Transcriber: Rhonda Jacobs Reviewer: Peter van de Ven
Thank you very much. Thank you very much.
So I'll tell you a little bit about what we in the lab have been doing,
but also some of the exciting things in the field of gerontology.
And first I start by saying
that the medical field has really turned into a Band-aid field, right?
So we wait until somebody develops cancer
and then we use chemotherapy or other therapies
that do some good and kill cancer cells but also kill the normal cells.
Or with Alzheimer's,
we wait until somebody's brain is very damaged beyond repair,
and then we put a Band-aid on it, essentially,
and try to keep the person from progressing further in their dementia,
but it doesn't really do much good.
But even if we were able to be very successful
in curing some of these diseases, I always ask this question,
and guess how much longer we will live
if we were good enough to completely cure cancer.
What do you think?
Twenty years?
Twenty-five years?
It actually turns out that it's only about three or four years, right?
And what if we were good enough to cure cancer, heart disease,
stroke and diabetes today?
And the answer is about 13 years.
And the reason for this
is that if one disease doesn't get you, something else will.
(Laughter)
And this is why, instead, if we -
In the aging field, we're really saying,
well, why does a mouse get cancer after one-and-a-half years of life
and people never get cancer when they're one and a half years old, right?
Well, we get it after 40, after 50, after 60.
And the reason for that is the mouse and the people,
we age at a different rate.
So the one-and-a-half years for the mouse
is equivalent to 40 years for people.
So if we were able to delay aging,
just half as effectively as we've already done for mice,
we would then get about 30 years of extended life.
So treat aging, and most people say, well, if you're going to treat aging,
we're going to have all these people that are going to live longer,
they're going to have Alzheimer's,
they're going to have all these bad diseases,
so what's the point?
But it turns out that if you look at some of our work
and work of others,
and these on the right are the long-lived organisms.
The first one on the left is yeast - you have a normal-lived one
and the dwarf one lives up to ten times longer
than the one on the left.
And the flies in the center, same thing - the small ones live twice as much.
And the mice, finally, the small one lives about 40-50 percent longer.
But what's amazing about these mice
is that they get diseases at a lot lower incidence
compared to the regular mice.
And the only difference is a single mutation in the growth hormone receptor,
so the little mice are lacking this growth hormone receptor.
So years ago, we knew that this simple organism,
the yeast live longer, it was very healthy;
their DNA was very much protected.
And we knew that the mice also had this record longevity.
But even though they lived longer,
50 percent of them never developed any diseases,
compared to the regular mice -
only about ten percent of them, or less, never developed diseases.
So we started looking for people around the world
that had the same mutation and asked the question:
Is it possible that people can also be so protected against aging
but also against the age-related diseases?
And it turns out that they seem to be so.
I started a collaboration with Jaime Guevara,
who's an endocrinologist who is following all these people down in Ecuador,
and particularly in the Andes mountains in southern Ecuador,
we were able to follow very closely about 100 of these subjects.
And it turns out that they almost never develop cancer,
and in fact, only one in all these years that I've been monitoring -
in over 30 years - only one has died of cancer.
And you can see, instead, in the relatives,
you have what you expect, about 22 percent incidence of cancer deaths.
And then, when we look at diabetes,
even though in Ecuador, the obesity prevalence is about 12 percent,
in these people, these little people have a prevalence of obesity
which is much higher, over 20 percent.
And so any endocrinologist or diabetologist would tell you,
these people for sure are going to have diabetes,
and instead, it turns out that instead of the five percent prevalence -
so five out of 100 people in Ecuador have diabetes,
so far in the case of these little people, none of them have developed diabetes yet.
So they're very much protected,
but the field, particularly starting in the '90s,
we were all confused about "How do you stay young?"
How do you find out about aging, and how do you regulate aging?
If you look around the world and you ask
(Laughter)
people who have record longevity -
this was the oldest lady in the world at the time,
living in Los Angeles.
And she felt that by not drinking and fooling around -
that's how she got to be 115 years of age.
(Laughter)
And I'm embarrassed to say, in the next slide,
actually, Salvatore Caruso in southern Italy agrees with her.
And so he came up with "No wine, no smoking and no women"
as a motto for longevity.
(Laughter)
But, of course -
(Laughter) (Applause) (Cheers)
But Madame Calment of France obviously disagrees.
And not only she disagrees, but she got the record, right?
She made it to 122-and-a-half years of age.
And now you're saying, okay, this shows that you can do whatever you want.
Wrong. Right?
And in fact, I just visited there, and since yesterday,
the oldest woman in the world is an Italian lady, Emma Morano,
and everybody says, well, she eats three eggs a day and steaks, etc., etc.
But then when you look deeper,
it turns out that a lot of people in her family live to 100, 102, 103.
And that tells you it's so difficult to make it to 100;
and that tells you the genetic make-up of these families is such
that they're much, much more likely,
potentially hundreds of fold more likely than everybody else
to make it to such an old age,
and this is why they can sometimes do whatever they want -
like in her case, smoking to 117 years of age.
And by the way, she quit smoking, not because of health reasons, obviously,
but because she was embarrassed that she couldn't light up anymore,
(Laughter)
and that was her reason for quitting smoking.
You know, a lot of us in the field, mostly 20 years ago or longer,
we started saying, well, we can never figure out how people age
because it's too complicated, so let's turn to very simple systems.
And some of us turned to bacteria, the unicellular baker's yeast,
what's used to make bread and wine;
some people studied worms.
But something that I first had described many years ago
was if you starve these organisms,
you switch them from a lot of nutrients to water, they live longer.
It's very counterintuitive - you think you starve them to death, but no.
Not only they didn't starve, they lived longer,
they were very protected.
So that was a very surprising finding that I had made back in the days at UCLA.
And now, decades later, we actually have - don't worry about the details here -
but we now have a network; we understand why fasting works.
Particularly, fasting works because amino acids in the proteins of the diet
activate one pathway which is called TOR pathway
and another one called growth hormone IGF-1,
and then sugars in the food activate the second pro-aging pathway,
a pathway that accelerates the aging process called PKA, right?
And the other surprising thing we were wishfully thinking for
was that this is conserved,
conserved from simple organisms all the way to humans.
It turns out that it probably is.
The focus of my talk - we now clearly know that these pathways, these genes,
these [inaudible] genes can protect
and make all kinds of organisms live longer.
And fasting can have a major contribution or orchestrate these genes.
But something that happened in one of the experiments in my lab
that Chia-wei Cheng was doing, which was we fasted mice,
and when you fast the mice, they become very protected against chemotherapy,
and all kinds of different toxins,
but chemotherapy is one of the ones we used
and are running a lot of clinical trials on.
But the more surprising thing
was that even though the mice were protected from chemotherapy,
after six cycles of fasting and chemotherapy,
only in the mice that were fasted for the six cycles,
the white blood cell number went back to normal.
And so that was very strange, and we said,
this is not possible by protection; how can they just go back to normal?
And so we started thinking about regeneration.
Is it possible that fasting is telling the body,
"Okay, now I want to make new cells; I want to regenerate the immune system."
And so I started thinking,
well, maybe the body has everything in it to fix itself,
to regenerate and rejuvenate.
So I started thinking about how does a couple of 40-year-olds
generate a perfect baby, a zero-year-old baby, right?
And then, if you think about it, you have old sperm and an old egg, right?
And they get together in the same body,
and then, all of the sudden, it just ... perfect, right?
So then the body knows how to do it,
we just - we don't know how to make the body do it.
So is it possible that fasting is one of the ways
to push the body to do exactly that -
go into this regenerative, rejuvenating mode?
And evidence for that comes from the mice.
When we took mice and started at middle age,
and give them what we call "fasting-mimicking diet."
Now that we know how each ingredient orchestrates this genetic network,
we can play with the diet to make mice - and people, as you'll see in a second -
think that they're fasting, right?
And so with this diet that we start at middle age,
and then we feed it to the mice twice a month for four days,
and then we return them to their regular diet.
And it turns out that you see the level of white blood cells
in the young mice is very high,
and then in the old mice it goes to a very low level.
And then on the far right,
you see the old mice that have been on this periodic fasting-mimicking diet.
So now the level of white blood cells is back to the youthful level
that they had at four months of age.
So you know about the connection between the immune system and cancer,
so one of the things you would expect
is the immune system is getting stronger as I just showed you,
and rejuvenated, the level of tumors goes down,
and actually goes down dramatically,
so the mice that have been on the diet periodically
have about half of the tumors.
But these tumors also occur later,
and you see there on the right,
the red dots are the mice that were on the fasting-mimicking diet,
and the grey dots are the mice that are on the regular diet.
So a lot less cancer, later in life,
and a lot of the tumors are benign in nature
instead of the malignant ones
that are developed by the mice on the regular diet.
Okay, so, regeneration from within - how does that happen?
I'll just summarize it very quickly, but what happens in these mice
is you have these genes that I already told you about, IGF-1 and PKA,
and these genes basically keep the stem cells in a stalled mode, right?
And you have a high level of immune cells, but a lot of these cells are damaged.
This explains a lot of the autoimmunities that people have, right?
So they're not necessarily functional or functioning well,
especially in older people,
so when the mice or people fast,
now this stem cell, this IGF-1 and PKA genes are reducing their levels,
and now the stem cells are activated, the hematopoietic stem cells,
so the stem cells of the blood are activated,
and actually the immune cell level goes down, right?
So the patient or the mouse is temporarily immunosuppressed, right?
And then, the trick happens when you re-feed.
Now the stem cells that were activated during the fasting,
they go to work, and they start regenerating new immune cells.
So in the mouse it's really dramatic
because the level of immune cells goes down to about half
and then back to the normal level.
So within days, the mice are able to regenerate half of their immune system.
And the result of that is what we call longevity extension,
so these mice are now living longer,
particularly when you look at the average survival.
Okay, so what about people?
We can do this in mice, but can this be translated to people?
And most people think that we can go maybe ten days without food.
It turns out that most people, most of you, can go for 60 days, right?
You can be with no food at all for two months, right?
And actually, like the Emperor penguins from the South Pole,
some people can actually go for six months with no food at all.
We completely forgot this used to be very common in all kinds of religions,
and now slowly, it is disappearing from all religions.
What happens during fasting,
the body, first of all, turns from a glucose, a sugar-burning mode,
into a fat-burning mode.
And you see there, those are the ketone bodies,
beta-hydroxybutyrate, the blue line, that is building up.
So after just a couple of days on this fasting,
your body completely reprograms.
And even your brain,
that for most of you, all your life is being fueled by sugar,
is now moving to a fat-based metabolism, right?
This is why people usually get a headache after they fast for the first time.
And so we developed, again, the mouse fasting-mimicking diet;
we developed the human fasting-mimicking diet.
And again, the point of this is to trick the body into thinking it's fasting,
like in water-only fast.
And so we tested this in a group of 100 subjects at USC,
and these people were asked
to go on three cycles of this fasting-mimicking diet,
between 800 and 1,100 calories per day, and the diet lasts for five days,
so they were asked to do three of these.
So in three months, essentially they did 15 days of this fasting-mimicking diet.
And the results, I think,
are again, in agreement with regeneration and rejuvenation,
although we can't prove it in humans yet.
But for example, if you see blood glucose,
in the normal people that had normal fasting glucose,
it dropped just a little bit after these three cycles of the diet.
But in pre-diabetic, it dropped a lot.
So it went from 104 or so to 92, back to the normal level.
And if you look at IGF-1, one of the key markers,
risk factor for cancer,
people that have a normal level of IGF-1 to begin with,
it was a small drop.
But people that were at risk for cancer, they had very high levels,
it dropped a lot more.
And the same thing also for one of the major risk factors
for cardiovascular diseases, C-reactive protein,
it's an inflammatory marker,
and so people that have high levels of this marker
are at risk to develop cardiovascular diseases,
and you see that there is no change for the people that had good levels of it
from the beginning,
and a big change for people that had very high levels of it.
The circulating stem cells in the normal diet,
the stem cells in the body of the patients was low,
and then when you fast them, it goes way up.
You know, what happens in life because of diet, aging, toxins, etc.,
we accumulate damage,
and this damage can lead to all kinds of diseases.
And the fasting-mimicking diet switches the clock back a little bit
by promoting this regeneration, rejuvenation effect,
and now we're seeing effects
that are consistent with protection against all kinds of diseases,
including diabetes, cancer, cardiovascular diseases and Alzheimer's.
So to summarize, I use my mentor at UCLA, Roy Walford.
And Roy was one of the pioneers of calorie restriction.
He, back in 1990, I think it was,
had the bad idea to lock himself up with another seven people
in a place in Arizona called Biosphere 2.
So eight of them went inside this place,
and then inside of this place, they became calorie restricted,
And when they were calorie restricted, this is what they looked like.
So this is very extreme, right?
They went to this very extreme calorie-restricted diet.
But the point I'm trying to make is about organs.
If you look at Roy Walford in the middle, while he was in the Biosphere 2,
his organs had shrunk to very small levels.
Like for example, his liver was probably about half of the normal size.
So half of the size that it was before he entered Biosphere 2 on the left, right?
And then he exits Biosphere 2 -
and by the way, I was there when they came out,
and it was a very stressed out group of people -
(Laughter)
but you see now, that's Walford six months after he exited Biosphere.
He went back to the same weight,
and the organs, whether it was the muscle, the heart, the lungs,
all the different systems are now regenerated, back to the normal size.
And there's really not many other ways to do that,
but to turn on stem cells and regenerate very much in the same way
that the zygote and the blastocyst
and the cells during embryogenesis are forming the embryo,
so we think that that's probably the most powerful way
to get this coordinated response,
regenerating multiple systems back to a more youthful state.
And I just want to end with my last slide and with Salvatore Caruso,
who, by the way, was married and had children,
so this idea about the women maybe was a little bit made up.
(Laughter)
But I think, you know, the diet helped him a lot,
but also a big factor, I think, for Salvatore was he wanted to live,
he wanted to have the record.
And he was always looking around the world, like, "Who's older than me?
How many years I have to live to make it there?"
So it was great.
And I'm just going to end with this song.
(Guitar music; Salvatore singing in Italian)
Thank you very much.
(Applause)