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This is a painting from the 16th century
from Lucas Cranach the Elder.
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It shows the famous Fountain of Youth.
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If you drink its water or you bathe in it,
you will get health and youth.
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Every culture, every civilization
has dreamed of finding eternal youth.
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There are people like Alexander the Great
or Ponce De León, the explorer,
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who spent much of their life
chasing the Fountain of Youth.
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They didn't find it.
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But what if there was something to it?
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What if there was something
to this Fountain of Youth?
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I will share an absolutely amazing
development in aging research
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that could revolutionize
the way we think about aging
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and how we may treat age-related
diseases in the future.
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It started with experiments that showed,
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in a recent number
of studies about growing,
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that animals -- old mice --
that share a blood supply with young mice
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can get rejuvenated.
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This is similar to what you might see
in humans, in Siamese twins,
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and I know this sounds a bit creepy.
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But what Tom Rando, a stem-cell
researcher, reported in 2007,
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was that old muscle from a mouse
can be rejuvenated
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if it's exposed to young blood
through common circulation.
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This was reproduced by Amy Wagers
at Harvard a few years later,
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and others then showed that similar
rejuvenating effects could be observed
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in the pancreas, the liver and the heart.
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But what I'm most excited about,
and several other labs as well,
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is that this may even apply to the brain.
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So, what we found is that an old mouse
exposed to a young environment
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in this model called parabiosis,
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shows a younger brain --
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and a brain that functions better.
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And I repeat:
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an old mouse that gets young blood
through shared circulation
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looks younger and functions
younger in its brain.
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So when we get older --
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we can look at different aspects
of human cognition,
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and you can see on this slide here,
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we can look at reasoning,
verbal ability and so forth.
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And up to around age 50 or 60,
these functions are all intact,
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and as I look at the young audience
here in the room, we're all still fine.
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(Laughter)
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But it's scary to see
how all these curves go south.
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And as we get older,
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diseases such as Alzheimer's
and others may develop.
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We know that with age,
the connections between neurons --
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the way neurons talk to each other,
the synapses -- they start to deteriorate;
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neurons die, the brain starts to shrink,
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and there's an increased susceptibility
for these neurodegenerative diseases.
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One big problem we have -- to try
to understand how this really works
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at a very molecular mechanistic level --
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is that we can't study the brains
in detail, in living people.
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We can do cognitive tests,
we can do imaging --
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all kinds of sophisticated testing.
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But we usually have to wait
until the person dies
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to get the brain and look at how it really
changed through age or in a disease.
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This is what neuropathologists
do, for example.
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So, how about we think of the brain
as being part of the larger organism.
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Could we potentially understand more
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about what happens in the brain
at the molecular level
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if we see the brain
as part of the entire body?
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So if the body ages or gets sick,
does that affect the brain?
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And vice versa: as the brain gets older,
does that influence the rest of the body?
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And what connects all the different
tissues in the body
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is blood.
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Blood is the tissue that not only carries
cells that transport oxygen, for example,
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the red blood cells,
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or fights infectious diseases,
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but it also carries messenger molecules,
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hormone-like factors
that transport information
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from one cell to another,
from one tissue to another,
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including the brain.
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So if we look at how the blood
changes in disease or age,
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can we learn something about the brain?
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We know that as we get older,
the blood changes as well,
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so these hormone-like factors
change as we get older.
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And by and large,
factors that we know are required
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for the development of tissues,
for the maintenance of tissues --
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they start to decrease as we get older,
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while factors involved in repair,
in injury and in inflammation --
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they increase as we get older.
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So there's this unbalance of good
and bad factors, if you will.
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And to illustrate what we can do
potentially with that,
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I want to talk you through
an experiment that we did.
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We had almost 300 blood samples
from healthy human beings
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20 to 89 years of age,
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and we measured over 100
of these communication factors,
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these hormone-like proteins that
transport information between tissues.
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And what we noticed first
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is that between the youngest
and the oldest group,
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about half the factors
changed significantly.
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So our body lives in a very
different environment as we get older,
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when it comes to these factors.
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And using statistical
or bioinformatics programs,
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we could try to discover
those factors that best predict age --
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in a way, back-calculate
the relative age of a person.
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And the way this looks
is shown in this graph.
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So, on the one axis you see
the actual age a person lived,
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the chronological age.
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So, how many years they lived.
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And then we take these top factors
that I showed you,
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and we calculate their relative age,
their biological age.
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And what you see is that
there is a pretty good correlation,
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so we can pretty well predict
the relative age of a person.
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But what's really exciting
are the outliers,
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as they so often are in life.
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You can see here, the person
I highlighted with the green dot
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is about 70 years of age
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but seems to have a biological age,
if what we're doing here is really true,
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of only about 45.
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So is this a person that actually
looks much younger than their age?
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But more importantly: Is this a person
who is maybe at a reduced risk
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to develop an age-related disease
and will have a long life --
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will live to 100 or more?
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On the other hand, the person here,
highlighted with the red dot,
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is not even 40,
but has a biological age of 65.
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Is this a person at an increased risk
of developing an age-related disease?
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So in our lab, we're trying
to understand these factors better,
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and many other groups
are trying to understand,
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what are the true aging factors,
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and can we learn something about them
to possibly predict age-related diseases?
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So what I've shown you so far
is simply correlational, right?
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You can just say,
"Well, these factors change with age,"
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but you don't really know
if they do something about aging.
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So what I'm going to show you now
is very remarkable
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and it suggests that these factors
can actually modulate the age of a tissue.
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And that's where we come back
to this model called parabiosis.
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So, parabiosis is done in mice
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by surgically connecting
the two mice together,
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and that leads then
to a shared blood system,
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where we can now ask,
"How does the old brain get influenced
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by exposure to the young blood?"
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And for this purpose, we use young mice
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that are an equivalency
of 20-year-old people,
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and old mice that are roughly
65 years old in human years.
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What we found is quite remarkable.
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We find there are more neural stem cells
that make new neurons
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in these old brains.
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There's an increased
activity of the synapses,
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the connections between neurons.
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There are more genes expressed
that are known to be involved
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in the formation of new memories.
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And there's less of this bad inflammation.
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But we observed that there are no cells
entering the brains of these animals.
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So when we connect them,
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there are actually no cells
going into the old brain, in this model.
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Instead, we've reasoned, then,
that it must be the soluble factors,
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so we could collect simply the soluble
fraction of blood which is called plasma,
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and inject either young plasma
or old plasma into these mice,
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and we could reproduce
these rejuvenating effects,
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but what we could also do now
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is we could do memory tests with mice.
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As mice get older, like us humans,
they have memory problems.
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It's just harder to detect them,
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but I'll show you in a minute
how we do that.
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But we wanted to take this
one step further,
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one step closer to potentially
being relevant to humans.
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What I'm showing you now
are unpublished studies,
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where we used human plasma,
young human plasma,
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and as a control, saline,
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and injected it into old mice,
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and asked, can we again
rejuvenate these old mice?
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Can we make them smarter?
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And to do this, we used a test.
It's called a Barnes maze.
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This is a big table
that has lots of holes in it,
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and there are guide marks around it,
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and there's a bright light,
as on this stage here.
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The mice hate this and they try to escape,
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and find the single hole that you see
pointed at with an arrow,
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where a tube is mounted underneath
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where they can escape
and feel comfortable in a dark hole.
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So we teach them, over several days,
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to find this space
on these cues in the space,
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and you can compare this for humans,
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to finding your car in a parking lot
after a busy day of shopping.
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(Laughter)
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Many of us have probably had
some problems with that.
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So, let's look at an old mouse here.
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This is an old mouse
that has memory problems,
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as you'll notice in a moment.
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It just looks into every hole,
but it didn't form this spacial map
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that would remind it where it was
in the previous trial or the last day.
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In stark contrast, this mouse here
is a sibling of the same age,
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but it was treated with young
human plasma for three weeks,
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with small injections every three days.
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And as you noticed, it almost
looks around, "Where am I?" --
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and then walks straight
to that hole and escapes.
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So, it could remember where that hole was.
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So by all means, this old mouse
seems to be rejuvenated --
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it functions more like a younger mouse.
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And it also suggests
that there is something
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not only in young mouse plasma,
but in young human plasma
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that has the capacity
to help this old brain.
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So to summarize,
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we find the old mouse, and its brain
in particular, are malleable.
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They're not set in stone;
we can actually change them.
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It can be rejuvenated.
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Young blood factors can reverse aging,
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and what I didn't show you --
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in this model, the young mouse actually
suffers from exposure to the old.
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So there are old-blood factors
that can accelerate aging.
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And most importantly,
humans may have similar factors,
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because we can take young human
blood and have a similar effect.
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Old human blood, I didn't show you,
does not have this effect;
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it does not make the mice younger.
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So, is this magic transferable to humans?
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We're running a small
clinical study at Stanford,
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where we treat Alzheimer's patients
with mild disease
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with a pint of plasma
from young volunteers, 20-year-olds,
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and do this once a week for four weeks,
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and then we look
at their brains with imaging.
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We test them cognitively,
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and we ask their caregivers
for daily activities of living.
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What we hope is that there are
some signs of improvement
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from this treatment.
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And if that's the case,
that could give us hope
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that what I showed you works in mice
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might also work in humans.
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Now, I don't think we will live forever.
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But maybe we discovered
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that the Fountain of Youth
is actually within us,
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and it has just dried out.
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And if we can turn it
back on a little bit,
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maybe we can find the factors
that are mediating these effects,
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we can produce these factors synthetically
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and we can treat diseases of aging,
such as Alzheimer's disease
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or other dementias.
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Thank you very much.
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(Applause)
