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The Role of Mitochondria in Aging and Disease - David Sinclair

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so one of the big questions in biology

is why don't we live forever maybe one

day we will but until we understand why

we grow old and get diseases such as

Alzheimer's diabetes cancer

cardiovascular disease we will not have

a chance to greatly extend our lifespan

one of the main reasons for this is that

currently we address one disease at a

time and even though we have

breakthroughs in say cardiovascular

disease other diseases such as

Alzheimer's are rather a calcitriol

very difficult to right now to prevent

and cure and so what happens is that we

have the decline one disease and another

disease accelerates in its in its

frequency and we're not living much

longer than we did ten thousand years

ago unfortunately so really what we're

trying to do as a field in us biologists

who study aging is to understand what's

at the root cause of this decline that

we all go through unless we're unlucky

enough to be to die early so one of the

major theories that's been around really

since the 1940s 1950s is the idea that

aging is caused by a decline in

mitochondrial function so what a

mitochondria well these as many of you

will have known from high school biology

are the bags within our cells that

generate chemical energy they do other

things they process fat and also allow

us to to make other molecules that allow

for cells to grow but really for this

topic what we want to talk about is

their role in making chemical energy

called ATP and I draw this like a bag

with my hands it's really just a double

membrane the inner membrane is ruffled

and there are lots of proteins within

that bag that carry out these chemical

reactions to make ATP and energy now

what's really interesting about

mitochondria is that they're actually

another organism living within each of

our cells

and unlike the textbooks there isn't

just one or two mitochondria per cell

there's hundreds encased some cases

thousands of these and they're not just

single bags they're actually networks in

there we're learning that they they

divide and then they fuse and then they

they can do the cell can destroy the bad

ones and improve the healthy ones there

are some unfortunate people throughout

the world who have mitochondrial

diseases and when the mitochondria don't

function well from birth patients tend

to have a number of neurological disease

diseases traits and there are other

muscle loss of muscle functions as well

so mitochondria are critical for life we

know that in fact if you poison the

mitochondria say with cyanide you be

dead within about 30 seconds so we

really need to understand not just how

mitochondrial function but how to keep

them healthy throughout our life and one

of the main theories of aging is that

over time well we start out young and

there's lots of mitochondria in the

healthier and they know how to function

they make lots of energy we feel great

we've got energy we can run we can fight

off diseases our brain functions well we

can remember and we don't get diabetes

we don't have dysfunctional muscles for

example but over time let's say people

like me who are now midlife we are

starting to lose our mitochondrial

function that's a fact and then by the

time we're in our 60s and 70s it's even

worse and in 80 to 90 year old we'll

have much much lower mitochondrial

function and they'll have less ATP and

this is a problem and we scientists

think that one of the major causes of

diseases during aging is caused by this

loss of the ability of ourselves to make

energy now as I mentioned mitochondria

are free living organisms in our cells

they joined ourselves about two billion

years ago they were originally what are

called alpha proteobacteria we find

these free living bacteria right now in

the world but they're genetically

related and functionally related to our

own mitochondria and what's important is

that these mitochondria have their own

DNA they brought their own genome with

them when they joined ourselves to make

eukaryotes

and today they still have many of those

genes in their genome the other genes

that used to be in in that genome it's a

circular genome have been transferred to

the nucleus and so we're really just a

mishmash of two species living together

and the genomes exist separately but

they need to communicate very well

together

to maintain their coexistence and be

healthy and later I'll tell you that one

of the problems with aging might be that

these two genomes within ourselves lose

the ability to communicate but first I

want to tell you about an older theory

of aging that still holds some weight

what we're starting to think is that

this is more of a later stage of Aging

so back in the 1940s and 50s I was

telling you that the mitochondrial

theory of aging was born and that's the

idea that during metabolism there's a

lot of free radicals or we call these

reactive oxygen species that can damage

macromolecules the idea is that as the

mitochondria when we're young are

functioning they're producing these

radical free radicals that damage the

enzymes and particularly the DNA within

the mitochondria and over time we start

to lose the code that's in our

mitochondrial DNA we get mutations we

get big deletions so for example if we

took my DNA from pretty much any cell

except perhaps my germ cells in my

testes these cells would have a large

number of mutations and deletions

already which is rather disturbing and

the idea is that if we could slow down

this damage to our DNA

we would have a way to delay aging we

could prevent these mutations and we

would actually be healthier to into long

and have a longer life now this theory

still had has some merit you can find

these mutations in it in anybody even

newborns have some mutations already

which is a scary thought one of the

problems with their theory has been that

the ability to extend lifespan by

slowing down these mutations has been

rather a

difficult battle we haven't really had

success feeding antioxidants to mice for

example or other organisms hasn't had a

big impact on their lives and in fact

one of the the new theories is that free

radicals might be somewhat beneficial

and can extend the lifespan if you take

a little worm for example and give it

antioxidants they can actually have a

negative impact on its long life so it's

not as simple as we once thought where

the field is settling now is that the

damage to mitochondrial does occur it

seems to be important but it might be

most important for the later stages in

life let's say after your 50 60 70 but

what's going on in someone like me who's

40 what's why am I already experiencing

a decline in my mitochondrial function

well it may not be to do with mutations

and the reason is that we have found

just recently studying Meissen and human

cells is that if you catch aging early

enough and the mitochondrial dysfunction

early enough it's actually reversible

one of the the new leading theories in

aging and mitochondria is that the

communication between the nucleus and

the mitochondria breaks down early

during aging and let's call that stage

one of aging now what what carries out

this communication is that so if we have

the nucleus here in the mitochondria

here there are proteins that are made in

the nucleus by our main chromosomes and

those proteins travel across the

cytoplasm into the mitochondria and they

help the mitochondria be healthy they

make it make just the right amount of

energy to match what the cell needs and

what we found is that during aging in

the early stages this communication

these proteins that move across to the

new from the nucleus to the

mitochondrion they start to lose their

activity and you don't have as much made

anymore in the cells now the good news

now is that if we could restore that

communication we might have a chance of

reversing aspect of aging if we catch it

early enough

now the analogy that I like to make is

that the nucleus and the mitochondrial

genomes these two genomes are like a

married couple

when they move in together early though

they're in love they communicate well

they talk they share ideas and that's

what our souls are like when were young

but over time they don't they don't talk

as much they develop different interests

and what happens is they stop talking

over time and we know that that's the

worst thing that can happen for a

marriage and we think the same thing

happens for the marriage of these two

organisms these two genomes in ourselves

and what our job is now is to test what

happens if you can restore that

communication again and that get them

talking again and just in December of

2013

our lab published an interesting paper

that showed the following it showed that

one of the main causes of

miscommunication is that the nucleus

doesn't think it's getting enough energy

anymore and it doesn't it doesn't send

the signals to the mitochondrion to make

them produce the energy anymore we track

this down to the loss of a small

molecule called called nad we think nad

is critical for cells health and their

ability to maintain this healthy

communication so what we did was we

simply raised the nad levels back up in

a mouse to their youthful levels so a

mouse when it's young has let's say this

amount of nad over time the nad levels

drop by half and we found well first of

all we ask the question if we raise

these levels back up to youthful levels

of nad what happens can we restore this

communication and we did that that the

way you do that actually is quite simple

you inject the mouse with a molecule

that the animal turns into nad you can

buy this from a chemical company you

inject it for a week and we ask does

this have a benefit restoring the

communication and the answer was yes now

after one week of raising nad the

nucleus was now re-establishing

communications to the mitochondria they

were talking again

and then we could ask does this improve

health does it restore the energy of the

cell which we think is a cause of Aging

and the answer was quite remarkably yes

the mice when we looked at their muscle

and their heart they had a restoration

of youth the mitochondria were revved up

again after just a week and they were

making energy and as far as we could

tell looking at all these functional

assays of the mitochondrial activity

their ability to make energy their

genomes activity the amount of DNA they

had they went straight back to being

young again so we actually couldn't tell

the difference between a two-year-old

mouse and a six-month-old now so what

that really is like is saying we could

take a 50 60 year-old human muscle and

make it like a 30 year old again now I

mean that would be great if it's true in

humans we only know in mice so far but

we are gearing up to test this in humans

we think that if we could give this

molecule that raises nad in a pill or an

injection we think that we within a week

if we're right then we could reverse

aspects of Aging in humans and that

would be something really quite

spectacular and if we can do that

there's a possibility that we could

actually not just see people get old and

an experience diseases and slow down one

disease at a time with with two

traditional medicines we might be able

to actually if we catch the dis event

early we could reverse mitochondrial

aging and if everything turns out to be

correct that I've said then what we

expect is that humans will not develop

diabetes even cancer heart disease

Alzheimer's until much later maybe into

their 90's hundreds or further and so

that we're looking at a future where we

might be able to restore youthful

energetics in cells prevent

mitochondrial aging keep this organism

within our bodies healthy and live much

longer healthier lives

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