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VOICEOVER: Coming up on Catalyst,
is it possible to reverse ageing? It's not science fiction,
it's science now.

NARRATOR: A Great Dane can last
around nine years before the diseases of ageing
take their ultimate toll.

Although it's the same species, a sausage dog can last
more than twice as long.

The secret to its longevity
lies in its DNA. The average life span of humans
is about 80 years old in the Western world. In every country and continent, there are people who have
exceptional longevity.

By uncovering the genetic secrets
of animals and humans who live unusually long lives... The way you look at life,
at the world. ..scientists are finding
extraordinary ways to wind back our cellular clocks, extend our life span
and even our fertility. What you've done just by
giving them a supplement is turned an older egg cell
into a younger one. That's exactly what's happened.

Trialling one of these ways myself... It's the strangest feeling. ..I rejuvenate my body and cut
my own risk factors for disease in just five days. MAN: In general you responded
better than most people and more like mice respond. Right now it's pretty common
in my field of ageing to be able to extend the life span
of a mouse by 30% to 50%. It's only a question of,
can we translate that into humans? Is it possible to live long
and die young?

It's a common Jewish blessing - "may you live until 120."

Here in New York, there's a lot
of those blessings going on. It's home to one of
the biggest communities of Ashkenazi Jews in the world. DEBBIE TROCK: Many of them live
independently in their own homes. Nurse Debbie Trock has been
tracking down the oldest of them to take part in a study
on super-agers. We've been looking at what we call
centenarians that are 95 and older in the city here,
in their own apartment. In fact right here we have
the apartment of Mr Sol Rosenkranz. This is Sol's house?
Yep. 15th floor.

Sol Rosenkranz
hasn't yet made it to 120... I set 'em up differently
every morning.

..but by the way he's looking at 98,
he may very well get there. Come on in, please. Hello.
Hi! Sol is very close to his
immediate family, who literally live in
the next door apartment. RITA: He's physically fit,
for his age, especially. His mind is intact. His faithful recall of
his early years immaculate. You know, extraordinary. I knew only one grandfather
from both sets. What do you think it is
that keeps you young? I believe it's a combination
of things. The way you look at life,
at the world, what you eat, how much you eat.

So what are your favourite foods? I eat anything that's edible,
that's fresh. DEBBIE TROCK: I think we've looked
at over 600 participants in the centenarian study. What seems to be consistent
is that many of them have not given up old habits.

While the diet and social
surroundings of centenarians like Sol have been analysed as part of
the longevity genes project, results suggest they're not
the determining factor for exceptionally long life.

We have a woman who smoked
for 95 years. She died at the age of 110. Exercising is less than
half of the people. Vegetarian is very rare. So those guys as a group
didn't do something special. In fact, they lived long in spite
of doing some wrong things.

Here at the Albert Einstein
College of Medicine, researchers are digging deeper
than lifestyle by unravelling the secrets
in centenarians' DNA.

They're looking for genetic variants that might protect against
the diseases of ageing. If you want to pass the age of 80, we kind of know what to do,
the doctors tell you. But those special people
who get over the age of 100, they have something more.

Genetically, Ashkenazi Jews
are already unique. Big family gathering.
Yes. Their ancestry can be traced back
to a DNA bottleneck of just a few individuals. And they've continually married
within their own community. This is my wife, Solly.
Yeah. And this is my sister-in-law. So they ended up being similar
more to each other than to the other
white population around them. And this similarity is really
very important for genetics, because when everything
is more similar, whatever is difference
sticks out much, much better.

Instead of looking for
genetic variants that protect against
a single disease, the team at Albert Einstein
are interested in those that protect against several. We believe that if you delay ageing,
you delay all diseases and we need to make sure
that everybody understand what is the biology of ageing
and consequence.

In the super-agers, they've already
found several markers of interest.

Two of them are in
the cholesterol metabolism. And everybody thinks of
the good cholesterol as prevention of heart attacks, but actually we have as strong
if not stronger data to indicate that the people with this genotype are protected against Alzheimer's and cognitive decline. So if it protects
against cardiovascular disease and it protects against Alzheimer's, we think it's probably
in the mainstream of ageing, maybe it regulates
the rate that we age.

Another interesting finding is a
significant number of the super-agers are short. This group tends to have
a low level of insulin-like growth factor
in their blood, a trait which has been found
in a number of labs to extend life.

The growth hormone is
a really fascinating story in the sense that dwarfs
or dwarf models live longer. For example, small dogs
live longer than the large dogs. And when we do genetic manipulation or it happens that mice
are born a dwarf, they all live longer. And the questions for us is,
does it apply to humans too?

So the point is not only
the discovery, but the fact that you can translate
genetic discoveries into drug therapy.

The laboratory here at the
Albert Einstein College of Medicine is just one of a number worldwide pinning down the molecular pathways
to longevity. For the rest of us
who aren't super-agers, they may open up the doorways
to a long and healthy life.

At the University of New South Wales, they've already opened up
one of those doorways.

They've successfully reversed
aspects of ageing in animals.

Their target is a specific chemical
in the body called NAD.

NAD is a central molecule for life. And without it,
we're dead in 30 seconds.

Without NAD, our bodies
can't make energy.

PROFESSOR DAVID SINCLAIR: One of
the major problems with ageing is that we lose our ability
to make energy through these little power packs
called mitochondria which exist in every cell. What we've discovered is that NAD levels control how many of these
mitochondria you have in your cell. And what happens, when we're young
we have high levels, and over time it goes down to
about 50% of what we once had.

And we think that the levels of NAD
are critical for our body to be able
to defend itself and heal itself and live a longer life.

By adding a supplement
to the drinking water of older mice, researchers can artificially
raise levels of NAD in cells.

The effects are rapid
and extraordinary. So some of the things we've seen are an age reversal in the muscle
within a week.

And they can run almost twice as far without ever having
exercised before. And other things we're seeing
is protection from cancer, from chemotherapy and even diabetes.

Something astounding
happened to the ladies too. So most of our experiments
were done on male mice. They just happen to be simpler
biochemically than females. But then we started
studying female mice and what we noticed was that the old
mice that were given our molecule were able to reproduce for longer.

One of the most exciting experiments
I've personally ever seen is happening just behind
this doorway. By giving the supplement to older
female mice in their drinking water, scientists in this lab have managed
to reverse ageing in egg cells.

So what we're looking at here is
an egg cell from a young mouse. It's the equivalent
of a 20-year-old. What you see here in the blue is DNA which is wrapped up
in these chromosomes and these chromosomes have to divide
evenly between two cells. Now, what happens during old age, the strings which attach
normally to the chromosomes, which are in blue, are completely
dysfunctional and disorganised. So it looks essentially like a broken
egg. The DNA has gone everywhere. And as a result, the offspring will either not have
the correct number of chromosomes or won't even develop or become
fertilised in the first place. And what we found is that
by taking an old mouse and then feeding it
with a supplement, we're able
to completely normalise that. So that's the equivalent
of a how old year-old woman? 55-year-old woman. And how soon do you think you might be able
to get that out among people? I mean, there's going
to be very keen women out there to get this supplement. We're working as hard as we can
on that.

The postmenopausal mice only took
the supplement for three weeks before their old egg cells
became youthful once more. Theoretically
it would be the same pill. This is the amazing thing. It's really hard to believe
that the same pill that would protect you
against Alzheimer's and cancer and heart disease would also reverse ageing in ovaries and allow you to have children
for longer.

While it sounds promising,
human trials are yet to begin.

One of the problems with developing
drugs that target ageing is that until now, they haven't been considered
a legitimate way to fight disease. The tradition is to research
and treat each one separately. We have an institute for diabetes
and kidney and for the heart, lungs and blood
and for the cancer and they're silos. I think the new revolution
is for people to now realise what we have realised 20 years ago - that the major risk for any one
of those diseases is ageing and when I say major risk,
I'm talking about thousand-fold risk when you go from 30 to 80 for heart disease, diabetes,
Alzheimer's and cancer.

Dr Barzilai and his colleagues
have broken new ground by getting FDA approval for the world's first
clinical drug trial targeting ageing. But they're using
a drug already on the market. It's called metformin. The interesting thing
about metformin is that it's been around for 60 years. It's safe,
it also happens to be cheap. There's no drug company
that is helping us. Metformin is a common generic drug
used to treat diabetes. But it's also been shown to make worms and mice live longer
in the lab. Multiple studies suggest
it could do the same in people. Why do we think the drug
is going to work? There are lots of evidence. When you give it to people with
diabetes in a very controlled way, it prevents cardiovascular disease
significantly in several studies. People who have diabetes
and are treated with metformin have significantly less cancers. Although most evidence comes from
people with diabetes, one very large retrospective study reported diabetics on metformin lived longer on average than
their healthy matched counterparts even though the reverse was expected. So we have evidence already that metformin not only prevents
all those diseases but delays the mortality.

In an ambitious randomised trial, the Albert Einstein College
wants to give metformin to 3,000 elderly people who
either have, or are at risk of, cancer, heart disease or dementia. Taking the 750mg in the morning once
and then in the evening. If it's successful in delaying
diseases they don't yet have, the TAME trial, short for
Targeting Ageing with Metformin, will set a big precedent.

As the college seeks funding
for their trial, I'm keen to know
if there's any other way.

Personally, I've never been
too enthusiastic about the idea of popping a pill
for the rest of my life, especially when I feel healthy, so today I'm leaving New York
to meet another scientist who has developed
a simple, drug-free intervention that reaps amazing results.

Professor Valter Longo is the director
of the Longevity Institute at the University
of Southern California. For more than a decade he's been researching how growth can
interfere with the body's ability to protect and repair itself.

If you're investing in growth
and investing in reproduction, you don't put so much energy
into protection.

The trade-off between growth
and maintenance is again apparent when you look at dwarf versions
of certain species. This mouse on the right
is half the size of a regular mouse because it has
what's known as Laron syndrome.

The little mice here have a mutation
in their growth hormone receptor. And so does this mice
have a longer life span? Yes, so these mice live
about 40% longer than normal mice. The dwarf mice are also incredibly
healthy right into old age. Their fur looks better, they're more active, they're
cognitively also more robust.

And so it was obvious to ask the
question, "Well, what about people?" Is it possible that you have yeast
and flies and mice and they all have
this...they're dwarf and they live so long
and they're so healthy and people would be an exception? And it turns out that people
were not an exception.

In a remote region of the mountains
of Ecuador live a group of villagers
with the same genetic mutation as the Laron mice. They lack
the growth hormone receptor. They're very small,
about 3.5ft tall. Despite high rates of drinking,
smoking and obesity, there hasn't been a single case
of diabetes among those who have Laron syndrome,
and there's next to no cancer. Over 30, 35 years of observation, so far we have only seen
one single case of cancer death. And their relatives live in the same
houses in the same villages, they get cancer like everybody else. To find out why,
Valter's team collected blood from the Laron syndrome villagers and added the serum to human cells
growing in a Petri dish. Then they exposed the cells
to a chemical known to damage DNA. PROFESSOR VALTER LONGO:
And it was very interesting because if the cells were exposed
to the blood from the Larons, the DNA was protected. But B, if the damage does occur,
then you kill that cell.

The two effects -
protection of healthy cells and destruction of cells
with damaged DNA - are key weapons against disease.

Because the villagers
don't respond to growth hormone, many factors in their blood
associated with growth are lowered. They have a coordinated reduction
in all of these genes pushing the body
to reproduce and grow and we think that the combination
of them is what's so protective. That's all great
for Laron syndrome villagers, but what does it mean for us?

My name is Becky.
Hi, Becky. I'll be helping you
with your blood draw. Thank you.
Can I have your name, please? Anja. Anja Taylor. And your birthday?

Luckily there's a simple way to manipulate those same factors
in our blood.

Want me to hold the needle a bit?
Oh, I got it.

I'm getting baseline measurements before attempting a prolonged fast
developed by Valter's labs.

It's not a total abstinence from food but instead what's known
as a fasting mimicking diet. In this disturbingly light box
is my food for five days.

PROFESSOR VALTER LONGO:
So the fasting mimicking diet is a low protein, low essential
amino acid, low sugar diet that is relatively high in fat,
actually.

The aim of this mix is to lower
growth signals in the body like IGF-1, insulin and glucose, so my body goes into
maintenance mode. Enough protein is very important,
but people are now eating 50%, 100%, 200%, 300% more than normal.

And this is pushing the system to
try to grow but there's no growth.

And so the consequence could be that you put an accelerator
on all these systems and you just really push them
to the limit and then they fail.

So I'm halfway through the first day.
I'm feeling pretty good. I've got a little bit of a headache because I haven't had
my morning coffee but other than that feeling OK. And lunch is a cup of soup
and some crackers.

I'm really hoping
hibiscus tea grows on me because what happened
in animal and human trials has been simply astonishing.

Mice in Valter's lab began
their first fast at middle age and continued twice a month
until the end of their life. They extended their lives
on average by 11% but they also increased
their health span dramatically. PROFESSOR VALTER LONGO:
We saw a reduction in inflammation, dermatitis, we saw a major reduction in tumours,
about 50% lower, but also a postponement and also the switching
of the two modes from the more malignant type
to more benign type. So it's really a triple effect.

Then we also looked
at cognitive function and they were improved
in every measure that we looked at and they made less mistakes, so they were a lot sharper, they
could learn and remember better. We also saw visceral fat loss. Another thing that was remarkable - there was no loss of muscle mass.

Another extraordinary effect - mice that periodically fasted had higher bone density by the end of
their lives than those that didn't. That's something I try to focus on
as the next meal is served. I'm here at my friend Federico
and Vimo's house and it's lunch. Day two of my fast
and they are having pizza.

And I am having...four olives. Here you go. Thank you.

It takes about two days for the body to begin to fully turn
into this alternative mode. Your entire body starts switching from utilising glucose
and other nutrients to breaking down fats. The good news for the people
that want to lose weight - it turns out that instead of
taking the subcutaneous fat, it goes mostly after
the visceral fat, so abdominal fat. It's good news that my brain is
currently chewing up fat from my gut but it's never functioned
this way before.

The feeling is a little surreal. It's not that I can't think straight, but everything feels,
well, a bit spacey.

Midday, day four. It's the strangest feeling. I feel like I have
nothing to power my legs. Like...there's no fuel in my muscles. I feel like lead.

A three-hour hike is not on
the recommended list of activities. I should be taking it easy,
but then all I do is think of food.

Despite endless temptations, I do make it to the end
of the fasting diet and after my final blood tests, I head back to Valter
to get my results. How are you?
Good. I did it. Yeah? Yeah, good. And how was it? It was pretty easy actually.
I was surprised at how easy it was. I mean, I felt hungry and I had a bit of a mild headache
all the way through. OK, but this was the first time
you did it, right? Yeah.
Yeah. So the first time is usually
much harder for almost everybody. It gets easier the second time and it gets much easier
the third time you do it. It didn't feel like a fast, so I'm keen to see
if I have actually any results. Yeah, there are results.
So let me show you. Some of them are pretty dramatic
actually. In general, you responded better
than most people and more like mice respond. Along with a nearly 20% drop
in my blood glucose, my insulin plummeted to nearly 0, lowering my risk factors for diabetes and cardiovascular disease. And because my diet contained
almost no protein, my insulin-like growth factor, the same one that was low
in the Laron syndrome villagers, dropped by 30%. To start with,
you had low levels of IGF-1. If you put all the studies together, this would suggest that
you should be highly protected against a variety
of age-related conditions. But to me the most interesting result is the fact that a third of my white
blood cells have been wiped out. Which is a major reduction. It is more what we see in the mice. In people, on average,
we don't see as much response. It sounds alarming, and mice studies indicate it's not
just cells in my immune system that died off during the fast but lots of cells in my organs
as well - but they're ones I didn't really
want anyway.

We suspect there are
two major things that happen. One is the killing
of a lot of bad cells, but also a lot of not-so-bad cells
but they may have been old. So you fast and every day
of the fasting, the organs are getting
a little bit smaller and they're getting rid of cells
because they have to save energy.

Then eventually when you re-feed, these organs and cell systems,
they have to return to normal and that's really a remarkable way
to replace and rejuvenate almost every component of the body.

The fast primed my stem cells
for action so when I finally
get to eat normally again, they get busy creating
healthy, young, new cells to replace the ones I lost. It doesn't mean that you are
replacing 100% of it. It could be even 5%. You could see how if you did it
three or four times a year, this could have
a very beneficial effect and this is true for the liver,
it's true for the blood system, and many other systems in the body. Fasting around once
every three months has been shown in people
to lower risk factors for disease over the long term. What we observed was whether
it was a risk factor for cancer or inflammatory markers and risk factor
for cardiovascular diseases or a risk factor for diabetes, we saw that the people that had
the biggest problem at baseline, so when they started,
had the biggest effect. And so suggesting that it's more
regeneration and rejuvenation of multiple systems, leading to the cells working
more like when you were younger.

The rejuvenation of cells is really the crux of what
anti-ageing is all about. All this research
gives me enormous optimism, not because I want to live forever, but the notion that I may be one of
the lucky ones who avoid disease and die one day quietly in my sleep is now a lot more
than just a faint hope.

When you ask non-elderly people
what disturbs them in ageing, it's really the big suffering and all those diseases and spending
time in hospitals and other things, so everybody will understand
that ageing can be healthy ageing. It's not science fiction,
it's science now.

For details on the various studies
featured in this program, and to find out more about
the effects of Professor Longo's diet on cancer and multiple sclerosis,
visit the Catalyst website.

VOICEOVER: Next time on Catalyst, chronic stress may accelerate
the spread of cancer. The stress is sort of acting like
a fertiliser and helping the tumour cell
take hold and colonise those other organs. And Pluto's extraordinary
secrets revealed - mysterious skies, ice volcanoes
and liquid nitrogen lakes. It was going to be
just a plain, frozen ball of rock but it's anything but. Connect with Catalyst on Facebook, Twitter, Instagram, YouTube and our website.

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