0:00

It's Aspen ideas to

0:02

go from the

0:04

Aspen Institute. I'm

0:06

Tricia Johnson. You've

0:08

probably heard about

0:10

scientific work being

0:12

done to try

0:14

and slow aging,

0:16

but it's not

0:18

just for humans.

0:21

People are making

0:23

advances in lifespan

0:25

for our furry

0:27

friends too. K-9 biology is very

0:30

relevant to human biology too, so what

0:32

we learn at dogs is not going

0:34

to be one-to-one to human, but could

0:36

potentially be much more compelling than, you

0:38

know, just working a mouse. Within a year,

0:40

dog owners might be able to buy a

0:42

drug that would extend their dog's life and

0:45

hopefully keep their pet healthier for longer.

0:47

Long-term studies for dog health are

0:49

also growing and providing new insights all

0:51

the time. Aspen Ideas to Go

0:53

brings you compelling conversations presented

0:55

at the Aspen Ideas Ideas

0:57

Festivalues Festival. Neuroscientist Salin Hallewa

1:00

has always been an

1:02

animal lover and founded her

1:04

biotech company Loyal when she was

1:06

just 24. Loyal is getting close

1:08

to bringing a drug to market

1:11

that will extend dogs lives.

1:13

Daniel Promislow has been studying

1:15

aging for three decades comparing rates

1:18

of aging among and between species.

1:20

He leads the Dog Aging Project

1:22

which is collecting data on dogs

1:25

across the country for a long-term

1:27

study. Elliot Gerson, the

1:30

Aspen Institute's executive

1:32

vice president, moderates

1:34

the conversation. Here's Gerson.

1:37

Saline, let me just start.

1:39

Why dogs? Why did you focus

1:41

so early on dogs and

1:43

become interested in extending

1:45

the life of these

1:48

wonderful creatures? Yeah, so hi

1:50

guys. I've always been an animal

1:52

person. I've been vegetarian my entire

1:54

life. I grew up with 15

1:56

cats, four dogs, a grackle is

1:58

a broken ring. a turtle we

2:00

rescued from the side of the

2:02

road. I wanted to be a

2:04

vet for a really long time,

2:07

but I actually got really passionate

2:09

about age-related diseases and preventative medicine.

2:11

When I started in undergrad and

2:13

I started in neuroscience, because a

2:15

lot of neurodisorders are age-related diseases

2:17

that increase in likelihood and probabilities

2:19

you get older, and they're also

2:21

really, really difficult to treat. So

2:23

I remember I was working in

2:25

a lab in San Diego that

2:27

was working on stem cell replacement

2:30

for Parkinson's disease through basically trying

2:32

to graft in new dopenergic neurons

2:34

to replace the neurons that degrade

2:36

and die out. in Parkinson's, and

2:38

it was just such a complex

2:40

problem, right? You had to, you

2:42

know, at the time this was

2:44

embryo derived. They had to, you

2:46

know, get the right kind of

2:48

subtype of openergic neuron from the

2:50

embryo, they had to differentiate it

2:53

and to exactly what they needed,

2:55

they had to put this very

2:57

frail patient under anesthesia to try

2:59

to, you know, put these stem

3:01

cells in there, and long story

3:03

short while the thesis and in

3:05

some of the cases was actually

3:07

very... successful, it was just so

3:09

many variables to go wrong and

3:11

so complicated. I just remember very

3:13

specifically staring over a thing of

3:15

cells and thinking, Why aren't we

3:18

working on preventative medicine? Why aren't

3:20

we working on reducing the risk

3:22

of somebody getting diagnosed with this

3:24

in the first place instead of

3:26

waiting decades for them to get

3:28

diagnosed and then ending up kind

3:30

of in this arms race that

3:32

we just are losing over and

3:34

over again? So to get to

3:36

your question on why dogs, I

3:38

was trying to figure out how

3:41

to work on this for humans.

3:43

But for reasons that actually don't

3:45

have to do with the biology

3:47

at all, it's much more logistical,

3:49

health care system, economics, all these

3:51

other things that I'm happy to

3:53

I'm happy to go into for.

3:55

you can't get a drug approved

3:57

for lifespan extension in humans today,

3:59

but I had a crazy hypothesis,

4:01

which was probably fueled by being

4:04

very naive, that you could do

4:06

it in dogs, because dogs, you

4:08

know, they live a much shorter

4:10

life, big dogs live a much

4:12

shorter life than smaller dogs, as

4:14

the owner of a senior Rottweiler.

4:16

unfortunately, very aware of that. And

4:18

you can show efficacy in a

4:20

period of time that's reasonable. And

4:22

I'm not independently wealthy. And so

4:24

that was very, very important, because

4:26

I had to raise venture capital

4:29

to do all of this. We've

4:31

raised $125 million. We haven't made

4:33

a dime of revenue besides maybe

4:35

like the, I don't know, interest

4:37

payments due to the high interest

4:39

rates right now. Yeah, basically the

4:41

thesis is show longevity in dogs,

4:43

and then if it, you're much

4:45

more an expert on this, but

4:47

canine biology is very relevant to

4:49

human biology too. So what we

4:52

learn in dogs is not going

4:54

to be one to one to

4:56

human, but could potentially be much

4:58

more compelling than, you know, just

5:00

work in a mouse. So Daniel,

5:02

just one question before we get

5:04

to dogs strictly, as an expert

5:06

in aging generally, let me just

5:08

ask, why do we age? Why,

5:10

given the power of natural selection,

5:12

haven't some species adapted to live

5:15

longer, reproduce longer? And so, why?

5:17

It's a great question. First of

5:19

all, thank you for the chance

5:21

to come here and talk about

5:23

dogs and all of you for

5:25

showing up. Why do we age

5:27

if natural selection is so powerful?

5:29

Why does everything fall apart? The

5:31

answer actually goes back about a

5:33

hundred years and it's a big

5:35

idea, so it's appropriate for a

5:38

festival of big ideas. We all

5:40

inherit new mutations from our parents

5:42

and grandparents and Those of you

5:44

like me who have no mechanical

5:46

abilities, if you open up the

5:48

hood of a car and close

5:50

your eyes and hit the engine

5:52

with a hammer, it's gonna be

5:54

worse, not better. That's what mutations

5:56

are like. Most mutations that we

5:58

get, if they really do bad

6:00

things, they're not gonna be passed

6:03

on to our kids because we're

6:05

not gonna survive to have kids.

6:07

But if we have mutations that.

6:09

Maybe don't have their effects until

6:11

we're older. Saline was talking about

6:13

Parkinson's disease. We're thinking about Huntington

6:15

disease. Typical Huntington patient, we don't

6:17

see the effects until we're 50.

6:19

So all of those mutations that

6:21

we carry, they have a fuse

6:23

on them. If it's a really

6:26

short fuse, it may go off,

6:28

and most of those mutations go

6:30

off when we're embryos, and we're

6:32

never even born. As all of

6:34

you, I'm sure know, most pregnancies

6:36

are terminated before we even know

6:38

about them. But here's the big

6:40

idea. Some of those ticking time

6:42

bombs, those mutations we got from

6:44

our ancestors, have fuses that are

6:46

60, 70, 80 years. There's no

6:49

selection against them because by the

6:51

time we have our kids, they

6:53

haven't gone off yet. We've passed

6:55

those mutations onto our kids. They

6:57

carry them. So as we get

6:59

older, more and more of these

7:01

tens, hundreds, thousands, tens of tiny

7:03

little ticking time bombs inside of

7:05

us are going off. and there's

7:07

no selection to get rid of

7:09

it. If you look at a

7:11

mortality curve of humans, for most

7:14

of our lives, it's so low

7:16

down, you can't see it, and

7:18

then it just takes off exponentially,

7:20

as all those time bombs that

7:22

have accumulated over evolutionary time go

7:24

off, and it's true for us,

7:26

it's true for the fruit flies

7:28

in my lab that I study,

7:30

and it's certainly true for the

7:32

beautiful little dogs like that little

7:34

guy sitting right there, and all

7:37

dogs. Thank you. And I know

7:39

that there's a lot of wind

7:41

here, so I'm going to try

7:43

to speak even louder and ask

7:45

all of us to do that

7:47

as well. So, Saline, just tell

7:49

us about loyal and your developments,

7:51

and how are these drugs going

7:53

to work, and how soon are

7:55

we going to see them? So,

7:57

Gus can get one. Yeah, that's

8:00

why you invited me here. All

8:02

makes sense now. This is a

8:04

borrowed guss, by the way. Last

8:06

time I moderated with a dog

8:08

on the stage was my own

8:10

dog named Guss, so but go

8:12

ahead. Oh, interesting. Okay. Yeah, so

8:14

we started on this. big dog

8:16

short lifespan theory. So this idea

8:18

that the bigger a dog is

8:20

a shorter life span is and

8:22

at the extremes you see a

8:25

two X differential. So a great

8:27

Dane might live seven or eight

8:29

years while Chihuahua might live 17

8:31

to 18 years. And for context

8:33

it's pretty strange to see a

8:35

two-ex differential and expected lifespan within

8:37

the same species. I'm relatively short,

8:39

especially in these shoes. I'm not

8:41

going to live twice as long

8:43

as some of the tall people

8:45

in the audience, right? And long

8:48

story short, the kind of aha

8:50

moment for me and the company.

8:52

or that kind of genesis the

8:54

company, was that when you look

8:56

at the genetics of dog size,

8:58

there's really no one gene that

9:00

controls a human size, but you

9:02

can actually sequence a dog and

9:04

tell them about 10 pounds how

9:06

big they are, the confidence interval

9:08

being how much food the dog

9:11

owner does or does not give

9:13

the dog, right? And so, and

9:15

the reason why, there's only about

9:17

six genes that predominantly control dog

9:19

size, and about four of them

9:21

are in this longevity pathway. called

9:23

growth hormone IGF1. So it was

9:25

this kind of intersection point that

9:27

basically this very well validated and

9:29

understood longevity pathway where you see

9:31

the exact same phenotype. So if

9:34

you make a mouse have really

9:36

high level to growth hormone on

9:38

IGF1, you get a big mouse

9:40

that lives a very short period

9:42

in time. And additionally, the longest-lived

9:44

mouse is a low IGF1 growth

9:46

hormone mouse that's very very small,

9:48

very small, very small, that's very

9:50

small, very small. for me because

9:52

I've always been a big dog

9:54

person. It's actually been a development

9:56

area for me as a CEO,

9:59

because it's really bad as a

10:01

dog CEO to go up to

10:03

a small dog and then cower,

10:05

because I have big dog energy,

10:07

apparently. But it was really interesting

10:09

because it connected what aid gave

10:11

traction, an extremely, extremely complex phenotype.

10:13

Aging is about as complex as

10:15

it gets. B, it connected something

10:17

I believe the agency and the

10:19

general scientific community already understood, which

10:22

is that dog. have diseases due

10:24

to historical inbreeding that we gave

10:26

dogs genetic mistakes when we turned

10:28

the wolf into the poodle and

10:30

into the chihuahua and into the

10:32

Great Dane. And you know German

10:34

Shepherds hip displays drug goldens gifts,

10:36

different forms of cancer, and this

10:38

just happened to be another disease,

10:40

quote unquote, that we gave big

10:42

dogs when we selectively bred them

10:45

to be large. And so it

10:47

connected something the agency and the

10:49

scientific community already understood with something

10:51

what I wanted to work on,

10:53

which is a drug where the

10:55

only use case is a extend

10:57

the lifespan, primary claim, and the

10:59

health span, secondary claim of the

11:01

animal. Like that was the goal,

11:03

to go to your vet and

11:05

say, I want my dog to

11:07

live a longer healthier life. Here

11:10

you go, this is the drug

11:12

for that. The dog has to

11:14

be diagnosed as anything. It's just

11:16

an Asian weight criteria. And so

11:18

that was the original inspiration. We

11:20

now have drugs that are also

11:22

being developed for a senior dog

11:24

lifespan extension for dogs of most

11:26

sizes and most breeds. But that

11:28

was really kind of the foundational

11:30

work. And I'm happy to dig

11:33

into any of the stuff that's

11:35

interesting to be clear like I

11:37

had like the very initial idea

11:39

But this has been the work

11:41

of a lot of help how

11:43

quickly may we okay? I know

11:45

what you want to get to

11:47

We all want to get it.

11:49

Yeah, so I mean Our first

11:51

drug, if everything stays on track,

11:53

we'll hopefully earn FDA approval at

11:56

the beginning of next year. We

11:58

last year announced that we earned

12:00

the first ever, it's called Reasonable

12:02

Expation of Advocacy, basically the effect

12:04

of his dossier approval for this

12:06

big dog Fort Lifespan drug. So

12:08

basically the FDA said, A, they

12:10

acknowledge that the drug can be

12:12

approved for Lifespan Extension, and B,

12:14

they said that our data supports

12:16

market approval, conditional market approval for

12:19

Lifespan Extension. Which as far as

12:21

I'm aware, we're, we're the first

12:23

company, we're the first company. We're

12:25

the first company. to achieve that

12:27

in any species. So a really

12:29

important milestone for us and us

12:31

personally and this kind of goal.

12:33

Great. So Daniel, tell us a

12:35

little bit about the dog aging

12:37

project and the key learnings so

12:39

far and what's next? I mean,

12:41

it's. It's vast. Yeah, thanks for

12:44

asking. So the dog aging project

12:46

is a nationwide community science project

12:48

to study companion dogs, pet dogs

12:50

in people's homes, people like you,

12:52

from all across the country, to

12:54

learn about the environmental factors and

12:56

the biological factors that shape healthy

12:58

aging. Why are some dogs healthier

13:00

agers longer lived than others? So

13:02

far we've enrolled. 48,000 dogs from

13:04

every state in the United States,

13:07

including Alaska and Hawaii. We are

13:09

still open for recruitment. If you're

13:11

interested, Dogaging Project.org, all dogs, young,

13:13

old, male, female, intact, intact, sterilized,

13:15

mixed breed, purebred. And so we're

13:17

like, for those of you who

13:19

know about the human longitudinal studies,

13:21

like the Framingham Heart Study, the

13:23

women's health initiative, We're like framing

13:25

him for dogs. We're collecting huge

13:27

amounts of data from dog owners,

13:30

and we also collect biospeciments. We

13:32

do the biology of those biospeciments,

13:34

blood and hair and urine and

13:36

all of that. And the goal

13:38

is to really understand how dogs

13:40

age. And by following them every

13:42

year for their entire lives, we

13:44

then have the power to go

13:46

back in time and ask about

13:48

what are the things that we

13:50

did to your point, Saline. What

13:52

did we do that helped prevent

13:55

disease in some dogs compared to

13:57

those others that weren't so lucky?

13:59

We are a lot of things,

14:01

and I will momentarily get to

14:03

your question, Elliot, about what we

14:05

found so far. But I think

14:07

one of the things that I

14:09

think a lot about, and that

14:11

is so true of the discourse

14:13

that we see here at the

14:15

Aspen Ideas Festival. The Dog Aging

14:18

Project is trying to understand aging

14:20

in dogs, but it's... also engaging

14:22

all the participants. It's about the

14:24

power of paying attention. That means

14:26

you watching your dog and sharing

14:28

what you observe with us. And

14:30

really importantly, the 48,000 people who

14:32

have signed up their dogs come

14:34

from all walks of life. We

14:36

don't ask who they vote for.

14:38

We do ask about their annual

14:41

income. They don't have to share

14:43

it, but we have rich and

14:45

poor. We have rural, urban and

14:47

suburban. And we surely have. Democrats

14:49

and Republicans and Independents, and they

14:51

all come together over the most

14:53

important thing about the dogaging project,

14:55

which is motivated not only by

14:57

the fact that dogs are the

14:59

most variable species on the planet

15:01

after broccoli, maybe, and that they

15:03

get our diseases and live in

15:06

our environment and have the sophisticated

15:08

health care system, but people love

15:10

dogs, and we really need a

15:12

lavily or frick us. So just

15:14

very briefly, what have we learned

15:16

so far? So so far we've

15:18

just been analyzing the first year

15:20

of data. That means just a

15:22

slice of time. We haven't yet

15:24

started going back and looking at

15:26

what did we see three, four

15:29

years ago that's affecting what we

15:31

see now. We're beginning to do

15:33

that. Some important things we've learned

15:35

that aren't surprising, dogs that exercise

15:37

more tend to be healthier. Dogs

15:39

that have a healthy body condition.

15:41

tend to be healthier. Like in

15:43

humans, obesity is a risk factor

15:45

for all kinds of diseases and

15:47

dogs. Some interesting things that raise

15:49

really cool questions, and we are

15:52

collecting the molecular data to answer

15:54

why we see what we see.

15:56

For example, dogs that eat once

15:58

a day are also dogs that

16:00

tend not to have GI and

16:02

pancreas problems. That doesn't mean you

16:04

should feed your dog once a

16:06

day. Our late dog Frisbee had

16:08

pancreas problems, and the vet said,

16:10

don't feed her once a day,

16:12

feed her multiple times a day.

16:15

So that might be the correlation.

16:17

So we're beginning to make all

16:19

these observations, and with the molecular

16:21

data, we'll begin to get at

16:23

the mechanisms for why it is.

16:25

that dogs are short or long-lived.

16:27

And the last thing I'll say,

16:29

of those 48,000 dogs, about 1%

16:31

of our dogs are also enrolled

16:33

in a clinical trial testing a

16:35

different class of drugs from the

16:37

one that loyalists testing, a drug

16:40

called rapomice, which has been shown

16:42

to extend lifespan in mice and

16:44

flies and worms in the lab,

16:46

which of course raises the really

16:48

important question of when. the owner's

16:50

consent to put the dog in

16:52

a clinical trial for a healthy

16:54

lifespan, what does the dog have

16:56

to do with it? Amazing. Saline,

16:58

Gus, before he left the stage,

17:00

wanted me to ask you, how

17:03

do you balance the desire for

17:05

longer life with assuring a healthy

17:07

and happy life? Yeah, so I

17:09

think it's actually a false dichotomy.

17:11

It would, I think a lot

17:13

of people associate working a lifespan

17:15

extension with kind of extending out

17:17

that unhealthy last couple of years

17:19

of life because that's what a

17:21

lot of age-related disease therapies unfortunately

17:23

have to do. Everybody knows someone

17:26

who's gone through, you know, a

17:28

really rough chemo treatment or some

17:30

of the, you know, Parkinson's and

17:32

Alzheimer's interventions I was talking about

17:34

are pretty difficult. and can induce

17:36

or perpetuate a pretty terrible quality

17:38

of life. An aging drug doesn't,

17:40

at least aging drugs that we're

17:42

working on, wouldn't work that way

17:44

at all. The really good way

17:46

to think about it is kind

17:48

of pulling out those healthy middle

17:51

years. You take an animal that's

17:53

relatively healthy already. Hopefully you see

17:55

some reversal, really big air quotes.

17:57

aging is not defined, but improvement

17:59

in certain known drivers of pathological

18:01

unhealthy aging. But you also see

18:03

a retention of the dog in

18:05

that healthy state longer. So that's

18:07

actually what we're really looking for

18:09

in our studies is looking at

18:11

can we perpetuate basically round out

18:14

the curve, right? So if this

18:16

is kind of the quality of

18:18

life over time of the animal,

18:20

can we make it more like

18:22

this? Were the dogs healthy, healthy?

18:24

and then whatever takes about the

18:26

end is a relatively fast process.

18:28

Which if and when achieved, especially

18:30

for humans, will completely change how

18:32

we think about aging, right? It's

18:34

very linked that you get older

18:37

and you have a worse quality

18:39

of life, but it doesn't necessarily

18:41

have to be. So Daniel's sort

18:43

of the same kind of question.

18:45

How do you look at that

18:47

balance if there is one in

18:49

your own research? And what about

18:51

the dog's opinions in all of

18:53

this? So to the first question,

18:55

I think one of the great

18:57

powers of the dog aging project

19:00

is that we are following these

19:02

dogs longitudinally. Some enroll young, some

19:04

enroll old, but we follow all

19:06

of them for their whole lives.

19:08

And so because everything happens so

19:10

much more quickly in dogs, in

19:12

dogs. five or 10 times more

19:14

quickly than in humans, we have

19:16

the opportunity to ask whether the

19:18

longer-lived dogs are healthier longer or

19:20

if they're experiencing longer lifespan with

19:22

more disease. So that's the first

19:25

thing. And like Saline in our

19:27

own study with rapomycin, we will

19:29

certainly be asking whether it prolongs.

19:31

healthy lifespan or what we call

19:33

health span, which is what we

19:35

want both for dogs and of

19:37

course for our own loved ones.

19:39

As for who is asking the

19:41

dog, it's important to recognize that

19:43

all the care that we give

19:45

our companion animals, whether a dog

19:48

or a cat or a budgy

19:50

or a turtle, is without their

19:52

spoken consent. Well, maybe some birds

19:54

talk. And we do it with,

19:56

ideally, working closely with the veterinarian.

19:58

We know our companion, beloved companion

20:00

animals, better than anybody else. And

20:02

we have to make the decision.

20:04

But keep in mind that we

20:06

do this all the time as.

20:08

parents when our children, especially when

20:11

they're pre-lingual, and then even once

20:13

they speak, and my own son

20:15

when he was a teenager with

20:17

testosterone poisoning, his frontal cortex was

20:19

not working very well, not making

20:21

great decisions. We also have to

20:23

make careful decisions about the care

20:25

that we provide and we ask.

20:27

physicians to provide to our own

20:29

kids. My wife is a physician

20:31

scientist, and she enrolls the pediatric

20:33

patients that she works with in

20:36

clinical trials to figure out ways

20:38

to heal them better. So we

20:40

do that all the time. I'll

20:42

mention that in the dog-aging project,

20:44

aware of these challenges, we have

20:46

a team ethicists. So we have

20:48

about 100 people that run the

20:50

project. One is a pediatric bioethicist.

20:52

And then we have a veterinary

20:54

bioethicist who's independent of the team,

20:56

because we think it's really important

20:59

to have constant oversight. But if

21:01

there's a way to, I mean,

21:03

I have experienced the suffering that

21:05

my own dog experienced, and even

21:07

if she lived the same long

21:09

16 years that she did, but

21:11

with less pain and suffering, that

21:13

surely would have been a good

21:15

thing. How do you think the

21:17

research and work you're doing could

21:19

be applied to humans, if at

21:22

all? Yeah, so I would say

21:24

there's a direct way to indirect

21:26

way. The direct way is, we

21:28

talked about how you went to

21:30

much more detail of how. The

21:32

way a dog ages, teachers is

21:34

a lot about how humans age.

21:36

They've co-evolved with us, they share

21:38

an environment with us, they're exposed

21:40

to the same environmental pollutants. They

21:42

eat, if they're like my dog,

21:45

they eat a lot of similar

21:47

food as what we eat. And

21:49

really importantly, they develop age-related diseases

21:51

over time. only kind of big

21:53

variance between what dogs get versus

21:55

what humans get is dogs don't

21:57

get cardiovascular disease in the same

21:59

kind of subtype. as what humans

22:01

get. But otherwise, actually, the incidence

22:03

rate and prevalence between humans and

22:05

dogs at age-related diseases is very,

22:07

very similar. And many of the

22:10

times, it's random, it's natural, it's

22:12

due to a lot of what

22:14

you were talking about. And so

22:16

if a drug works to extend

22:18

across, because, like, for example, we

22:20

are also obviously running studies, and

22:22

we're currently enrolling a thousand dog,

22:24

pivotal lifespan extension studies, it'll be.

22:26

500 placebo, 500 on our drug,

22:28

following them for four to six

22:30

years. We'll see how the stats

22:33

work out, hopefully, in the lower

22:35

end, to hopefully show pivotal efficacy

22:37

for mortality risk reduction. And that's

22:39

going to be dogs all over

22:41

the US. Dogs of all breeds,

22:43

you know, mutts, pure breeds, and

22:45

all of that. And that's really

22:47

important because if an intervention actually

22:49

shows efficacy in that, again, it's

22:51

not one to one to be

22:53

relevant to a human, but it's

22:56

pretty compelling evidence. For context, and

22:58

you're obviously the scientist scientist here,

23:00

but. When you study many of

23:02

these age-related diseases in lower organisms,

23:04

it's often induced. You know, most

23:06

mice die of cancer. You don't

23:08

get as a complex, for example,

23:10

Nordicinem disorders, naturally, in mice as

23:12

you do in a dog, versus

23:14

you get canine cognitive dysfunction, one

23:16

of my favorite indications from a

23:18

scientific standpoint. It's just really compelling

23:21

that if you can show some

23:23

movement or some traction on these

23:25

very complex age-related diseases and these

23:27

dogs, that maybe you're onto something

23:29

for humans. That's one. And then

23:31

two, the reason I think that's

23:33

actually a little bit less intuitive

23:35

is I don't know if you

23:37

want to go more into this,

23:39

but it's just the complexities of

23:41

developing a drug, especially in the

23:44

US today. If you're trying to

23:46

develop a new pharmaceutical for human

23:48

use, It costs about a billion

23:50

dollars, it takes about seven to

23:52

10 years, and you're basically just

23:54

externalized R&D for big pharma. So

23:56

the companies that get 100 million,

23:58

200 million, half a billion in

24:00

funding, they're getting it because these

24:02

usually pretty established biotech VCs are

24:04

like, oh yeah, I know Pfizer

24:07

is going to want that. Or

24:09

Muderna is really interested in that.

24:11

So it's kind of, of course

24:13

there are exceptions, right, but generally

24:15

speaking, this is the pattern you

24:17

see. And these companies never make

24:19

revenue, they never bring a product

24:21

to market before they get bought

24:23

up by one of these big

24:25

pharma companies. And that's very effective

24:27

and efficient in certain ways. But

24:29

for what we're doing, where the

24:32

A, there's no kind of established

24:34

market for longevity drugs, and B,

24:36

it takes such a long time

24:38

to be humans, I think actually

24:40

having the revenue, which again, hopefully

24:42

starting next year, we'll begin to

24:44

have revenue, having the team that's

24:46

focused wholly in lifespan and health

24:48

span extension and no specific indications

24:50

besides that. And therefore, the leverage

24:52

I'm able to have as a

24:55

CEO as I've run my company

24:57

will allow us to work on

24:59

these moon shots in a way

25:01

that I don't think would fit

25:03

into the normal kind of biotech

25:05

economic ecosystem otherwise. Can I follow

25:07

up on this? Yeah, please. Two

25:09

quick things. First of all, in

25:11

my world is the biology of

25:13

aging. Many of us call it

25:15

geroscience, the study of aging. And

25:18

one of the big ideas in

25:20

geroscience is that... The single greatest

25:22

risk factor for all the major

25:24

killers in humans and in dogs

25:26

is not smoking, it's not lack

25:28

of exercise, it's not addiction, it's

25:30

age. If you compare the effective

25:32

age, it dwarfs all the other

25:34

factors. And one of the excitements

25:36

in the geroscience field is that

25:38

if there are ways to... slow

25:41

down, decrease, attenuate the effect of

25:43

age on all these diseases that

25:45

you get multiple benefits. And even

25:47

if people aren't living longer, they're

25:49

living healthier with respect to cardiovascular

25:51

disease and cancer and neurodegenerative disease.

25:53

And it's a big idea and

25:55

it's not. yet proven, but it's

25:57

an exciting idea. And then the

25:59

other thing that I want to

26:01

mention that you touched upon is

26:03

that dogs are living in our

26:06

environment, often COVID aside when we

26:08

were all working from home, they

26:10

spend more time in our environment

26:12

than we do because we leave

26:14

every day for 10 hours. Dogs

26:16

are really potentially a very powerful

26:18

sentinel. for all the risk factors

26:20

that we are surrounded by. Think

26:22

about the volatile organic compounds that

26:24

are coming off of our carpeting

26:26

and our furniture because of fire

26:29

retardants. Think about the microplastics that

26:31

we're ingesting in our water. We

26:33

don't know what's going to happen

26:35

because we live so darn long.

26:37

50 years is longer than the

26:39

lifespan of a graduate student, and

26:41

we make our graduate students do

26:43

all the work. Because dogs go

26:45

from middle age to old age

26:47

in just five years, they have

26:49

the power to be sentinels, the

26:52

canaries and the coal mine, for

26:54

not only the risk factors, but

26:56

also the good things that will

26:58

help us live healthy long life

27:00

spends. That was your group that

27:02

published that a couple weeks ago.

27:04

That's a really good paper. You

27:06

guys should check it out. So

27:08

you just answered the follow-up question

27:10

I was going to ask you,

27:12

Daniel, but let me ask a

27:14

question. It's sort of a footnote

27:17

based on what Saline just said,

27:19

which I hadn't really thought about

27:21

about about before. What is the

27:23

evidence about longevity of, as you

27:25

put it, mutts versus purebreds, and

27:27

are there lessons in that? Are

27:29

you asking me or do you

27:31

speak this? Well, so of the

27:33

48,000 dogs, we've enrolled almost exactly

27:35

half a male, half a female,

27:37

half a month, and half are

27:40

purebreds. In general, and this is

27:42

work we've done over the years,

27:44

the right dog for each of

27:46

you is the one you fall

27:48

in love that all that matters.

27:50

So I'm not saying you should

27:52

get this dog or that dog.

27:54

But on average, for a given

27:56

size, as Saline so eloquently said,

27:58

the large breed dogs are shorter

28:00

lived. for a given size, the

28:03

purebred dogs are about a year

28:05

shorter lived than the months. Recently

28:07

we put out a paper that

28:09

suggests that the diseases don't

28:11

differ that much, that whether

28:13

your dog is purebred or

28:15

mixed breed, on average, you're

28:17

going to see the same diseases.

28:20

Importantly, different breeds are at

28:22

risk of different things. So

28:24

there's this. gorgeous cavalier King

28:26

Charles Spaniel right in front

28:29

of me. Poor little guys

28:31

are often struggle with heart

28:33

problems. They don't get cardiovascular disease,

28:35

but they have heart problems. And

28:37

it's good to know because we

28:39

can keep an eye out. Half

28:41

of all golden retrievers, I am

28:43

sorry to say Mr. Annenberg, are

28:45

going to get cancer in their

28:47

lifetimes. They may not die of

28:49

it because there's awesome treatments for

28:51

cancer, but it's a big risk.

28:53

So interesting. and probably has something

28:55

to do with the inbreeding. But

28:58

that's what we know so far.

29:00

Yeah. Let me ask a different

29:02

kind of question I alluded to

29:04

earlier. More of a sociological question. What

29:06

if your drug is as successful as

29:08

we all hope it will be and

29:11

the kinds of things you're doing, Daniel?

29:13

What if dogs that are now living

29:15

to 15 could live to, and I

29:17

don't know what we're talking five years,

29:20

ten years? Let's say they could live

29:22

to 25 or 30 years. What changes

29:24

are there going to be in human

29:27

dog society, community, if you will,

29:29

if there's not a comparable increase

29:31

in human longevity? I mean, what,

29:33

I just... The dogs are going

29:36

to take over. They'll be running

29:38

to Aspen Institute. But I mean,

29:40

not a bad thing. But you

29:42

understand the question. I mean,

29:44

it would really change, I think,

29:46

so many things. Have you thought

29:49

about that through? I mean, I'm

29:51

not saying good or bad, but

29:53

there'd be profound changes in how

29:55

humans deal with their dogs, I

29:58

think. Yeah, should I start? Yeah. So

30:00

first and foremost, I don't think our

30:02

drugs will radically extend lifespan in a

30:04

way that will change things too much.

30:06

Where kind of our line we put

30:09

in the sand was one year of

30:11

healthier life, maybe it'll be more, maybe

30:13

it'll be less. We don't really know,

30:15

right? That was kind of the amount

30:18

that we thought would be, you'd be

30:20

able to tell from a population standpoint,

30:22

and that would be clinically meaningful. But

30:24

yeah, of course there'll be V2 drugs,

30:27

V3 drugs, etc. and maybe we'll start

30:29

getting closer to those numbers. I think

30:31

one of the really interesting biases that

30:33

people have is anchoring towards whatever we

30:36

have now as being the right thing

30:38

and deviation from that being the wrong

30:40

thing. And so I think if, for

30:42

example, I'm a horse girl. Shocker, right?

30:44

And horses live to 25 or 30.

30:47

And that's totally normalized. It's fine. Nobody

30:49

bats an eye at that. Cats can

30:51

live to 19 or 20. So I

30:53

think people really just kind of get

30:56

used to whatever is normalized in their

30:58

society. And as things change, they become

31:00

used to it too. Again, I think

31:02

it's a long time before we have

31:05

30-year-old great Danes running around. But I

31:07

think it's a little bit of an

31:09

interesting thought exercise to go through. Yeah,

31:11

I, one of the things I really

31:14

love about the dogaging project, as I

31:16

alluded to at the beginning, dogs connect

31:18

all of us. And what we learn

31:20

about aging in dogs, is very likely

31:23

to teach us a lot about aging

31:25

in people. I think also it's likely

31:27

to help us think about the nature

31:29

of being human. all the time. We

31:32

don't like to talk about it in

31:34

our own lives, but we can learn

31:36

a lot about how to deal with

31:38

end-of-life care for ourselves and our loved

31:41

ones by thinking about it with dogs.

31:43

Similarly, one of the questions that I'm

31:45

really interested in thinking about has to

31:47

do with the fact that many of

31:49

my colleagues are now saying publicly that

31:52

they believe that we will figure out

31:54

how to make... people live to 150

31:56

or 200 years. Let's say we figure

31:58

out how to make people live to

32:01

121 years, which is the longest known

32:03

lifespan of anyone, Madam Jean Kilma. How

32:05

would that change society? How would it

32:07

change it in terms of family structure,

32:10

economics, sociology, all of these things? And

32:12

so I don't know the answer to

32:14

your question. I think Saline is the

32:16

closest of anyone to getting to getting

32:19

to. help us think about that answer

32:21

if her product is successful. But I

32:23

also want to encourage all of us

32:25

to begin asking those questions of ourselves.

32:28

What would society look like if we

32:30

suddenly had a pill that we could

32:32

give a 50-year-old and it would, on

32:34

average, give them 10 or 15 extra

32:37

years of lifespan? I would wager that

32:39

that would dramatically change society. And so

32:41

we ought to start thinking, encouraged by

32:43

the work that loyal and the dog

32:46

agent project and others are doing with

32:48

dogs. to think about the societal implications

32:50

of lifespan extension. There are many trials

32:52

now in humans looking at age-related disease

32:54

using the discoveries from geroscience lab. So

32:57

now is the time to be asking

32:59

this question. I don't have the answer,

33:01

but we need to come together in

33:03

places like this to talk about it.

33:06

Salina comment and then we'll turn it

33:08

to the audience. We were before the

33:10

panel we were talking about this a

33:12

little bit and joking about the effect

33:15

on society of a 150 year old

33:17

musk. So there. And the context of

33:19

that which was a question I would

33:21

have asked which is what if that

33:24

pill for to allow someone to eat

33:26

leave to 150 or 200 costs a

33:28

hundred million dollars? And what are the

33:30

implications for society if we allow that

33:33

to happen? Yeah, I mean, so a

33:35

quick aside on that, one of the

33:37

things I really love about working on

33:39

dogs, so my other life besides aging

33:42

and dogs and horses and stuff, with

33:44

actually health economics. and specifically the economics

33:46

of preventative medicine. We didn't have really

33:48

good access to health care. My parents

33:50

are both not American citizens, and as

33:53

was before, there was a lot of

33:55

kind of the broad insurance support for

33:57

lower income. And so I was really,

33:59

really aware from a young age that

34:02

health care costs a lot of money.

34:04

And at the incentives are not very

34:06

aligned between you and the health care

34:08

provider, especially if you're on like a

34:11

really, you know, crappy, bare minimum health

34:13

care plan, or none at all. And

34:15

one of the things I love about

34:17

dogs is that the incentives are 100%

34:20

aligned. You care about your dog today,

34:22

and you care about your dog 10

34:24

years from now. There's barely any insurance,

34:26

but it's like 1% of US dogs

34:29

are insured. So it's all cash pay,

34:31

which means you have to really think

34:33

about cogs. We optimize our manufacturing costs

34:35

so much to make sure our drug

34:38

will be accessible and affordable to the

34:40

majority of Americans. It's the thing I

34:42

get the most crap for my VCs

34:44

about, but it's really, really important to

34:47

me personally. incentivized to invest that money

34:49

to help their dog live a longer

34:51

healthier life because they're on the hook

34:53

if and when their dog gets sick

34:55

or gets cancer. And so I love

34:58

that incentive alignment you get there and

35:00

I hope that will hopefully, I think

35:02

we're starting to see the beginnings of

35:04

that with some of the consumerization of

35:07

human pharma we're seeing it with the

35:09

glips and these direct selling of drugs

35:11

where you know you there's a lot

35:13

of debate there but if you can

35:16

align the incentives better within the system

35:18

that we have, which it's not gonna

35:20

change any time soon, I don't think.

35:22

You can really start optimizing for more

35:25

preventative care, which is much more effective,

35:27

much more efficient. And I was the

35:29

second thing I was gonna say, my

35:31

hot take is that actually longevity drugs

35:34

are one of the best things we

35:36

could do for socioeconomic mobility. Again, like.

35:38

Thankfully, my parents are healthy. If my

35:40

parents hadn't been healthy, I wouldn't be

35:43

sitting on the stage. Because I wouldn't

35:45

have been able to go to school

35:47

and focus on that. I wouldn't have

35:49

been able to go across the pond

35:52

and go do a PhD over there.

35:54

I wouldn't have been able to make

35:56

some bet and move the Silicon Valley

35:58

and work for free and like 24-7,

36:00

right? Because I would have been having

36:03

to take care of them because they

36:05

wouldn't have had coverage. who live a

36:07

longer healthier life, that gives their children

36:09

more mobility. And yeah, you're gonna have

36:12

these fringe negative effects on the tail

36:14

end of the spectrum, but I think

36:16

the vast majority of people need better

36:18

preventative care, and I think that type

36:21

of aging drugs we're working on have

36:23

an opportunity of delivering that. Okay, to

36:25

the audience, saw lots of hands earlier,

36:27

and I think we have microphones, there's

36:30

one right in front of you, and

36:32

then we'll go over to this side.

36:34

advertising. How much of a difference does

36:36

that make compared to prescription kibble from

36:39

your vet? I don't think anybody's run

36:41

that study. But you will note that

36:43

they, I mean, interrupt me if I'm

36:45

wrong, but they do all advertise around

36:48

helping your dog live a longer healthier

36:50

life. I think Farmer's Dog literally has

36:52

long-lived dogs on their box. Do you

36:54

have anything? We are collecting that data

36:57

every year from all of the participants

36:59

and a few years from now we'll

37:01

be able to look back and tell

37:03

you about which dogs live longer depending

37:05

on the food, there are certain prescription

37:08

foods that are absolutely necessary for certain

37:10

dogs. And the most important thing there

37:12

that you can do is ask your

37:14

vet if there's a particular illness that

37:17

the dog has that it can't handle

37:19

standard foods. Over here, actually in the

37:21

front row, Ken? The dog food cabal

37:23

is going to come after you for

37:26

that. Ken Davis, given

37:28

the mechanism of action of your

37:30

drug, you're going to include small

37:32

dogs in the trial, and do

37:34

you think it's going to work

37:36

for small dogs? And if it

37:38

does, how much would we hope

37:40

it would work for? Yeah, sorry

37:42

for not being clear. So we

37:44

actually have two mechanisms of action.

37:46

We started with the big dog

37:48

short lifespan, which is around us

37:50

growth hormone, IGF1, access. But you're

37:52

right. That's very specific to large

37:54

and giant breed dogs. Maybe there's.

37:56

We're not running that study. The

37:58

other drug we're working on is

38:00

actually a different explicit mechanism. but

38:02

kind of similar broad mechanism to

38:04

what they're working on, rapid mice

38:06

and around metabolic fitness improvement, which

38:08

is much more broad. It's applicable

38:11

to as far as we know,

38:13

basically every organism that if you

38:15

improve metabolic health and fitness, you

38:17

hopefully will extend lifespan too. And

38:19

so that's the product we're working

38:21

on for dogs of all sizes.

38:23

And that's the first one going

38:25

to clinical trials right now. It'll

38:27

hopefully be approved, fingers crossed next

38:29

year. Lots of work to do.

38:31

Bonnie. And then the gentleman right

38:33

in front of you. Oh, I've

38:35

read, and I'm not remembering exactly,

38:37

like in scientific news or just

38:39

something like that, that different animals,

38:41

different species have different heartbeats, different

38:43

number of heartbeats, different speed of

38:45

heartbeats, animals with, if I'm remembering

38:47

it right, slower heartbeats live longer.

38:49

If I've got that right, faster

38:51

heartbeats live. typically are smaller animals

38:53

and they don't live as long.

38:55

Well, anyway, how does this relate

38:57

to dogs all have similar heartbeats?

38:59

They have similar speed of heartbeats?

39:01

So one thing I could tell

39:03

you across species of mammals, on

39:05

average, whether you're talking about a

39:07

mouse or an elephant, they roughly

39:09

have the same number of heartbeats

39:12

in a lifetime. Mice very quick,

39:14

elephants very slow. It turns out

39:16

that that doesn't determine lifespan, and

39:18

it's important to recognize that bats,

39:20

for example, have a slower metabolism

39:22

and are quite long-lived. Birds, for

39:24

their size, have very high metabolism

39:26

and are very long-lived, so it's

39:28

not so simple. As for dogs,

39:30

I'm not sure about heart rate.

39:32

It's a good question and one

39:34

that I now want to go

39:36

off and look like that. That's

39:38

a better piece and some dogs.

39:40

And then this gentleman right here.

39:42

ethical considerations you think about like

39:44

for example could unscrupulous dog breeders

39:46

use this drug to extend the

39:48

life of their breeding stock beyond

39:50

what is healthy or for that

39:52

matter thoroughbred resource breed do that?

39:54

Well we actually would technically have

39:56

a label exclusion for breeding dogs

39:58

although I don't know if that's

40:00

up the unscrupulous type. No I

40:02

mean I think it's if it

40:04

works it should work by the

40:06

health span first and then that

40:08

follows on the lifespan. So you

40:10

could argue about the knock-on effect

40:13

of a dog in a less

40:15

optimal environment but hopefully there's not

40:17

going to be a ton of

40:19

interaction between an unethical dog owner

40:21

and a... somebody who's willing to

40:23

pay for a longevity drug for

40:25

their dog. Horses is also interesting.

40:27

There's only 10 drugs approved for

40:29

horses. FDA approved drugs for horses,

40:31

fun fact. Can I make a

40:33

quick comment? Sure, and then the

40:35

microphone to him, and then we'll

40:37

go back here. I just want

40:39

to come back to this whole

40:41

conversation of funding for aging, and

40:43

Saline has done extraordinarily well. I

40:45

congratulate you. I said earlier that

40:47

aging is the single greatest risk

40:49

factor for all the major killers.

40:51

in human populations, certainly after the

40:53

age of 50. Of course, we

40:55

have major challenges in early adulthood.

40:57

Interestingly, if you look at the

40:59

National Institutes of Health, all the

41:01

different institutes that are targeted at

41:03

cardiovascular disease, cancer, kidney disease, and

41:05

so on, one of the least.

41:07

funded institutes is the National Institute

41:09

on Aging. And that's certainly something,

41:12

those of you who read about

41:14

us in the New York Times

41:16

in January might have seen, that

41:18

we've run into challenges with funding

41:20

from NIH. We actually created the

41:22

Dog Aging Institute to try and

41:24

fund our work. But in general,

41:26

I think it's important to keep

41:28

in mind that aging has such

41:30

a dramatic impact on our health

41:32

and our experience. Congress gives a

41:34

small slice of the budget to

41:36

the National Institute on Aging. And

41:38

I don't work for the NIA,

41:40

but I think that's something that

41:42

has to change any of you

41:44

who have any power over these

41:46

things. Yeah, I agree. Right here,

41:48

please. Thank you. If it's a

41:50

useful. question, could you say a

41:52

little bit about the technology environment

41:54

in which you guys are pursuing

41:56

this knowledge and these advancements? And

41:58

I'm thinking about things like the,

42:00

you know, the validations around the

42:02

MRNA tools for vaccines, the gene

42:04

editing tools, machine learning tools, just

42:06

no detail, but is this a

42:08

miraculous time to be doing the

42:10

work or is that just all

42:13

background noise? Yeah, so I actually

42:15

came out of a gene therapy

42:17

lab at Oxford, and so it

42:19

was like hammer nail, right? I

42:21

was like, oh, I'm gonna develop

42:23

a gene therapy to extend dog

42:25

lifespan. And I actually ended up

42:27

not being the right way to

42:29

go about it, because of actually

42:31

the cog's bit that we were

42:33

talking about, and actually also safety.

42:35

So we haven't really talked about

42:37

this, but I know both of

42:39

us have very aligned views in

42:41

this, that if you're going to

42:43

give a relatively healthy animal, a

42:45

drug to extend their lifespan, and

42:47

keep them healthy, it better life.

42:49

damn safe, right? There's no tolerance

42:51

for side effects or adverse events.

42:53

And so... Actually, one of our

42:55

philosophies now is to be radically

42:57

boring. Like basically the only thing

42:59

we innovate on or like spicy

43:01

on is this idea of a

43:03

drug to extend lifespan. Now some

43:05

of our distribution strategies are a

43:07

little spicy too. But everything else

43:09

is like super safe, super long-term

43:11

data, super validated mechanisms, and we

43:14

thought that was really important for

43:16

V1. That's why I was saying

43:18

earlier, I don't think we're enough

43:20

30 year old dogs, because we

43:22

didn't optimize for efficacy for. and

43:24

as minimal a downside as possible

43:26

with the data we have. Just

43:28

one follow-up that is related to

43:30

that, I think this is actually

43:32

the most exciting time in the

43:34

history of our species to be

43:36

doing science about human health and

43:38

dog health. And the new tools

43:40

that we have not only enable

43:42

us to develop things like MRNA

43:44

vaccines, but also to understand that

43:46

with a real kind of depth,

43:48

just how every single one of

43:50

us is like each other and

43:52

different. So we have a paper

43:54

that we're about to submit studying

43:56

a drug and fruit flies that

43:58

makes them a little longer showing

44:00

that. across 200 different genotypes, they

44:02

all respond very differently. And we

44:04

now have the tools to begin

44:06

to understand why. In humans, we

44:08

call it precision medicine. So we

44:10

can think about precision veterinary medicine

44:12

to understand what's the right dose

44:15

and right drug. And it might

44:17

be that loyal is going to

44:19

discover that for some dogs, this

44:21

is the maximum. appropriate dose

44:23

and the right drug. And for

44:25

other dogs, maybe it's a different

44:27

drug altogether. And we are only

44:29

able to do that now in

44:31

the last decade because of all

44:33

of these tremendous molecular advances that

44:35

allow us to understand the uniqueness

44:37

of every individual. Well, I'm sad to

44:39

say our time is up. We could

44:42

go on all afternoon. I just liked

44:44

again to thank our guest Saline Adé.

44:53

Saline Hallewa is the CEO and founder

44:55

of Loyal, a biotech startup developing

44:57

drugs intended to help dogs live

45:00

longer, healthier lives. Since founding Loyal

45:02

in 2019 at the age of

45:04

24, Hallewa has raised more than

45:06

125 million from top venture capitalists.

45:09

Prior to loyal, she studied the

45:11

economics of gene therapy at Oxford

45:13

University. Daniel Promislow is a bio

45:16

gerontologist and senior scientist at Tufts

45:18

University. His research has focused on

45:20

why rates of aging differ among

45:22

species and among individuals within species.

45:25

Since 2008, Promislow has been

45:27

researching aging and dogs. He

45:29

co-founded and leads the Dog

45:31

Aging Project, a long-term study

45:33

on factors that influence healthy

45:35

aging and companion dogs. Elliot

45:37

Gerson is an executive vice

45:39

president at the Aspen Institute,

45:41

responsible for policy programs and

45:43

relations with the Institute's international

45:45

partners. Gerson also administers US

45:47

Road Scholarships. Today's show was

45:49

programmed by the Aspen Ideas

45:51

Festival team and produced by

45:53

Natalie Jones and me. Our

45:55

music is by Wonderly. I'm

45:57

Tricia Johnson. Thanks for listening.

46:02

You