[Rhonda]: I guess some of Richard Veech's, have put some ideas out there about the...
[Dom]: Ketones, direct effect, yeah, on that, too.
[Rhonda]: Yeah, it's so funny because in my mind I always think about like, well, if you're
inducing your mitochondria to work more, you're going to make more reactive oxygen species,
right, and that's, sort of, what I think would be a driver of killing abnormal cells, cancer
cells that are primed to die.
They're expressing way more pro-apoptotic proteins they've countered it with anti-apoptotics.
All they need is a little push, a little reactive oxygen species pushed to death.
[Dom]: And that's increased initially.
[Rhonda]: It is.
[Dom]: So yeah, it actually activates like a Nrf2.
So when someone gets on a ketogenic diet, it's a stress to the body and you...
[Rhonda]: Yeah, so you are...you aren't making more, because if you are causing your mitochondria
to only work, right, that's the only way you can make energy, then you'd think that you
have to be making reactive oxygen species.
At least if you're looking in the context of a cancer cell, which just would be glycolytic
and not using the mitochondria at all, right?
Then definitely there would be a much more, an increase in ROS.
So ketone, so you're saying that it can suppress ROS.
Is that through some of what Richard Veech has put out there in the semi-ubiquinone,
how it's like...
[Dom]: Oxidize Q, makes it less available.
[Rhonda]: Yeah, right, because that's the most...
[Dom]: If Q is oxidized, yeah, so.
[Rhonda]: So Q being ubiquinone.
[Dom]: Yeah, ubiquinone.
If ubiquinone is oxidized, which is achieved with our beta-hydroxybutyrate metabolism,
if that's oxidized, then you have less availability for that electron to react with molecular
oxygen in the metabolic pathway.
So you would produce less superoxide anion, which is your precursor to more reactive oxygen
species.
And that's been shown elegantly in a number of models including the cardiac model, which
he did, the Langenhorn [SP] model, the perfused heart preparation showing that you get a greater
hydrolic efficiency of the heart in the presence of ketones.
You know, with a given amount of oxygen, you can generate proportionally more ATP, energy
currency.
[Rhonda]: Is there another way that ketones also suppress ROS?
Or is that through the hormetic effect of activating mitochondria, then increasing Nrf2
and things like that?
[Dom]: Yeah, that would be a secondary effect.
I would say from a acute point of view, as simply as a metabolic fuel through the mitochondrial
efficiency is greater.
So you have a greater mitochondrial membrane potential, a greater driving force for ATP
synthase to make ATP.
So it energizes the mitochondria in a way that would be expected from a metabolic fuel
that's, sort of, superior from a bioenergetic point of view.
So you have a greater capacity to generate ATP for a given amount of oxygen that's available.
So with that occurring, the metabolic efficiency of the cell would be, sort of, preserved,
you're using less oxygen to make the same amount of ATP, less reactive oxygen species.
And, of course, if you're shifting away from glycolysis and shifting towards oxidative
phosphorylation...
[Rhonda]: So in the context of a cancer cell.
[Dom]: In the context of, yeah, any kind of cell, like our tissue, really, skeletal muscle
or cancer cell, yeah, you are forcing the body in a way and to stress, initially, to
upregulate mitochondrial machinery, really, and more mitochondria will start budding off
and creating mitochondrial biogenesis.
[Rhonda]: So it increases mitochondrial biogenesis.
[Dom]: Yeah, the number of mitochondria.
Then, the proteins that are associated with the electron transport chain, those proteins
are upregulated.
[Rhonda]: That's very interesting.
It acts very similar to lactate.
I don't know if you're familiar with any of, like, the brain work, and George Brooks, and
lactate.
[Dom]: Yeah.
I...very interested in lactate as a graduate student.
[Rhonda]: Because it does the same thing.
Goes to the same transporter, right?
[Dom]: Yeah, at MCT.
I studied lactate as, sort of, an undergrad and graduate student, like, I am studying
ketones now as an alternative fuel.
[Rhonda]: Oh, really?
We're you looking at it in the brain?
[Dom]: Yeah, during hypoxia.
So I studied the neural control of autonomic regulation, so brain hypoxia and what our
brains do under hypoxia.
And lactate is a big player in preserving brain function, viability, health, and I studied
lactate as an alternative energy source under hypoxia.
And now, I think of ketones as, like, the alternative energy source when your brain
is under normal physiology.
And I think there are some uses for lactate, too, as a fuel.
I think when we exercise we're creating lactate and we feel good, it's not really talked about.
It's something that I want to study and maybe talk about a little bit more is that the lactate...you're
also sending, not only are you sending ketones to your brain, but you're sending lactate
to your brain, and I think that's maybe not talked about that much, but there's a potential
out there for lactate supplements.
[Rhonda]: George Brooks in UC Berkeley, he's...I don't know if you're familiar with any of
his work.
[Dom]: A little bit, yeah, peripherally.
[Rhonda]: He pioneered the whole lactate shuttle theory, but he's been looking at the effects
of lactate generated during exercise, for example, when you're forcing your muscle cells
to work harder and you're making more lactate, it gets over, it crosses over the blood-brain
barrier gets into neurons.
So neurons themselves actually use lactate generated from astrocytes.
So they are using, I mean, neurons actually using lactate.
It's also a thermodynamically and energetically favorable source of energy much like ketones.
And so neurons like doing that because, one, it's easier, and two, because glucose can
then be freed up to be shunted into the pentose phosphate pathway, which can be used to generate
NADPH, which is important for glutathione recycling.
[Dom]: Antioxidant capacity, yeah.
[Rhonda]: Right, which makes sense why...
Probably, I think there's a lot of parallels between ketone bodies and ketone supplements
and how they're not only being used as a preferential source of energy in the brain.
Do you know anything about this, about, like, how frees up glucose then to be used for other...
[Dom]: Glucose sparing.
[Rhonda]: ...metabolic pathways?
Yeah, glucose sparing.
[Dom]: Yeah, it's thought that some of the work by Stephen Cunnane, I think, is shedding
light on this, too.
[Rhonda]: Where is he at?
[Dom]: He's in Canada.
I forget the institute that he's at.
Joe LaManna has done some similar work and he's at Case Western and looked at the, kind
of, the interaction of what does the brain prefer...what's the preferred fuel source
for the brain.
I get this question a lot.
I think it depends on, you know...I don't know if it's right to say that the brain always
prefers ketones.
[Rhonda]: The brain cell we're talking about, for one.
The neuron, astrocytes.
[Dom]: Neurons and astrocytes.
But, yeah, I guess, I mean, maybe we're definitely biased towards understanding neurons relative
to astrocytes.
[Rhonda]: I think most people that ask me that question are....
[Dom]: Astrocytes are fascinating.
I think we need to study that more.
But I think in the context of, like, aging and a context of traumatic brain injury or
pathology, I think the brain will really prefer to use ketones because...or in the context
of some kind of stress hypoglycemia or something like that, I think the brain will also prefer
to use ketones.