Dr. Aubrey de Grey and Dr. Rhonda Patrick Talk Aging

October 7, 2019 0 By William Morgan


[Rhonda]: Dr. Rhonda Patrick here.
In this adventure of the “FoundMyFitness”
podcast, I’m in Mountain View, California
at the SENS Research Foundation.
And I have, sitting here with me, Dr. Aubrey
Grey in the house.
Aubrey is a biomedical gerontologist, and
he is founder of the SENS Research Foundation.
And as far as I know, the SENS Research Foundation
has taken on quite an ambitious goal.
And that goal is to help prevent and cure
aging.
And I think that Aubrey sometimes refers to
aging as a disease.
And so I’d like to talk a little bit about
that.
But thank you for being here, Aubrey.
And can you please tell us a little bit about
the SENS Research Foundation.
[Aubrey]: Certainly.
The SENS Research Foundation is a biomedical
research charity.
So we’re a 501(c)(3), which means taxpayers
can get tax benefits if they give us money.
And we do research into the diseases and disabilities
of old age.
And I’m a little bit cautious in using words
like cure and disease in relation to aging
because we have to remember always that aging
is it’s a side effect of being alive.
It’s the consequence of the accumulation in
the body of various molecular and cellular
changes that are inevitable consequences of
what the body does to keep us alive from one
day to the next.
Those changes are things that I call damage.
And that damage is harmless for a long time
because the body is set up to tolerate a certain
amount of it.
But of course, only a certain amount, which
means that eventually, this damage exceeds
our tolerance, and we start to decline both
mentally and physically, and that’s what the
diseases and disabilities of old aging are.
So when I talk about cures and about disease,
I’m always a little bit careful.
I think that the oversimplification that most
people make with regard to the difference
between diseases on the one hand and aging
on the other hand is an extraordinary damaging
over simplification, because it makes people
unjustifiably over-optimistic about the possibility
of curing age-related phenomena that they
do think of as diseases, let’s say Alzheimer’s
or cancer, most cancers, or osteoporosis,
or whatever, but it makes them also over pessimistic
about medical advances to prevent and preempt
the aspects of age-related ill health that
they don’t think of as diseases, like loss
of muscle or a decline in function of the
immune system, or whatever.
The best way to think about this is that all
of these things are part and parcel of the
same phenomenon.
They are interdependent but nevertheless individual
aspects of the accumulation of molecular and
cellular damage in the body.
And the only way that we’re going to bring
them under control is by developing a panel
of interventions that we can use to periodically
repair those various types of damage, and
thereby leave the overall abundance of damage
in the body below that threshold, such that
it’s harmless.
[Rhonda]: Right.
So let’s dig a little bit more into these
types of damage because I talk quite frequently
about damage myself.
And so typically, when I think of aging, I
also think of the degeneration, the accumulation
of damage, and degeneration of tissues of
cells as a consequence of the accumulation
of this damage, and at the same, the inability
of our capacity to repair damage, to prevent
the damage, also declining.
So it’s what sort of that this balance, imbalance
that begins to have we have more damage accumulating
and less capable of repairing the damage as
you mentioned.
[Aubrey]: Okay.
So I think I actually would like to stop you
there for a moment because a very important
thing that an enormous number of even the
even gerontologists tend to overlook is that
this change in the balance between damage
and repair has to be caused by something,
right?
You do indeed get in old age, a more rapid
creation of damage, and a less rapid removal
of damage, repair of damage, and thus, you
get an accelerated accumulation of the overall
amount of damage.
But why?
The answer is because of the damage that was
accumulating early in life, throughout life,
even starting before we’re born, that we could
never repair at all.
That is the clock of aging, it’s the accumulation
of damage that we simply don’t have any genetic
capability to repair even when we’re young.
When that accumulates, it does two things.
It accelerates the accumulation, the creation
of other damage, and it also impedes everything
about the body, including the damage repair
mechanisms that we have.
So we get less good at repairing the damage
that we used to be good at repairing.
[Rhonda]: Yes, that actually makes perfect
sense.
The accumulation of this damage is that we
do not repair, we simply cannot repair during
our youth, will eventually either damage the
DNA inside of our cells and that will change
the function of certain genes, maybe possibly
repair genes or genes that help us deal with
this damage.
They may change the function of the cell itself
so the cell might become more stiff, and that
changes the way the cell is functioning, or
they may change the way proteins are the function
of proteins because now proteins become aggregated
and all sorts of changes happen.
But in addition to that, it also may lead
to epigenetic changes, which also can change
the expression and function of genes.
And so I think that putting it that way does
make sense.
[Aubrey]: Well, actually, you bring up another
important point, especially with your mention
of epigenetics, because epigenetics is terribly
fashionable within gerontology right now.
[Rhonda]: Can you explain what epigenetics
is for people?
[Aubrey]: Epigenetics basically is the study
of the changes that happen in cells whether
as a result of aging or as a result of anything
else, that cause differences in which genes
are turned on and which genes are turned off.
So typically, these will range from things
at the DNA level itself, methylation of cytosines
for example, up through modifications of histones,
these proteins that DNA is wrapped around,
up through higher level changes to the packing
of chromosomes and to chromatin an awful lot
of different things change the behavior with
which a cell actually decides which proteins
to express and which ones not to.
But this…
[Rhonda]: Let me just interrupt real quick.
And for those of you that don’t know what
express or turn on or off, it just essentially
it means, what he’s referring to is that when
a gene is turned on or if it’s expressed,
it’s active, it’s doing the function it’s
supposed to do.
If the gene is turned off or not expressed,
that just means that the gene is there but
it’s not doing its function.
It’s almost as if it’s not there.
[Aubrey]: But here’s the thing.
When you see a change late in life, you always
have to ask yourself if this change happening
as part of aging, or is it happening as an
adaptation to part of aging?
Is it happening, in other words, to minimize
the pathogenic consequences of some other
change?
And epigenetic changes in aging are pretty
much entirely that latter thing, they’re adaptations
that are good for us, to make the best of
a bad job, namely the non-genetic things that
are happening elsewhere.
We know this simply because they are coordinated.
When we look at tissue in bulk, when we look
at lots of cells all at the same time and
we ask, “What’s happening in terms of the
gene expression changes?”
what we’re seeing is a coordinated response.
It’s got to be coordinated because otherwise,
it wouldn’t be happening at all in the bulk
of cells on average.
So it’s bound to be an adaptation, it’s genetically
programmed.
It’s happening because the cells know what
their environment is, whether intracellular
or extracellular, and they’re responding to
that environment in the same way that they
might respond to an infection, or to inflammation,
or whatever.
The only way you can actually ask questions
about epigenetics that are meaningful with
regard to actual aging, rather than adaptations
to aging, is by looking at individual cells.
Look at individual cells, single-cell analysis,
then you can quantify the noise, the amount
of variation that’s happening without any
kind of genetic direction.
And we’re actually doing that.
We have had a project for a few years now
in the Albert Einstein College of Medicine
in New York looking at precisely this.
We’re looking specifically at methylation
rather than the other aspects of epigenetics.
And we’re asking, does the epigenetic noise
in various tissues increase with age (wouldn’t
be much).
And the hypothesis that we are pursuing is
one that I put forward some time ago now,
which is essentially that no, it won’t, or
at least not to a detectable degree.
And the reason it won’t is because the quality
of DNA maintenance and repair, whether genetic
or epigenetic, is driven, in an evolutionary
sense, by the need not to die of cancer before
you’ve reproduced.
Cancer is, by far, in my view, the biggest
problem of DNA repair and maintenance, because
it can kill you with just one cell going seriously
wrong in the wrong way.
Whereas, anything that doesn’t have to do
with the cell cycle has to affect an awful
lot of, a high proportion of the cells in
a given tissue, before it starts to be pathogenic.
And that means a lot of cells.
[Rhonda]: Yeah.
So this is all very interesting.
Are you familiar with the work that’s come
out of UCLA from Steve Horvath, I think?
So he’s shown that from multiple tissues from
humans, blood cells, and also different biopsies
from different samples, that there’s a pattern
of methylation that appears to be specific
to age.
And it’s so precise that researchers can look
at this methylation pattern from, for example,
lymphocytes taken from a person and they can
identify the person’s age plus or minus four
years with 96% accuracy.
[Aubrey]: Yeah, okay.
So let me talk about that actually.
Because yes, I know Steve’s work pretty well,
and I’ve discussed it with him.
And actually, a lot of people have oversimplified
what he’s been doing and what he’s seeing
from this.
So you’re right, there’s this extraordinary
correlation R-squared of 96% that he’s got.
He’s found this particular set of CpG islands
of things that change during age in terms
of their methylation that change so uniformly
that you get this amazing R-squared.
Now, what does all that actually mean?
Well, first of all, you’ve got to remember
that actually if you look in the adult part
of life, let’s say 23 to 70 or 80, then the
R-squared is much lower.
It’s like 70%, something like that.
Second thing you gotta remember is that that’s
a good thing, because it means you’ve got
some variation to actually work with.
If you actually really had something totally
linear, right, then first of all, it wouldn’t
tell you who’s aging more quickly and who’s
aging more slowly.
But secondly, it would tell you that your
signature is the list of the least important
things in aging, the things that are just
trundling on in a trajectory that was set
during development because evolution hasn’t
had the faintest motivation to stop them trundling
on.
[Rhonda]: Well, what I found interesting from
the research was more the clusters of genes
that this was involved around.
They were a DNA repair…
[Aubrey]: Kinda.
Kinda.
But that’s always dangerous.
I mean I was actually involved in the very
early days of the gene ontology.
And I always had doubts about whether it would
be misused.
And I feel that it is being misused in some
ways here.
I think that one…Well it’s very hard to
factor out the multiple hypothesis problem
when you’re using that kind of analysis of
GO terms.
Essentially, you’ve got to ask yourself how
many different types of gene, whether it’s
in terms of function, or process, or whatever,
and how many…I mean, what proportion of
those genes are affected.
It’s terribly, terribly easy to run with the
first thing you see when you half close your
eyes when you look at that kind of data.
And I think a lot of people have been doing
that.
But I’ll do what I’m interested in with regard
to Horvath’s work and related work.
What I’m interested in is when they have looked
not at the enormously good R-squared, but
at the variations from the R-squared, that’s
why I said that it’s good that the R-squared
not so high if you look at adults.
The thing there is that, then you can actually
ask questions like, “Does the subset of the
population that are changing that signature
of that group of methylation sites more rapidly
than average, do they actually exhibit a greater
pathology at a younger age?”
Or, loss of function in some other way that
you can measure even at a relatively young
age.
Very recently, just a few weeks ago, there
was an extremely interesting paper that came
out of a group in New Zealand where they had
done exactly this question.
They had basically looked at, I can’t remember
how many people they looked at, but they did
a longitudinal study over if I remember rightly
12 years, and there were early adults here.
We’re talking, I think the ages were something
like 26 through 38.
And they looked for this kind of variation.
If we can combine that kind of analysis with
the kind of methylation analysis that Horvath
has developed, then I think we’ll be able
to ask some very intriguing questions about
the predictability of age-related ill health.
But now I want to finish my answer by talking
about what this means for our work.
And this is actually really important because
a lot of people overlook this.
It’s terribly, terribly fascinating that some
people age more quickly than others, and some
species age more quickly than others, and
the whole of gerontology, for more than a
century now, has been essentially founded
on the idea that if we understand that variation
really, really well, we might be able to translate
that variation into some kind of therapeutic
regimen to turn fast agers into slow agers.
And that I wouldn’t object, that would be
great.
But we’ve got to remember a couple of things
about that approach.
Number one, it doesn’t work so well if you
only apply it late in life, because all it
does is slow down the accumulation of damage
rather than repairing damage, which is what
we’re all about.
So that’s bad enough.
We’d like to help people who have the misfortune
to be in middle age already or maybe older.
The other thing is no one’s actually having
success in this.
Why not?
Because metabolism is really complicated.
Messing around with this vast network of undocumented
spaghetti code that keeps going from one day
to the next the idea of stopping it from doing
the thing we don’t want it to do, the creation
of damage, without also stopping it from doing
things that we need it to do it’s crazy, it’s
never going to happen.
So I really don’t think that even if we learn
plenty by these methods, that it’s going to
have all that much impact on the development
of actual therapies.
[Rhonda]: What about some of the more recent
methods, for example the CRISPR where this
technology where now, I’m going to totally
oversimplify this for people.
But the ability to specifically target a gene
and clip it out, and replace it with another
gene or a version of the gene that’s more
active or less active depending on what it
is you want.
I think that this new technology for CRISPR,
for example, dramatically changes a lot of
things because…I mean, even if we look at,
for example, centenarians, semi-centenarians,
which live to be about 105, or semi-supercentenarians
live to be 105, and then the supercentenarians,
which are about 110 plus.
A recent study came out from I think it was
Tokyo, and Newcastle, I think.
I don’t know if you’re familiar with the study.
But essentially what the study did, and it
was the largest cohort of the semi-supercentenarians
and the supercentenarians.
And what they found was that they looked at
a variety of different biomarkers.
So they looked at inflammatory biomarkers,
they looked at lipid profiles, glucose, they
looked at immunosenescence.
So when your immune cells no longer are living
and dividing, they basically sit around, and
they’re not dead, but they’re doing more damage,
because they’re producing more inflammatory
things that are damaging other cells.
So it’s like spreading more nasty stuff around.
They looked at immunosenescence, and then
they also looked at telomere lengths.
And then they also looked at like diseases,
and then they looked at organ, for like liver
function, kidney function.
And so, anyways, they’re correlating all these
factors.
And what they found was that inflammation
was the only thing that drove aging in all
the groups.
So inflammation, the higher the inflammation,
the higher the risk of death of non-accident,
you know?
So age-related diseases, cardiovascular disease,
cancer.
And this was true for all the groups.
But what was really also interesting was that
the centenarians, there was a positive correlation
between inflammation and immunosenescence,
which was essentially lost in the super centenarian
group.
And I don’t know why that is, but the immunosenescence…So
essentially the inflammation went up and then
the supercentenarians as the inflammation
went up, they died.
There was a positive correlation.
But the immunosenescence seemed to stay around
the same for whatever reason.
So in my mind, I think, “You know, well, we
know that these supercentenarians, that’s
possibly around a 25% to 30% increase in human
lifespan.”
So human lifespan in the United States is
average around 79 years old.
If we could live to be 115 and live to be
healthy, that’s fantastic.
So we know that it can be done with these
supercentenarians, and we know that that there’s
a lot of genetic factors that are playing
a role on this, I mean, obviously these people
have lower inflammation compared to non-centenarians,
they also showed that.
And so, and inflammation is upstream of a
lot of damage.
It’s upstream of the damage that’s damaging
DNA, proteins in the cells, lipids etc., etc.
So if we can use CRISPR technology to go in
and replace say, give it more anti-inflammatory
capabilities, and this has been shown also
in mice.
I don’t know if you’ve seen this study, but
NF-kB, which is a gene that produces a protein
that regulates a lot other genes that are
pro-inflammation, so they cause inflammation,
but it also has an anti-inflammatory component
to it.
And when you take away that anti-inflammatory
component and put it in mice, what happens
is every time there’s an immune response,
every time inflammation happens, which leads
to chronic damage, as you talk about, there’s
a low level inflammation and it drives aging
prematurely in mice.
[Aubrey]: All right, so.
Big question there.
[Rhonda]: Yes.
[Aubrey]: Let me just give a fairly big answer.
Let me start with a very simple thing.
Overtly clear that inflammation is a double-edged
sword.
That we need it, the reason we have it, as
with anything that’s genetically carried over
that hasn’t just mutated into oblivion over
evolutionary time, is because it’s good for
us.
Because it’s an essential component of how
we survive infections.
However, there are certain aspects of age-related
damage accumulation, which because they are
only age-related, are not very interesting
to evolution.
And therefore, evolution has not taken the
trouble to improve the precision of the inflammatory
response so as to discriminate between things
that the inflammatory response can actually
help with, namely the elimination of infections,
and things that the inflammatory response
actually exacerbates, namely the accumulation
of damage that is not an infection, like oxidized
cholesterol, or whatever.
So that means that, yes, it’s likely that,
it’s no surprise to us, that when you look
at a very, very elite population, the population
that live to 105, 110, then they will overwhelmingly
have a weak inflammatory response, because
that is the only way that they will have been
able not to succumb at the age of 80 or 90
to atherosclerosis or Alzheimer’s, which are
definitely driven partly by the inflammatory
response.
However, what also needs to be taken into
account is that plenty of people aged 80 and
90 and 100 die of infections.
So, yes, these people got genetically lucky
because they didn’t get an excessive inflammatory
response to those age-related problems, but
they also got environmentally lucky in that
they didn’t die of infections.
Or maybe they just had a really strong adaptive
immune system that compensated for the weak
inflammatory response, and so on.
So there’s a real trade-off here and what
this adds up to is that we cannot conclude
that it would necessarily be a good idea to
take people in their, let’s say, 60s or 70s
and damp down their inflammatory response.
[Rhonda]: What about bump up their anti-inflammatory
response?
[Aubrey]: It amounts to the same thing.
If we’re talking about the strength of the
inflammatory response, as opposed to the strength
of other aspects of the immune system, like
T cells and B cells, then we are engaging
in a change of a trade-off.
We are giving people less…We are reducing
people’s risk of rate of…Well, likely rate
of progression of atherosclerosis and Alzheimer’s
and such alike, but we were also increasing
their risk of dying pneumonia.
Simple as that.
And the best way to deal with this is to find
a best of both worlds solution, to let people
have the strong inflammatory response that
they need in order to be protected well against
infections, but to fix the problem of maladaptive
activation of the immune response.
And what we’re kind of doing exactly that,
not by changing the inflammatory response
itself, but rather by changing the targets.
Ultimately, what’s happening in atherosclerosis
is that the inflammatory response is being
activated by the accumulation of indigestible
waste products, specifically oxidized cholesterol,
in macrophages in the artery wall, which turn
to foam cells, and generally make cells around
them angry.
If that didn’t happen, if we could get rid
of that oxidized cholesterol, then it wouldn’t
matter at all how strong your inflammatory
response was.
You would not get atherosclerosis.
Same for Alzheimer’s.
Ultimately, Alzheimer’s has an inflammatory
response because the stuff it’s reacting to,
it’s amyloid and tau and so on.
If we can get rid of those materials, stop
them from accumulating to an inflammation-triggering
level, then we won’t get an inflammatory response
even in people with a strong inflammatory
genetic profile.
[Rhonda]: Has the SENS Foundation considered
using some technologies that are sort of already
present in the body?
For example, you mentioned Alzheimer’s disease,
and recently this glymphatic system has been
discovered where we now, when we sleep, we
know that cerebral spinal fluid squirts up
into our brain and literally washes out the
amyloid plaques and other buildup of these
extracellular aggregates that are in our brain.
Has the SENS Foundation thought of any way
to use that system somehow?
[Aubrey]: We’re looking at it.
We’re very interested in all ways of getting
rid of molecular garbage, whether the garbage
is intracellular or extracellular, and whether
the getting rid of is destroying it on site
or flushing it into a place where it gets
destroyed in other ways we’re into all of
this thing.
We keep our eyes very open and our minds very
open with regard to what’s going to work.
[Rhonda]: That’s good to know.
What about the new…I find this very interesting,
the parabiosis where we can take, we, I mean
scientists, can take blood from a young animal
and transplant it in an old animal, and essentially
reverse some biomarkers of aging in multiple
organs.
[Aubrey]: Yeah, it’s very exciting.
We’re actually funding a postdoc at Berkeley
doing, working in this area, in one of the
top labs in this area.
Of course parabiosis itself is not a therapeutic
regimen.
I mean, presumably, you would not be too keen
to do that.
[Rhonda] Right.
[Aubrey]: But it’s definitely a great way
to make discoveries.
And it, of course, leads to alternative versions
like plasma exchange and phoresis ways of
altering, of taking things out of the old
blood, or putting things into the old blood,
so as to achieve the same effect that parabiosis
would.
Of course, in order to do that, you need to
know what to take out or put in.
And a lot of the problems that parabiosis
research faces at the moment is that that’s
really laborious and tricky to find out in
any kind of systematic way.
The few hits that people have had so far in
terms of factors that seem to actually have
some kind of causal role like GDF11…And
so these things we found more or less serendipitously.
And everyone knows that there’s likely to
be a number of others out there, perhaps very
likely to be ones that are more central to
the effect, but which have not been found
just because they’re a little more counterintuitive.
[Rhonda]: So I envision if these factors can
be identified, GDF11, growth differentiation
factor 11, was thought to be possibly playing
a role in causing muscle stem cells to divide
and proliferate, and possibly in the brain
as well.
But others have not been able to confirm that,
but if…
[Aubrey]: Yeah, watch this space.
That’s going to run and run.
[Rhonda]: Yeah.
I mean, I’m not sure.
I mean, all I know is that I’m excited about
the research in general.
And whatever the factors are, I envision possibly
making recombinant proteins.
I mean, people are using EPO, erythropoietin.
I mean human growth factor.
So some the same sort of deal.
[Aubrey]: The big thing that needs to be taken
into account here is that the factors that
change in their abundance in the blood during
age, whether up or down, and that may have
an effect in terms of if you like transmitting
pathogenic damage from one place in the body
to another, those things are, first of all,
they’re not necessarily just proteins.
We also have to worry about cells, the fact
that you have changes in the relative abundance
of different types of T cells for example.
And there’s also a small molecule, glutathione,
things like that.
You know, things that may simply not be amenable
to rejuvenation by measures like plasma exchange,
but only by, from that parabiosis.
Then we would have to look at a different
model.
But I want to also emphasize something I just
alluded to a moment ago, which is that we
are talking here not about mechanisms whereby
damage is created.
We are talking about mechanisms whereby damage
is transmitted from one part of the body to
another.
After all, that’s what the circulation is,
it just takes stuff from one place to another.
It doesn’t create damage.
The damage comes from somewhere.
So we always need to be looking out for the
possibility that we can find the cells that
are the source of the changes in the blood,
and change those cells back to a rejuvenated
state, and by that means, rejuvenate the blood.
[Rhonda]: Well, I think that the source of
damage, in the sense of the circulation and
the blood cells the immune cells in the blood,
are just that.
You know, when you activate macrophages, they
dump out hydrogen peroxide and all sorts of
reactive nitrogen species.
[Aubrey]: Yeah.
That’s not really what I’m talking about.
I mean, I’m talking about, for example, well,
let’s take the thymus for example.
The thymus itself shrinks, as we were saying
earlier, and that is largely responsible for
the fact that in an older person, there are
fewer naive T cells and more memory T cells.
You know, if we can fix the thymus, then we
fix that problem.
And, yeah, I can make many other example.
[Rhonda]: Yeah, that really makes sense.
Something else talking about this damage and
you and I both agree that…I mean, I think
the accumulation of damage, intracellular,
so inside the cell, outside of cells, on cell
membranes, proteins, DNA, on and on.
I mean, I think that is a driver of aging
and essentially causes aging.
[Aubrey]: I would say is aging.
[Rhonda]: Yeah.
And I focus more on an easier solution, which
is the nutritional aspects of preventing,
or of allowing your body to metabolize and
produce energy the best it can.
And even though you’re still going to age,
like even if you’re at the optimal amount,
I mean, even if you have the optimum amount
of micronutrients, you have these minerals
and vitamins that are essential to run your
metabolism, they’re essential to run enzymes
that repair damage so on.
The fact is you will still age.
The question is how much better will you age?
[Aubrey]: So, I should put…
Yeah, exactly.
The question is how much better?
And I’m all for all of that work, you know.
A large part of why Bruce and I became friends
long time ago was because I absolutely endorse
the idea that we need to do the best we can
for the population to get them to an average
level of nutrition.
But I think the critical thing to understand
is average.
If you ask about the difference in terms of
health expectancy and life expectancy between,
let’s say, the middle 10% of the population
and the bottom 10%, it’s a large difference.
And that’s the difference that we’re talking
about here, the difference that Bruce is trying
to do something about by making sure that
if the poor won’t eat fruit, then that we
find a multivitamin and so on.
But if you look at the opposite end of the
spectrum, if you look at the difference between
the middle 10% and the top 10% in terms of
health expectancy and life expectancy, it’s
basically nil.
Of course, I’m factoring out genetics here,
I’m talking about lifestyle.
I’m talking about things that we can modify.
And that’s really important to remember, because
it’s so easy from the popular press and so
on to get the impression that if you just
do what your mother told you to and do it
really well you eat a really good diet, and
you get a lot of exercise, and you never drink
anything, you never smoke, and so on, then
you’re actually going to live 20 years longer
than you otherwise would.
When in fact, the message of all of the data
we have, epidemiological or anything, is that
it’s probably closer to two years, if that.
You know, I mean other example I like to give
is just a very simple one looking at national
life expectancies.
So people laugh at the USA a great deal because
of the fact that it sits at number something
like 45 in the league table of longevity among
the industrialized world, despite the fact
that you guys spend far more per head on medical
care than anybody else.
But if you look at the absolute numbers and
you look at the actual difference in number
of years in life expectancy between the USA
and the number one big country, namely Japan,
it’s only four years, only four years.
[Rhonda]: Yeah.
No, I’m familiar with this data.
It’s five years actually.
The average lifespan experienced in the United
States is 79, and Japan, it’s 84.
And, what’s really interesting…So first
of all, I’m not sure that Japan has the optimal
diet in general, they they’re getting all
the micronutrients.
I mean there’s a lot of factors here.
But what I do find interesting is if you look
at the data…So right now, the average difference
is five years.
And in between males, it’s four years, between
females it’s six years.
If you look at the data from 2012, 2013, Japan
has gone down in their life expectancy.
So their average life expectancy has gone
down by a year.
U.S. has gone down by a year.
So there was a bigger difference, it was six
years.
But what’s really interesting is that the
male life expectancy in Japan has gone down
by almost four years, three points or so.
[Aubrey]: Okay.
So those are the kinds of fluctuation in data
that I find very untrustworthy.
[Rhonda]: Yeah.
I mean, I think that it’s possible that Japan’s
becoming more westernized, males also smoke
like chimneys over there.
So I mean, there’s a lot of other factors
that come into play.
[Aubrey]: Okay, that could be quality of data,
you know…
[Rhonda]: Could be quality of data, exactly.
I think that if…Like you mentioned earlier
if you really want to look at the effect of
diet on lifestyle, then looking at obesity.
Obesity is associated with a seven-year reduction
in lifespan.
Morbid obesity is associated with a 14-year
reduction.
[Aubrey]: Oh, don’t get me wrong, of course.
But that’s the low end versus middle that
I was talking about.
[Rhonda]: But it’s growing problem in the
United States.
You know, obesity is…
[Aubrey]: Well aware of that.
Jay Olshansky of course has been very prominent
in publicizing this problem and predicting
that unless we do something very serious about
basically epidemic, then we are in danger
of seeing a fall in the life expectancy in
the USA.
But of course, we haven’t seen that yet because
the problem is too new.
[Rhonda]: It’s what?
[Aubrey]: The problem is too new.
[Rhonda]: Too new, yeah.
So I do think that I talk a lot about what
role micronutrients have in diet, and metabolism,
I mean, B vitamins are running your mitochondria,
magnesium’s needed for gene repair enzymes,
vitamin K is needed to coagulate, blood coagulation,
on and on.
So it also plays a very important role.
And I do think it absolutely affects the way
you age, especially if you’re talking about
living in an unhealthy eating refined carbohydrate
sort of diet versus eating your greens, and
exercise, and things like that.
But even with that said, and doing all those
things, you’re still going to age, because
you can’t stop the breathing in oxygen and
eating food, this process that is coupled
together to make energy.
Well, it’s, inherently makes damage, yeah.
And there’s no stopping it.
I mean, no matter what amount of nutrients
you get.
[Aubrey]: Which of course is exactly where
I came in, back in 2000, with the realization
that even though we couldn’t stop this damage
from being created, we could go in and comprehensively,
not necessarily 100%, but very, very comprehensively,
repair that damage, and thereby, keep its
overall level of abundance to a level that
the body is set up to tolerate with full function.
[Rhonda]: So with these discoveries, CRISPR
technology pluripotent stem cells…
[Aubrey]: These are huge things.
[Rhonda]: Is this advancing your research?
[Aubrey]: Absolutely, absolutely.
It’s advancing our research just as it’s advancing
everybody else’s.
These are techniques, technological innovations
that, just like the fact that we can now have
the sequence of a human genome, they just
make things easier and faster.
CRISPR I would single out as a particularly
important advance, because there are definitely
quite a few things we’re going to have to
do in getting this damage repair to be comprehensive
that involve genetic modifications.
And some of those genetic modifications are
going to be possible to do ex vivo, in stem
cells that we then reinject into the same
person.
Some of them are not.
Some of them are just going to have to be
done by bona fide somatic gene therapy.
And as we know, somatic gene therapy has had
a rocky ride over the past 20 odd years, because
it’s really difficult to make it safe.
And the fundamental reason it’s so difficult
to make it safe is because the viruses, the
vectors that are used to get engineered DNA
into places are not easy to control in terms
of where they insert themselves into the DNA.
And thereby, they are not easy to control
in terms of what damage they may do, making
a cell cancerous, etc.
CRISPR on the other hand, started out being
pretty good at its site specificity.
And better than that, as time’s gone on, very
rapid advances have been made such that now,
it’s just out of site site-specific.
It’s incredibly high fidelity.
That means that one can increase the titer,
the amount of engineered DNA that you stick
into their body that’s supposed to go and
modify cells.
And by increasing the titer, you can increase
the penetrance, the proportion of cells that
are actually modified in the way you want,
without increasing the off-target effects,
because the off-target effects are being eliminated
by the nature of CRISPR.
[Rhonda]: Yeah.
I think that using CRISPR, I think there’s
obviously a lot of things that need to be
overcome, like getting it to the right tissues.
I mean, you still have to have some sort of
targeting sequence to say, “Okay, we want
CRISPR.”
It’s easier to do ex vivo when you take your
blood cells.
I think…
[Aubrey]: Ex vivo is always going to be easier.
[Rhonda]: Right.
But saying we want to get this to the liver,
or we want to get this to the heart.
[Aubrey]: On muscle, yeah.
That’s right.
[Rhonda]: Or muscle.
Yeah, much more difficult.
And some of these technologies that you were
describing, about engineering cells to have
certain viruses that make them go somewhere
or change a gene, also we don’t know what
their effects are in terms of putting them
in our body.
Are they gonna cause cancer.
I see sort of the same challenges with the
induced pluripotent stem cells.
So being able to make tissue…for example,
take a skin cell from your body and give it
the right genetic combination to trick it
and reprogram it into becoming a stem cell,
a pluripotent stem cell, so that it can form
any cell in the body, that also is takes some
viruses at this point, I think…
[Aubrey]: Well, first of all, no, there are
plenty of ways now that have been perfected
that induce pluripotency without actually
using viruses at all.
The most recent one that got a lot of attention
a month or two ago was when Helen Blau’s group
at Stanford showed that they could do it with
messenger RNA.
But it’s also been done just by electroporating
proteins in.
Of course, the problem here is that the actual
efficiency is rather low in many cases.
But that’s improving.
The other thing is the quality of the reprogramming.
So the original Yamanaka factors, they work
pretty well.
But Jean-Marc Lemaitre in France a few years
ago showed that if you use six factors, then
you can get a much more high fidelity reprogramming,
you can even reprogram senescent cells, which
you couldn’t do with the regular Yamanaka
factors, and so on.
You know, these are things are…you know,
it’s an enormous field, and it’s progressing
really fast, simply because they can.
And I’m overjoyed it’s going to make a lot
of things easier.
[Rhonda]: That’s really exciting.
Are you familiar with the fact that placenta
is a good source of pluripotent stem cells?
[Aubrey]: Doesn’t surprise me the slightest.
[Rhonda]: Yeah.
And that it’s just being trashed every day.
[Aubrey]: But the point is, of course we want
to treat people who are already in middle
age, right?
So they don’t have their placentas any more
than they have their umbilical cord or whatever.
And if we can do the reprogramming well, then
that’s fine.
[Rhonda]: Well, if you have enough placentas
being banked, sort of like blood, then you
can potentially find a match.
[Aubrey]: Oh, well, of course.
Now, we’re talking about falling short of
true autologous administration.
As far as I’m concerned yes, it’s good to
have matches that cut out some of the immune,
the reaction response because of MHC compatibility.
But the fact is, the real McCoy is taking
cells from the prospective recipient, reprogramming
them, doing whatever you want, and putting
them back into the same person.
And the only reason that that at the moment
is not what everyone’s looking at is because
it costs a lot of money to do that on a personalized
basis.
But as time goes on, and we get better and
better at these things, that cost is going
to reduce, and all this banking stuff is going
to be obsolete.
[Rhonda]: Do you know if the reprogramming
of a skin cell into, say a pluripotent stem
cell, do you know if it’s been shown that
everything gets reprogrammed, the epigenetics,
I mean, because you’re essentially talking
about if you take it from an adult who’s 50
years old, it’s a 50-year-old skin cell, I
mean…
[Aubrey]: So this is what I was saying…Well,
this relates to what I was saying a moment
ago about using the original Yamanaka technique
versus refinements of it.
So for sure, it’s been shown by a number of
groups that the standard methods of creating
induced pluripotent stem cells do not 100%
erase the epigenetic state that the cell came
from.
There is a retention of some “epigenetic memory,”
as people are calling it.
That epigenetic memory is considerably less
in this system where you use six factors,
that I mentioned.
And of course, other people are looking at
other ways to eliminate it even further.
Then again, of course, you’ve got to ask how
much elimination is needed for a particular
person.
Is it in fact fine for cells that started
out being skin, but you’re going to use them
for blood to actually have a little bit of
skin behavior in them?
You know, does it actually matter?
You know, these are the questions that people
are asking all the time all over the world
right now.
[Rhonda] Yeah.
Well, I’m less worried about that and more
worried about the fact that you may now have
certain genes that should be more highly expressed
at a younger age, to make it younger, not…So
for example the cell cycle regulator, ARF
p16(INK4a).
During early youth, early development, as
we’re younger, it’s silenced, epigenetically
silenced.
The reason for that is because if it’s not
silenced, stem cells stop dividing, it essentially
says, “stop.”
And so you want the stem cell to divide.
[Aubrey]: So there’s two answers to that.
The first answer is that this is reprogramming,
right?
So if you’re erasing the whole of the epigenetic
state of a cell, and taking it back to how
it was in the embryo, then you’re going to
re-differentiate it in the direction you want
to the extent that you want.
And that’s going to make it into let’s say,
an oligopotent skin stem cell, with its p16
suppressed, the way a regular oligopotent
stem cell would be, and the way that you make
sure that’s true is just by knowing what to
do in the re-differentiation process.
So my friend and colleague, Mike West, at
BioTime, has been working on this for a while.
And that’s the main thing that BioTime is
really good at, this method that controls
and systematizes the redifferentiation process.
The other thing to mention though, is that,
yes, if you take a bunch of skin cells from
an older person, then there’s going to be
a spectrum of level of expression of, let’s
say, P16.
Now, it may be that the process of dedifferentiation,
getting it back to the iPS state in the first
place, is actually going to be affected by
that, such that the cells that actually give
rise to your iPS cells will be preferentially
the ones that happen to have low P16 in the
sample that you took from the original person.
So what, really.
[Rhonda] Yeah.
So you had brought up this idea a little earlier
of kind of at least I think it’s somewhat
of an antagonistic pleiotropy, when you’re
talking about for example the immune system.
You know, it’s sort of, you want an active
immune system because you want to survive
through reproduction, you want to not die
from some bad nasty infection, but also, this
inflammatory process as you get older can
accelerate aging.
[Aubrey]: Yup.
So you got to be very careful with antagonistic
pleiotropy.
It’s a overused term.
I’m not even sure that one should call the
inflammatory response an example of antagonistic
pleiotropy.
Because remember, the situation in an older
individual includes the fact that the rest
of the immune system has declined, so that
you kinda need a high inflammatory response
just to fight off infections.
And maybe it’s a good tradeoff even in the
elderly, irrespective of the fact that it
was a different tradeoff earlier in life.
[Rhonda] Yeah, I think that’s less of an example.
More of a better example would be something
like growth hormone, or IGF-1, which is very
important for development, for growth, it
causes muscles to repair damage, it actually
grows new neurons.
I mean, it’s a great growth factor.
But, as you get older and you have more cells
that have accumulated damage, that have more
damaged DNA having too much IGF-1 around allows
these cells instead of to die to grow.
So basically…
[Aubrey]: Well, so actually, I would say that
that’s an example rather similar to the inflammatory
one, in the sense that, rather being strictly
speaking antagonistic pleiotropy, good in
the young, bad in the old, this is a case
where it’s good in the old and bad in the
old in different ways.
So you want more growth hormone in order to
have better muscle, you want less growth hormone
in order to have less cancer.