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Welcome

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episode, we bring you stories about developments

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0:11

Susan Battlett. Before we begin,

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0:44

The aging brains people with Alzheimer's,

0:47

Parkinson's, and other neurodegenerative diseases

0:50

have telltale aggregates of proteins

0:53

in or around their neurons. How

0:56

these protein clumps might

0:58

be harming the neurons is often

1:00

still unclear. but they are hallmarks

1:03

of the conditions. And until now,

1:06

they have been associated almost exclusively

1:09

with elderly brains. That's

1:11

next. Quanta

1:15

magazine is an editorially independent

1:18

online publication supported by

1:20

the Simons Foundation to enhance

1:22

public understanding of science.

1:27

A recent study by a team of

1:29

Stanford University researchers suggests

1:32

that protein aggregation may

1:34

be a universal phenomenon in

1:37

aging cells. it could be

1:39

involved in many more diseases of

1:41

aging than was suspected. Their

1:43

discovery points to a new way

1:45

of thinking about what goes wrong

1:47

and cells as they age and

1:49

potentially to new ways of

1:51

staving off some consequences of

1:54

the aging process. Della

1:56

David is a researcher on aging

1:58

at the Abraham Institute

1:59

in Cambridge, England, who

2:02

wasn't

2:02

part of this study. It's really nice that

2:04

they've done this study over lots of different

2:06

organs. That

2:07

sort of has been sporadically done

2:10

in a few

2:10

organs in mice but not at this scale.

2:13

What

2:13

I think is really important is that it shows

2:15

that protein aggregation is really

2:17

a problem that the organism has to

2:19

deal with, and this is conserved throughout

2:21

evolution. And this is why it's fed. It's

2:23

not just one specific tissue. It's

2:25

lots of different tissues. The research

2:27

also highlights that protein

2:29

aggregation is tightly bound

2:31

up with essential mechanisms that

2:34

allow cells to regulate their

2:36

physiologies with exquisite delicacy.

2:39

Biologists will need to assess carefully,

2:42

possibly on a case by case basis,

2:45

protein aggregates represent a

2:47

threat to cells or defense

2:49

they've created. The new work

2:51

was posted to the bioarchive dot

2:53

org preprint server in March.

2:56

It's the first attempt to quantify how

2:58

much protein aggregation occurs

3:01

throughout the body during the natural

3:03

aging of a vertebrate animal.

3:06

In this case, a very short lived

3:08

fish. The study shows

3:10

that protein aggregation probably

3:12

contributes to the gradual deterioration

3:15

of many tissues over time. The

3:18

findings even offer a hint about

3:20

why these aggregates are so

3:22

much more obvious in the brain

3:24

than in other tissues. It may

3:26

be because have been evolving

3:28

so rapidly. Dan

3:30

Yerosch is the Stanford Systems

3:32

biologist who oversaw the experiments

3:35

with his geneticist colleague and

3:38

Brunei. I

3:38

think that the thing that was really unexpected to

3:41

me in this paper was how often

3:44

proteins that when mutated

3:46

are associated with the degenerative disease

3:49

wound up aggregating in their wild

3:51

type form in the old animals

3:53

and in different tissues. It

3:55

has made me wonder whether

3:57

many more diseases of age

3:59

that we don't presently connect to protein degradation

4:02

might in fact it.

4:04

Eros says the African turquoise

4:06

killer fish is the shortest lived

4:09

vertebrae that can be bred in captivity.

4:11

It lives in ephemeral ponds

4:13

in East Africa. that dried

4:15

up. And basically, all of its life,

4:17

thus happens in four to

4:19

six months, and the amount of time

4:21

that it's spends in youth middle

4:23

age and advanced age are,

4:25

you know, as a fraction of life span, very similar

4:27

to us. And over the

4:29

six months that it might live, it gets

4:32

cancer and cataracts. It's

4:34

just those things happen in weeks rather

4:36

than decades. The fish can even

4:37

develop brain related changes

4:40

that resemble neurodegenerative disorders

4:42

like Alzheimer's and humans. It's

4:45

brief lifespan, much

4:47

shorter than that of a lab mouse. and

4:49

rapid

4:49

natural aging.

4:51

Make it an ideal model for

4:53

studying, aging, invertebrates. Dario

4:56

Valenzano is an evolutionary

4:58

biologist at the Max Planck

5:00

Institute for the Biology of Aging

5:03

and the Livenet's Institute on

5:05

Aging, both in Germany. He

5:07

did his post doctoral training with

5:09

Brunei. He says these fish

5:11

have a very high mutational load

5:13

to begin with.

5:14

In other words, already when they're

5:16

born, they're filled with

5:18

bad variance, like disease variance.

5:21

So this is not something that has to do

5:23

with how many mutations accumulate

5:26

throughout the life of an individual. But this is the

5:28

burden of mutations that you're born with

5:30

that will lead you on a quite

5:33

predictable downwards trajectory

5:35

when it comes to disease

5:37

onset after sexual moderation. which

5:39

is what we call aging. And

5:41

what's striking about this fish is

5:44

that it's not just protein aggregation

5:46

or heart failure or

5:48

brain dysfunction that occur

5:50

with aging, but pretty much any organ

5:52

and tissue that we look at

5:54

will undergo some quite

5:57

catastrophic

5:57

transformation during aging.

5:59

And

5:59

so it's, in other words, it's a natural experiment

6:02

of multilevel complex

6:05

aging that just unfolds

6:07

before our eyes.

6:08

The Stanford team conducted an

6:10

extensive analysis of the proteins

6:13

in killer fish at various stages

6:15

of youth and maturity. In

6:17

the aging killer fish, they discovered

6:19

protein aggregates in all

6:21

the tissues that they looked at. not

6:24

only the brain, but also the heart,

6:26

gut, liver, muscle, skin,

6:28

and testes. More than

6:30

half of the aggregating proteins seemed

6:33

to show an intrinsic tendency

6:36

to aggregate in further experiments.

6:38

But precisely which

6:40

proteins aggregated differed

6:42

substantially from one

6:44

tissue to another. Many of

6:46

the proteins were expressed at essentially

6:48

equivalent levels in multiple tissues,

6:51

Yet, while they aggregated in one,

6:53

they did not clump at all in others.

6:56

Here's our researcher, Della Davitt,

6:57

the extent of tissue specific of

7:00

the aggregating proteome is

7:02

amazing. We have evidence

7:04

that certain proteins aggregate

7:06

in certain tissues and organs

7:09

but not in others.

7:10

But it's sort of adding Doto whereas

7:13

here you've got this beautiful study

7:15

which shows how specific this

7:17

is. Dovid and other researchers think

7:19

the reasons for those differences reflect

7:22

how cells maintain the quality

7:24

of their proteins. cells

7:26

have elaborate machinery for ensuring

7:29

that the long chain like

7:31

peptide molecules making up

7:33

proteins get folded properly

7:36

and even for making sure that the peptides

7:38

are eventually chopped up for recycling.

7:40

The different tissues rely

7:42

to different extent on different

7:44

accesses of their protein quality control

7:47

machinery, and they're

7:48

using different strategies. And

7:50

that raises the question

7:51

how that changes with age. because

7:53

there is some evidence as well that certain

7:56

cell types will rely on a certain

7:58

branch of the patient

7:59

quality control in young and then that

8:02

changes over in aging. It

8:04

also says that the organism really

8:06

must have a lot of different ways to

8:08

protect itself against aggregation.

8:10

Cynthia

8:10

Kinion, Vice President of

8:13

Aging Research at the Biotechnology

8:15

Company, Calico Life Sciences,

8:18

says this is really important because

8:20

one of the huge mysteries of human

8:22

biology is why

8:24

these neurodegenerative diseases

8:27

are so tissue specific. Kinion

8:29

wasn't involved in the Stanford paper.

8:31

No one really knows for example

8:34

why the amyloid protein plaques of

8:36

Alzheimer's disease form in the

8:38

hippocampus of the brain and the aggregates

8:40

and Parkinson's disease are

8:42

specific to dopamine neurons.

8:45

Kenyon says the possibility that

8:47

various cells maintain their

8:49

protein quality differently

8:51

at least provides a possible explanation

8:54

for why different tissues

8:56

should behave so differently. There's

8:59

good evidence from studies of

9:01

worms and flies, but if the

9:03

machinery that preserves the stability

9:05

of proteins is perturbed, animals

9:07

age more rapidly. If the

9:10

protein quality control pathways

9:12

are genetically enhanced, the

9:14

animals tend to live longer. None

9:16

of this means that protein

9:18

aggregation causes aging, but

9:20

it strongly implies that the

9:22

two are tightly correlated.

9:25

To further probe the relationship between

9:27

protein aggregation and aging.

9:29

The Stanford researchers looked more

9:31

closely at the proteins in a

9:33

mutant variety of killer fish that

9:35

ages unusually quickly. These

9:38

fish have a mutation in their gene

9:40

for the enzyme telomerase which

9:43

preserves the length of the dividing

9:45

chromosomes. Animals with

9:47

telomerase mutations typically

9:49

age quickly. Yurush

9:52

says he and his colleagues expected to

9:54

find that there would be fewer

9:56

aggregates in the gut and other

9:58

tissues that grew or placed

10:00

themselves rapidly. Extra

10:02

cell divisions would give rapidly

10:04

growing tissues more opportunities to

10:06

clear away aggregates and

10:08

reset themselves. But the opposite

10:10

was true. Fast

10:12

growing tissues had more

10:14

misfolded and aggregated proteins,

10:17

and they aged more rapidly than tissues that

10:19

grew slowly. Once again,

10:21

problems with the cells control

10:23

over the quality of its proteins

10:25

may be the explanation. If

10:28

cells lose control over the

10:30

processes that maintain the quality

10:32

of their proteins, more

10:34

damage from aggregates may

10:36

build up with each cell division.

10:38

Tissues that grow rapidly may age

10:40

faster because they have more

10:42

chances to accumulate that

10:44

harm. Why proteins

10:46

sometimes aggregate is

10:48

complicated? Surprisingly, part

10:50

of the answer turns out to be

10:52

deeply connected to an essential

10:54

mechanism called condensation

10:57

that cells use to control their

10:59

proteins. Here's your

11:01

roast again.

11:01

protein condensation. It looks

11:03

like in development is really

11:06

important and adaptive.

11:08

Right? It's helped us to become what

11:10

we are. Whereas, what looks

11:12

like a very similar phenomenon, but

11:14

probably in a less organized and orchestrated

11:16

way later in life is associated

11:19

with pathology. So trying to understand that

11:21

difference in how much of it is

11:23

about the different structures that an

11:25

aggregated protein might adopt

11:27

and how much of it might be about the context

11:30

is, I think, very interesting.

11:31

The complex three d shapes that

11:34

peptides fold into were historically

11:37

seen as dictating the activities

11:39

and functions of the proteins they

11:41

made up. But in the last decade or

11:43

so, researchers discovered that

11:45

a growing list of proteins have an

11:47

intrinsically disordered

11:49

region that doesn't fold into a

11:51

stable shape. Under the

11:53

right conditions, multitudes of

11:55

these proteins gather into

11:57

droplets or condensates, a

11:59

reversible

11:59

process akin to the phase

12:02

separation that makes oil

12:04

form droplets in water.

12:06

It can enhance enzyme activity

12:08

by concentrating enzymes together

12:11

with their substrates or

12:13

suppress activity by sequestering

12:15

enzymes away from their substrates.

12:17

By altering the local

12:19

concentration of substrates and

12:21

enzymes within themselves. Cells

12:23

can use condensates to

12:26

finely tune their protein activity.

12:28

But the disorder regions of

12:30

proteins can also cause them to

12:32

stick together more permanently as

12:34

aggregates gumming up cells

12:36

and wreaking havoc. Worse,

12:38

some defective proteins, not only

12:41

misfold and aggregate themselves,

12:43

but also cause other

12:45

proteins of the same type to misfold.

12:47

leading to a chain reaction of

12:49

aggregation. This is

12:51

conceptually similar to what happens

12:53

in Mad Cow disease, and

12:55

variant Korotzfeld Jacob syndrome,

12:57

a fatal disease in which

12:59

abnormally folded proteins

13:01

called pre owneds. catalyze

13:03

a wave of abnormal protein

13:05

aggregation in the brain. Compensation

13:08

is therefore a control mechanism

13:10

that comes with risks, But

13:13

in evolutionary terms, Yerush

13:15

says its advantages are apparently

13:17

so substantial that

13:19

the cost a vulnerability to

13:21

many aging associated diseases

13:24

seems to be worth paying.

13:26

A clear illustration of

13:28

this emerged in a second preprint

13:30

posted in March, in which the

13:32

Stanford team honed in on a

13:34

protein called DDX

13:36

five that aggregates in

13:38

aging killer fish brains. DDX-five

13:41

is most active in its

13:43

condensate state. Here's Stanford

13:45

researcher Dan Yeroche. The

13:47

condensate goes from being an entity

13:49

that looks beautifully put

13:51

together It enhances activity.

13:54

Everything seems great about it. Then

13:57

over time, it will kind of

13:59

degenerate into a

13:59

much less well formed common

14:02

theme. Right? It becomes a solid and it's

14:04

completely inactive. And in fact, it

14:06

has this create online quality and that it

14:08

can converts soluble

14:10

protein or native protein into

14:12

the aggregated chain.

14:13

DDX-five serves a

14:15

variety of important functions in

14:17

the body. often helping to make

14:19

sure that other proteins are made

14:21

properly. Urosh says

14:23

from its amino acid sequence,

14:25

the researchers predicted that

14:27

DDX five was likely to

14:29

behave like a preon, and their

14:31

subsequent work confirmed that

14:33

it does. one misfolded

14:36

DDX-five protein promotes

14:38

the misfolding and aggregation of

14:40

other DDX-five molecules. but

14:42

the aggregation doesn't stop

14:44

there. The Stanford researchers found

14:46

a variety of other proteins in the

14:48

clumps of DDX five as well.

14:51

John Mabadier is laboratory at

14:53

University College London, studies

14:55

protein quality control

14:56

and aging. When these things

14:59

aggregate, they tend to form these kind

15:01

of, you know, sticky

15:03

blobs that are present in the cell, which then

15:05

starts to quest through lots of other unrelated

15:07

things as

15:08

well. meaning that other proteins are

15:10

trapped indiscriminately interfering

15:13

with cellular functions. Loveredia

15:15

says it suggests that we have

15:17

these proteins that aggregate with

15:20

age and that can actually catalyze

15:22

further aggregation of proteins

15:24

in a pre unlike manner, which wasn't

15:27

shown before. The Stanford

15:29

team carefully established which

15:31

region of the DDX-five protein

15:34

makes it possible for condensation

15:36

to control its activity. And

15:38

it turned out to be the same

15:40

region that also makes it prone

15:42

to aggregation. Control over

15:44

the protein's natural function and

15:46

its tendency to aggregate

15:48

are inextricably linked Here's

15:50

your Roche again. That

15:51

has been one of the fascinating shifts

15:54

in mindset for me. The disorder

15:56

domain, of course, it isn't required

15:58

for the activity that's very

16:00

narrowly defined. But in terms of how

16:02

that activity is really deployed in

16:04

a living system, that's actually

16:06

extremely important.

16:07

Symphia Kenyon says exactly

16:09

what triggers aggregates to

16:11

form and how much trouble they

16:13

cause for cells. remains

16:15

a huge fantastic big

16:18

controversy in the field. On the

16:20

one hand, Aggregates sequester

16:22

DDX five and other proteins

16:24

effectively eliminating important cellular

16:27

functions. But aggregates may

16:29

also have a protective effect

16:31

on cell survival. A

16:33

good example of the protective effect

16:36

emerged from studies of the

16:38

Huntington protein, which is

16:40

most abundant in the brain. Huntington

16:42

is essential for the healthy development

16:44

of nervous systems. But in

16:46

people with Huntington's disease,

16:48

a mutation causes the Huntington

16:51

protein to be abnormally long.

16:53

The long protein then gets

16:55

chopped up into smaller toxic

16:57

segments, that damage the

16:59

nervous system. Steve

17:01

Finkbiner is a researcher on

17:03

aging at the Gladstone Institutes.

17:05

and the University of California San

17:08

Francisco. In two thousand four,

17:10

he was studying aggregation of

17:12

Huntington protein in

17:14

cultured neurons. his

17:16

team showed that although all the

17:18

neurons expressing the abnormal

17:20

Huntington protein died over time,

17:22

the neurons that had aggregates of

17:25

Huntington survived longer than

17:27

those that did not. Fink

17:29

Biner says it was the

17:31

first evidence that aggregate formation

17:33

was a coping response to

17:35

other submicroscopic forms

17:37

of the misfolded protein that were causing

17:40

the trouble. He and others have shown since

17:42

then that this protective aggregation

17:44

response occurs in other

17:46

neurodegenerative diseases as

17:48

well. Fink Biner says it may explain

17:50

the repeated failure of experimental

17:53

trials for treating Alzheimer's disease

17:55

by targeting plaques. if

17:58

the amyloid plaques characteristic

18:00

of the disease formed to protectively

18:02

bind up the defective protein,

18:05

than breaking up the plaques might do

18:07

more harm than good. Think

18:09

Biner says it's a hard concept

18:11

for humans to grasp. since

18:13

it seems intuitive that things that

18:15

look abnormal should be bad

18:17

and pathogenic. He points out

18:19

that biology is complex and full

18:21

of many feedback loops, so it's

18:24

important that people don't get fooled by

18:26

jumping to conclusions. The

18:28

picture emerging clearly now is

18:30

that protein aggregation isn't a

18:33

phenomenon restricted to neurodegenerative

18:36

diseases. It's part of every cell

18:38

that lives long enough to

18:40

age. Many normal developmentally important

18:42

proteins like DDX-five have a

18:45

tendency to aggregate, and

18:47

coping with this clumping is

18:49

a universal challenge that every

18:51

cell has to address. Since

18:53

cells have been dealing with this

18:55

problem for a very long time,

18:58

preventing aggregation may have been a

19:00

major force in the evolution

19:02

of protein sequences because

19:05

abundant proteins are prone to

19:07

aggregation. and mutations increase

19:09

that tendency. Natural

19:11

selection against mutations in

19:13

abundant proteins is likely to

19:15

be very strong. conclusion is

19:18

supported by the observation that in

19:20

young animals, more abundant

19:22

proteins tend to have lower

19:24

mutation rates. so scarce

19:26

proteins may evolve more quickly than

19:28

abundant proteins, and a

19:30

faster evolutionary rate

19:32

should correlate with a propensity to

19:35

aggregate. Brunei and Yeroch

19:38

observed that this effect was most

19:40

pronounced in the brain of

19:42

the The researchers speculated that

19:44

those aggregating proteins may

19:46

have been keys to innovations in

19:48

the organ. If

19:50

so, The evolutionary changes in

19:52

the brain that made it such an important organ

19:54

in vertebrates may also have

19:57

made the organ more vulnerable to

19:59

degenerative diseases caused by

20:01

aggregation. Indeed,

20:03

uroch says it's likely that every

20:05

tissue and organ has to find

20:07

a different balance or trade off between doing

20:10

its job and managing protein

20:12

aggregation. Every tissue

20:15

has unique functional requirements

20:17

and constraints to obey.intestinal cells

20:20

turn over constantly.

20:22

Endocrine cells make and secrete hormones.

20:25

immune cells bring into action when

20:27

they detect invaders. The

20:29

brain processes information. different

20:32

jobs demand different proteins,

20:35

which means the evolved strategies

20:37

for coping with protein aggregation

20:40

will vary from tissue to tissue and from

20:42

animal to animal. Because

20:44

the vertebrate brain has in

20:46

the relatively recent past,

20:49

evolved so much more extensively

20:51

and quickly than, say,

20:53

the muscles. It's team

20:56

quality control machinery may not have

20:58

had enough time yet to

21:00

evolve adequate protections against

21:02

the aggregation of relatively

21:05

new proteins. here's dalidabid. The whole interest

21:07

of this is

21:07

that these are proteins that are

21:09

normal proteins in the cell that the

21:12

organism has to deal with

21:14

every day. The idea that these proteins have

21:16

an intrinsic propensity to

21:18

aggregate, the organism has to protect

21:20

against the aggregation. It's

21:22

not some specific irrigation happening

21:24

during disease

21:25

or during massive stress.

21:27

It's something physiological that we

21:29

all have to deal with.

21:31

And so this means that there's lots of

21:33

different mechanisms to deal with it, but so has to

21:35

deal with it.

21:36

And David says the fact that

21:38

protein aggregation throughout the body is a

21:40

factor in the aging of organisms as

21:43

disparate as yeast, worm,

21:46

flies, fish, and

21:49

humans means her field should be

21:51

paying a lot more attention

21:52

to it.

21:54

Matt

21:58

Karlstrom helped with this

21:58

episode. I'm

21:59

Susan Vallett. For more on this

22:02

story, read Vivienne Collier's

22:03

full article. protein

22:05

blobs linked

22:06

to Alzheimer's affect

22:07

aging in all cells on

22:10

our website, quantum magazine

22:13

dot org.

22:13

Explore more

22:14

science mysteries in the Quanta book.

22:17

Alice and Bob meet the wall of

22:19

fire, published by the MIT press.

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Available now at amazon dot com,

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barnes and noble dot com, or

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your local bookstore.