There's a widely accepted hypothesis

that mitochondria with excess energy

leads to problems. Many people that that

are listening have probably heard of

reactive oxygen species. This is forms

of oxygen that become reactive and end

up spinning out and damaging proteins

and nucleic acids. And I think it is

widely accepted that one of the

contributors to that is mitochondria

that have too much energy. Basically,

the form that energy takes when it's

extracted from the food we eat and

before it's converted to ATP is powering

the mitochondria. And when that

mitochondria is overpowered, that leads

to a state that is very susceptible to

generation of these reactive species

that end up damaging our genome,

creating mutations and damaging proteins

and creating many of the problems that

we see. Welcome to the Hubberman Lab

podcast, where we discuss science and

science-based [music] tools for everyday

life.

I'm Andrew Huberman and I'm a professor

of neurobiology and opthalmology at

Stanford School of Medicine. My guest

today is Dr. Jared Ruer. Dr. Jared Ruer

is a professor of biochemistry at

University of Utah and an investigator

with the Howard Hughes Medical

Institute. He is one of the world's top

experts in the biology of mitochondria

and metabolism. Mitochondria are known

as the powerhouse of the cell. But as

you'll learn today, they do far more

than just power our cells. They also

determine how much energy goes into

making new cells, to making sure that

cells stay healthy, and to fighting off

disease. Today's conversation explains

how mitochondria do that, and clarifies

what your metabolism really is. And in

doing so, you will learn that you don't

have one metabolism. Your metabolism as

it's called is actually a reflection of

the constellation of all the metabolisms

of all the cells in your body. So

today's conversation will teach you the

real biology of mitochondria and it will

provide a framework for you to make

better decisions on the behalf of your

health. So what follows is a

conversation about mitochondria and

metabolism unlike any that you've heard

from one of the world's premier experts

in this topic. Before we begin, I'd like

to emphasize that this podcast is

separate from my teaching and research

roles at Stanford. It is however part of

my desire and effort to bring zero cost

to consumer information about science

and science related tools to the general

public. In keeping with that theme,

today's episode does include sponsors.

And now for my discussion with Dr. Jared

Ruer. Dr. Jared Ruer, welcome.

>> Thank you. Thanks for having me on.

>> I have many questions about metabolism,

mitochondria, and I know many people do

as well. Most people hear the word

metabolism and they think calories in,

calories out. They hear the word

mitochondria and they probably think the

powerhouse of the cell and that's all

great. People are becoming more educated

about cells and their bits and pieces

and what they do. You have a very

different perspective that is very

important I believe for people to

understand. Maybe we could start off by

talking about how the metabolism of any

one cell in our body relates to what we

call our metabolism, the collective

metabolism of all those cells. And as

you go, if you could take any liberties

you want to tell us what we probably

don't know about the quote unquote

powerhouses of the cell.

>> Yeah. You know, when we think about

metabolism, as you say, I think all of

us think about metabolism in terms of

our body's metabolism, our metabolic

rate, as you say, calories in, calories

out. What that is really our body's

metabolism is basically

the the sum total of what we ingest, you

know, what we eat, what we drink, what

we breathe,

that enters our body and gets processed.

And the results of that processing are

individual molecules, amino acids and

sugars and so forth that then distribute

throughout the body go into individual

cells and enter this process that we

call metabolism and we call cellular

metabolism.

And I think it's reasonable to think of

cellular metabolism as almost like a

map. There's an entry point. A molecule

of glucose or sugar comes into a cell

and that sugar can be chemically

modified in a variety of ways to fulfill

the needs of that cell. And then that

cell does whatever it needs to do with

the molecules it takes in to fulfill its

particular functions. And then that

leads to the um release of waste

products that we eliminate from our

body. And that is sort of the organismal

metabolism, the metabolism of our body.

And as you allude to, I think something

that maybe many people don't understand

is that cellular piece of it. The

metabolism of our body is really the sum

total of the metabolism of each one of

our 30 trillion cells or so. That's

really where my passions lie are those

individual cells and how they choose to

take up certain nutrients, how they

choose how to process them, turn them

into other things, how they use them to

fulfill their particular functions, and

how that's regulated. the masterful

coordination of each of those cells

working together to allow us to be

sitting here talking to one another and

go out and run or whatever we do. It's a

beautiful orchestration, but that

happens at the level of of individual

cells. And I think that's one of the

fascinating things that is maybe a

little bit less understood. if we were

to just take the single cell view for a

moment and I know that aging isn't a

like your specific area of interest but

one thing that's always intrigued me

because my postto adviser once came down

the hall and said why do I have so much

less energy than I used to and he had a

ton of energy so that I like I wonder

what he used to be like but it's a great

question he used to do this every once

in a while like just ask these very

basic questions that no one else on our

halls at Stanford could really answer

why does a kid have so much energy and

when we're older We don't what people

say well people are moving less the

tissues are wearing out but at the level

of energy production are we aware as

biologists at this point in history as

to why a young cell could be muscle cell

it could be neuron whatever versus an

older version of that cell why it it

either produces less energy I don't know

if it does I'm guessing it might but why

the whole body just seems to have less

get up and go do we have an answer for

Yeah, I think we have a partial answer

for that. I think that's a that's

definitely a frontier of science is

trying to understand exactly what goes

wrong during aging. There's many aspects

to it. As you alluded to, one of my

passions also is the mitochondria. And I

think it's almost universally the case

that mitochondria become less energized,

less effective, let's say, as we age.

And the reasons for for that are to some

extent clear but I think largely unclear

but that is definitely a feature of the

aging process. You know there there is

this sort of aspect of accumulation of

damage. You know living in the world we

live in as I alluded to before this

orchestration of metabolism that happens

throughout the body. That's hard. It's

expensive. And it's expensive not only

in terms of what we need to eat to fuel

it, but it's expensive in terms of the

damage that can come as a side effect of

that. And the accumulation of that

damage over time is certainly correlated

strongly with aging. And I think there's

some really nice evidence in models

where we can do genetics, you know, in

in animal models that suggests that that

accumulation of damage is a big part of

the aging process. And it's a huge area

of interest in the field is trying to

understand how you can decrease the

onset of damage, how you can reverse

damage that comes. One thing that I like

about how you ask that question is

thinking about that in the context of

the cell, which again I don't think we t

tend to think of aging as a cellular

phenomenon, but I think fundamentally it

almost has to be. We are made up of

cells and the processes that lead to

aging are the accumulation of processes

that happen at the level of individual

cells. And I think in a way we're at the

precipice of understanding a lot of this

because of the tools that we are um

starting to have access to that will

help us better understand cause and

effect and the specific molecular

features of of the aging process. Let's

talk about mitochondria. Perhaps

surprisingly, I'm going to ask you why

you study them with the caveat that they

are incredibly interesting. They are

involved in energy production and

metabolism. But what what specifically

drew you to mitochondria versus all the

other pieces of cells or parts of the

body or organs that you could have

worked on? Why the mitochondria? What

what's so sticky about those as a place

to I mean you devote a significant

fraction of your life to them? Yeah,

it's an area of cell biology, an area of

sort of the details of how life works.

One of these things that is, in my view,

just a brilliant example of taking in

chemistry of incredible complexity and

making it work effectively

inside of a a living cell. Mitochondria

are believed to have been the result of

an endo symbiotic event where a

bacterium a free-living bacterium

was engulfed by another cell and in a

way kind of domesticated.

So wild to think about totally wild. I'm

sure people are following, but in case

there's somebody who's not,

>> what Jared is saying is that our cells

basically were invaded by a bacterium

and then that bacterium became part of

our stable genome going forward. It went

into the what we call the germ line and

therefore was propagated from parents to

kids. And so now mitochondria live in

us, but they didn't start off living in

us.

>> That's right. And I and we hear that

about the gut microbiome like we have

these trillions of bacteria that live in

us and we colonize and we can recolonize

take antibiotics and then you need to

replenish eat your yogurt and so on. But

but the fact that the mitochondria made

it stably into our genome and are

transmitted from one generation to the

next. We think of them as us but you're

saying there is solid evidence that they

came from outside of humans.

>> I think that's the only model that I

think any of us as scientists have any

good reason to believe. And you know

that's fascinating history, right? That

there was a bacteria and another cell

that got together and and together that

combination could do things that that

any one of either of them on their own

could not do and that they work together

in in some way to enable the evolution

of complex life. you know ukarotes which

are the the type of cell that resulted

from that combined situation that we

were just talking about. These are all

the organisms that we see around us.

Plants, animals, fungi even are all the

result of these two cells getting

together and making peace so to speak

and uh teaming up to make this

synergistic cell.

>> Is it synergistic? for forgive me for

interrupting, but when I think about

viruses, I think viruses have their own

sort of intelligence. They kind of they

hijack the genomes of cells and they

either kill those cells or if they're

really smart, they keep them those cells

alive and use those cells to continue to

live and then propagate through like the

behavior of an animal like the rabies

virus like, oh, let's get this animal

aggressive so that it bites and then I

mean viruses don't think, but they have

an intelligence. Do we know that the

mitochondria were benefiting the cells

and the cells were benefiting the

mitochondria or could have this been a

takeover by the by the mitochondria?

>> I mean, this is a a bit of a

philosophical question. Of course, we

don't have a record of of what exactly

happened when and who benefited in real

time, but one thing we do know is all of

complex life resulted

from cells that underwent that event.

One time or multiple times, but all of

complex life evolved from that. And I

think that tells us that more than

likely complex life could not result

from a bacteria on its own or the archa

the the the cell that became the host

for that bacteria. So I think you can

make a compelling argument that this was

beneficial. And one reason it was

beneficial because it enabled a form of

metabolism that wasn't possible before

and enabled now a more complex cell to

be able to do things metabolically to be

more metabolically efficient and and and

diversified that it could enable you

know again complex life to evolve and

totally fascinating history but I think

as you alluded to also has very

interesting implications for life today.

I would like to take a quick break and

acknowledge one of our sponsors, JWVE.

JWVE makes medical grade red light

therapy devices. Now, if there's one

thing that I have consistently

emphasized on this podcast, is the

incredible impact that light can have on

our biology and our health. Now, in

addition to sunlight, which I've talked

about a lot on this podcast, red light,

near infrared, and infrared light have

been specifically shown to have positive

effects on improving numerous aspects of

cellular and organ health. These include

faster muscle recovery, improved skin

health, wound healing, improvements in

acne, reduced pain and inflammation,

improved mitochondrial function, and

even improvements in vision. Nowadays,

there are a lot of red light devices out

there. But what sets Juv lights apart,

and why they're my preferred red light

therapy device, is that they use

clinically proven wavelengths, meaning

they use the specific wavelengths of red

light, near infrared, and infrared light

in combination to trigger the optimal

cellular adaptations. Personally, I use

the Juv whole body panel about three to

four times a week, usually for about 10

to 20 minutes per session. And I use the

Juv handheld light both at home and when

I travel. If you would like to try JWV,

they're offering up to $400 off select

products for listeners of this podcast.

To learn more, visit juv, spelled

jv.com/huberman.

Again, that's jovv.com/huberman.

Today's episode is also brought to us by

BetterHelp. BetterHelp offers

professional therapy with a licensed

therapist carried out entirely online.

I've been doing therapy for a long time,

and while it's not always easy, every

time I do a therapy session, I come away

feeling better and knowing that the time

was well spent. With BetterHelp, they

make it extremely easy to find an expert

therapist who can help provide the

benefits that come through effective

therapy. And the data say it works.

BetterHelp has an average rating of 4.9

out of five for its live sessions based

on over 1.7 million client reviews.

Also, because BetterHelp is done

entirely online, it's extremely

timeefficient. If you would like to try

BetterHelp, go to

betterhelp.com/huberman

to get 10% off your first month. Again,

that's betterhelp.com/huberman.

Could we explore a little bit of how

mitochondria getting into these cells

were able to make it stably into their

genome and propagate? This isn't going

to be a conversation about genetics per

se, but I maybe as a just two points of

background for people like if any of our

cells have something put into them, but

let's say a physical object like a

splinter, little tiny piece of splinter

stays in the cell and then you procreate

with somebody, you don't expect that

child will have that little bits of

splinter in their cells. But if the germ

line, right, so the the eggs or the

sperm have something incorporated into

them, then potentially it could

propagate is why they call germline as

opposed to sematic cells. I think most

people aren't aware of that. It makes

perfect sense once you hear it, but

you're talking about many, many, many

years ago

>> a cell having this bacterium go into it

and then it was somehow able to stably

represent itself in the genome. So that

that propagated forward and eventually

>> it has to be in the germ line of

whatever you know primordial homo

sapiens were there otherwise

>> your kids I you wouldn't have

mitochondria in us how do we think that

might have happened

>> the main genome of the cell the cellular

genome DNA contained typically in the

nucleus of the cell mitochondria exists

in the cytool outside the nucleus one of

the interesting things about

mitochondria which I think is totally

fascinating and has really interesting

disease implications and worthy of

talking about. We may or may not come

back to it is that mitochondria have

their own separate genome that is sort

of a relic of the bacterium that they

are the descendants of. It's in a circle

like the bacterial genomes. Whereas the

nuclear genome of a ukareotic cell is

linear chromosomes. And that genome

performs very essential functions and

codes very important proteins that

enable our mitochondria to function as

the powerhouse of the cell which we uh

know them to be to enable the extraction

of usable energy from the food that we

eat. So, as you alluded to, those

cytoplasmic mitochondria

somehow make it from generation to

generation. And one of the interesting

features of them being cytoplasmic

is they're completely inherited from the

mom, from the egg, cuz as you know, when

the sperm invades the egg, the the

genome from the sperm gets into the the

egg, fertilizes it. The cytoplasm of the

sperm does not. So the mitochondrial

genome of you came completely from your

mother. Mine came completely from my

mother. And again that has interesting

implications for the inheritance of uh

diseases that are mitochondrial on

origin. But that's sort of how we think

it works. It basically propagates from

the egg upon fertilization. Then it gets

distributed to all the cells including

the the germ line that that fertilized

embryo will have and then gets passed on

to the next generation in [snorts] the

same way

>> ratcheting toward the actual functioning

of mitochondria. Maybe um you give a

beautiful picture of the mitochondria

not uh in the nucleus of the cell but in

the cytoplasm. So still inside the cell

and most people probably remember from

their high school biology a picture of a

cell always looks round. Mhm.

>> I'm guessing you're going to tell us

that the mitochondria can be distributed

lots of places in a cell cuz a lot of

cells aren't round. A lot of them look

hairy or they have long extensions like

neurons.

Is it fair to say that you can find

mitochondria everywhere in a cell? So no

matter what shape it is, it's got

mitochondria everywhere. And if so, what

is the importance of having mitochondria

distributed spatially through the cell?

So maybe we go so people know where

we're going. We we'll talk about the

spatial distribution because it turns

out that's very important. We'll talk

about the functioning and then I want to

talk about time as a factor and that can

be a little bit abstract for people. So

we'll come to that.

>> Yeah. Spatially,

you know, I I one of my scientist

colleagues might call me on this but to

my know I can't think of a place that

exists in cells where there aren't

mitochondria.

And I think as you alluded to I it's a

little bit dangerous for me to talk

about neurons with a neuroscientist. I

am not a neuroscientist but one of the

brilliant bodies of work that's been

done on mitochondria has been done in

neurons. It's fascinating these these

neurons that have one meter long

projections and mitochondria

transit from the cell body down those

projections and as best we can tell

those mitochondria play essential roles

at the ends of those projections

typically being able to generate again

usable energy. They're extracting the

energy from the food that we eat and

powering the neurotransmission the the

functions of those nerve nerve

terminals. And I think that's true of

virtually every cell in our body. The

extraction of energy and turning it into

use a usable form typically in the form

of ATP adenosine triphosphate. Obviously

that is the energy currency that's used

by almost every cell in our body and

that is a key function of mitochondria.

We'll probably come to functions of

mitochondria that are outside of just

extracting energy, but that is a

critical function of mitochondria and

that ATP is needed in virtually every

place of every cell and by having local

production that makes it more efficient.

So I think spatial distribution is a key

part of that. It's fascinating. There's

been beautiful work that's shown that

when a cell is crawling as cells

sometimes do you know like an immune

cell that sees something it's chasing

there will be a distribution of

mitochondria towards that leading edge

of the cell which is very energetically

expensive to crawl for a cell requires a

lot of ATP and mitochondria will

congregate at that leading edge where

that ATP is being consumed to make ATP

right there so it can be used I think

it's fascinating example of that local

uh demand for energy.

>> I'm asking some highle questions I

realize, but is there any reason to

believe that a a given mitochondria

knows what cell it belongs to?

>> Like the like are they different? Is is

are the mitochondria in one cell type so

very different than the mitochondria in

another cell type? or the mitochondria

between like let's say a neuron of the

eye versus let's get out and since

you're saying you don't want to talk

neurons as a per se like is two adjacent

skin cells they're both skin cells they

have mitochondria in them but do they

know which cell they belong to

>> and do your mitochondria I'm guessing

because they came from your mom's genome

they know that they're different than my

mitochondria but how much identity do

they have

>> yeah I would say this is a topic that is

at the frontier of what we No, you're

you're asking some questions that are

right at the edge of our current

knowledge. Yeah, mitochondria are

different. To a first approximation, you

could say that virtually every cell in

our body has slightly different

mitochondria

that are particularly suited to the

demands of that cell. a heart muscle

cell, a cardiammyioite, that cell

kind of has one job and that's to

contract

every second of every minute of every

hour of every day for our entire life.

And when it coordinates that contraction

with the other cells in the heart, that

enables our heart to beat. That's what

its job is.

>> Is there any turnover of those cells? We

know neurons don't tend to turn over.

>> Very little. Very little.

>> Well, that's reassuring.

>> Very very little. I'm glad you

>> you can imagine that it would be hard to

replace that in real time, right? That's

a I'm a hockey fan and that's a change

on the fly scenario of biblical

proportions. So that those

cardiammyioytes,

>> their mitochondria is wired

>> to consume whatever it has available and

make ATP because that ATP is is going to

be incredibly important to enable that

contraction of that cell and the beating

of the heart. mitochondria and other

cells. For example, like cells that line

that that are the stem cells that that

enable our intestinal lining to be

turned over every 5 to seven days, which

is amazing. By the way,

>> your whole gut

>> your whole gut is turning over every 5

to seven days. The the lining of that of

your gut, it is it is amazing. Those

stem cells, ATP

is not the major demand of those of

those cells. They need to completely

duplicate themselves constantly every

day or less. So their metabolic program

is very different from a cardiammyasite

which just needs to make ATP to a first

approximation. They need to make a whole

new cell. So we talked about you know

the metabolism of of the organism. The

metabolism of those cells is very

complex because it needs to replicate

all the DNA, duplicate it to go into a

new cell, duplicate all the proteins,

duplicate all the membranes, the lipids,

and that needs to happen rapidly. And so

that metabolic wiring is is completely

different. And again, the mitochondria

are fundamental to that. So those

mitochondria

are wired in a way that enable them to

produce

the biomass that's required to make a

new cell quite different from the

mitochondria of a cardiammyioite. And

that diff distinction plays out in

virtually all cells in our body, right?

Every one of our cells has some

particular purpose, some particular

function that it serves uh for the body

and the demands of the mitochondria

therefore of that cell are different

depending on the unique functions and

demands of that cell. And so it's a

fascinating topic, this diversification

of mitochondria. I think again that's

something that we're learning about. One

of the developments that's really been

happening over the last few years, very

much a frontier field, is you might

imagine a cell that has a complex set of

demands. There's actually evidence most

prominently published recently by Craig

Thompson at at Sloan Ketering that

showed that in one cell you can have two

different kinds of mitochondria that

have two different functions and they're

distinct in one cell.

>> What what's each of them doing?

>> Yeah. One of them tends to be more

biosynthetic, maybe producing biomass,

and one of them tends to be more energy

extracting and producing ATP. That's a

an overly simplified but generally

accurate way of thinking about it. It

really emphasizes this unique function

of of mitochondria that can be adapted

again for the needs of the cell.

>> Okay. So, I eat some food and uh that

food's absorbed and I get glucose

circulating in my bloodstream. I've got

some stored energy in the form of

glycogen etc. And I'm curious how greedy

are the different mitochondria? Is the

name of the game that every cell is

trying to get as much energy as it can

to produce as much ATP as possible or

are they communicating and is it energy

being allocated in some way that's a

little bit more um democratic that's one

question then framed within that um I

could imagine two scenarios one non

mutually exclusive where like the

vasculature just distributes the glucose

very well to everything so everybody

every cell gets gets access to some of

this glucose and and then is just greed

needy trying to make as much ATP as

possible and the whole system works

beautifully. I could also imagine a

situation where there's some shuttling

to important structures like the brain,

you know, like keeping you alive like

breathing, heart that there's a

prioritization of of organs. I'm talking

about under non-stressful conditions.

>> So, yes. So, how is energy allocated to

cells and then how are cells divvying up

the the goods? Yeah, it's a brilliant

question and a fascinating area of

physiology. As you allude to, when we

eat, our digestive system starts

extracting the constituents of what we

eat. Again, sugars, amino acids, fats

from that food that then triggers

signals of different kinds, GLP-1 being

one, insulin being another. Those

signals then are hormones. They get

secreted and they go to many cells

throughout the body and that tells each

individual cell we just ate. And the

implications of that are different from

each cell. Some cells don't care. Some

cells don't pay attention to that and

they just keep on doing what they were

doing. Some cells care a lot. Aipocites

for example, these are the fat cells,

the cells that make up our fat tissue.

They care a great deal about that. And

when they see insulin, what they do is

they turn on a protein. They start

making a protein that will cause glucose

to be taken up into that adiposite, that

fat cell. And that glucose will then be

converted through a series of chemical

reactions into a fat molecule. And then

that fat molecule will be stored away in

a way that is very safe and enabled to

be stored for potentially a very long

time.

And again, it's a beautiful way for the

organism to coordinate.

I just ate our energy status as an

organism, as a body is great. It's very

good. So let's squirrel away some of

that energy in the form of fat that can

be stored in our adiposytes again very

safely and can be then used when we go

through a period of prolonged fasting

which doesn't happen for us all that

frequently but happened for our

ancestors probably much more frequently

and those atyposites full of fat from

when we ate probably kept our ancestors

alive when they went through the periods

of prolonged fasting.

Insulin has other effects on muscle and

and other cells throughout the body that

again this is the brilliance of this

coordination. The response of different

cells to the fed state is different

depending on the the the needs and and

functions of that cell. Again, some

cells don't care at all. They're going

to just go about and do their business.

And some cells completely rewire their

function depending on the the metabolic

state the fed fasted state of the

organism. So the picture you just

described leads me to conclude that

basically every cell obviously knows its

job and is not greedily but is um

diligently fulfilling that role.

>> Yeah. And somehow the whole thing is

orchestrated so that like we work which

I know I think for some people it might

be like duh but like just like think

about that crazy

>> like a liver cell isn't really talking

to the brain cell in any kind of direct

way about how much glucose it has access

to. What you describe makes me really

understand for the first time the

brilliance of having this hormone signal

insulin not just as a shuttle because I

think most people we think like insulin

sensit most people listen to this

podcast or just existed in the world

today they're like oh you want to be

insulin sensitive you want your cells to

recognize this signal but we've never

actually talked on this podcast about

what exactly that signal is we think

about insulin as a shuttle

>> but the size of that signal is saying

what's likely to be there and I realize

has all sorts of cool implications that

can prepare the cell to like oh I'm

going to go to work hard now to be the

little squirrel that I am of a fat cell

and like squirrel away as much as I can

or be a brain cells like let's go

>> I'm ready to fire action potentials if I

need to and some cells like the photo

receptors in the eye are just doing that

>> eyes closed they're firing eyes open

well it's tricky but they're more or

less firing it's a not worth going into

obviously but in every one of these

cells mitochondria are the ones that are

essentially going to drive this ATP

>> thing right and that seems extremely

efficient, too, to just have essentially

one major cellular energy source. So, if

you could walk us through what happens

as glucose gets into the cell and and

and really what we've not done ever on

this podcast and I I don't think I've

heard elsewhere on any podcasts,

>> maybe it's out there, but is how you go

from ATP to actually the cell being able

to perform its roles. Yeah.

>> And I realize there's a lot of

biochemistry there, but you've worked on

some really lynchpin molecules in that

pathway that perform very specific

roles. And so like maybe we could really

talk about basically gets us from ATP to

pyuvate, which might scare some people

away, but you'll you'll educate us as to

why it's not scary. It's just super cool

and why it's so important to have these

signals that that aren't just like

chemicals. They actually mean something

for the cell. Cuz for me, forgive me for

going a little long here, but then I'll

shut up. I think if people can really

internalize this idea that yeah, like

hormones go up, hormones go down.

Cortisol goes up with stress, it goes

down. You wake up, cortisol goes up.

Melatonin when you're sleepy. It's not

just that it's there, but that the size

of the signal says a lot more than just

be sleepy. It's saying what once

happened is different than what's

happening now. It sets a stage for what

happens next. And this is really like

the verbs of biology that are harder to

communicate even in video. Yeah.

>> So, take us from glucose to ATP and ATP

to this thing that we call energy.

>> Yeah, there's a obviously a lot to

unpack there. Glucose is the dominant,

let's say, carbohydrate, the dominant

sugar that most our cells are consuming.

And when glucose is brought into a cell,

it goes through again a series of

chemical reactions that we call

glycolysis.

And I I'm going to simplify because

there's obviously this is the subway map

of New York. There's a lot of branches

going all over the place that we're

going to

>> go north or south.

>> North and south,

>> which is pretty much the only direction

you can go on the cell. I'm I'm not a

New Yorker. I'm kidding. I realize you

can go across across the aisle.

>> Yeah. Don't insult the New Yorkers

anymore. Yeah.

>> So glucose

comes into a cell, goes through a series

of chemical reactions, and you mentioned

it gets to pyrovate. That's the end

point of glycolysis, this set of

chemical reactions. And then pyrovate

there's a decision that has to be made

by that cell. It can either

take that pyrovate into the mitochondria

and burn it essentially

oxidize it which is essentially burning

it combining it with oxygen and that is

a very effective way to extract all the

energy that can be extracted from that

glucose via pyrovate.

>> Tell us a little bit about pyrovate.

Yeah. What's the best way to like

conceptualize pyuvate for for somebody

like me?

>> It's an intermediate. It's a midpoint

let's say from glucose. Glucose is a

sixcarbon molecule complex chemical

sixcarbon chemical that gets again

chemically modified down to this

pyrovate which is as I alluded to in a

way kind of a pivot point

>> in the metabolism of that glucose. And

the reason why we became really

fascinated with pyrovate

is because of that bifurcation that

happens. Pyrovate can either be again

taken into mitochondria and burned and

that's very effective for generating ATP

for extracting all the energy that can

be extracted and that's what

cardiammyioytes for example really love

to do take that everything they can from

the circulation burn it make ATP keep

our heart pumping and again other cells

on the other hand don't do that they

don't need as much ATP so those

intestinal stem cells that I talked

about that are the factory in a Okay,

that's enabling the repopulation of our

gut lining every week. They do something

different with that pyrovate. They

instead of burning it turn that pyrovate

and other molecules intermediates in

glycolysis into biomass into the stuff

that will enable that one cell to

duplicate itself. And I've become

totally fascinated with this

bifurcation.

Food can either be converted to energy

or it can be converted to biomass. I

think that's maybe a bit overly

simplistic, but I think a good baseline

way to think about the what we get out

of the food that we eat.

Energy or building blocks that can be

used to make a new cell to repair a cell

that's been damaged for a B cell and

immune cell that are the ones that make

antibodies. making a bunch of

antibodies, which an activated B cell

needs to do. That's a lot of stuff that

needs to be made. That requires that B

cell to have a lot of amino acids that

can be turned into proteins, which are

antibodies are proteins. And and and

that again, that's a very important part

of our immune system that keeps us

protected from invaders that might

otherwise kill us. And so that that

distinction that lands at the point of

pyrovate I think is a is a super

fascinating pivot point in metabolism

that I think many of us are fascinated

by exactly how the cell

>> organizes itself to make the right

resource allocation decisions. You know

every one of our cells is all every

second of every day is making resource

allocation decisions. What does it do

with the stuff that it has? And and this

is one that I think is really

fascinating.

>> So we are probably like seven I'm

insulting the cell biologists but

probably seven steps away from sandwich.

So sandwich goes in the mouth into the

gut gets absorbed right we get glucose.

Glucose gets into the cell. We got some

important biochemistry that you know is

in this uh ATP generation pathway and we

get to this like key node that you're

describing as pyuvate and pyuvate is

either going to say let's make more you

called it biomass but stuff of cells.

>> Yeah.

>> So we're like you have lumber arriving

maybe might be a decent enough analogy.

You're either going to use it to build

more house or you're going to burn it

>> for heat energy.

>> Great analogy. Um, and let's look make a

add a condition where you need to burn

some of that lumber for heat energy to

keep the construction project going.

>> Exactly.

>> Okay. So, we're at this key bifurcation,

this key split point. Is it just as

metabolically demanding for a cell to

use pyuvate to keep itself going like a

cardomyioite versus making biomass or is

one more costly? I'm thinking again as

you beautifully pointed out at the

beginning about thinking about that our

metabolism as a whole body as a person

is is the sum total of all these these

things is it equivalent in terms of like

>> how much sandwich relatively speaking is

going into maintaining us and rebuilding

us what you call biomass what I'm

calling building you know allocating

lumber for the for the house itself

>> versus to uh fuel the fire so to speak

>> that's hard math to do there's a lot of

nuance rough percentages. I won't hold

you to it.

>> Yeah. No, I mean one way to think about

that, many of us are probably

unfortunately aware of PET imaging,

right? This is this is something that

happens that's often used to diagnose

cancer

emission tomography.

>> An FDG PET, which is the most common

form of PET, is basically you're giving

cells a form of glucose that can then be

visualized with this PET scan that many

people are aware of. And the reason we

do that is because tumors

take up a lot of glucose and FDG PET is

fluoroxy glucose. This is a a labeled

version of glucose. So the reason we do

FDG PET is to see the cells where in the

body is taking up a lot of glucose and

tumors take up a lot of glucose. So FDG

PET is used to diagnose cancer

frequently very effectively. So that is

one metric for this. A cancer cell is

again a cell that is making a resource

allocation decision all the time. But in

the context of of that cell when it

transforms into a cancer cell that

resource allocation becomes very much

about building more cells. That's why a

tumor is a tumor is because that one

cell that was the first bad actor

decided instead of doing the thing it

was supposed to be doing decided to

duplicate itself and duplicate itself

again and build a cluster of cells that

then become a tumor.

>> Okay. I have a pseudo philosophical

question but it's really a scientific

medical question about tumors. Bacteria

have the opportunity to hijack genomes

of cells. viruses certainly probably the

the easiest example for people to

understand is like a herpes virus like

HSV1 or something which lives on neurons

>> doesn't kill the neuron which is

convenient for the virus

>> right because if it killed the neuron it

too would die because if the neuron is

expressing that virus it's hijacked the

genome

>> so this earlier I was saying like

viruses have their own quote unquote

intelligence

>> like stay alive but keep the host alive

too and transmit and in the case of

rabies it's the most easiest one to

conceptualize like impact areas of the

brain that trigger aggression would that

trigger

>> right

>> biting and and people have speculated

like does the virus know that it's doing

this like probably not right doesn't

they're not brains but pretty impressive

level of quote unquote

>> uh adaptive behavior and intelligence

>> I think of cancer as just a bad thing

all around right that these cells are

greedy they're taking glucose they're

making more of themselves it's cell

turnover gone arry tumor gets big, it

starts to encroach on other tissues,

metastasize, boom, you kill the host.

>> That's not a great strategy from the

perspective of the tumor. So, it

obviously isn't thinking about its

long-term outcome in any kind of

adaptive way.

>> But has anyone ever looked at tumors in

the same way that we think about

viruses? Like the logic there is the

same.

>> Yeah.

>> Except it it seems that their goal is to

kill the organism. I'm not trying to

anthropomorphize about cells and

cellular processes, but I think

is there a a potential set of answers

about how to deal with tumors and and

think about cancer that could be

borrowed from any of those other

examples or am I or am I going down the

wrong path?

>> Yeah, it's an it's an interesting

question. You know, viruses and

bacteria, similar to how you were

describing viruses, some of the same

principles apply to bacteria in you

know, parasitic bacteria. Viruses, as

you allude to, their goal that, you

know, if you do want to anthropomorphize

them, their goal is to propagate, right?

They are under evolutionary pressure.

The way that that virus survives is to

make more of itself, go infect another

organism and have that other organism

make a bunch of additional viruses that

will then go and infect another

organism, right? That is the

evolutionary game

>> and that's what viruses do. And they're

very good at it. And you described some

really interesting biology where viruses

will actually affect the behavior of the

host to make them better at getting into

the next host. It's amazing.

>> I wish we had a better language for this

thing because intelligence is not really

it because it's not of brains,

>> but it's this adaptive logic.

>> Yeah, that's a good uh phrase for it,

adaptive logic that enables the survival

and propagation of that virus. And and

this is how evolution works, of course.

If that virus had a mutation that made

it better able to do that, that virus

then would infect better

>> and it would get into hosts better,

propagate better, and it would

eventually take over the population of

that virus. That is the process of

evolution. And I think again it makes

intuitive sense. You know, you asked

about cancer. Cancer is obviously

fundamentally different in one key way.

If I get a virus and I come in here and

we're sitting across the table and I'm

hacking and whatever and I spew across

the table at you, you might get the

virus,

>> get sick, build a bunch of additional

virus, and then you give it to

co-workers and that's viral propagation,

which we all sadly know about. There's

very little evidence that cancer is

infectious.

>> What about Tasmanian devils?

>> You know about this, right?

>> No, I don't know about this.

>> Okay, I don't know if this held up, but

there was this idea for a while. Someone

will tell us in the comments. This is

what's fun about doing this on the

internet.

>> That Tasmanian devils fight and that

there's wound induced propagation of

cancers. These very disturbing as an

animal lover, you know, very disturbing

images of these cute little animals with

these little teeth. They're they have a

viciousness to them and they have these

like tumors growing at the at wound

sites and it turns out those are cancer.

So there's somehow like

>> fighting and wounds and viral, it might

it might be bacterial. I don't know.

That's outside my expertise,

>> but there was this idea that you that

they could transmit cancers to one

another through fighting.

>> Interesting.

>> Which I thought was sad but fascinating

nonetheless. And Australia is a weird

place, you know.

>> A lot of stuff happens.

>> I mean, the world's upside down there,

so after all. No. Um but but right,

you're right. In general, yeah, we don't

actually think that um people are

catching cancers from one another.

>> So when you think about the evolution of

a cancer, the scope of that evolution is

different, right? The scope of that

evolution of a a cell in me

>> is limited to me.

>> Cancer cells undergo evolution in the

exact same way. You know, if one cell in

my body starts propagating, it acquires

a mutation that enables it to divide and

divide faster and maybe it, you know,

get out from underneath the limits that

are being placed upon it by the immune

system and by other systems that control

propagation of cells in the body. It can

then divide and divide again. And that's

basically the continuous process of

cancer development is the acquisition of

mutations that make that cell better

able to evade the immune system, to

duplicate itself, evade um the the

problems that would come with DNA

damage, which many cancers have, and to

continue to make it make cells that

survive. And that is in a way an

evolutionary process playing out at the

level of individual cells. But how that

interacts with the host is obviously

different because again a virus has this

sort of evolutionary drive to get from

one organism to to another to another to

enable its propagation.

Cancer you isn't fueled by the same

motivations let's say because again as

far as we're aware that very rarely if

almost never happens to get from one

organism to another. And so the

motivations are different, but the

evolutionary process underlying it, it's

the same principles at play in both.

>> I'd like to take a quick break and

acknowledge our sponsor, AG1. AG1 just

launched their newest formulation called

AG1 Pro. And right now, you can get an

extra 20% off your first subscription.

AG1 takes the clinically backed AG1

formula, which is a blend of vitamins,

minerals, probiotics, and adaptogens,

and adds three important new

ingredients. Creatine monohydrate,

calcium HMBB, and zinc carnosine. It has

5 g of creatine monohydrate to support

muscle strength and performance along

with brain health, calcium HMBB to

support muscle recovery and reduce

muscle breakdown, and zinc carnosine to

support and improve the lining of your

gut. Some of these ingredients I

personally was already taking separate

from the AG1 formula. So, it's great to

see all three of them now in the new AG1

Pro. As you may know, I've been taking

AG1 every single day for about 14 years

now. That means I discovered it and

started taking it daily long before I

even knew what a podcast was. I continue

to take it and back it here on the

podcast because it is an excellent

formula. And it's now even better with

the AG1 Pro formula. For a limited time,

you can get an extra 20% off your first

subscription to AG1 Pro by going to

drinkag1.com/huberman

and using the code backtoine. So that's

with the numeral 2 back numeral 2

routine. Just go to

drinkag1.com/huberman.

Today's episode is also brought to us by

eight. Eightle makes smart mattress

covers with cooling, heating, and sleep

tracking capacity. One of the best ways

to ensure you get a great night's sleep

is to make sure that the temperature of

your sleeping environment is correct.

And that's because in order to fall

asleep and stay deeply asleep, your body

temperature actually has to drop by

about 1 to 3°. And in order to wake up

feeling refreshed and energized, your

body temperature actually has to

increase by about 1 to 3°. Eight

automatically regulates the temperature

of your bed throughout the night

according to your unique needs. I've

been sleeping on an eightle mattress

cover for nearly 5 years now, and it has

completely transformed and improved the

quality of my sleep. The latest eight

model is the pod 5. This is what I'm now

sleeping on, and I absolutely love it.

It has so many incredible features. For

instance, the Pod 5 has a feature called

autopilot, which is an AI engine that

learns your sleep patterns and then

adjusts the temperature of your sleeping

environment across different sleep

stages. It'll even elevate your head if

you're snoring, and it makes other

shifts to optimize your sleep. If you'd

like to try eight, go to

eight.com/huberman

to get up to $350 off the new Pod 5.

Eightlee ships to many countries

worldwide including Mexico and the UAE.

Again, that's eight.com/huberman

to save up to $350. I'll take us down

one more estuary, then we are actually

going to talk about mitochondria and

pyuvate again and your contributions to

this critical node of where pyuvate puts

its efforts building more stuff of the

cell or using energy. Anytime I have a

serious cell biologist, which isn't that

often on this podcast, or somebody who

thinks about the pieces that make up us,

I try and ask this. I'm bothered by this

one thing I heard once, which is that

like it's so easy to think about

evolution. It's like, okay, we're all

adaptively trying to make more of

ourselves, care for our young, and go

forward. That's like what every spe

every you know, mamalian species does.

That all makes sense until I learned

about the gut microbiome from my

colleague Justin Sonnenberg and he said

you know every time you shake hands like

we exchange microbiome today

>> and we're sharing in the air and skin we

shook hands you see and like there is

this one model of like all of this

that's very purely biological that we

are just shuttles for the microbiota

>> and everything that we're doing like

building electric cars and uh holding uh

debates and protests and um sending kids

to school and all of that we think is

about us but the microbiota are just

like they've hijacked this process and

like they're not sitting there going

these [laughter] humans they think this

is all about them and we're just trying

to spread and make sure that we continue

and maybe long after they're gone we're

just going to keep going and I can't

poke any holes in this it's like too

good a theory but I keep hoping

somebody's going to tell me at least

from a purely biological perspective

that like that's not true but it kind of

scares me every once in a while I think

Maybe I'm just a bunch of micro biota

shuttle just the vehicle.

>> We're just a shuttle. But we got this

brain which is very convenient for them,

right? Because it makes me want to go

out and do things and I think about

failures and successes and how I want to

do better and what I want to do at

different stages and like maybe it's

just all about them getting as far and

wide as they can.

>> Well, unfortunately, Andrew, I'm not

sure I'm going to be able to provide you

the concrete proof that that's not true.

It's a it's a fascinating

>> kind of eerie, right?

>> Yeah, very eerie. We definitely don't

like to see think of ourselves as

anything other than the pinnacle of

evolution and the reason for everything,

>> right?

>> But there's no question to to your

point, the microbiome are the bacteria

that live in our gut and on our skin,

they're being driven by the same

evolutionary pressures that we've been

talking about for viruses and for us.

They're trying to propagate themselves

and fill the niche that they live in,

fill the little chunk of of the universe

that they live in and do it better than

their com their competing neighbors. And

if they can do that, then their genome

is going to get passed on and again and

again. And it's fascinating to think

about the role that we play for them and

they play for us. This is a phenomenon

that's been known for a long time, but I

think the implications of the microbiome

is something that really has only been,

I think, experimentally dealt with in a

really serious way in the recent decade

or so. And I think we're still learning

about the implications, but there's no

question that they're big. Tell us about

MPC 1 and 2. I'm asking about

biochemical steps and a key process of

energy production and and allocation.

And normally when people hear acronyms,

they don't understand. and they kind oh

my goodness like what are we doing here?

But like

I think it's so important that people

understand like this business of us this

metabolism having energy whether we're

young or old have a lot of it or less of

it healthy or dealing with cancer like

this is a key node and what I want to

know truly is how do you actually

discover something like this because and

this is where I think we we can really

illustrate the scientific process in a

way that like most people just don't

understand. You need cells first of all.

You need to be able to find the mic

mitochondria. You need to be able to

know what's ATP and what's pyuvate. And

then you know they're going to two

different pathways cuz someone else said

that and you can observe it down a

microscope.

>> Yeah.

>> But then how do you find this thing and

then tell us what it's doing perhaps or

tell us what it's doing. But I think it

would be very useful for people to get a

picture of how this is done because we

hear this stuff like oh this molecule MC

and people go oh is there a peptide for

that? It's like hold off. Let's think

about how we come to understand these

these essential aspects of oursel I

think would be so useful.

>> I appreciate you asking about that. It

allows me to reminisce a little bit

about the process of discovering that

which was you know a fun time in my

career and was fueled by the brilliant

people in the lab that did it. So MPC

this is a case where the acronym

actually makes sense. It's the

mitochondrial pyrovate carrier. So you

don't have to be a scientist.

>> Uh we did not name it. that was it was

named before. I'll I'll tell you that

one story cuz I don't like acronyms that

aren't informative.

>> MPC,

>> aptly named

>> is the carrier

>> that enables pyrovate to get into the

mitochondria. Mitochondrial pyrovate

carrier. That's what it does. Sits in

the mitochondria and basically provides

a very specific hole in the membrane to

enable pyrovate to get in so that it can

then be burned by the mitochondria to

again extract all the energy to make

ATP. That's that's basically what it

does. The history of this is really

interesting. It's been known for

60 or 70 years that mitochondria must

have a carrier to enable pyrovate to get

in. But it was not identified what that

protein was, how it worked.

And

fast forward to 2008 or nine or so, and

our laboratory had just recently become

again fascinated with mitochondria. I

would say the motivating piece of of

information that convinced us to start

working on mitochondria was the

realization that many of the proteins

that make up mitochondria that do the

stuff that mitochondria do we don't know

what their functions are and that

suggested that this organel powerhouse

of the cell we kind of I at least felt

like we knew a lot about what

mitochondria do there's mysteries there

that we don't have answers for. And so

we started just taking some of these

proteins that we know are in

mitochondria, we don't know what they

do, and trying to figure out what they

do. And two of those turned out to be

MPC1 and MPC2. Way back when I I

observed and was taught, I didn't do a

ton of this, that like if you want to

figure out what proteins are in a cell,

you get a bunch of those cells, which

you can do

>> and then you

>> you kind of grind them up and then you

run them through a bunch of columns and

like literally tubes.

>> Yeah.

>> And those tubes have filters that either

let big, less big, small, or very small

things through, what we call

fractionation, right? And then you kind

of test the the different stuff that

comes through for its ability to do

something in some sort of cell. It's

like how did you actually find MPC2? Was

it done by like

>> sort of hardcore what we call hardcore

biochemical purification? That was kind

of the old way of doing it. Or well, let

me ask this. Do we know the total number

>> of proteins in the in a given human

heart cell?

>> I think we know. Yeah, I think

>> we know everything that's in a heart

cell. I think we know all the proteins

in a heart cell. Again, you can get into

the nuances of slightly modified

versions, but we know the proteins

because they are encoded by our genome,

right? We know the human genome that's

been sequenced. We know what that is,

>> but we don't know that everything that's

expressed in a given cell. That's right.

>> That that's true. And there there are

some very interesting features there.

>> Can I sorry, I'm interrupting on

purpose. 20 years ago, could you say

what you just said

>> with much less confidence that I than I

can now? say heart cell, but we don't

actually know all the all the bits in

it. But now we do.

>> Now I think we we know

>> essentially everything. Again, there's

going to be subtle nuances that we don't

know, but I think we know almost

everything.

>> That's good.

>> Doesn't mean we know what all those

things do. And that's maybe the frontier

for the biochemistry frontier for the

next generation of scientists to to

figure out. We don't know what they all

do, but we know more or less what they

all are. knowing what they are but not

knowing what they do motivated us to go

take these two proteins that were in the

mitochondria.

We could make a very strong hypothesis

that they were important because they

were in every cell that has mitochondria

down to a yeast that's a single-sellled

organism and plants and animals.

Everything that has a mitochondria has

these two NPC1 and NPC2 proteins. And it

would probably uh take too long to

explain on this podcast this the

processes that we went through to try to

identify the function of this MPC 1 and

2, but this was a a brilliant

collaboration and I think one of the the

highlights of my career.

different people in my lab and in the

lab of my colleague Carl Thumbl that

worked together. Carl was a fly

geneticist or is a fly geneticist that

used his unique skills and and resources

and we were using yeast as a model

system as well as human cells and

triangulating all that data. We came up

with data that suggested that this might

be the mitochondrial pyrovate carrier.

these two unknown proteins that happened

to be sitting in the mitochondria and

that was now been validated many times

over that these are the proteins that do

this transport of pyrovate into the

mitochondria. It was a really fun time

for me as a scientist to to see that

happen. And you know, you kind of

alluded to this when you asked the

question, what was maybe even more

exciting than the discovery of the

mitochondrial pyrovate carrier, which

Carl and I did, and we published a paper

and the lab of JeanClaude Martin and

Geneva published a paper at the same

time showing the same discovery. What's

been really fun since then is to see the

implications of that and starting again

to understand what role this protein

plays in the allocation of that pyrovate

that we've been talking about because

now the MPC

is the first step towards one

destination of that pyrovate. So it kind

of pulls it into the mitochondria so to

speak and once that pyrovate is in the

mitochondria it's going to be used for

something in the mitochondria instead of

maybe being used for something else in

the cytool. And so that's been work that

that we've done a lot of since is what

are the implications of that. And I

think it's been exciting to see in

different cell types what that means.

And so cardiamyiotes for example again

these are cells that want to make ATP to

to allow cardiumes to continue to

contract. They need to extract every bit

of energy they can make as much ATP as

they can. They use this MPC extensively.

How do they ensure that that these

cardiammyioites make sure that they make

just enough to maintain themselves so

they they're not so busy burning up all

the lumber that they end up going, "Oh

my goodness," and the house fell apart.

>> Yeah.

>> Do they consistently devote 90% of of

their ATP to energy utilization and that

they just know 10%. Like how

quantitative are these these these

pathways?

>> Because you can't you can't have the

walls fall down. It doesn't matter how

much energy you produce, right? It's a

brilliant question and and it's

definitely not programmed like like

there's a a spigot with a diverter valve

that 90% goes this way and 10% goes that

way. What actually happens and this

doesn't just happen in cardiammyioytes

it happens in every cell is that

basically the cell is measuring the

outputs again to anthropomorphize and I

have to say there are some scientists

that hate us when we anthropomorphize

having an intelligence or an adaptive

logic. So it's okay.

>> I think you've provided cover for me to

do it on for cells. Then

>> cells basically are measuring

their resources all the time.

>> I think you could make a compelling

argument that every cell almost all

cells know how much usable energy ATP

they have all the time. And when it gets

low,

they will initiate a series of reactions

to that, responses to that to bring it

back up. They'll turn off processes that

use ATP. They'll start pulling glucose

out of the circulation to make more ATP.

There's this really profound response to

ATP depletion. And I think that's true

for many of the endroducts of our

metabolic map. Again, these are the the

the products of the metabolic map are

the amino acids that make proteins. And

the nucleotides that are required to

make DNA and RNA, our genome,

>> there's a greediness to all these cells.

If the fat cells are greedy, you could

really see a problem like if we're not

ingesting enough glucose. Let's let's

hold off on ketosis for a second and

alternate metabolic pathways. But we

will touch on it. But if the fat cells

are also very self- serving then you

know at some point are they just forced

to liberate this stuff. But like

ultimately fat cells just want to get

bigger and bigger and that but if this

cardomyite it doesn't have enough

glucose eventually it's like it could

shut down any number of things like you

can remodel the house down to you know

just the fireplace and a little bit of

structure around it but eventually

>> you need the resource. So then what

happens that atyposite liberates the

energy. Yeah.

>> And and cells everybody gets a little

bit and you just hang on. So it's a

famine type situation.

>> Exactly. I mean just as insulin tells

the body I just ate.

>> We're good. Take that energy that's

available in the form of glucose.

Squirrel it away. Use it. There are

hormones that do the opposite. Glucagon

is one of them. And glucagon again has

become a little bit more popular

recently because it's now being combined

in some of the GLP-1 uh more newer GLP-1

drugs. Glucagon is called a fasting

hormone. So glucagon in many ways does

the opposite of insulin. It will go to

the fat cell, bind to the vat fat cell,

tell the fat cell to take the fat that

it has squirreled away and release it.

And now that can go to other cells in

the body, the heart. Heart is very good

at consuming fatty acids that come from

atapost tissue. And so so that's good.

>> I'm actually relieved to hear that.

>> Yeah.

>> Right. Because if if god forbid there's

a shortage of food that lasts long

enough, like that's definitely an organ

I don't want shutting down.

>> Exactly. And and most of us have fat in

our fat cells. And and you could make an

argument that the key destination of

that fat is the heart to keep it alive.

And you know in a normal human I think

it's estimated 70 to 80% of the energy

extraction that happens in

cardiammyioytes and heart muscle cells

is happening from fat. You said under

fasted conditions is that

>> especially under fasted conditions but

even in fed conditions fat is is uh is

available for the heart to use and and

>> dietary fat or fat from adapocytes

>> both whatever fat is in the circulation

the cardiammyioite is pretty good at

taking it up and burning it making ATP

from it

>> yeah the brain likes glucose but it can

use maybe now we I'm not super versed in

in the ketogenic pathways but I know

that our brain can thrive on ketones

>> so carbohydrates are not quote unquote

essential. You know, all the ketogenic

folks love to say that there's no such

thing as an essential carbohydrate. That

doesn't change the fact that like the

preferred fuel source for most every

cell is glucose. But anyway, that's a

separate issue.

>> You don't want the brain to shut down

either.

>> Yeah.

>> So, if the form of energy changes, is it

still once you get to mitochondria,

pyuvate, MCP, and downstream, is it all

the same? is essentially like energy is

energy at that point or is or is there

are there multiple pathways depending on

the fuel source?

>> Yeah, the ability of neurons to consume

fatty acids is limited. I I think it's

traditionally been thought that it's

very close to zero. I think that's being

questioned now, but it's limited. As you

allude to neurons are particularly fond

of consuming glucose and use that

glucose to make their ATP. And you know

that obviously puts a very

stringent demand on the body to always

have glucose available. Glucose is one

of these things that's fascinating the

the systems that we have in our body to

maintain glucose. You know diabetes is

defined as high blood sugar. That is the

definition the clinical definition of

diabetes when basically our body does

not adequately limit the circulating

glucose and that is destructive damaging

but it's damaging on the in the course

of years right a person can live with

diabetes for years before succumbing to

it if glucose is too low you die within

minutes if not seconds and that I think

for a few different reasons but probably

the most important one is the brain

requires some amount of uh glucose to

keep it functioning. So you know again I

I alluded to this before this very

elaborate dance that is happening by

these individual cells taking up

different nutrients out of the

circulation

using them for their own unique purposes

and and neurons again are are very adept

at taking in glucose and burning it and

making ATP from it. I think again the

heart I I feel like is really

fascinating because it'll it'll eat

anything. It's an omnivore. Fats,

glucose, lactate,

ketones, amino acids. It will make ATP

out of just about anything that ATP can

be made out of. And again, that's

important for us to enable us to live no

matter whether we just ate or not. Heart

is very good at that. So I think this

elaborate dance that we have going on in

our body all the time between different

cells cells doing it different way

taking in different fuels and uh using

them for their unique purposes.

>> What is the consequence of eliminating

the M MCP a shuttle like you get like if

you take a mouse you're at the

University of Utah let's give a shout

out to Mario Kapi whose life story is

amazing who won a Nobel Prize for

essentially developing what are called

knockout mice among other things. um you

can eliminate genes to test the role of

a particular protein downstream of that

gene. If you make a mouse that lacks

these proteins, do you get a dead mouse?

So

>> they do not survive to birth. Yeah,

>> you can get sperm egg and a and that

somehow the

>> it can become a a mouse.

>> Yeah, it'll start to develop and then I

think if I remember right, it's about 12

or 13 days of development, which is

>> you know 2/ird of the way from

fertilization [clears throat] to birth

of the mouse, it will die and and you

won't get a live mouse. But what has

been done and and obviously you were

probably getting there is because of the

technologies that Mario developed and

then others following after him, we can

now make mice that lack the MPC only in

the liver or only in the heart or only

in the muscle or only in the brain and

many of these things have been done.

>> Sorry, I should have been given credit.

He developed a technology that would

allow for organ and cell type specific

deletions or additions of genes. forgive

me but you reminded me like in all much

to so

>> yeah and many people have been

contributing that technology and

different ways to use it for decades now

and as you might imagine given the

unique demands of

different cells the effects are

different the heart is again very

focused its metabolic program is focused

on generating ATP so what if we

eliminate the MPC in the heart so we

have now made ATP P generation from

glucose less efficient. We've we've now

cut off the ability to use mitochondria

at least in the conventional way. So I

actually think the results of that

experiment are fascinating and this is

work that has been done by a few

different labs. Akmed Clinton who's a

postoc now running his own lab at

Rutgers was the one who started this and

uh other people have contributed. What

essentially happens to that heart is

that it lives and the animal lives for

weeks after that. But eventually the

animals die. And when you look at what

they die of, they have a massive heart.

They die of heart failure. And what has

become clear as we've gone and done more

sophisticated analyses of this heart and

why they die. It's pretty clear that

they don't die from an inability to make

ATP

because they can burn other things to

make ATP. We talked about this. They can

burn fats. They burn fats just fine.

What they appear to die from, and I

would say I'm speculating a bit here, we

don't have all the answers to all the

questions, is they have made a resource

allocation decision that turns out to be

pathological for them. And instead of

using the glucose that they take in to

burn it and make ATP, they start making

biomass. That that again we talked about

that that bifurcation. We've eliminated

their ability to make ATP from it at

least as effectively and instead they

make biomass. They grow. And when

cardiamyioytes grow that creates

structural problems for the heart.

Almost every human that succumbs to

heart failure will end up with a big

dilated heart that's less effective at

pumping. And that's what we see in in

the mouse really. And that maybe tells

us something about the fundamental

importance of this resource allocation

decision. And this is obviously just in

the context of cardiammyioytes. But

again, that resource allocation decision

is happening in every cell in our body

all the time. And that's one reason why

I'm fascinated with this field is we're

just starting to understand how those

resource allocation decisions are made.

What are the implications of making them

correctly and incorrectly? And maybe

even more excitingly, can we go and fix

that? When a cardiamyioite or when a

heart more aptly is making a resource

allocation decision that is

pathological,

can we fix it? Can we find a a

therapeutic that will go and correct

that and rewire it in the appropriate

and healthy way and can that then

restore the proper function of the

heart? Again, I think we're at the at

the frontier of this field, but it's a

really exciting place that that our

field exists now where we're starting to

understand the problems and we're

starting, I would say, early in

developing the right agents to act and

to manipulate this metabolic map that

might be able to fix things. I'd like to

take a quick break and acknowledge our

sponsor, Function. Function provides

over 160 advanced lab tests to give you

a clear snapshot of your bodily health.

This snapshot gives you insights into

your heart health, your hormone health,

autoimmune function, nutrient levels,

and much more. They've also recently

added access to advanced MRI and CT

scans. Function not only provides

testing of over 160 biomarkers key to

your physical and mental health, it also

analyzes these results and provides

recommendations for improving your

health from top doctors. For example, in

a recent test with function, I learned

that some of my blood lipids were

slightly out of range. As a result, I

decided to start supplementing with

nattokinise, which can naturally help

reduce LDL cholesterol, and it did. In a

follow-up test, I could confirm that

this strategy worked. My blood lipids

are now back exactly where I want them.

Comprehensive lab testing of the sort

that function offers is just so

important for health. I mean, how else

are you going to know what's going on

under the hood? And while I've been

doing blood work for years, it used to

be timeconuming, complicated, and

expensive. In fact, I used to spend

thousands of dollars per year trying to

get this kind of data. And the data,

frankly, were not all that good. But now

with Function, it's extremely easy and

affordable. A Function membership is

only a dollar a day, $365 a year. And if

you think about the information it

provides and the health challenges it

helps you avoid and the proactive things

that it can do for you to enhance your

health, I truly look at it as a savings.

To learn more, visit

functionhealth.com/huberman

and use the code hubberman for a $50

credit towards your membership. Again,

that's functionhealth.com/huberman.

So, is it fair to say that the

allocation of energy, which is made

pathologic in this mutant mouse, but

also in people who have these uh cardiac

conditions and die of heart attack