vitamin E,
something that's
[984] going to potently sequester reactive oxygen species, actually allows tumors
to grow faster.
[985] And this has been [inaudible 01:06:35] in research.
[986] [Dom]: Yeah, N-acetylcysteine, too, and NAC.
[987] [Rhonda]: NAC, as well, yeah.
[988] [Dom]: With metastatic melanoma, I think, came out, yeah.
[989] [Rhonda]: Yep, yep.
[990] And then also there's one in lung cancer.
[991] I think it was the same group publishing that, too.
[992] But so I think that part of the reason...because cancer cells are so smart
that I think that
[993] not having their mitochondria active is very beneficial to them because.
[994] [Dom]: Or less mitochondria, too, as... [Rhonda]: Yeah, less mitochondria.
[995] [Dom]: So just a deficiency.
[996] And there's, yes, reports.
[997] So there's debate are the mitochondria defective or are there just a
decreasing number of mitochondria?
[998] I think it's both.
[999] I think mitochondria are structurally and functionally impaired, and I think
there's
[1000] a deficiency of them.
[1001] [Rhonda]: You mean in cancer cells or [crosstalk 01:07:21] normal?
[1002] [Dom]: I think in cancer cells, but I think in just normal cells, if you if
you're drinking
[1003] alcohol and bombarding the liver with oxidative stress that you're damaging
mitochondrial...you're
[1004] damaging the mitochondria, and over time, you are going to... [Rhonda]: Of
course.
[1005] Normal metabolism.
[1006] [Dom]: ...induce the Warburg effect by causing progressive damage,
mitochondrial oxidative
[1007] phosphorylation the cell's ability to maintain energy status through
mitochondrial oxidative
[1008] phosphorylation will be, its capacity will be impaired.
[1009] So it will activate oncogenes and oncogenes that drive the glycolate.
[1010] You'll have, some cells will die, the ones that survive are the ones that go
on and activate
[1011] the complementive genes that cause the transformation of a normal cell to a
cancer cell.
[1012] And that's how I, sort of, say that this progressive damage, you could do it
with radiation, you
[1013] could do it with chemotherapeutic agents, you could do it with inflammation,
chronic
[1014] inflammation is damaging respiration.
[1015] And it's that damaged respiration that can kill off cells and the ones that
survive,
[1016] that are hardy enough to activate the genetic program that allow them to
survive are kicking
[1017] on the oncogenes that will then go on and produce a Warburg phenotype.
[1018] So that's sort of the metabolic theory of cancer in a nutshell.
[1019] And it differs from what the thought leaders in the field are saying that
it's more of
[1020] default state to ensure the preservation of the cancer that that exists, but
not the cause,
[1021] but there's still this elusive enabling factor that we still don't know and
I think the metabolic
[1022] theory nicely explains is a pretty elegant explanation as to how a normal
cell converts
[1023] to a cancer cell.
[1024] And there are other genes involved, definitely, but, I mean, at the very
most, the most we
[1025] can link hereditary effect to cancer is maybe about 10% 7%, I think, was a
number that is
[1026] being thrown around now, but about 10% of cancers are from hereditary, but
this, the
[1027] epigenetics, I think, is something that will, yeah...and that's something
that's evolving
[1028] very fast.
[1029] [Rhonda]: I mean, I think that DNA damage, and that's been pretty well-
shown, damaging
[1030] DNA, both mitochondrial and nuclear DNA, the damage that can lead to
aberrant cells metab-,
[1031] like, cells.
[1032] [Dom]: And I think the mitochondria are more important because the
mitochondria have less
[1033] of a robust DNA repair mechanism.
[1034] And also the DNA of the mitochondria have more coding regions.
[1035] So if you bombard cells with radiation classically, radiation biologists are
taught that that
[1036] radiation is directly damaging nuclear DNA and then that kicks on, causes
the genomic
[1037] instability that causes cancers, but I think what is being more appreciated
now is that
[1038] the mitochondria are selectively vulnerable because their DNA repair
mechanisms are far
[1039] less robust.
[1040] They have much greater coding regions within their DNA, and they are the
ones kind of calling
[1041] the shots, they're making the energy, and if the energy status of the cell
goes down,
[1042] that's going to trigger the nucleus, that's going to trigger an energetic
crisis in the
[1043] nucleus, and the nucleus is going to kick on oncogenes to transform the cell
from a
[1044] normal to a cancer cell.
[1045] So the stability of a nuclear genome is tightly regulated to the energetic
state of the cell.
[1046] [Rhonda]: Yeah, so I have a little bit of a different way of thinking about
it mostly
[1047] because I'm also doing a lot of research on this experimentally.
[1048] So I measure damaged DNA, and I measure mitochondrial function after I
induce radiation in some
[1049] sort of... [Dom]: In primary cells?
[1050] [Rhonda]: In humans, in blood cells, yeah.
[1051] But so, mitochondria, you mentioned that nuclear, they have more repair
mechanisms, and that's
[1052] true, but mitochondria have very elegant and beautiful way of repairing
damage through
[1053] fusion, right, mitochondrial fusion and fission.
[1054] And this is a process, I mean, this is how we are able to repair damaged
mitochondria
[1055] because they're constantly fusing with healthy mitochondria changing, I
mean, exchanging
[1056] their DNA content, protein, things like that, and fissing back part.
[1057] So, of course, when those mechanisms become impaired, then that's, we start
to have more
[1058] accumulation of damage more because they can't repair.
[1059] [Dom]: Fission proteins, the production of the proteins that cause that are
also tightly
[1060] linked to oxidative stress.
[1061] [Rhonda]: Yeah, so I mean there's lots of different ways to repair damaged
mitochondria.
[1062] I also did a lot of work in graduate school.
[1063] But I don't think it's clear, I don't think that the metabolic theory of
cancer...
[1064] [Dom]: Far from clear.
[1065] [Rhonda]: You know, when you drop the ATP status in the cell, what happens
is the cell
[1066] dies and apoptosis gets trigger, and that's the primary...before oncogenes
are activated,
[1067] the cell dies.
[1068] [Dom]: Unless it's if it's more gradual, then you have the activation.
[1069] And most cells die.
[1070] So you have 999 cells die and then you have one that, kind of, activates the
complement
[1071] of genes that can, allows it to survive, gives it survival advantage.
[1072] That's what you get with chemo, too, or radiation when you blast a tumor
with radiation.
[1073] You get, there's few that can survive.
[1074] And if you do that over and over to the tumor or over the course of chemos,
you're kind
[1075] of making a super-cancer because you're increasingly selecting for the most
aggressive, glycolytic
[1076] hardy stem cell-like tumor cell by hitting it with more chemo, you're just
causing more
[1077] DNA damage and more transformation, mutagenicity.
[1078] Do you see it like that?
[1079] [Rhonda]: I don't know.
[1080] [Dom]: I'm not against standard of care, but I'm in favor of.
[1081] [Rhonda]: I wanted to believe, in graduate school, I wanted nothing more
than to believe
[1082] that mitochondrial dysfunction is the cause of cancer, but I just couldn't,
just couldn't
[1083] attribute to myself.
[1084] You know, I kept trying and trying, it would have been easier for my
graduate...
[1085] My graduate career would have been shorter, for one, but I just couldn't
enough evidence
[1086] to convince myself of it.
[1087] And that doesn't mean that it doesn't, it's not true, it just means, I
just...so far don't...I
[1088] don't think that's the origin of cancer.
[1089] I think that metabolic dysfunction plays a very important role in causing
cancer.
[1090] Most primarily through inflammation through all the effects of, like the
insulin signaling
[1091] and the inflammation, the reactive oxygen species.
[1092] All these things that are damaging the cell, but I don't necessarily see it
the way that
[1093] you, sort of, described it as them... [Dom]: An initiator.
[1094] [Rhonda]: Yeah, them changing or activating oncogenes.
[1095] I don't think that's really been shown.
[1096] [Dom]: I don't think anyone's studying that because...or studying it in the
way that would
[1097] make it clear, and I think it may vary between cancers like leukemia and
lymphoma and relative
[1098] to glioblastoma.
[1099] I mean, we know these are just, they have a different metabolic and a
different gene
[1100] signature.
[1101] Glioblastoma has hundreds, if not thousands, of genetic mutations.
[1102] You know, so hence the name glioblastoma multiforming, you have all these
different cell types and
[1103] everything.
[1104] Whereas other types of, like, for leukemia, for example, Gleevec works
marvelously well
[1105] because it's targeting something that's very specific.
[1106] So I think it will be impossible to get a clear answer to this and I don't
think it's...
[1107] I think maybe I'm a centrist.
[1108] So I'm somewhere in between the genetic versus metabolic, but leaning more
towards a metabolic
[1109] origin for many solid tumors, but there's some cancer that just, kind of,
throw me a
[1110] curveball like different types of lymphoma and leukemia, testicular cancer.
[1111] And they're all responsive to chemo, many of them are.
[1112] [Rhonda]: So what about, like for me, when I think of mitochondrial
dysfunction, to me,
[1113] that leads more to neurological dysfunction, neurological disorders, less
for cancer, less
[1114] of cancer like when you...mitochondrial mutations, genetic mitochondrial
mutations in mitochondria
[1115] genes, there's much more it has much more of an effect on causing certain
types of neurological
[1116] disorders rather than, like, cancer, right?
[1117] There's one, I think, the succinate dehydrogenase complex II, one of the
components.
[1118] I know this because I was trying to figure this out in graduate school, it
was, like,
[1119] a huge question.
[1120] [Dom]: And the really bad diseases, yeah, these mitochondrial disease, yeah.
[1121] [Rhonda]: So that's what I usually think of, when I think of mitochondrial
dysfunction,
[1122] I always think of it as being more of a, playing a causal or initiating role
in neurological
[1123] disorders and neurological dysfunction, and not so much as, plays a role.
[1124] I think that mitochondrial dysfunction and abnormal metabolism plays a role
in cancer,
[1125] but I don't think it's that initiator the way you were describing it.
[1126] I just don't think that's been shown.
[1127] [Dom]: I'm going to prove you wrong.
[1128] Well, our lab is we're not, we're just trying to find the answer.
[1129] And I think that as we move forward and develop the tools, I think the
answer will start to
[1130] get a little bit more clear at least using the models that we're using.
[1131] But I think regardless even of the origin...the origin is important because
if we...the way
[1132] we treat and prevent cancer is going to be different if we know the origin
for sure.
[1133] You know, if it is a mitochondrial versus genetic origin or whatever origin.
[1134] And, I mean, there's a case for viral origins of cancer, too, but these
viruses are, sort
[1135] of, the ones that damaged mitochondria, too.
[1136] I've been, sort of, interested in the viral origins of cancer.
[1137] It will influence how we prevent cancer.
[1138] So in addition to developing therapies, we want to study animal models, and
maybe inducers
[1139] of carcinogenesis and then adapt them, or to treat them prior to, or put
them on a therapy
[1140] prior to letting them live out their lives if they're prone to spontaneously
forming
[1141] tumors, or letting them live a few months prior to the introduction of a
carcinogenic
[1142] agent, and then seeing after X amount of time, whether the tumors form.
[1143] So can we prevent this does have profound implications for people who have
been, went
[1144] through chemotherapy or had cancer in the past, and should they be on some,
kind of,
[1145] preventative, should they do a therapeutic fast?
[1146] I get this question a lot for four or five days to a week every two or three
times a
[1147] year.
[1148] Should they do that?
[1149] Will it help them purge their body of pre-cancerous cells and put that
metabolic stress?
[1150] And these are important questions that no one is really trying to answer at
least from
[1151] a point of a prevention, sort of, idea.
[1152] So I think that's sort of on my horizon as the next big thing.
[1153] Can we develop and implement have these protocols available for someone to
do?
[1154] It could be intermittent fasting.
[1155] I personally like ketogenic intermittent fasting, where you're taking in
ketogenic fasting,
[1156] ketone supplements throughout the day and through 20 hours of the day and
you have a
[1157] 4-hour window where you eat a well-balanced ketogenic meal that's rich in
vegetables and
[1158] high in fats and protein.
[1159] And I think that could be something that could be implemented and something
that I personally
[1160] am interested in writing up a protocol for that.
[1161] The work, the studies done with metformin and showing that people who, type
2 diabetics
[1162] that are taking metformin have a 62% less chance of getting pancreatic
cancer.
[1163] We need to study that, you know?
[1164] Should that be a part of a comprehensive preventative therapy that people
should do?
[1165] I mean, I question, should I have my parents on this?
[1166] Like, should they, you know...?
[1167] [Rhonda]: On metformin?
[1168] [Dom]: Or yeah, on metformin, or my mom actually had cancer years ago.
[1169] Should she be on something like this?
[1170] Should everybody be after the age of 50 if most of their family members have
died of
[1171] cancer?
[1172] [Rhonda]: Have there been any long-term studies on the effects of metformin?
[1173] Because I'm very interested in it, but I'm always hesitant with any drug or
anything
[1174] that's perturbing biological systems.
[1175] [Dom]: Yeah, well, there's hundreds of thousands, if not millions, of people
on metformin so
[1176] I'd say, yeah, there's a long-term data out there whether...and a lot of
retrospective
[1177] studies have been done.
[1178] It's a relatively safe drug.
[1179] Lactic acidosis could be a problem in higher doses for some people maybe
with renal insufficiency
[1180] or impaired liver function.
[1181] And then, another thing that creeps up could be vitamin B12 deficiency.
[1182] So if you are...our ability to absorb vitamin B12 as we age is decreased, so
maybe a sublingual
[1183] form or even B12 injections in people that are older?
[1184] [Rhonda]: Why does metformin affect B12?
[1185] [Dom]: That's a question I don't know an answer to, but I can speculate that
it may influence
[1186] the transporter, and it also tends to make stools loose for some people.
[1187] Things go through you a little bit faster and impairs...
[1188] "Impair" is not a good word.
[1189] It changes the gut microbiome favorably.
[1190] So "Nature"....the paper there's that came out about two weeks ago showing
that there's
[1191] a favorable shift in the gut microbiome...
[1192] [Rhonda]: Now the reason why it's interesting.
[1193] [Dom]: ...with metformin, and that may explain it's type 2 diabetic it's
glucose-lowering
[1194] effects.
[1195] That sort of hit me as, "Wow, I had not really given that a whole lot of
thought, but it's
[1196] something that I think we should be looking into."
[1197] So I was like, "Yeah, we need to collect all the start collecting the feces
from these
[1198] animals that we're doing metformin on to figure out what's going on with the
gut microbiome,"
[1199] but I think it's influencing the absorption of B12 in some way that I don't
really know.
[1200] [Rhonda]: Does metformin...is it doing anything in addition to mimicking a
lot of the same
[1201] signaling pathways that caloric restriction does?
[1202] Like, is there something additional that...you know?
[1203] [Dom]: Yeah, yeah, AMP kinase, for sure.
[1204] So without a doubt, I mean, it's mimicking many of the pathways of
associated with calorie
[1205] restriction and with fasting.
[1206] To what degree it's mimicking that relative to a length or duration of
fasting?
[1207] I don't know.
[1208] We're doing some work right now looking at AMP kinase and mTOR, and
downstream and upstream
[1209] signaling insulin and these things, and trying to get a picture of this, at
least in a rodent
[1210] model.
[1211] And then, I'd like to ultimately replicate some of this stuff in humans, but
what I think,
[1212] I think metformin would be best used maybe in pulsing it a few times a year.
[1213] A lot of these things, metabolic interventions tend to work best when you
cycle them, I think.
[1214] And I really have not been doing that, but I think it's a theory that I have
been working
[1215] on.
[1216] I need my scrapbook.
[1217] [Rhonda]: Why do you think that is?
[1218] [Dom]: Because your body is similar with ketoadaptation that your body can,
kind of, reset to that
[1219] level, initially fasting on the ketogenic diet is sort of a stress and it
can induce
[1220] a hormetic effect in gene transcription and then we, sort of, get used to
that.
[1221] You know, our gluconeogenesis is upregulated to that level, but I think it's
good to maybe
[1222] pick probably not a high-carb diet, but maybe a Paleo diet a low-carb
ketogenic diet and
[1223] maybe something in between and do some intermittent fasting on occasional
days.
[1224] So I think this promotes metabolic flexibility.
[1225] It allows our body to adapt to different situations without being, kind of,
overwhelmed by the
[1226] stressor of it.
[1227] So I think, to some extent, it is hormesis.
[1228] And interestingly, metformin causes mitochondrial stress, and actually,
mitochondrial damage.
[1229] Some researchers coined the term that it's stimulating reactive oxygen
species production
[1230] and causing mitochondria dysfunction, metformin is, and this is kind of well
known in the
[1231] field.
[1232] So the general feeling is that, "Well, if I take metformin and I go
exercise, why is
[1233] it not killing my exercise capacity or my VO2 max or making me lethargic or
tired?"
[1234] It's not doing that, actually I think it's enhancing.
[1235] There was a [crosstalk 01:25:34] study.
[1236] [Rhonda]: Does it affect biogenesis?
[1237] [Dom]: It does.
[1238] So yeah, so the thought that it's kind of stimulating, there's a hormetic
effect.
[1239] It's damaging the mitochondria, some people believe this, and you get a
secondary, yeah,
[1240] effect through that way, like it's, kind of like an exercise drug.
[1241] But I approached it from the perspective that metformin could lower blood
glucose at least
[1242] if it was high and it activated AMP kinase, and it may decrease circulating
insulin.
[1243] So I approached it as a cancer drug from that perspective, but the more
conferences we go
[1244] to, there's a plethora of data coming out of metformin and a lot of people
are studying
[1245] it from the perspective of impaired complex I or complex II activity in the
mitochondria.
[1246] So they're looking at it from that perspective.
[1247] [Rhonda]: Interesting.
[1248] [Dom]: I know.
[1249] [Rhonda]: Yeah, it's super interesting.
[1250] Especially, you're giving its effects on longevity and cancer.
[1251] [Dom]: Yeah, yeah, and I think our most recent data did show an increase in
ROS production
[1252] in our cell line.
[1253] [Rhonda]: I wonder if that's how it's also killing the cancer cells.
[1254] [Dom]: Yeah, it could be.
[1255] [Rhonda]: You mentioned when you were talking about gluconeogenesis, you
triggered something
[1256] in my mind.
[1257] I wanted to ask you, I forgot.
[1258] So when you're in nutritional ketosis or fasting-induced ketosis, you need
to make glucose you still
[1259] need glucose, your red blood cells have no mitochondria and your red blood
cells are
[1260] important, right?
[1261] So you're making glucose through this process that you mentioned called
gluconeogenesis.
[1262] [Dom]: Glucose does not bottom out.
[1263] It's not like one or the other.
[1264] You're pulling fuel source from...
[1265] [Rhonda]: So I wanted to ask you about, like, how...
[1266] Has anyone looked at where...so if you are on a pretty strict ketogenic diet
or whatever
[1267] it is you're doing to get into ketosis, what...so does the liver use, like,
glycerol, lactate,
[1268] like, both as a primary source to make glucose?
[1269] Is that glucose predominantly going to red blood cells or does it go has
that been looked
[1270] at to see, like, where, you know...?
[1271] So red blood cells, like, are they getting enough of their glucose or they,
you know?
[1272] [Dom]: I think so.
[1273] I mean, you'd probably have to severely calorie restrict.
[1274] In those cases, you could become anemic or impair...your immune system is
also, too,
[1275] highly dependent to some extent on glucose and glutamate.
[1276] So, yeah, you have lactate, you have the glycerol backbone, the fats...
[1277] [Rhonda]: But they always have mitochondria.
[1278] [Dom]: Yes, yes.
[1279] So glycerol backbone of fatty acids or of triglycerides, for sure, lactate,
yes, and
[1280] amino acids, gluconeogenic amino acids in your diet also are a source of
glucose.
[1281] So gluconeogenic amino acids in your skeletal muscle your muscles constantly
breaking down
[1282] or remodeling especially in athletes.
[1283] So they're all sources.
[1284] The contribution of each of these gluconeogenic sources in each individual
probably varies
[1285] tremendously, but I would say that...
[1286] So glucose is always going to be there, and the body ensures through very
powerful homeostatic
[1287] mechanisms that your glucose is going to stay, rarely go below three, maybe
2.5 millimolar,
[1288] mine will drop two, go to four and stay within a very tight range, but what
does change considerably
[1289] from a glucose regulation standpoint is the insulin.
[1290] Insulin bottoms out to the point where I've seen enough blood work to show
that in many
[1291] cases, insulin and IGF-1 is below the reference range.
[1292] So insulin signaling goes down.
[1293] So if insulin's down, all those insulin pathways that you see on your
flowcharts are all going
[1294] to be suppressed and IGF-1, obviously, it's going to be lower and I think
that's a really
[1295] important consideration to factor in as it relates to cancer therapeutics,
cancer biology,
[1296] cancer prevention, even.
[1297] But also from the perspective of muscle metabolism.
[1298] And I think by keeping insulin signaling sort of low, you upregulate factors
that make you
[1299] more responsive to insulin.
[1300] So I think, and ketones can kind of compensate for a deficiency in insulin,
and that was,
[1301] a lot of the reviews by Richard Veech talked about that.
[1302] And the ketones themselves are anti-catabolic for protein sparing.
[1303] So if you're in a state of ketosis, you're protecting gluconeogenic amino
acids and skeletal
[1304] muscle from being degraded.
[1305] So you are as a metabolic fuel, but you're also, there's evidence that
you're inhibiting
[1306] proteolytic enzymes and pathways that would otherwise be chewing up your
muscle tissue
[1307] over time.
[1308] [Rhonda]: That's super-cool.
[1309] [Dom]: So it's anti-catabolic, yeah, so ketones are anti-catabolic in that
part.
[1310] [Rhonda]: So then you're probably not using, I mean, the gluconeogenic amino
acids as much...
[1311] [Dom]: From skeletal muscle, yeah, not as much.
[1312] So the idea is that you want to keep pumping in the fat, too, if you're on a
ketogenic
[1313] diet.
[1314] If it's not sufficient with ample amounts of fat, you're probably much more
catabolic.
[1315] So you want to ensure that you're using the fatty acids, go to the
mitochondria that uses
[1316] fuel, they keep the mitochondria happy as do the ketones.
[1317] Then the glycerol is kind of,shuttled and it's a very nice kind of an
elegant pathway
[1318] to ensure that we have that flux of glucose for vital functions like the red
blood cells
[1319] and making...there's an number of neurotransmitters and hormones that
require a baseline level
[1320] of insulin or glucose to be used.
[1321] [Rhonda]: Yeah, and we talked about... [Dom]: A lot of things, yeah.
[1322] [Rhonda]: Yeah, it's just so many things to discuss, but I'm really, like,
thankful that
[1323] you...
[1324] [Dom]: We can probably talk for, like, four or five days non-stop before we
like collapse
[1325] from...
[1326] [Rhonda]: You see how I get, I get, like, really excited and I'm like,
"Okay, wait,
[1327] I got to ask you this question.
[1328] I have this idea."
[1329] And then you're just, like, full of information.
[1330] So it's kind of neat.
[1331] [Dom]: A fun field to be in, right?
[1332] [Rhonda]: Totally, I guess.
[1333] [Dom]: I mean, I'm always, I feel like I'm so lucky to be in an area of...be
in an occupation
[1334] where discovery, we have the potential to discover something new that can
impact the
[1335] population and get paid for it.
[1336] [Rhonda]: Okay, that part, I get.
[1337] Because you totally, I'm sorry to change the subject, but you're talking
about glutaminolysis
[1338] and I have done a lot of research on this, and there are questions that I
would love
[1339] to be answered, but haven't been.
[1340] So, since you're looking at this and you have resources, I'll just throw it
out there.
[1341] Obviously, you said this is well-known literature that glucose and glutamine
are both source...cancer
[1342] cells love them.
[1343] It's like crack for cancer cells, both glucose and glutamine, and I've done
a lot of studies
[1344] on various types of cancer cells and these are in vitro.
[1345] So this is not in an animal model where I can, I withdraw glucose and the
cancer cells
[1346] will proliferate slower, some will die, but if there's glutamine there...
[1347] [Dom]: What's your level of glutamine?
[1348] [Rhonda]: Two millimolar.
[1349] [Dom]: Two millimolar, yeah.
[1350] [Rhonda]: Yeah, so then I would start withdrawing the glutamine and
glutamine withdrawal, this
[1351] is all in vitro, though.
[1352] Glutamine withdrawal would kill them within 24 hours, but.
[1353] [Dom]: Pretty lethal, yeah.
[1354] [Rhonda]: Very lethal, and has been shown at least some of the studies that
were initially
[1355] done by Ralph DeBarardinis when he was with Craig Thompson, and later when
he established
[1356] his own lab where he radiolabeled and showed that, actually, it was being
used predominantly
[1357] for macromolecular synthesis and not for which is...of course, that makes
sense because a
[1358] lot of tumor cells aren't using the mitochondria.
[1359] [Dom]: Making fatty acids, actually.
[1360] [Rhonda]: Making fatty acids, proteins, like, for new synthesis.
[1361] [Dom]: Like, cell membranes and stuff.
[1362] [Rhonda]: Right, so the question for you...the question that I have and this
is...
[1363] So that's one of the spectrum.
[1364] Okay, glutamine seems bad when you're looking from an in vitro perspective
and I did these
[1365] studies, but many people have published on this.
[1366] You're familiar with the literature.
[1367] But then there's the other perspective where really glutamine really is
believed, like,
[1368] to gut, to cells, it's very, very healing and therapeutic for gut, and when
you take
[1369] glutamine orally, the gut takes it, it's not getting into your bloodstream,
It's not being
[1370] so...
[1371] [Dom]: The gut and the liver take its share and very little of it actually
gets into the
[1372] bloodstream.
[1373] [Rhonda]: Right, so that's what I'm getting at.
[1374] The question is, if you have a mouse model of a solid tumor that's not gut-
oriented,
[1375] so it's not colon cancer, like let's say it's you got a pancreatic cancer
or...
[1376] [Dom]: Brain tumor.
[1377] [Rhonda]: ...brain tumor, then you give the mouse glutamine, is that really
is it really
[1378] going to affect the tumor or is it just going to help the gut?
[1379] I mean, of course, it can indirectly affect it, but the question for me, in
my mind, is,
[1380] well, yeah, if you had tumor in the gut, man, that's like crack for the
tumor.
[1381] Do not take glutamine, do not, you know...
[1382] But on the other hand, if you've got gut issues, you know...
[1383] [Dom]: It can be helpful.
[1384] [Rhonda]: Right, do you see what I'm getting at?
[1385] [Dom]: This is something that I have thought about.
[1386] [Rhonda]: You have?
[1387] [Dom]: Yeah, I think about stuff like this, yeah.
[1388] [Rhonda]: I'm not alone, yeah, well, in vitro is very different because the
way our bodies
[1389] are working and the way glutamine when we take glutamine, it's affecting our
gut, it's
[1390] very important.
[1391] I mean, it helped.
[1392] It's helped me.
[1393] [Dom]: I used to take it.
[1394] [Rhonda]: It's helped me with gut, but then there's this whole, like,
conflict in my head
[1395] around...cancer cells love it, but the question is if I'm taking it orally,
and I have some
[1396] cancer cells, in my, I don't know, my liver or something, then I guess you
said liver
[1397] is one that does.
[1398] it does use it, but, so the question is, is that harming me or is it helping
me?
[1399] [Dom]: Should you take it or not?
[1400] Yeah, I get that question a lot.
[1401] For GI cancers and liver cancer, I would say do not supplement glutamine,
and I would say
[1402] under most conditions...I always say in those states, I actually tried to
look up the glutamine
[1403] content of food, and you might want to avoid it or minimize glutamine, high
glutamine-containing
[1404] foods.
[1405] Otherwise, I wouldn't really pay too much attention.
[1406] Some patients really stress out about it but I think if you just keep your
protein low
[1407] to moderate, or keep your protein at a level to ensure proper regeneration
and just, kind
[1408] of, replenishment of your normal cells, and prevent protein deficiency, and
being in a
[1409] state of ketosis will help with that to some extent, but glutamine is pretty
low on...
[1410] [Rhonda]: The classical ketosis, right, where it's 10% protein?
[1411] [Dom]: Yeah, yeah, and I think that will lower your blood glutamine levels,
just being on
[1412] a ketogenic diet will do that.
[1413] And then, you could further lower it by selecting protein food sources that
are lower on the
[1414] end of, are glutamine.
[1415] I'm not for avoiding protein types of supplements, avoiding glutamine
supplementation all together.
[1416] And you may be able to further suppress glutamine by taking a supplement
that's like high branched-chain
[1417] amino acids, high essential amino acids.
[1418] So taking a supplement that is formulated in a way that, kind of, gives you
essential
[1419] amino acids, excluding glutamate, of course.
[1420] Glutamine is not an essential amino acid.
[1421] It's conditionally essential.
[1422] But then you...I don't think you'll run the risk of being deficient in
glutamine in any
[1423] way, but I would avoid, I would pay attention to it if you have a GI cancer
or liver cancer,
[1424] and then if... [Rhonda]: The liver, I didn't know, but yeah, GI was...
[1425] [Dom]: So if you have, say, for example, like, a brain tumor and you're
taking a drug that
[1426] can impair systemically, you're taking something that impairs your GI
function, and it may
[1427] be helpful to take a little bit of glutamine because I don't...I really
don't think...the
[1428] gut's going to be very greedy when it comes to glutamine.
[1429] [Rhonda]: It's very greedy.
[1430] [Dom]: So I think just maybe even 5, 10 grams of glutamine to help repair
your gut.
[1431] We know that if your gut permeability is impaired, that can wreak havoc in
your body as far as
[1432] systemic inflammation.
[1433] So try to...and there's other ways to repair your gut, too, but I think
glutamine may be
[1434] a factor in helping to ensure proper gut.
[1435] [Rhonda]: Yeah, there's definitely other ways.
[1436] I mean, I think that you know, like I was saying, fiber, good diet, and
things like
[1437] that.
[1438] [Dom]: Exactly.
[1439] But glutamine has been used in oncology.
[1440] So, yeah, glutamine is for helping people with chemo combating the issues
with chemo.
[1441] And then glutamine has almost been like a staple, you know...
[1442] [Rhonda]: So they give it to chemo patients, kind of...
[1443] [Dom]: Help them recover part of the immune system, too.
[1444] [Rhonda]: Because your gut regulates the Immune systems well.
[1445] [Dom]: Your gut is, like, what, 70%, 80% of your immune system, right?
[1446] So it's huge.
[1447] So we want to keep your gut as healthy as possible.
[1448] And there are many drugs out there that really impair gut mobil-, or...
[1449] [Rhonda]: And diets, too.
[1450] [Dom]: Yeah, and diets, too.
[1451] [Rhonda]: Yeah, so, cool.
[1452] All right, Dom.
[1453] [Dom]: Endless amount of things we can talk about, right?
[1454] [Rhonda]: I know, right.
[1455] Just keep going, Dom.
[1456] [Dom]: Yeah, I've had, like, 100 things pop into my head.
[1457] I was like, "Should I bring that idea or should I not?
[1458] No, no, no."
[1459] [Rhonda]: Bring it up, I'm always interested in new things, so...
[1460] [Dom]: We do have ketone esters here and not too many people are brave
enough to try them,
[1461] but we have a lot of studies going on using a wide range.
[1462] See, they're all different types of ketone supplementation, and I know
that's, kind of,
[1463] was like one of your main interests that you wanted to hit on.
[1464] [Rhonda]: Yeah, yes.
[1465] [Dom]: And I would say stay tuned because we have so much going on right now
with, like,
[1466] all these studies looking at ketone supplementation and the answer that I
want to really focus
[1467] on is what, kind of, benefits are we deriving?
[1468] There's been so much work on the diet what kind of, benefits can we mimic
with just purely
[1469] a ketone supplementation?
[1470] And can we further augment the therapeutic efficacy of the ketogenic diet
with supplementation?
[1471] So with diet and then we supplement 10%, maybe 20% of the calories with some
form of ketone
[1472] supplementation.
[1473] Hopefully.
[1474] we work to formulate it in a way that makes it pleasurable to taste and not
taste like
[1475] gasoline, if we can do that.
[1476] [Rhonda]: Does it taste really like gasoline?
[1477] [Dom]: Yes, yeah, like jet fuel, really.
[1478] It's pretty bad, but the ketone esters do, but we're working on the ketone
salts that
[1479] you might know of, KetoCaNa, ketone, there's a couple ketone products out
there.
[1480] [Rhonda]: Are there benefits or drawbacks taking one or the other?
[1481] [Dom]: The salts are like as far as ketogenic potential, are pretty similar
to MCT.
[1482] So they're another level up from MCTs, I would say right now, but they're
being formulated.
[1483] We're formulating them and testing them in ways to make them closer in
potency to the
[1484] ketone esters.
[1485] And I think... [Rhonda]: Are these available, like, to consumers?
[1486] [Dom]: Not for human use yet, but we're working on doing all the safety
studies and then all
[1487] the palatability work and formulating them in a way that probably within the
next six
[1488] months to a year, that they will be out.
[1489] [Rhonda]: Oh, so soon?
[1490] [Dom]: We're tracking them for therapeutic purposes.
[1491] So for clinical trials, for specific diseases, and then, they kind of work
backwards to the
[1492] consumer broad market eventually.
[1493] But, and for oxygen toxicity, obviously.
[1494] That was the original application for oxygen...
[1495] [Rhonda]: Yeah, I'm also really interested in it just for movement
disorders.
[1496] My mother has orthostatic tremor, and she's not the kind of person that is
very compliant.
[1497] I mean, she may try something for, like, a couple of days, maybe a week.
[1498] [Dom]: That's typical.
[1499] [Rhonda]: Very typical, and drives me crazy because I feel like I have so
much knowledge,
[1500] I could help her, and it's just very hard to get her to do, to get any
movement, but
[1501] I would...I'm very interested in the potential use of ketone esters or
whatever delivery
[1502] method that's the best in potentially helping reduce her tremor because when
she stands
[1503] still, her legs shake and it's very, it's inhibiting to her life, I mean
having to...
[1504] When she's walking, I mean, she's fine, but if she stands, stands in line...
[1505] [Dom]: From sitting to standing, and just...
[1506] [Rhonda]: No, even walking to standing, just standing.
[1507] So standing still, it's called orthostatic tremor, and it's common enough...
[1508] [Dom]: Yeah, yeah, I've heard about it.
[1509] [Rhonda]: ...that, but it's not like, it's not as common as essential
tremor, but she
[1510] also has essential tremor, as well, [crosstalk 01:43:13] kind of
interesting.
[1511] Yeah, so I'm extremely interested in the potential benefits of nutritional
ketosis, yes, but,
[1512] like I said, she's not very compliant.
[1513] So I'm, sort of, like, okay possibly giving her some sort of ketone ester
see how that
[1514] would affect...because then again, if she...
[1515] [Dom]: You might want to start with MCTs.
[1516] I mean, something, what I showed you today, the MCT Powder by Quest
Nutrition is really
[1517] pretty close it's very potent from a ketogenic perspective and if you were
to take four to
[1518] six to up to eight scoops a day, which would be tolerable in a course of a
day, she would
[1519] be in a mild state of ketosis and would be getting the benefits from it.
[1520] [Rhonda]: Really?
[1521] Do you think that would be easier than, like, the MCT oils?
[1522] [Dom]: From perspective of GI tolerance, yeah.
[1523] Many people I would say up to 40% or 50% of people are going to have some
tolerability
[1524] issues with liquid MCTs.
[1525] At least a big dose that gets you up into sustainable ketosis.
[1526] You can incorporate MCTs in your food, even salad dressing is cooked with
it, mix it in
[1527] with different things, but the MCT powder I found was, is you can get levels
about twice
[1528] as higher than you can with the oil just simply because your GI tolerance is
much better in
[1529] a powder form.
[1530] So it's formulated in a way that, kind of, allows us to sustain the slower
release of
[1531] the MCT instead of a liquid which tends to...some people just can't tolerate
the liquid at all.
[1532] I can tolerate fairly high amounts relatively speaking, but I could tolerate
much higher
[1533] amounts with an MCT powder.
[1534] [Rhonda]: You can put it, like, and you can mix it with water, coffee, tea
or whatever.
[1535] [Dom]: Yeah, I could put it in coffee.
[1536] [Rhonda]: Yeah, [inaudible 01:45:05]..
[1537] [Dom]: Yeah, and you liked it, right?
[1538] [Rhonda]: Yeah.
[1539] [Dom]: I mean, it's like great.
[1540] [Rhonda]: It's like creamer, but, you know.
[1541] [Dom]: So they really nailed that product.
[1542] [Rhonda]: The coffee makes her tremors worse so she doesn't drink caffeine.
[1543] [Dom]: No stimulants, yeah.
[1544] What about decaf coffee or something like that?
[1545] [Rhonda]: Um, I think she... [Dom]: It's a good vehicle for MCTs.
[1546] I mean, you could put, like, butter and MCT.
[1547] I know you don't like sweeteners, but I just put in a little pinch of stevia
in there.
[1548] [Rhonda]: Stevia is okay.
[1549] [Dom]: And it makes it a really enjoyable drink for me.
[1550] [Rhonda]: Yeah, that's great that it's available because I'm, kind of...that
would be something
[1551] that we probably try, seeing if that has any effect on her tremors.
[1552] [Dom]: As you know, diet is key, though.
[1553] [Rhonda]: Diet is key, yeah, because if you're, like, eating a bunch of
refined crap and processed
[1554] foods, and just terrible diet, it's not much that ketones are going to do.
[1555] Right?
[1556] [Dom]: Yeah, and what I find in people that are resistant is that if you can
introduce
[1557] foods that replace other foods which is good, and I think Quest Nutrition,
too, is making
[1558] a line of... they're not out yet, but I've tried everything from a ketogenic
Oreo to
[1559] a ketogenic brownie to ketogenic chocolate bars.
[1560] So these are foods that when you eat them, you're in ketosis, and they taste
as good
[1561] or good as their high-sugar counterparts that are on the market.
[1562] So I see that as almost like the next frontier, like, designing, developing
ketogenic food
[1563] products from whole food ingredients that are from natural sources and not
synthetic
[1564] sweeteners or artificial flavors and things like that, that will allow you
to...will ensure
[1565] greater compliance of nutritional ketosis.
[1566] Mainly at first, maybe targeting disease populations, but undoubtedly people
from all walks of life
[1567] will be wanting to use these foods especially if they taste good.
[1568] And I can tell you from kind of a beta tester point of view that it is
possible to create
[1569] a line of food products from crackers to chips to, you name it, really.
[1570] It's possible to...it's pretty easy to make something taste good when you're
working with
[1571] fat because fat has...fat and salt kind of make things, are really good on
our palate.
[1572] And they're very satiating.
[1573] So we'll eat it a little bit, and it's just enough to sustain us and give us
the energy
[1574] that we need without overeating.
[1575] [Rhonda]: Yeah.
[1576] [Dom]: So I'm excited about the ketone supplements, obviously, but I'm
excited about a line of
[1577] ketogenic diet food products that can ensure compliance in people who really
need it.
[1578] Because I say that's where...there are people who know the diet would help
them from a therapeutic
[1579] standpoint, but they just lose interest after trying to follow through with
the diet.
[1580] [Rhonda]: Yeah, and it would help eliminate a lot of suffering especially
for some of
[1581] these people with these, like you said, drug-resistant seizures.
[1582] [Dom]: Yeah, for sure.
[1583] [Rhonda]: That, so, yeah.
[1584] Well, super-cool, Dom.
[1585] Thanks for speaking with me and for doing all this really cool research.
[1586] I'm going to keep following your researching.
[1587] [Dom]: Thanks for visiting.
[1588] [Rhonda]: If you want to learn more about your research, what you do, things
you talk
[1589] about anything related to your research, where can we hear more about you?
[1590] [Dom]: I would say I'm working on a more interactive, but broader site, but
for right now, ketonutrition.org,
[1591] I think, would be the site to go where I compile a bunch of links on there
with dietitians,
[1592] ketogenic-savvy, registered dietitians that I recommend, books, talks from
IHMC, which
[1593] I'm excited to listen to your IHMC talk this week because that's on there.
[1594] So I would say that ketonutrition.org would be the site...
[1595] [Rhonda]: Ketonutrition.org.
[1596] And what about social media, do you have any?
[1597] [Dom]: Yeah, Facebook.
[1598] You can find me on Facebook, on Twitter, LinkedIn, Pinterest, maybe I go
there sometimes.
[1599] But Facebook, Twitter, and LinkedIn are sites where I will post information
about our research
[1600] or related research in the area of nutritional ketosis and metabolism.
[1601] [Rhonda]: Awesome.
[1602] Thanks a lot, Dom.
[1603] [Dom]: Thank you.
[1604] Thanks for having me.