Peter Attia, M.D. on Macronutrient Thresholds for Longevity and Performance, Cancer and More
[Rhonda]: Hello everyone, I’m very excited
to be sitting here with Dr. Peter Attia who
has a medical degree from Stanford University.
And he has done a residency in surgery, I
believe, and also some research in surgical
oncology with Dr. Steven Rosenberg, I believe.
Very interesting background, broad interests.
I know of him from being on Tim Ferriss’ podcast,
where he talked a lot about some of his self-experimentation
using a variety of different dietary techniques.
But I’m really excited to talk with Peter
today because we have a lot of overlap in
our interest in longevity, particularly the
role of diet, nutrition, and other lifestyle
factors like sleep, exercise, stress in longevity.
So thanks for being here, Peter.
[Rhonda]: So maybe we could start a little
bit with what are you eating, then, to try
to delay the aging process like what is…so
diet obviously plays a very important role
in aging and I’m trying to figure out exactly
the best diet to eat and talk a little bit
about what I think, but I’d love to get some
of your thoughts.
[Peter]: So I mean think the short answer
is we don’t know definitively, and I don’t
think we’re going to know definitively if
you define “definitively” as a randomized
clinical trial of longevity in humans.
We have to posit that we’re never going to
figure that out.
So instead we have to rely on proxies.
So we look at proxies in animals where you
can do virtually anything you want in a totally
controlled setting but then you run the risk
of two things.
One, are you identifying diets that are clinically
and biologically meaningful to your host?
For example, if you put a humanized diet into
a mouse what you learn may or may not extrapolate
to the human.
And then secondly, you’re really hindered
by the idea that you’re studying that animal
in an artificial environment and when you
reduce the risk of a subset of death, a subset
of causes of death which is effectively metabolic
disease, you’re often unable to measure what
in my opinion is an underappreciated risk
that comes on, which is, sort of, the more
sudden and traumatic causes of death that
we take for granted, especially in the case
of caloric restriction.
So that’s the problem with animals.
Then what we do in humans is we kind of rely
on our best proxy biomarkers that we think
reflect the systems that drive aging and we
can measure those things over time and sort
of estimate what we think is the effective
this dietary change or that dietary change
or this lifestyle change or that drug change
on those things.
And so I basically try to focus my efforts
on, sort of, converging those two worlds but
acknowledging that we’re never going to know
the answer for certain and we’re going to
have to use our best judgment around those
things and hope that in time certain other
things do become available.
For example, it would be really great if there
is a way in the blood to measure the activity
We don’t have that.
It would also be great if we could measure
other growth pathways like the RAS pathway
without having to rely on tissue biopsies
and things like that.
[Rhonda]: So just for people that don’t know
what mTOR is, can you explain why that’s really
So there are probably, depending on who you
talk with, I would say there are two or three
major growth pathways in the body that are,
kind of, responsible for growth both in the
positive sense and in the pathologic sense.
The two that I focus on the most are the IGF
pathway and the mTOR pathway.
Now, mTOR stands for mammalian target of rapamycin.
I think for the sake of time I will not tell
my favorite story, which is a story that is
both the discovery of rapamycin and perhaps
more interestingly the elucidation of how
But suffice it to say the compound rapamycin
was identified first long before a really
amazing guy named David Sabatini as a PhD
student at Hopkins in 1993, 1994 as a side
project in a lab made the discovery that this
thing, rapamycin, was actually working by
inhibiting a protein complex of which TOR,
target of rapamycin, as it became named was
the central piece.
We now know today that it can form onto two
One is called mTOR complex 1 or mTORC1 and
the other is mTOR complex 2, mTORC2, and we
also know that it exists in different tissues
and it has different activities in different
Like most things in the body, too much or
too little is a bad thing.
So if you have no mTORC1, for example, in
your muscles, you’d wither away and that would
be a debilitating condition.
In fact, for people with muscular dystrophy
one of the things you want to do is figure
out how to alter that pathway.
But similarly, we know that overactivity is
predisposing us to aging and, of course, certain
diseases of aging like cancer.
[Rhonda]: So for people that…you know when
Peter mentioned that if you don’t have any
mTORC1 activity you might cause muscle wasting,
well, that’s because mTOR does a very important
role in protein synthesis.
And what’s very interesting is that both the
two pathways that you mentioned in being evolved
in aging, mTOR and IGF-1, IGF-1 actually increases
mTOR activity so you know they’re in this…
These aren’t independent pathways, yeah.
And what’s also very interesting is that they’re
both regulated by amino acid intake, right?
[Rhonda]: So IGF-1 is also a growth factor
that you do need as well.
So it’s one of those things where you don’t
have any IGF-1, well you’re going to be in
I mean, there’s a lot of positive things about
IGF-1, muscle growth, muscle repair, neuronal
But too much IGF-1 also can allow damaged
cells to continue growing.
But are you familiar with, like, any of the
dietary nutritional research on IGF-1 and
mTOR and specifically with amino acids and
I mean that’s, sort of, my biggest obsession,
I think, is probably around those topics.
So it’s complicated.
I think we have probably a better understanding
I mean I think it’s very clear that mTOR is
amino acid driven.
In fact, what’s today?
Last Thursday, eight days ago, David Sabatini
and his group at MIT published a paper in
“Science” that identified the amino acid sensor
Now, it’s always been suspected what it was,
which was leucine was the highest affinity,
but in fact he’s now crystallized that structure.
So if you even think about it through the
lens of, like, “Why do bodybuilders or people
who love lifting weights, want to take Branched-Chain
Amino Acids while they’re exercising?”
The reason is largely through this empirical
observation that it enhances muscles growth
and/or prevents muscle degradation during
What I think is really interesting is that
we now know exactly what’s going on.
So the Branched-Chain Amino Acids, there are
three, leucine, isoleucine, and valine.
It turns out that isoleucine and valine are
It’s pretty much all leucine.
And what’s really clever just from an evolutionary
perspective is that mTORC in muscle has a
much higher affinity for leucine than mTORC1
in fat or in hepatocytes.
Now, that’s a good thing because you’d like
to believe that in times of nutrient deprivation
even a trace sign of leucine should preferentially
provide the muscle with its growth signal
before providing the adipocyte or hepatocyte.
So from a nutrient-sensing pathway, what you
could infer from that is too little leucine,
probably a bad thing, too much leucine, probably
a bad thing.
Now, what too much and too little are I think
remains to be seen.
The other thing to keep in mind is…you know,
because one of the questions a friend of mine
asked me recently, actually a mutual friend,
Tim Ferris, is “Can we take too much leucine
during a workout?”
And again, I don’t think we know the answer
but extrapolating from the animal data I think
5 grams of leucine during a workout, probably
And it also doesn’t stick around very long
because when we take amino acids in a workout,
if you, sort of, sip them throughout the workout
you’re taking a free amino acid, so it’s got
a relatively short stay in the body.
In fact, one of the pharmacointerests on this
front, which is to treat diseases of muscular
wasting, is to actually come up with molecules
that are not necessarily more potent agonists
of the leucine receptor but would stick around
a lot longer.
Because that’s actually the problem with the
nutrition side, is we can’t keep leucine around
long enough to stimulate muscle growth.
So that’s the easy story.
Now the hard one, IGF.
So two schools of thought on this, I am in
one camp but I will acknowledge the other
One camp says IGF-1 is driven exclusively
by amino acids.
The other camp says, no, it’s actually driven
by amino acids and carbohydrates.
And carbohydrates indirectly via insulin.
[Rhonda]: Why are those mutually exclusive?
[Peter]: The way I define it when I’m…there
are certain people who I will not name that
are prominent in the field who will argue
that the carbohydrates play no role, it’s
virtually all protein.
[Rhonda]: But there is a role that they do
play that’s been shown, depending on…
[Peter]: I believe it has been shown but,
I mean, there are wonderfully erudite people
in this field who believe it is entirely an
amino acid issue.
And it is true, methionine has probably been
shown to be the most active amino acid in
driving IGF pathway.
However, as it sounds like you agree, it’s
pretty clear that as insulin levels go down
IGFBP-3 goes up…sorry, as IGF binding protein
3 goes up…maybe it’s worth me taking a moment
why that matters.
[Rhonda]: Yeah, probably explain that.
[Peter]: So most of these things, as maybe
the listeners know when you have hormones
floating around the body, whether it’d be
testosterone, whether it’d be cortisol, whether
it be thyroxine, these things, because they’re
typically hydrophobic, they can’t just travel
through the bloodstream freely.
They have to be bound and carried just as
And so it’s these binding proteins that we
often don’t think about that play an important
role in determining how much active or bioavailable
hormone is free.
So in the case of IGF-1 it gets trafficked
by this IGF binding protein, and most of these
binding proteins actually bear an unbelievable
relationship to insulin.
So sex hormone-binding globulin goes up when
insulin goes down.
It’s very interesting, there’s always this
complaint that free testosterone levels will
drop, all things equal, in someone who restricts
And I remember through hearing that empirically
and not really thinking much about it until
I started to, one, observe it and, two, understand
And it’s quite obvious because again, all
things equal, when insulin goes down, which
is usually what happens when you restrict
carbohydrates, sex hormone-binding globulin
That means if you have no change in testosterone
level or even estradiol level, free testosterone
will go down.
Less testosterone is around to be unbound
to the sex hormone-binding globulin.
So it’s for that reason that I think that
insulin and carbohydrate do play an important
role in the IGF pathway.
And I also think empirically, not that I like
to refer to ecology or epidemiology, but when
you look at ecology and epidemiology of cancer,
to my knowledge the content of highly refined
carbohydrate and sugar is more predictive
of cancer in a society than the variety in
In other words, there are cultures that have
consumed larger and lesser amounts of protein
that have been without mass amounts of cancer,
but the same cannot be said with large amounts
of these things.
Now by these things, I mean sugars and high-glycemic-index
The problem with that is, of course, you can’t
infer cause from that, but the negative to
me is suggestive that at the very least, carbohydrate
content matters when it comes to IGF-1 signaling.
[Rhonda]: Absolutely, and the way I like to
think about it actually when you’re discussing
these two things is IGF-1 is not a cancer
initiator, like, it’s not going to cause the
initial damage that can make a normal cell
aberrant, a normal cell that acquires whatever
problems it acquired to make it turn into
a cell that’s not cancer.
What IGF-1 is really good at doing is taking
that cell that’s already acquired the damage.
[Peter]: It’s an amplifier, yeah.
And saying, “Here, keep growing.
Like, no, don’t die.
I know there’s signals in your body that are
trying to kill you, but don’t die.”
You know, whereas the refined carbohydrates,
the way I always think about is that leads
to a variety, a plethora of physiological
processes in your body, inflammatory processes
a lot of different pathways that are causing
damage, that are initiating the type of damage.
So it’s like, well, if you have someone that’s
eating a terrible diet, they’re eating refined
carbohydrates, they’re they’re releasing endotoxin
in their gut, they’ve got this some constant
inflammatory process going on, they’re releasing
hypochlorite damage they were damaging mitochondria,
damaging DNA, blah, blah, blah.
Well, and then so they’ve acquired all these
damaged cells and then they’re eating a bunch
of protein and activating the IGF-1 pathway,
it’s like dynamite.
It’s like, here’s the damage cell and here’s
the signals to, like, keep living and keep
So I kind of…
I mean, so you obviously alluded to this and
I think many patients when I talk to them
are sort of surprised to learn that every
one of us has cancer.
I mean, at this moment I have millions of
cancer cells in my body, as do you.
The good thing is virtually all of the time
the problem gets eradicated, right?
So either we talk about the apoptotic pathways
that you describe, but even when those pathways
fail our immune system is remarkable.
I did my post-doc in immunotherapy so I spent
about two and a half years working with T
cells specifically regulatory T cells in looking
at this problem, and we just take for granted
how good the humoral…the cellular immune
system is, rather.
So for those, again, maybe not familiar with
the immunology you have your B cell system
and your T cell system.
These T cells, which are the ones that fight
viruses, are unbelievable.
When you think about how many antibiotics
we have in our arsenal to fight bacterial
infections, it’s remarkable.
Think about how many antiviral drugs we have
relative to antibiotics.
We have very few and we certainly don’t have
them for the most common viruses we acquire.
And yet, virtually all of us recover in the
end unharmed from the typical viral infection
we get two to three times a year.
That’s a testament how amazing our immune
And when you unleash it against cancer, it’s
effective 99.9% of the time.
So, yeah, the name of the game is avoid the
Now, the other reason why I think this is
an important concept that goes beyond cancer
but now gets to the broader aspect of aging
is, when you look at the people who live the
longest, when you look at these people who
live to 100 and beyond, for the most part
they die of the exact same diseases as the
rest of us schleps.
They just get them later.
That’s really important because I think it
offers an insight into longevity that is often
So if the people who lived to 100, 105 were
all dying in car accidents and plane crashes,
you might make the argument that there’s two
classes of citizens, right?
There’s the people who get chronic disease
and then there’s people who will never ever,
ever get it and eventually they just die of
Because remember, the fourth leading cause
of death or the fifth leading cause of death
starts to become accidental stuff, once you
get outside of the chronic stuff, but that’s
not the case.
The point is we’re all, sort of, preprogrammed
to go through this process, but if you want
to live longer the name of the game is delaying
the onset of the big three, the big three
being the diseases that will kill 75% of us,
so cerebrovascular and cardiovascular, cancer,
And so that brings us back to why we’ve got
to have IGF and mTOR in check, because we’ve
got to prevent them from being able to, sort
of, amplify that.
[Peter]: I still haven’t answered your question
which is, “How do you do this with diet?”
[Peter]: So I will explain conceptually how
you do it.
How you do it at the individual level is empirical
and I think prescriptive, meaning you have
to be able to try something, iterate on it,
and make a measurement.
But here’s the conceptual way to do it.
The conceptual way to do it, at least the
way I do it, is you consume more or less the
least amount of protein you can consume to
maintain and grow muscle mass.
But you don’t need any more than that.
So it depends on the individual, it depends
on the timing of that protein ingestion, the
quality of that protein and the type of metabolic
and conditioning stimulus you put into it,
but there’s an amount.
But for most of us I think we’re probably
over consuming protein relative to that actual
need, so we raise protein level until we hit
Carbohydrate, we do the opposite.
Carbohydrate, we are basically lowering it
until we reach the highest point…or pardon
me, the lowest point that we can tolerate
where we can maintain, and again, this is
quick and dirty but it’s the lowest possible
And in my mind I typically like to see that
at below 3 or 4 as IU of insulin.
And you want to limit, sort of, post-meal
And I actually use a standardized test which
is an OGTT which has its limits because it’s
liquid, you’re drinking liquid glucose.
I like to limit that postprandial hyperinsulinemia
to a number and I use a checkpoint of 30 that
I want to be able to see within one hour of
a 75-gram glucose challenge if you can keep
insulin below 30.
So in my mind, because I can’t do what’s called
an AUC, an area under the curve.
So the really rigorous way to do this would
be I’d put a catheter in your arm and I would
sample your blood every 30 or 60 minutes over
the course of a day while you ate.
And I’d integrate that function and there
would be an area under the curve of insulin,
and that’s actually the number I care about.
But since I can’t do that outside of a research
setting, I rely on these other proxies.
So the bottom line is your carbohydrate content
is highly variable by the individual, by their
insulin sensitivity, by their muscle mass
and their capacity to dispose of glucose and
a host of other factors.
But the bottom line is you don’t want to consume
any more carbohydrate than you can without
blowing through those parameters, and you
don’t want to consume any more protein than
you need to to preserve that.
And then basically, fat becomes the fill.
And so the point here is that that becomes
a highly different diet for different people.
For some people that’s 40% carbohydrate and
20% protein, and the remainder of fat.
For others that’s 20% carbohydrate and 15%
protein and the remainder of fat.
[Rhonda]: So your approach seems to really
look at insulin response.
It’s looking at obviously the IGF-1, mTOR,
dietary nutritional factors that are influencing
those pathways and then, of course, the rest
For me, I like to think about food as what
you’re putting in your body not only to activate
these pathways or try to keep the pathways
from being too active.
But also, I like to think about it at the
level of the gut because the gut, one, regulates
the immune system, big time.
I mean that’s you’ve got more immune cells
in your gut than you do in any other organ
of your body and your gut bacteria, the interaction
between your gut bacteria and your gut are
also, you know regulating the types of immune
cells that you’re making, regulatory T cells
being put in that.
And also because it’s the major source of
inflammation, and inflammation,even very recently
has been identified to be a driver of the
So eating things that are good for your gut
like fiber and avoiding things that are going
to cause a lot of gut damage.
So I think about those things as well.
And then micronutrients which is also a very
Micronutrients are cofactors for a variety
of enzymes and proteins in the body.
It makes sure they’re functioning proteins
that are involved in these processes we’re
talking about, keeping cancer cells in check.
You know, like p53 zinc-dependent proteins,
magnesium which is important for repairing
damage, things like that.
Are those things that you consider at all
when you’re thinking about the influence of
diet on the aging process?
[Peter]: I don’t think about it as much as
a lot of people do.
And I would hate to use the term I’m a gut
skeptic because I think that conjures up a
whole bunch of negative images but…so I’m
going to be a late adopter on this one, all
So there are a whole bunch of facts that everybody
can rattle off about the gut.
A lot of them by the way are kind of BS.
So the cells in the gut outnumber the cells
in our body 10 to 1, that actually turns out
to be false.
[Rhonda]: So you mean bacterial cells?
[Peter]: Yeah, sorry, the bacterial cells
within our gut.
So putting all that stuff aside, there are
a whole bunch of really interesting facts.
But it reminds me of what a good friend of
mine once told me when I was trying to rationalize
something I needed to do or thought I needed
to do to him.
He said, “Why are you doing this?”
And I said, “Blah, blah, blah.”
And he said, “That’s a fact, but is it a reason?”
And so that’s kind of how I feel a little
bit about the gut.
Like, there’s a whole bunch of really interesting
stuff but I don’t know that it actually matters
that much, right?
I’ll give you a really idiotic example.
The number of ants on this earth outnumber
us 10 to 1.
I’m making that up.
Ergo, we should be doing more to protect the
ants by avoiding climate change.
[Rhonda]: Yeah, but that’s irrelevant.
[Peter]: And I’m saying, “No, that might be
There might be more ants than us, but we’re
the species of interest.”
So that’s my first, sort of, kind of, lack
The second is I don’t really know what to
do with it, right?
So I’ve been through it all, I’ve gone through
all the sequencing, I’ve done it with patients,
and I have found that it’s like there’s a
very crude set of tools that I can use in
really obvious cases.
So, all right, a patient that came to me two
years ago who had a history of sinusitis,
horrible history of sinusitis.
So she probably had to do an Augmentin course
six times a year because of recurrent sinusitis.
She had three surgical procedures, just couldn’t
So I started working with her.
It became pretty clear to me that there was
something in her diet that was creating an
inflammatory environment that wasn’t a structural
So we made a lot of dietary changes, things
got better, but in parallel to that I sort
of suspected that 10 years of 6 cycles of
Augmentin probably altered her gut.
And so, yeah, she’s an example of someone
where I would do a sequence and can be like,
“Lo and behold, you’re all yeast.”
Not surprisingly, and disproportionate bacterial
Okay, so she’s an example of someone in whom
the signal was so big that I felt like there
was an intervention I could make which was
both fixing her diet but also utilizing agents
that could alter that.
But for the most part, I don’t have a clue
what to do.
And all the people I see who claimed to know
what they do, like, they can’t convince me
that they’re knowing what they’re doing.
Now, that doesn’t mean that you can’t…I
mean I’m talking outside of a couple of really
So we’re familiar with how C. diff colitis
works and the reversal of C. diff with stool
So those are remarkable examples, but some
of the other stuff I’m still not clear of.
So I guess what I’m saying is I’m happy to
be convinced but I’m not convinced yet that
this is a reason and not just a fact.
[Rhonda]: So I think that focusing on the
gut microbiome and the number of bacterial
cells that supposedly outnumber our human
cells and all that, I don’t think that’s the
You know, so I’ve become very interested in
the gut mostly because of a colleague of mine,
Mark Shigenaga, who has been working doing
gut research at Children’s Hospital in Oakland,
and is brilliant.
He’s been showing me data and I’ve just been
convinced more and more that gut health, making
sure that you’re keeping the mucin which you’re
gut goblet cells are producing that disgustingly
slimy mucus-like material that’s keeping and
separating the immune cells in your gut from
all the microorganism in your gut.
And that’s very important because when that
starts to break down, the immune cells recognize
bacteria and they start [crosstalk]…
[Peter]: Is there…and I’m not asking this
rhetorically, I just don’t know.
Is there an effective way to diagnose that
[Rhonda]: So the problem is that endotoxin
released into the blood system would be the
way to measure it and to diagnose…
[Peter]: I see, so you could measure it through
the lack of barrier basically.
[Rhonda]: You can measure the endotoxin levels
in someone’s blood which is a marker, a proxy,
if that helps.
[Peter]: Yeah, like the throughput, yeah.
[Rhonda]: But the problem is that there’s
also a lot of false positives.
So that’s the only concern until that test,
the diagnostic test can be defined…
[Peter]: Because it seems to be a stool test
would be a more effective way to measure that.
[Rhonda]: Yeah, there might be.
There might be a way to do that, to measure
it in a stool.
That would be an interesting thing to explore
because the…so what I’m getting at here
is I’m a scientist, obviously, you’re a scientist
and like to understand the mechanism and see
solid data before you think something is true.
And I’ve become more convinced that the endotoxin
released from the gut which is a constant…I
mean, really the major source of inflammation
in the body is coming from the…
[Peter]: And to be clear Rhonda, I’m not disputing
So to be clear, I bought that thesis actually
when I was a surgical resident because we
would see endotoxemia, right?
A surgical procedure gone bad endotoxemia,
I know what that looks like in its most extreme
What I think I’m more of a skeptic of, and
again, a skeptic waiting to be convinced,
is that I can make that diagnosis in a non-catastrophic
case which is basically the chronic case and
make an intervention either through some alteration
in the microbiome itself or meaning directly
or indirectly through diet or other variables.
And I think that it would be very interesting,
sort of, path to go down but, again, there’s
so many things I don’t know at the moment,
I’m just trying to focus on the ones that
I do know.
There is some interesting work coming out
of, like, Justin and Erica Sonnenburg Lab
over at Stanford.
I recently had a discussion with them on looking
at the role of fiber and certain types of
fiber in fueling different species of bacteria
in the gut and how those are generating short-chain
fatty acids and other signaling molecules
which are regulating hematopoiesis, they’re
regulating the number of Tregs that we’re
So it is very interesting that feeding our
gut certain types of fiber which are present
in vegetables and a variety of fruits even,
do have a positive effect on the immune system
via the signaling molecules that are being
made in the gut.
So that’s very interesting, and it is one
thing that I consider when I’m thinking about
the effects of diet on longevity.
You know, I’ve focused on insulin for a long
I’ve been very interested in insulin.
When I was doing research at the Salk Institute
in La Jolla, before I went to graduate school,
I was working on aging and specifically doing
different genetic manipulations in C. elegans
to look at the effects on aging.
So insulin signaling was like obvious.
Decrease insulin signaling you’re gonna increase
this worm’s lifespan by, like, up to a 100%,
which was, like, very profound.
So I’ve been very focused on insulin for a
long time…reducing the insulin signaling
pathway, reducing the insulin response all
However, I think that as I continue to look
in humans we’re very complex organisms and
there’s lots of interactions between the things
going on, between different things that are
happening in our diet, in our lifestyle that
are affecting the way we age.
And one of those I do think is gut health.
I, sort of, began to become interested in
what sort of diet is good for my gut and what
is not good for my gut.
And I think we were talking a little bit about
this before we start filming this, and that
is one thing I’m also very interested in these,
the effects of fat on the gut.
Because fat can be very hard on the gut but
I think that also depends on a variety of
factors, if you’re eating it with protein
if you already have an unhealthy gut, if you’re
not exercising or you are exercising, things
Also, genetic factors play a very important
role certain polymorphisms in…
[Peter]: Don’t ask me about ApoE.
[Rhonda]: PPAR gamma?
[Rhonda]: Influence saturated fat versus polyunsaturated.
I’ve actually got one ApoE4 allele, so I’m
very interested in ApoE and I’m actually writing
a paper on ApoE4 and its role in Alzheimer’s
[Peter]: Well, I’ll tell you my take on
that, which I’m sure you’ve seen the literature
But I actually think it’s the phenotype that
matters more than the genotype.
So in other words, I think it’s the amount
of ApoE that’s expressed that matters, not
the ApoE, not the genotype.
In other words, just as we measure ApoB as
a surrogate for LDL particle number and VLDL
and remnant VLDL particle, we can measure
There’s no clinically used or CLIA-approved
assay for that yet, but there are labs that
are doing it for experimental purposes.
And there’s a paper that I saw maybe six months,
nine months ago that actually showed that
if you take the ApoE 3/4s and 4/4s…so I’m
sure better than I do, a 3/4 genotype just
on a hazard ratio is about a 2x increase over
the 3/3 in terms of Alzheimer’s disease.
A 4/4 of course, is anywhere from 10x to 20x
depending on the series.
Okay, so if you’re out there and you’ve got
an ApoE 3/4, or especially if you’ve got a
4/4, you’re worried, right?
And I’m worried for my patients who are 4/4s.
I have four patients who are 4/4s.
But when I saw this paper what it showed was
actually…and just so the listener would
know, the majority of people with Alzheimer’s
are not 3/4 or 4/4, they’re still 3/3.
The difference is this…because remember,
the 3/3 is the majority of the population.
I mean the 3/4 is actually pretty big, it’s
But the 3/3 is the largest one, so having
a 3/3 doesn’t protect you from Alzheimer’s
and having a 3/4 doesn’t guarantee you’re
going to get it.
And, by the way even a 4/4 doesn’t guarantee
you’re going to get it.
So the key is there’s something else that’s
more predictive, and I think it’s the phenotype.
So when they measured the serum level of ApoE
it turned out to be more predictive of Alzheimer’s
disease than the genotype.
So my hope is that we can get a clinically
approved assay in a relatively short period
of time that will allow us to actually do
that, especially for the patients who are
3/4 and 4/4, which says, “Are you able to
reduce your risk?”
So let’s say I could measure you today and
your ApoE level was here.
And then we could say, “Well, look, there’s
We believe that reducing or increasing insulin
sensitivity of your brain, you know reducing
the probability that pyruvate dehydrogenase
is going to cause an energy shortage in your
neuron is going to improve your odds for delaying
or eliminating AD from the list.”
And then we could measure your ApoE at a point
in time and it were lower, that would give
me some confidence that we’re moving in the
right direction because…
So you’re saying that the higher the…
[Peter]: The higher the expression, the higher
That’s what this…
[Rhonda]: Higher expression in the plasma.
[Peter]: In the plasma, the higher the risk.
[Rhonda]: Okay, So a couple of things, one
[Peter]: I’d be happy to show you the paper
[Rhonda]: Yeah, that’s interesting because
from my understanding, you make ApoE in the
liver and you make it in the astrocytes.
But one of the important things is that it
plays an important role in bringing cholesterol…
[Rhonda]: …from the astrocytes to the neurons,
but also in repairing damage that’s done.
So, you need to have neurite outgrowth to
repair any sort of damage that’s done, damage
with normal brain aging or traumatic brain
injury, which is like damage in real-time.
I was under the impression that there’s less…so
there’s less ApoE expression in ApoE4 and
so there ends up being a problem because the
LDL receptor is very important for bringing
the cholesterol to the neurons, to getting
it there and so…
But the plasma, I don’t know.
And the other thing is I think the…and by
the way, I could be wrong.
It’s been nine months since I read this paper,
so I could have it backwards.
But I think the more important thing is, I
think there’s two separate things going on,
So the ApoE4 gene also plays a role in…because
my real interest clinically is, of course,
lipidology, that’s my clinical obsession.
And that’s the place where I think we’re becoming
pretty clear now that the ApoE 4/4 or the
3/4 is not a death sentence in cardiac disease,
especially the 4/4.
The 4/4 was really viewed as, “Boy, you’re
guaranteed to have an MI before 60.”
And I think the evidence today suggests that
once you normalize and correct for LDL particle
number or ApoB, it stops mattering.
Those are definitely probably more important.
And so loosely speaking, this is an oversimplification,
if you’re a 3/4 or 4/4, in theory you should
have a harder time clearing LDL particles
But I think that that’s not entirely the issue
that you’re alluding to, right?
I think there’s two issues you’re talking
One is the clearance issue and then one is
the cholesterol transport, the central part.
I mean, and there’s also the different issues
in the brain versus the liver.
So, I mean, we’re talking about, like, the
astrocytes are almost like little livers in
a way but not really.
You know, I think looking at the effects on
the brain and then looking at the effects
on recycling LDL and all the other things
going on in the periphery are different.
But by the way, I did just want to mention
that between 65% and 80% of all cases of Alzheimer’s
disease at least, you know…
[Peter]: At least 4?
[Rhonda]: At least one has a 4.
Between 65% and 80% of all the Alzheimer’s
[Peter]: So the majority are 3/4s then?
[Rhonda]: The majority even have at least
But again, that’s…
[Rhonda]: Having just one allele.
[Peter]: …based on the hazard ratio, we
know that that’s just a numbers game because
20% to 25% of the population is 3/4.
[Rhonda]: Right, exactly.
But the point is is that there’s something…
[Peter]: But the 3/3 doesn’t protect you from
[Rhonda]: No, it doesn’t.
[Peter]: So someone walking around with a
3/3 you shouldn’t assume that, “Well I’m never
going to get AD.”
[Rhonda]: No, it does not protect you, but
there is definitely something…
[Peter]: Does the 2/2 protect you?
[Rhonda]: The 2 does actually protect.
I’m sure that some paper has the histogram
of 2/2, 2/3…
[Rhonda]: It’s protective.
Yeah, it is.
And so it’s very…
[Peter]: Because in cardiac disease it does,
and in cardiac disease the 2/4 is about the
same as the 3/3.
The 2 and the 4 cancel.
[Rhonda]: Wait, say that again?
So the 2/4s is…?
[Peter]: The 2/4 is about the same as the
[Rhonda]: Oh, good.
[Peter]: And again, just in hazard ratio.
[Rhonda]: I found that my mom was 2/4 and
it was for the cardiac problem that I was
kind of worried.
Anyways, okay, that’s very interesting.
So we’re totally going off on this ApoE tangent
but it’s something that…
[Peter]: No one is even watching at this point,
it doesn’t matter.
[Rhonda]: …I’m very interested in.
But there’s a huge, huge component for lifestyle
in risk for Alzheimer’s disease, particularly
with having an ApoE4 allele, and that’s where
I’ve become obsessed.
You know, I’ve been looking at mechanism but
also looking at the epi studies.
Looking at epidemiology, you see certain lifestyle
factors for example, drinking.
If you’re drinking in your ApoE4 because you’re
inducing damage that you can’t repair as well,
you’re going to fare worse.
You know, so anything that’s going to damage
your body worse, anything that’s going to
create inflammation…refined carbohydrate,
eating a bunch of refined carbohydrates, a
bunch of sodas with added sugars.
Like, all this stuff that’s terrible for you,
that’s not whole food, that’s not something
that’s nutritious, that’s going to cause inflammation.
Inflammatory molecules get across the blood-brain
You know, so blah, blah, blah, and all this
damage can continue to occur.
So obviously, diet, lifestyle play a very
important role in your Alzheimer’s risk.
And I think that understanding the biology
of what ApoE4 is doing because now there’s
research, a lot of it coming out of UCSF Gladstone
Institute showing that in addition to a loss
of function with the ApoE4 allele, there’s
also a dominant negative effect.
So apparently, the ApoE4, there’s this 2-amino-acid
substitution and structurally, if you look
at the structure of the protein, it starts
to get cleaved.
And so it itself starts to accumulate these,
like, aggregates that then you get more activated
microglia and it keeps, like, spiraling out
this whole inflammatory process in the brain.
So there’s also this dominant negative effect
that’s going on that’s interesting.
And you want to understand that as well.
But, yes, Alzheimer’s disease is one of the
neurodegenerative diseases that are up in
the top four or five, like you mentioned,
[Peter]: Well, it’s the top.
It’s the only neurodegenerative disease that’s
on the top 10 list of death.
[Rhonda]: Top 10, yeah.
So cardiovascular disease…
[Peter]: So cardiovascular is far and away
It’s not even…I mean, cancer in an aggregate
is number two, but as an oncologist I, sort
of, take an issue with that because cancer’s
a completely heterogeneic form of diseases.
So to put this in perspective, right…so
breast cancer, who’s not afraid of breast
cancer if you’re a woman?
Breast cancer accounts for 3% of deaths in
I was shocked to learn that, very low.
I would have thought much, much higher.
Now, cancer in women, all cancers, 20%, 21%.
Cardiac disease, 22% 23%.
So if you’re woman, if you ask any woman in
the street, “Are you more afraid of heart
disease or breast cancer?”
I think most women would understandably say
And yet, it’s dwarfed by cardiac disease by
a factor of seven and a half to one.
[Rhonda]: And we definitely know that diet
and lifestyle play a major role in your risk
for cardiovascular disease.
I mean, I think there’s no place where that’s
more obvious than actually in Alzheimer’s
disease for other reasons, which is…
I think so.
[Rhonda]: More than cardiovascular?
[Peter]: Well, I mean I say that just based
on what I called the existence principle,
So cardiac disease, I mean I think that’s
I think cardiac disease is inevitable.
And, while we’ve had a deterioration in our
lifestyle over the past 40 years, a pretty
precipitated and accelerated, sort of, move
in the wrong direction on that, it’s been
largely offset by pretty amazing medical advances.
So the three things that have, I think, allowed
cardiac disease to remain…in fact, it’s
actually come down.
If you look at the death rate from cardiac
disease, it’s come down.
So it’s still the number one killer but it’s
actually on a downward slope, I mean it’s
sort of plateauing.
But when you look at what, sort of, the three
biggest drivers are of cardiac disease, the
first one is not disputed.
So the data are really clear that if you could
only make one behavioral change to reduce
your risk of heart disease, it’s don’t smoke.
The next two are actually, because they are
so cross-correlated you can’t actually distinguish
which one is more important, are hypertension
and elevated ApoB or LDL particle number.
And, again, ApoB is the single best biomarker
or LDL-P to distinguish your risk of cardiac
It trumps LDL cholesterol, it trumps non-HDL
cholesterol, it trumps triglycerides, HDL
Those things don’t hold a candle to LDL particle
Well, think about it.
Think about the advances we’ve made in the
last 40 years on all of those, right?
So smoking has gone from 45% of the population
to 18% of the population.
So we reduced smoking.
[Rhonda]: In the U.S.?
[Peter]: In the U.S. that’s right.
Obviously, we haven’t done the same in the
Think of the litany of drugs we have for controlling
hypertension and think about the litany of
drugs we have to bring down ApoB.
So despite enormous improvements in the three
big picture drivers, it’s still the number
So it’s got to be lifestyle-driven but we’re
blunting the effect of that.
Whereas in Alzheimer’s disease, we don’t really
have any pharmacotherapy plays.
Like, we’re still arguing about what the environmental
Is it all diet-driven, is it sleep-driven,
is it stress-driven, what’s the combination
Is it is a virus?
Is it prions?
I mean I’ve heard every argument under the
But here’s what we do know.
We know that in the last 50 years, the prevalence
of Alzheimer’s disease has gone up about 2.5%…per
year, by the way.
That’s per year.
Whereas we know that our longevity has increased
at about 0.6% per year over that same period
Now, over a 50-year period, a 2% spread per
year of prevalence.
Actually, I think that might be incidence,
now when I think about it.
I think it’s incidence.
And longevity suggests that Alzheimer’s disease
isn’t just the natural response of getting
There’s something driving it.
And even if you accept that part of that increase
in incidence is a greater appreciation for
the diagnosis, it’s hard to argue that makes
up the full 2% spread.
And to me, that’s the most convincing case
for why there is something in our environment
that’s triggering Alzheimer’s disease and
it is not just the natural consequence of
So what are your thoughts as to what are triggering
Alzheimer’s disease in terms of our environment?
I mean, I think it’s probably a combination
But the most compelling evidence to me and,
again, this is probably, because I’m just
a simpleton and I like to start with Occam’s
razor, is it’s very hard to dispute the high
association between Alzheimer’s disease and
Type 2 diabetes and hyperinsulinemia.
And so I’m in the camp of which some neurobiologists
are, but not all.
This is still far from being settled.
I sort of view Alzheimer’s disease as brain
diabetes, and I think if the ApoE genotype
as basically just a susceptibility.
So I think anybody can get Alzheimer’s disease
with any genotype if there’s enough insulin
resistance, if there’s basically enough difficulty
in getting glucose through pyruvate dehydrogenase
and into the Krebs cycle.
So I think it’s a neuronal energy problem
more…and I think all of the other things
we see are results of that.
But in terms of what the driver is, I think
it’s a neuronal energy problem.
And I think all of the tau plaque, the neuronal,
the synapse stuff, I think those are byproducts.
And I think in animal models there’s some
very convincing data that you can…you know,
I mean you’ve seen the stuff I’m sure more
than I have, right?
Simultaneous injection of glucose and insulin
can transiently overcome deficit, administration
of exogenous BHB can overcome the deficit
by bypassing and going straight through alpha-hydroxybutyrate
into the Krebs cycle.
So where you can reverse the signs and symptoms.
Now, I’m not particularly in this space though
I find it really interesting.
There’s a guy by the name of, Richard Isaacson.
Do you know Richard?
He’s a neurologist at Cornell and he has a
practice that focuses on early cognitive decline
that utilizes very-low-glycemic-index diets
coupled with MCT and stuff.
So it’s basically like inducing ketosis without
a full-on ketogenic diet, which obviously
for many people is challenging.
And he’s seen very promising results.
I think he’s running a couple of clinical
trials as well.
And there’s a whole sort of…I don’t know
what the word to describe it is.
But there’s a whole network of people out
there with all of their interesting data that
are, because we don’t have controls, we just
don’t know if this is, like, a performance
bias we’re seeing or if there’s a true impact.
But anyway that’s sort of my hypothesis, which
is I don’t actually know what’s causing Alzheimer’s
disease, I don’t know how to treat it, I don’t
know if it’s treatable once it’s in a late
enough stage, but I firmly believe that if
you can be as insulin-sensitive as possible,
for you as an individual you reduce your risk.
Now, that doesn’t mean that the risk ever
goes to zero for any of us, regardless of
ApoE genotype, but I know that if I have to
choose between being very-insulin-sensitive
and not-so-insulin-sensitive I’m going to
be better off in this camp.
And I think that’s frankly true for every
There are other things.
There’s subtle things going on, of course.
IGF, of course, just to bring it back to where
IGF is really interesting because centrally
and peripherally you may actually want them
to be in opposite directions.
You probably know this, but Amgen had a drug
that was an IGF-receptor antibody.
It went into clinical trials, phase two trials
in pancreatic cancer, advanced pancreatic
cancer, and it failed.
Now it failed despite reducing IGF levels
at the receptor by 50%.
You could argue that that failure implies
that reducing IGF is irrelevant, reducing
IGF is irrelevant once the tumor burden is
established, reducing IGF to only 55% is irrelevant.
You could argue 100 different things.
What’s most interesting is that antibody does
not cross the blood-brain barrier.
And so today, there is ongoing research, it’s
all in animals at this point in time, that’s
looking at giving a diet that actually increases
IGF but giving it in the presence of this
The point being is can we raise IGF levels
totally, primarily centrally, and then block
the receptor peripherally.
So we ward off cancer and diabetes but we
ward off dementia.
And actually, there’s even evidence, though
I think this evidence isn’t as strong, that
elevated levels of central IGF also are protective
But, again, the problem is these are animal
data so you got to, sort of, take everything
with, like, a lot of speculation.
So to just, kind of, bring it briefly back
to the type, when you’re talking about diabetes
in the brain being Alzheimer’s, what’s really
interesting to me is the fact that neurons
are actually mostly using lactate from astrocytes.
Astrocytes are glycolytic.
The astrocytes are these brain cells in your
brain which are using glucose mostly, or using
glucose to generate lactate.
Lactate then gets shuttled into neurons, and
the reason why neurons like that is because
it’s thermodynamically favorable, much like
beta-hydroxybutyrate which you mentioned,
BHB, because it can shunt right into the TCA
cycle in the mitochondria…
[Peter]: But wait, how does the brain outcompete
the liver for lactate?
So, like, if I made you go out there and do
a bunch of burpies, right?
So the…I’m blanking on the name of the transporter.
[Peter]: MCT1 or MCT2?
Which one is the transporter out of the muscle?
[Rhonda]: I don’t know which one.
[Peter]: Okay, but the majority lactate is
going to be generated in the muscle.
So then MCT is going to transport that out.
And remember, it’s going to go through the
portal system…it actually it doesn’t go
to the portal, it passes through the cava,
but it’s still passing through the liver.
How does the brain managed to get any without
the liver taking it all into the Cori cycle,
which seems to me the preferential place to
So what’s weird is that…I don’t know the
answer to your question.
I know that many tissues…and this has been
shown through the work of George Brooks at
UC Berkeley who actually pioneered the lactate
shuttle hypothesis and the theory.
But it’s been shown that it gets taken up
by the liver, it gets taken up by the muscle,
it gets taken up by the brain.
In fact, exercise itself has been shown to
preferentially cause the brain to the take
[Peter]: Can we measure…I don’t know if
you read this literature but there was a lot
of really interesting work back in the ’60s
done at Harvard with real fasting experiments.
I mean 40-day fasts.
So you’d have inpatient subjects given nothing
but water and minerals for 40 days.
And it was done to basically demonstrate what
the steady-state fasting levels of glucose,
insulin, BHB, and acetoacetate would be.
And it’s actually quite interesting, right?
So you take a normal person.
We’d take you and let’s say your insulin level
is 10, your glucose level is 95, your BHB
level is unmeasurable because you’re on a
normal diet, and your acetoacetate level is
unmeasurable, and then we just fast you.
And it turns out that within about seven days,
you’ll be at a ketone level of 5 to 7 millimolar,
glucose will be down to 3 to 4 millimolar,
which is, call it 60 to 70 milligrams per
And you will stay at those levels in…you
know, at the end of the 40 days, they’re still
in those levels.
[Rhonda]: So they stay the same.
[Peter]: So glucose remember really goes away.
What’s changing is the consumption by the
neuron which goes from, at the initial state,
being about a 100% glucose…of course, I
don’t think they were measuring lactate then
so we don’t actually…
[Rhonda]: Were they looking at neuron or just
Was it astrocytes or neuron…
[Peter]: They were probably just looking at
But it would fall to maybe 40% or 50%, the
rest of it being made up by the combination
of the ketones.
And it’s interesting that they never went
to zero, right?
So even to your last day of life, if you’re
being starved to death, you still have glucose
in your blood.
And so it’s kind of interesting that, like…what
percentage of overall brain metabolism do
you think is driven by lactate?
It must be very, very small and reserved for
a very, very specific subset of neurons or
[Rhonda]: Well, the astrocytes are using the
glucose and they’re generating lactate.
So the lactate doesn’t have to get in.
[Peter]: So we’re not even seeing that, so
that might be the issue.
So that’s probably why the liver doesn’t matter
[Rhonda]: Yeah, during exercise, I mean.
But it has been shown that lactate will cross
over the blood-brain barrier during exercise
But that is why it doesn’t have…
[Peter]: But the dominant source is…
[Rhonda]: The astrocytes, yeah.
The astrocytes are making it in the brain.
And what’s fascinating is…
[Peter]: So astrocytes don’t have mitochondria?
[Rhonda]: They do.
[Peter]: So why do they make all the lactate?
[Rhonda]: I think they make the lactate because
that’s how the neurons are getting their energy.
I think that’s just the way it works out.
[Peter]: So it’s sort of a Warburg effect.
The Warburg effect, of course, to me is interesting
because I don’t buy the argument that the
Warburg is due to defective mitochondria.
[Rhonda]: It’s not.
Warburg showed that…I mean he…
[Peter]: No, there are still a lot of people
who think that it’s that cancer affects of
mitochondria, and that’s why the Warburg.
But I think it’s just that the cancer cell’s
smart enough and it’s optimizing for cellular
building blocks, and it sounds like the astrocyte
is doing the same thing.
We have to talk about this.
[Peter]: For different reason, but…
[Rhonda]: Yeah, it’s really interesting.
So we’re totally just hopping around all these
But, okay, to finish on the lactate thing,
fascinating work, traumatic brain injury also
brain aging in real-time, people with TBI
are much more likely to get Alzheimer’s especially
if they have ApoE4.
You know, up to 10 times, 20 times, depending
on how many alleles they have, but…
[Peter]: I used to do work with some professionals
athletes and for guys in the NFL.
If I saw that they were ApoE 3/4…and again
this is completely bogus but it’s the best
I think you can do, I would advise somebody
who’s an ApoE 3/4 entering the NFL that your
number of concussions should be fewer than
what is recommended.
I would actually go as to saying if you’re
ApoE with 3/4 that head trauma in general
is putting you at high risk for…
[Peter]: No, I completely agree but, of course,
when you’ve got a guy who’s about to make
$20 million to play football and he’s willing
to, like, play until he gets six concussions,
maybe you make it three.
So back to the lactate thing, very interesting.
Yeah, so read up on this, you know.
George Brooks, a friend of mine, he’s working
now with some other physicians at UCLA looking
at the effects of actually exogenous lactate
on helping treat TBI.
[Peter]: Why not just exogenous BHB?
[Rhonda]: Or, yeah, or that, exactly.
[Peter]: I mean have you see what Dom D’Agostino
[Rhonda]: I think I’ve read one of his studies
I think it was cancer.
You should see Dom’s work in TBI.
[Rhonda]: So this…oh, in TBI?
That’s how he got started.
[Rhonda]: That they’re the same?
[Peter]: He’s a neurobiologist.
[Rhonda]: Oh, okay.
[Peter]: The only reason he’s in cancer now
is because…he started out working a neurobiology…
[Peter]: …and using TBI models.
[Rhonda]: I didn’t know that.
Yeah, but it’s the same thing, lactate, beta-hydroxybutyrate,
it doesn’t matter.
They’re going through the MCT…
[Peter]: Yeah, they’re completely overcoming
[Rhonda]: Yeah, they’re both doing similar
They’re both thermodynamically favorable,
they allow glucose sparing, they allow glucose
to then be used to make glutathione, which
is important in the brain when you have damage.
But what’s interesting is that TBI also disrupts
astrocytes’ ability to make lactate.
And what I’m wondering when you were talking
[Peter]: But those two might just synergize.
[Rhonda]: They might.
[Peter]: Because I also think the trauma causes
an oxidative stress, so I think what’s happening
is pyruvate dehydrogenase is getting interrupted
and all of a sudden you’re having a transient
but violent interruption of energy to the
And this is obviously of high interest to
the military because of blast injuries, and
Dom would know this, so it’s absolutely worth
talking about this with him.
I’m sure the DoD is all over this.
I hope the DoD is all over this because the
interesting question is, do you have to have
the BHB or the lactate in your system at the
time of injury to prevent it, or can administration
be done immediately following the trauma?
[Rhonda]: Or is there a kinetics?
Is there a certain time?
I think because of the fact that it allows
glucose sparing which if you have a trauma
is…and this has been shown on animal models
for TBI, but this was done by putting glutathione
transcranially which obviously is not going
But anyways, they could prevent, like, over
50% of the damage because they were able to
sequester the reactive oxygen species that
start to cause all the damage in the inflammatory
pathways that start to get out of control.
So I think that if you allow that glucose
to be used for the pentose phosphate pathway
within a certain time frame…I don’t know
what that time frame is.
It was something within a couple of hours.
Then, independent of allowing you neurons
to get this easier source of energy…if the
neurons are using glucose because they need
energy but the glucose can’t be used to repair
that damage to the pentose phosphate pathway,
I think that’s one component of it in terms
of the temporal effects, like how soon after
But anyways, your Warburg thing.
I have to just quickly tell you, I spent six
years doing cancer metabolism at St. Jude
Children’s Research Hospital.
And I wanted nothing more than to believe
that mitochondria were dysfunctional and not…
[Peter]: Defective, yeah.
[Rhonda]: Yeah, because that would have made
my whole thesis, like, so much easier and
I wouldn’t have taken six years.
But I couldn’t find that.
I couldn’t find that the cancer was causing
the mitochondria to be so dysfunctional that
that’s why they were glycolytic.
There’s an amazing paper that Matthew Vander
Heiden wrote in 2009 in “Science” with Lou
Cantley and Craig Thompson.
Really, that’s when I, sort of, shifted my
point of view on that.
Well, you mentioned that cancer cells are
using it for…I agree with you, with the
fact at you know cancer cells, the reason
why they’re glycolytic I think also is because
it’s quicker and they don’t really give a
[Peter]: Well, they’re optimizing for the
building blocks to make more cellular machinery.
They’re basically saying, “I’m willing to
do an inefficient process of getting ATP in
exchange for something else.”
But here’s my other insight onto this, my
other, sort of, theory…
[Peter]: By the way I’m interested in how
to exploit that.
In other words, you don’t have to know why
that’s happening to figure out how to exploit
That’s what I’m interested in.
Well, here’s what I think, another reason
why they’ve figured out not to use their mitochondria.
I think the reason they’ve figured that out,
and this is why I also think why things like
anything that will activate pyruvate dehydrogenase
or anything like beta-hydroxybutyrate, anything
that’s going to force the mitochondria to
So like whatever it is because the mitochondria
are for the most part, not as active in the
I think that anything that’s going to force
them to work…the reason why cancer cells
don’t want them to work is because cancer
cells are primed to die.
So this is the whole basis, most of the basis,
behind how chemotherapeutic drugs work.
Cancer cells are primed to die in the sense
that our body has increased the amount of
all these pro-death signals, pro-apoptotic
proteins to say, “Die, die, die.”
Cancer cells have increased all of the anti-apoptotic
proteins and signals and say, “No, I’m not
going to die yet.”
So there are, like, balances here.
You know, they’re primed to die, they’re ready
All they need is a little push to the pro-death
So if they have a chemo, that’s another activating
more pro-death, it’s enough to push the balance
into pro-death, right?
Well, the mitochondria when they’re active,
when you’re highly metabolic using your mitochondria,
you’re generating reactive oxygen species.
[Peter]: Reactive oxygen species.
[Rhonda]: Which are a pro-death signal.
And I think that is one of the main reasons
why giving DCA, activating the pyruvate dehydrogenase
complex, can kill cancer cells.
I think that’s why ketogenic diets, which
are basically forcing the cell to use oxidized
fats which require a mitochondria, I think
that’s also why they’re very effective at…
[Peter]: And so that’s interesting, so you
would think, then, that all things equal,
a ketogenic diet would produce favorable cancer
outcomes versus exogenous ketones?
In other words, you could produce the same
hormonal milieu with both, but in one of them
you don’t have to undergo the machinery.
[Rhonda]: So, maybe.
And the reason I say this is…
[Peter]: And I find that interesting, I don’t
know the answer.
The reason I say that is because cancer cells
also want lipids.
They like to build more cells and you need
lipids to build…
[Peter]: Yeah, so that might offset it.
[Rhonda]: So I’m worried about that component
However, if you think about normal cells aren’t
primed to die.
So anything that’s activating your mitochondria
in normal cells isn’t going to kill them,
and I think that’s why it’s a much better
cancer therapeutic strategy than chemo because
chemotherapeutic drugs also kill normal cells,
You’ve got, your hair, your skin, whatever
is proliferating fast like a cancer cell.
So I actually think that it’s possible that
whether that’s fat oxidation through more
of a ketogenic diet, I think it’s something
that needs to be tested more.
Like I said I do have concerns just because
you are giving a cancer cell building blocks
for more cells, which of course is always
But I think that anything that is going to
force the mitochondria to become active and
generate that signaling reactive oxygen species
signaling to death to kill it, is good.
It’s also why taking supplemental dietary
antioxidants when you have cancer is very
dangerous because you’re blunting that whole
signaling pathway, right?
You’re basically blunting all the reactive
oxygen species that are usually signaling
for your cells that are primed to die, for
the cancer cells to die, and you’re sequestering
So it’s like and that’s been shown.
But it’s something that’s interesting to think
And I don’t know, it’s a possibility, it hasn’t
been proven, but I think that it’s certainly
an interesting hypothesis that should be looked
And for all those people out there that are
researching cancer and mitochondria, maybe
[Peter]: We’ll be looking at it.
All right, so I think we’ve talked about a
lot of interesting things.
And is there anything else you want to discuss
or talk about?
[Peter]: I mean, I think we could talk about
ISIS, but I feel like it takes us a little
bit off course, so probably not.
[Rhonda]: Yeah, probably, probably.