So, in neurons, like it's been estimated that in neurons that are active, during
normal activity, up to 50% of the ATP is used to drive the sodium pump and
the calcium pump to pump those ions back out after the neuron is fired.
So, when the neuron fires an action potential, when it's active, the sodium
and calcium rush in, then you get a voltage change across the membrane.
And then, that's propagated.
And it's important to rapidly remove the sodium, potassium
so that the charge across the membrane gets back to where it was.
And so, yeah, during normal aging, Alzheimer's, Parkinson's, if the
mitochondria aren't working even a little bit less well than they are,
there's a tendency for hyperexcitability.
And so, anyway, that's the destroyer part of the "Sculptor and Destroyer."
How much of a role would the GABA production from being
in ketosis help negate that?
Well, that's important.
That's a good question.
I think that, from a drug standpoint, drugs that enhance
GABA tone could be beneficial.
It's a tricky business because glutamate is critical for learning and memory.
And, you know, all our circuits, essentially, are glutamatergic.
So, you don't want them to go out of control, but you don't
want the activity to go too low so the function isn't optimal.
What about testing that with something like a ketone ester
to see, you know, transiently?
No, we've done that.
So, Richard Veech in, I can't remember what year again.
Anyway, bottom line is he sent Paul to come to my lab and what was his
name, Kashi [SP] , a Japanese postdoc.
And together with people in my lab, in a mouse model Alzheimer's disease.
They gave animals in the food ketone ester or not, and then we had isocaloric.
And then, we looked at the amyloid accumulation, the neurofibrillary
tangle, tau in learning and memory.
And the ketone ester was beneficial.
And now, I think the ketone ester is very promising.
A friend of mine up in Canada, Steve Cunnane, has done some
really nice work with PET imaging.
So, all right, so one can get images of relative levels of utilization of
glucose by brain cells or of ketones.
So, Steve Cunnane, used the radiolabeled glucose, 2-deoxyglucose,
and radiolabeled, he used acetoacetate, but it doesn't matter.
He didn't use beta-hydroxybutyrate.
Okay.
So, these are just initially normal people but he's doing studies on people with
mild cognitive impairment and Alzheimer's.
So, he had them, when they're eating carbohydrates, brain
cells use mainly glucose.
When they go on a ketogenic diet, the brain cells switch.
They clearly switch.
It's very clear.
They use a lot more ketones, maybe still using some glucose.
And then, in Alzheimer's disease, other investigators, decades ago, have shown
that very early on, you know, people with mild cognitive imapairment, even somewhat
during normal aging there's reduced glucose utilization by brain cells.
And however, we think, based on some of our animal studies, and some
preliminary studies in Alzheimer's patients of Steve's that, at least, in
people with early Alzheimer's disease, even though their brain cells have
problems using glucose, they still seem to be using ketones very well.
So, this is something that I'm excited about.
And there's a neurologist that was under me at NIA that he's actually finishing
up a study of intermittent fasting and people at risk for cognitive impairment.
And he may be one of the places where these ketone ester studies are done.
And then, you know, Kieran Clarke's work at Oxford with ketone ester
and elite British cyclists.
So, yeah, that's a big deal in endurance athletes.
You know, the cost, right, for the average person, the cost of the ketone ester
is way too much to make it practical.
And we don't know for sure.
What would be interesting to do like a comparison of someone, you
know, fasting versus ketone ester.
You know, then you could maybe sort out whether any endurance-enhancing
effect of intermittent fasting is in addition to ketone ester, or
if it's all due to the ketones.
But, yeah, bottom line is, I think that's really promising.
As you mentioned, the cost is very prohibitive for most people.
And I think of it.
So, I can tell you from just anecdotally, and I'm so sorry, I know you have to go.
It's great speaking with you.
As a sort of a foot in the door to like maybe someone who is not motivated to
try a ketogenic diet, perhaps they have cognitive decline or dementia, or maybe
even you know, early-stage Alzheimer's, when they notice a beneficial effect
from the ketone ester, and that's a lot more motivating for a person to
have a real-world piece of evidence where they feel an effect and say,
"Okay, well, maybe I can try this diet.
That's not, you know, that quite easy to do."
But they may be more motivated to do it.