Player is loading...

Embed

Embed code

Transcriptions

Note: this content has been automatically generated.
00:00:00
Because I thought that maybe you guys
00:00:02
would think that this is this this too
00:00:04
much in new in this and maybe nobody's
00:00:06
gonna show up and and I must say that
00:00:08
I'm neither a nutritionist and nor and
00:00:11
you're a scientist and just like
00:00:12
Rebecca sex was saying that she was
00:00:14
surprised I'm also extremely surprising
00:00:17
actually flattered that I'm here among
00:00:19
all you people to talk about some of
00:00:21
the work that you're doing and so
00:00:23
obviously have to thank Johannes and
00:00:25
and the organisers for inviting me here
00:00:27
is my first time here. And it's it's
00:00:29
wonderful. So I think the first talking
00:00:32
the session I was actually really
00:00:34
intimidated because we are very simple
00:00:36
minded people and we do simple
00:00:37
experiments and luckily doctor dancing
00:00:40
is start kind of you know back me up a
00:00:42
little bit that in fact eight system
00:00:46
exactly I don't exactly you system is
00:00:51
is is actually not too far away and we
00:00:53
really need innate immunity in fact and
00:00:56
that's the the the thing that you're
00:00:58
gonna discuss and which brings back you
00:01:00
know this question that my colleague
00:01:03
too much or about that that that much
00:01:04
other too much knows very well. And he
00:01:06
always say is that yes nuance brain
00:01:08
controls the body but in fact body is
00:01:11
very critical in controlling brain too.
00:01:13
So I think this would attach a little
00:01:15
bit upon those those issues. So I I I
00:01:20
will not belabour this point because I
00:01:21
think this is pretty clear to all of
00:01:23
you that there is indeed a silver
00:01:26
salami coming global And one is that of
00:01:29
course there are lots of us there are
00:01:31
no living longer. And and there are
00:01:34
more of us that are gonna be living
00:01:35
longer and this is a worldwide
00:01:37
phenomenon so by twenty fifty you can
00:01:39
see the predictions right here in both
00:01:41
developing as well as develop the
00:01:43
develop can please and if there are any
00:01:45
japanese females in the audience you
00:01:47
can see that they yeah the best hordes
00:01:50
of living longer. And and what is
00:01:53
stunning and I found this is actually
00:01:55
from the congressional budget office in
00:01:57
US which was a any kind of you know
00:01:59
negative kind of a statement that every
00:02:02
year of life expectancy "'cause" you
00:02:03
social security approximately fifty
00:02:05
billion. I mean that's pretty sad right
00:02:08
I mean that that you would think about
00:02:10
this in a totally unit in economic
00:02:12
perspective that's not the only reason
00:02:13
we should get about ageing because
00:02:16
that's that you're gonna be a burden on
00:02:17
the society but in fact these questions
00:02:19
are not new and and that's this really
00:02:22
brings me to the innate immunity and I
00:02:23
think those of you who are interested
00:02:25
in immunology and and and philosophy of
00:02:27
science would recognise this guy yeah
00:02:29
actually cough so of course he was the
00:02:31
guy who discovered by the sides and
00:02:32
macrophages and and hearing not very
00:02:35
far from your boss to institute. And he
00:02:37
is got the Nobel prize but but I like
00:02:41
others I mean he was really the founder
00:02:44
of innate immunity so this guy found it
00:02:46
in community and you know this rather
00:02:51
controversial book at that point of
00:02:53
time if if you guys I'm not retired
00:02:55
irish the read it it's actually quite
00:02:57
interesting. And and I was talking
00:02:59
about the location of life. But many of
00:03:01
you probably would not know that yeah
00:03:03
actually cough also was one of the
00:03:05
first guys or discovered appointed
00:03:07
tangent ecology and he said that
00:03:08
teaching is like any other signs which
00:03:10
can be started by exact method and so
00:03:14
in this book he talks about EG and
00:03:16
promulgation of life and and in fact he
00:03:19
was you could call and also the one of
00:03:21
the first nutritionists was interested
00:03:22
in immunology of course with some can
00:03:24
controversial ideas that like the bass
00:03:26
solos and we'll get and bulgarian
00:03:28
younger extends like spiral then and
00:03:30
those experiments of or soon were
00:03:32
completely would be and that he was
00:03:33
proposing. But maybe there was some
00:03:36
very interesting statements he made
00:03:37
which I in fact coming to now as you
00:03:41
know in twenty fifteen that he bait so
00:03:43
many years ago he got a lot of things
00:03:44
right and one of the things he said was
00:03:47
that defined the side or macrophages in
00:03:50
fact are critical to the biology of
00:03:53
ageing but these are the cells that are
00:03:55
critical for this and of course you
00:03:56
could say that or maybe just because I
00:03:58
discovered it so it's like you know is
00:04:00
too biased for it but in fact I'll show
00:04:02
you some data that would suggest that
00:04:03
this what William actually got
00:04:05
predicted could be fact we do to and of
00:04:08
course you made this this product that
00:04:09
that the pictures against infectious
00:04:11
disease would benefit you only to
00:04:13
reveal by madison's helplessly can read
00:04:14
this much better than my an accent
00:04:16
right and and this is in fact also very
00:04:19
controversial in those days because
00:04:20
people don't want to be in this this
00:04:22
this and this can actually happen and
00:04:24
in fact he's he's absolutely right and
00:04:25
as a as we can see others have already
00:04:28
shown you that and getting are the
00:04:31
biggest incidents and and the because
00:04:33
Burton it is really the chronic
00:04:35
diseases and in fact the same
00:04:36
degenerative diseases that India
00:04:38
predicted that we wanna live long and
00:04:40
that's what we're gonna have and it's
00:04:41
instructions that you've actually done
00:04:42
much better but you can see that these
00:04:45
are the because of that data from
00:04:47
institute of metrics an evaluation and
00:04:49
can see the majority of these these
00:04:51
chronic diseases and also I was of
00:04:54
course is is is the big one right. So
00:04:57
this this kind of brings this this
00:05:00
question in in the field of ageing and
00:05:02
of course which is a rather interesting
00:05:05
is that in fact if you look at one of
00:05:07
these chronic diseases of course is an
00:05:09
article scale it's just a schematic
00:05:11
representation that many of these
00:05:13
chronic diseases of course I decided
00:05:15
not one of them in this case selected
00:05:17
what a cancer heart disease diabetes
00:05:19
I'll sign on this this is a really
00:05:21
related okay. So what this means is
00:05:24
that in fact it is in fact every
00:05:26
because risk factor for chronic
00:05:27
diseases. And the argument or the
00:05:30
philosophical argument in the field by
00:05:32
some has been that the other biomedical
00:05:35
enterprise basically that those each of
00:05:37
this disease individually. So we spend
00:05:38
billions of dollars and heart disease
00:05:40
and billions on cancer and all that and
00:05:43
a and some people in the field would
00:05:45
like to argue or would like to state
00:05:47
there is this something intrinsic in
00:05:49
the biology of age she that needs to
00:05:51
this onset of many of these chronic
00:05:53
diseases and if we I understand that is
00:05:56
before forestry fact tackle all of them
00:05:58
in one goal of course is a is a big
00:06:01
task and we all know how or likes magic
00:06:03
about your event so so we have to all
00:06:06
be sceptical about these things but
00:06:07
that's one of the questions in the fee.
00:06:09
And and obviously on it's very simple
00:06:11
to know here that almost every one of
00:06:13
these chronic disease has an
00:06:15
inflammatory component right. So all of
00:06:17
you guys know this is basically what
00:06:19
happens that you know with ageing this
00:06:21
chronic inflammation. And and oh the
00:06:25
association between this chronic
00:06:26
inflammation several of these diseases
00:06:29
and the functional decline in
00:06:30
production and the health plan that we
00:06:32
see and In fact the the the cost of
00:06:36
data between here and here is actually
00:06:37
much less as as many of you or in
00:06:40
pharmaceutical industry would know that
00:06:42
our most of randy lemon is don't really
00:06:44
work in in in in several of these
00:06:46
chronic diseases in terms of the
00:06:47
efficacy. So obviously there's a lot
00:06:49
more going on what what we are
00:06:51
interested in is to understand how this
00:06:53
chronic inflammation is is happening in
00:06:56
in in in ageing and in other diseases
00:06:59
where there is no word infections and
00:07:01
obviously this involves interplay of
00:07:03
these several of these things
00:07:04
potentially that is metabolic this
00:07:06
balance where their emergence of what
00:07:08
was holding signals that was more going
00:07:10
by only massacre and these include like
00:07:13
a box bodies cholesterol eureka said
00:07:15
look my participation byproduct of
00:07:18
course these things can emerge from
00:07:19
mitochondria dysfunction these things
00:07:21
can also we more some altered product
00:07:23
microbiology just gotta be from your
00:07:25
from your body that can impact your
00:07:27
brain and of course the line infections
00:07:29
there are latent infections and the
00:07:30
billboard latent infections can in fact
00:07:32
also need to to information. And then
00:07:35
you know in this this the people
00:07:37
discuss inflammation of course
00:07:39
information imaging is actually very
00:07:41
different than the classical signs of
00:07:42
information on most of your already
00:07:44
available you don't see this type of
00:07:46
classical invited to the spot does that
00:07:47
happen in in a in a more well response
00:07:50
to infection. So what's actually going
00:07:53
on this is a very simple schematic
00:07:54
which is based on really Charlie Jane
00:07:56
ways a hypothesis that really was
00:07:58
developed that was one method of in our
00:08:00
department which is that you have to
00:08:02
have if you have to go to have
00:08:03
information you gotta have these two or
00:08:05
danger signals are dance dammit just so
00:08:07
should molecular patterns so these are
00:08:09
normally in case of immune system. you
00:08:12
might draw we can also be general
00:08:14
factors there are factors terrible
00:08:16
means that the non material orange And
00:08:18
these are things like unit crystals
00:08:20
which we know the costs caused out a
00:08:22
report about family there also
00:08:24
mitochondria damage that can be used
00:08:27
because the in and you want send and
00:08:29
they're like a toxic fatty acids
00:08:30
wendy's danger signals the present of
00:08:32
course they have to be sense by
00:08:33
something and union systems job is the
00:08:36
first job is just since these no damage
00:08:39
signals and try to repented enticement
00:08:41
in terms of injustices. And this
00:08:43
pattern recognition receptors you guys
00:08:46
know a whole lot about like receptors
00:08:48
and the red light receptors but I'm
00:08:50
gonna tell you a little bit more about
00:08:51
not like receptors or than five zones
00:08:53
in the course of time. And of course
00:08:56
their senses like antigen circus TC R.s
00:08:58
and VC R.'s for adaptive immunity would
00:08:59
not discuss that day these sensors
00:09:02
sense these damage or danger signals
00:09:05
well then you get the release of these
00:09:06
effect was and is mainly come from a
00:09:08
majority of them from the for lenient
00:09:10
cells and I'll tell you a little more
00:09:12
about the regulation of these two major
00:09:13
effect the second. it you know I want
00:09:16
be. So it's it is going to be lots on
00:09:19
and and I must say that I'm a huge fan
00:09:21
of your chocolate your job. And who
00:09:23
seminal work really let the discovery
00:09:26
of this complex and it was a huge loss
00:09:28
to the feel of his untimely passing
00:09:30
away what your shop was really the guy
00:09:32
who establish the LRP three and several
00:09:35
of these and a lot of Amazon every So
00:09:37
this is basically a schematic from one
00:09:39
of your review so here it basically
00:09:44
shows. So that I don't also these not
00:09:46
like receptors these sensors a very big
00:09:47
family. And it took a while for these
00:09:50
and large to come to be recognised
00:09:52
"'cause" they're actually absent in in
00:09:54
in in C elegance and sounds a lot. So
00:09:56
which means most of you actually have
00:09:58
it I think most of so but but that is
00:10:03
sort of talk to you mainly about the
00:10:04
analogue three because that's one of
00:10:06
you know a whole lot about okay. So so
00:10:10
based on work from your job in fact my
00:10:13
cousin wish products that look and feel
00:10:16
and several giants in the field you
00:10:18
know a whole lot about the activation
00:10:19
of this complex which is that this
00:10:21
complex is composed of finality
00:10:23
proteins and I'm not video one out
00:10:25
three it has an adaptor on is yes the
00:10:28
and of course the broadcast news ones I
00:10:29
mentioned to the way this routine
00:10:31
functions is that it needs to it's it's
00:10:33
type of the molecular velcro and it
00:10:35
samples by this up I didn't buy an
00:10:37
interaction with the ask probing and
00:10:39
this ask coding has a cast is
00:10:40
activation recruitment domain which
00:10:42
allows thing right but this broadcast
00:10:44
there's ones I imagine and once the
00:10:46
molecular velcro is a sample based on
00:10:48
the sense and that is done by this the
00:10:50
this uploading it causes the activation
00:10:53
of this inactive system produce
00:10:55
interactive system for oh that was one
00:10:58
on on this guest is one basically
00:11:00
control the post translational
00:11:01
processing of these two key molecules
00:11:03
on one data and I think you have you
00:11:05
heard a little bit about I would be the
00:11:07
probabilities talking one of these that
00:11:08
CD thirty not tolerable belies also
00:11:11
regulated in alzheimer's disease and
00:11:12
I'll tell you a little bit more about
00:11:13
it. So basically this in Flanders on is
00:11:16
actually very unique is very very
00:11:18
unique in the sense that you can sense
00:11:20
very broad type of these so called
00:11:23
bandage or danger signals which are
00:11:24
structurally not related. So for
00:11:26
example and always you request crystals
00:11:30
there are obviously very different from
00:11:32
fatty acids settlements and request one
00:11:34
which we've shown that will gonna was
00:11:36
on and and of course in I was on also
00:11:39
senses microbial there's an associate
00:11:40
molecular buttons that's the reason why
00:11:42
it is there and and the consequences
00:11:44
that that is activation of this gasp is
00:11:46
one there's a non canonical casters
00:11:48
haven't I don't have much time but most
00:11:50
mostly negative data that I don't have
00:11:52
time to show you but we can discuss
00:11:53
later if use questions and the point of
00:11:55
this light is that this activation of
00:11:57
this cast is one which can in fact have
00:11:59
multiple substrate controls that are
00:12:01
impacted that ourselves and also the
00:12:04
secretion of these two key from climate
00:12:05
aside. So what I'm talking about with
00:12:08
the blinders on activation. So these
00:12:10
are data from macrophages and it's a
00:12:13
readout of and by was on the division.
00:12:14
just the activation of this cast is one
00:12:16
problem Sistine pretty So I guess
00:12:19
there's one is get in a cell in smiling
00:12:22
itself so it is most almost all
00:12:24
macrophages and and microbial. So here
00:12:28
this is inactive gasp is when you
00:12:30
provide and this for the activation you
00:12:32
quite two signals in this case the poor
00:12:34
signal list you are for activation and
00:12:36
it does not cause the activation of the
00:12:38
implant is also this is the active okay
00:12:40
asp is one and then you provide the
00:12:42
second signal this is extra cellular TP
00:12:44
which comes from the dead cells what
00:12:46
you get the cleavage of this activation
00:12:48
and then more sodium you eight seven
00:12:50
like unique myself on date. well these
00:12:52
things in fact all these bands increase
00:12:54
with age and many of them increase do
00:12:56
several there's like a toxic fatty
00:12:57
acids increase with age in in the brain
00:12:59
itself and then you do not have an a
00:13:01
Petri this activation is basically not
00:13:04
there so it's a very specific but so so
00:13:07
we looked into this in in in in the
00:13:10
effort to understand what are the
00:13:11
mechanisms of age related information
00:13:13
and can we understand well I think
00:13:15
enough I was on this one of the
00:13:16
regulators and switching plan as long
00:13:17
as the major one so here. What you're
00:13:20
looking at Riley which is one of the
00:13:22
side because that require cleavage of
00:13:24
island beta it's easily measurable I
00:13:26
want belies not easily measurable in
00:13:28
this you know in in clean animals. So
00:13:30
here are levels about would be at every
00:13:32
age So the majority montel one type
00:13:34
animals it all back six and you can see
00:13:36
this yeah it is substantially age if
00:13:39
your remote and I think this is this is
00:13:41
reduced and if you remove the adaptor
00:13:43
idiocy this is pretty much nonexistent
00:13:46
so it means that probably other if
00:13:47
lattice homes that are involved in this
00:13:48
process. And then this non canonical
00:13:51
and Panasonic asked as eleven which
00:13:53
actually can sense LPS independently of
00:13:55
power like receptive for so it was a
00:13:57
lot of work but ms mainly negative data
00:13:59
that non canonical blinders on this
00:14:00
case is not required okay so these
00:14:02
animals are protected from each
00:14:04
selected information also having
00:14:05
improvement into goes on this data so
00:14:07
with ageing with inflammation these
00:14:09
animals become insulin resistance so as
00:14:11
to people and you could be the group
00:14:12
was excursion colours in the white that
00:14:15
animal and the enormity a code animals
00:14:17
they're about pretty much or normal
00:14:19
that so this is what's happening in the
00:14:21
benefit. And so and like I said I'm I'm
00:14:25
not and you're assigned is what we
00:14:27
would really challenged by my
00:14:28
colleagues in ageing fee and he said
00:14:30
that if there are it if you're
00:14:31
interested in information if
00:14:32
information is really that important
00:14:34
you have to look into the brain. So
00:14:36
after a lot of prodding resistance we
00:14:38
in fact did look into the brain and
00:14:39
this is the data from people campus. So
00:14:43
so this is broadcast is one in young
00:14:45
and old and or gonna or twenty not of
00:14:47
animals and this is the active ghastly
00:14:48
as you can clearly see that with ageing
00:14:51
there is an increase in the activity
00:14:52
should be in files on in the
00:14:54
hippocampus and in the absence of our
00:14:56
three this is substantially reduce this
00:14:58
is just the the the the qualifications
00:15:01
of cast as one and I below which is the
00:15:05
major side and that is regulated by the
00:15:07
involves some complex so so we looked
00:15:10
into this to the elliptical campus it
00:15:13
with the help of arguments where one of
00:15:15
my colleagues in a my former colleagues
00:15:17
in in Bennington whose studies the
00:15:19
brain and and you did be standing and
00:15:21
but you can look at is basically a
00:15:23
strictly this is because it was one of
00:15:24
the things that we were look at what
00:15:25
happened age so this is why I age
00:15:28
animals did you have a training and
00:15:31
here I a lot between a lot of these
00:15:33
animals have much more astral abuses
00:15:36
the data these are all normal animals
00:15:37
they're they're all back six something
00:15:39
that obviously do not develop a angles
00:15:42
and blacks like like the other all time
00:15:44
or also this is normal ageing which is
00:15:47
it we think is important in this
00:15:48
context. And I would not have the the
00:15:51
the basic premise of this is that the
00:15:54
absence of our media Nancy in the
00:15:56
hippocampus as well as cortex that is
00:15:58
right option in this keep rolling
00:16:00
planet we cited kind of age. So the
00:16:03
question is to okay how to actually
00:16:05
assess what's what's going on in in
00:16:07
these nice I mean people are a little
00:16:09
bit easier but we still have to work
00:16:12
with animal more for this early
00:16:13
discovery type of work and this right
00:16:15
is from one of my colleagues don Ingram
00:16:17
who in I developed this don't email and
00:16:19
always has has really pushed this idea
00:16:23
that if you have a study commissioned.
00:16:24
nice it you have to really look at the
00:16:26
right test because if you use it Morris
00:16:29
forum is for older animals majority of
00:16:31
the black six myself cataracts and
00:16:33
actually a blind. So so you're really
00:16:35
not measuring cognitive function you
00:16:37
just looking at blindness. So so So
00:16:40
what is done is used about this very
00:16:43
interesting amazed where myself
00:16:46
basically have to we just go box I'll
00:16:49
show you the video and there's just a
00:16:51
lot more so that because the mice just
00:16:53
need a little bit of post actually
00:16:54
waddled through it otherwise it will
00:16:56
not move. So to see how this works or
00:17:01
not the slightest that are quickly Al
00:17:02
also the law courts have substantially
00:17:04
improved cognitive function and you can
00:17:06
see the task is one type animals or
00:17:09
forming so this guy has to come out of
00:17:10
the way you have to find his to get the
00:17:12
ball box and here is I believe use them
00:17:16
out I would like would you find out. So
00:17:20
so these animals are so re errors and
00:17:22
you can quantify those errors this
00:17:23
guy's fast. So he's he's there and that
00:17:27
probably more like me an the I'm I'm
00:17:29
spatially probably challenge so yeah
00:17:31
but at the point of this this this this
00:17:34
is is is that and especially the storm
00:17:36
is you can actually counties errors and
00:17:38
and really quantify what's going on. So
00:17:41
here is the deal is is more than
00:17:42
blinded at what level but dining room
00:17:44
and board with Stella my colleague this
00:17:47
is from each month old animals and
00:17:48
these are from twenty formant animals.
00:17:50
So these lies as you can call the
00:17:51
errors these are different trials do
00:17:53
you give them trials and the the number
00:17:55
of errors they make so that not one
00:17:57
smart what you know the or white that
00:17:59
animals make more errors the littler
00:18:01
and slowly what we are between
00:18:03
knockouts they make much fewer errors
00:18:05
and learn faster in and in making use
00:18:07
are also suggested that improvements
00:18:09
and bug midi function. So when we
00:18:11
publish this data I just about the same
00:18:13
time from like a lots group and and
00:18:15
want that pollen again you mess and I
00:18:18
glasses now you're now in on that they
00:18:20
also should that that they cannot be
00:18:22
three is in fact activated in the
00:18:24
alzheimer's disease. And this is the
00:18:26
data from humans where they showed in
00:18:29
in people with alzheimer's the as you
00:18:32
can see in alzheimer's to disease
00:18:34
operations there is increasing gas as
00:18:36
one activation what we basically see
00:18:39
the campus of ageing animals and and
00:18:42
they they basically knocked out not be
00:18:44
three from this P be a PS model and and
00:18:48
showed that examples of improvement in
00:18:50
cognitive function. So indeed it seems
00:18:52
to be playing an important role as far
00:18:53
as a cognitive decline is concerned. So
00:18:56
since and when you assigned us I mean
00:18:57
really didn't know what to do they look
00:18:59
into each gene. So decided to the
00:19:02
transcript enrique analysis and and
00:19:04
which was pretty standing actually
00:19:05
would be found which is that I I that I
00:19:08
because you know I don't Petri imply as
00:19:10
long was mainly required was
00:19:11
translational processing you would not
00:19:14
really expect a huge changes in the
00:19:15
transcript number don't major changes
00:19:16
in transcript though because the of the
00:19:18
side effects that are secreted and so
00:19:21
here I typically not just don't do
00:19:22
these experiments because we like the
00:19:24
sort of itself this is whole
00:19:26
hippocampus and I think that's why are
00:19:27
these are kind of interesting because
00:19:29
you can capturing everything. you're
00:19:30
looking at is a down regulated with age
00:19:33
in in in green and red in in your up
00:19:37
regulated. And is resting probably down
00:19:39
regulated or regulated in both aged
00:19:42
analogue tape three And ask not also
00:19:44
remember ask is the the adaptor. And
00:19:48
they have been controversy in the field
00:19:50
regards to how critical is asked
00:19:52
because could have function outside of
00:19:54
the plan was all it's six important
00:19:56
kind of aside for that and it's pretty
00:19:58
clear to see that there are major
00:19:59
changes of core significantly
00:20:01
transcript don't and what's also
00:20:02
studies that will analogue media Nancy
00:20:04
regulate majority of these these these
00:20:06
targets. And and look into it a little
00:20:09
bit more detail so here in doing gene
00:20:12
expression comparing young horses or so
00:20:14
four hundred eighty six go off and try
00:20:16
to go down and then so this is a
00:20:19
compelling I want animals within or
00:20:21
between this right. And then comparing.
00:20:24
Why I do those with the ask not or in
00:20:27
brownish anyway the point of this late
00:20:30
is that the genes in this case in
00:20:32
ageing hippocampus hundred seventy six
00:20:34
of them there is probably a regulated
00:20:36
but all in all each other types okay so
00:20:40
you and you can see only few genes
00:20:41
actually really only three that are not
00:20:44
regulated but another BTNNTSC so both
00:20:47
of these strains our and Arcadia so
00:20:51
that the adaptor is see regulate the
00:20:54
the the transcript on in the
00:20:56
hippocampus and most of these changes
00:20:58
are all related to the planet re backed
00:21:00
away and it was it was very nice to
00:21:02
hear what everybody dances that that
00:21:04
information is the key which in fact
00:21:06
too. So it's nice to know that and and
00:21:10
we are coming in the field as agnostics
00:21:12
in I'm not a hippocampus and you or
00:21:16
degenerative export from any angle. So
00:21:19
so one of the things that we were very
00:21:21
excited to find in this was which is
00:21:22
very interesting was activation of the
00:21:24
complement pathway. So complement is
00:21:26
you know is is one of those plastic
00:21:27
innate immune regulators which is
00:21:31
critical for for innate immunity
00:21:32
defence against pathogens and and it
00:21:35
was quite stunning to find high amount
00:21:37
of complement in the brain and this is
00:21:40
is is the quite high up regulated with
00:21:42
each. And indian or if you not covered
00:21:44
almost all of these these compliment
00:21:46
division but without are down regulated
00:21:48
in the knockouts and of course there's
00:21:50
no effect with be cast is eleven. So
00:21:54
all summarise those we all the data as
00:21:57
to as to what we think is going on what
00:21:59
is at least ageing. And inflammation is
00:22:02
concerned and what is the role of this
00:22:04
particular innate immune sensor which
00:22:06
is in fact act activated all over the
00:22:08
body to what wherever there is a mile
00:22:10
in itself be durable and Austria
00:22:12
plastic be the idea was the show
00:22:14
macrophages or are you a Mike to be a
00:22:17
so happens is that with ageing what we
00:22:19
get is this energy and this increase in
00:22:22
several of this sort danger signals.
00:22:24
And marketing plans in this case is
00:22:26
very relevant because this is the only
00:22:29
one of them which can sense in fact
00:22:30
right that's why we're finding is
00:22:32
remarkable effect in these animals. And
00:22:35
so the way go with the canonical
00:22:37
battery basically what happens in this
00:22:39
case is that this involves on is
00:22:42
activated by these these different
00:22:44
danger signals and then you get these
00:22:46
in complex to be assembled and the I
00:22:49
guess there's one then please I won't
00:22:50
be a and I'll eighteen and this all
00:22:53
this list what is so all of them ageing
00:22:55
point at can't quite a lot of fun just
00:22:57
you what the point of this is that this
00:22:59
inflammation in that in these animals
00:23:02
if we apply these that way that it it's
00:23:05
it actually protects against not only
00:23:07
these all these different things but
00:23:08
alas added postage inflammation in fact
00:23:10
I'm a conclusion nobody here perhaps
00:23:12
get recorded except maybe double but
00:23:14
this is actually very remarkable people
00:23:16
type in these animals but maybe that
00:23:18
probably you guys are concerned with is
00:23:20
that they're protected from CNS
00:23:21
information at it and they actually is
00:23:23
really in the microbial. And we only
00:23:25
some of these effects on one below
00:23:27
dependent so which is also important
00:23:29
because there are audible antibodies in
00:23:31
the against I want data and not all the
00:23:34
effects here are actually mediated by I
00:23:36
want be okay. So this is this is the
00:23:39
question. I just quickly summarise the
00:23:42
would basically you finding is that
00:23:44
everything I was on it. this is
00:23:46
important in ageing and hippocampus by
00:23:48
regular actually assist. And it is one
00:23:51
P regulators of innate immune
00:23:52
activation the brain and so that that
00:23:56
if you use our continue I was on you
00:23:58
can prevent insulated increasing
00:24:00
compliment also in different that every
00:24:02
show you all the beautiful and
00:24:04
therefore we think that Lauren this
00:24:05
alright if I was an activation is
00:24:07
perhaps a good what are the strategies
00:24:09
that should be pursued. So that really
00:24:12
brings the question as to what is what
00:24:15
are the endogenous regulators of of the
00:24:17
of this if I was on and this was partly
00:24:20
question by one of the colleagues here
00:24:24
that what's happening in people that
00:24:26
have backs. And even though it data
00:24:29
causes all these things with innate
00:24:32
immune activation in those people the
00:24:33
protected is no inflammation. So there
00:24:35
must be something going on within
00:24:37
blinders on is deactivated despite the
00:24:39
presence of those dams and that is one
00:24:41
used a sense and that are those
00:24:43
metabolic input so we're very
00:24:44
interested in a in in identifying don't
00:24:47
identifying what those are so that we
00:24:49
can me to this this thing that had
00:24:51
interested in since my postdoc kind of
00:24:53
the NIH which is that the starvation
00:24:55
response okay so several of that you
00:24:57
guys would study nutrition would
00:24:59
immediately recognise this is because
00:25:01
if you're a negative energy balance and
00:25:02
you can restricted of course you you
00:25:04
know you actually get like extension
00:25:07
and maintenance of injustices. And what
00:25:09
we are interested in we also know that
00:25:12
you know this leads to a reduction
00:25:13
inflammation in in in in in several
00:25:16
models and would be trying to
00:25:18
understand is then you elicit this
00:25:20
adaptive starvation the sponsors not
00:25:21
just less calories at that point of
00:25:23
time was testament in home mistresses.
00:25:26
And and we're interested in what are
00:25:28
those factors androgynous factors that
00:25:30
are elicited by this intervention that
00:25:32
we can harness so there are experiments
00:25:34
one can do to understand the basic
00:25:37
biology of ageing by looking into this
00:25:38
type of intervention and finding out
00:25:40
potential new targets that we could use
00:25:43
to to restrain things that cost and on
00:25:45
that cost information. So so this was I
00:25:50
I don't have a lot of time to go into
00:25:51
this but this is a study that was
00:25:52
ongoing for last ten years course
00:25:54
calorie comprehensive so long acronym
00:25:57
basically study that was funded by the
00:25:59
national institute on ageing on multi
00:26:00
centre trial look at the effects of
00:26:02
calorie restriction people was we a
00:26:04
trial where people are probably
00:26:06
restricted for what was supposed to be
00:26:07
twenty five percent the automatic only
00:26:09
about fourteen percent. And and the
00:26:11
reason why I'm showing you this device
00:26:13
that it actually standing and this is
00:26:14
all unreported it should be will be
00:26:16
publishing this next year and hopefully
00:26:20
we use these days you never know but it
00:26:22
takes how long it takes to the
00:26:23
published but what what basically what
00:26:26
we looking at here is that in people
00:26:28
they actually able to get added
00:26:29
acquisition biopsies of these people
00:26:31
and you're looking at people are
00:26:33
baseline year one and year too bizarre
00:26:35
participants in these initially we did
00:26:37
the army sequence things. And you can
00:26:39
see that restriction this case has and
00:26:41
massive response at in the articles to
00:26:44
shoot. And and majority of this
00:26:46
response in the periphery is is all
00:26:48
related to slightly regulators majority
00:26:50
of them of course metabolism. And one
00:26:52
of the things that that's not this from
00:26:54
that that the thing was this elevation
00:26:56
in that you don't metabolism that was
00:26:58
identified from these from these
00:27:00
studies that just lost the question
00:27:03
what are the endogenous what are these
00:27:06
endogenous and metabolites or
00:27:08
regulators that elicited by this
00:27:10
intervention that could potentially
00:27:12
harness that that cross talks that the
00:27:14
the crosstalk between metabolism
00:27:15
immunity what can we learn from sold in
00:27:19
the us interactive starvation responses
00:27:21
not just less all of these you do this
00:27:23
you one of the things that happens is
00:27:24
you getting increasing the chip only
00:27:26
one or many of you guys already know
00:27:28
this that that that's your twenty one
00:27:30
so if you all would express it enhances
00:27:32
like spend in in mice a close to forty
00:27:34
five percent so it's a problem yeah but
00:27:36
you don't know and the way on the
00:27:39
things that it does is that the you
00:27:40
black agendas of the depleted in this
00:27:42
condition you have to utilise all the
00:27:44
facts that you have accumulated. And is
00:27:46
leading to increased the utilisation
00:27:48
and and you don't want production. And
00:27:51
as you guys know better than I do them
00:27:53
and of these larger that yes is not
00:27:54
possible in battery. So during adaptive
00:27:57
starvation responsibly pollution has
00:27:59
design that is basically you don't that
00:28:01
are the ones that are running the brain
00:28:02
right. So we're interested in this
00:28:04
question that macrophages which I
00:28:06
actually electrolytic cells and very
00:28:08
word like what happened how these cells
00:28:10
actually adapt in the situation if you
00:28:12
search the subject B cells are still
00:28:14
there when we can restricted what
00:28:16
happens if these macrophages instead of
00:28:18
logos happen out deal with details
00:28:20
right because we what we know now that
00:28:22
if you actually block black offices at
00:28:25
least in these cells that you know you
00:28:27
can switch the T at seventeen to direct
00:28:29
lineage so this is something that is
00:28:30
pretty pollution in immunology and the
00:28:33
question here is what what happened
00:28:34
what you can learn from this and
00:28:36
whether this has any that on about on
00:28:39
reducing inflammation and because we
00:28:41
think that these are kind of things
00:28:42
that could potentially be important. So
00:28:45
I I don't think you guys need to know
00:28:46
this everybody here knows this these
00:28:48
are these are data in fact is the yield
00:28:50
L George you how was the guy really
00:28:53
discovered that it on the really
00:28:54
important for brain along the
00:28:56
transcripts of course and and the point
00:28:58
is that retired possibilities made and
00:29:00
levers alternative energy source advise
00:29:03
the PCA goes into you see it was like a
00:29:06
SUS will collect and the keeping of
00:29:10
this of this of the slide is is is is
00:29:13
this hypothesis that it it actually for
00:29:16
and there's a supra fuel so when you
00:29:17
don't have a a sufficient amount of
00:29:19
glucose. And there are several reasons
00:29:21
for and and then all listed here I
00:29:23
don't have time to go into all of this
00:29:25
one one of the key things here is that
00:29:27
in fact that you know there for the for
00:29:30
the beach be to to produce these
00:29:32
countries actually applies only little
00:29:34
dramatic steps. So reduces the energy
00:29:36
couple so you get much less roles sorta
00:29:38
supposedly a much better fuel and as
00:29:40
opposed to have you know supposedly
00:29:42
better effect so what we did was to
00:29:44
understand how it potentially
00:29:46
regulating flight assault. And and here
00:29:49
is the structure of it I dropped pureed
00:29:51
it is best the bill rate which is
00:29:52
charging fatty acid which is made by
00:29:54
the micro by order. So if you starting
00:29:56
one a fasting about the the you can see
00:29:58
the levels around this if you're
00:29:59
starving it can reach up and many more
00:30:01
and and of course and I did to you
00:30:04
dress of those that's a huge problem.
00:30:06
So here is in in buttons on activation
00:30:08
acid. And what you're looking at again
00:30:10
is the cleavage of task as one in this
00:30:12
once we have the SA And EGP and when
00:30:16
you provide another drastic
00:30:17
possibilities after pages in this
00:30:19
condition what you get in the door I
00:30:20
don't inhibition of in files on such by
00:30:23
about five million molar concentration
00:30:25
you actually probably a plate you know
00:30:26
a eating masonic division. So this is
00:30:28
just this one and this is the active I
00:30:30
wanna be recipes seventeen subunit of I
00:30:32
would be like the one that actually
00:30:33
does on the all the stuff and the one
00:30:36
point nine marching the data is that
00:30:38
you read in fact has no effect on the
00:30:40
road between files. So what was also
00:30:43
quite interesting was that that we had
00:30:46
rocks impurities blocking blinders on
00:30:48
the spouse actually typed words that
00:30:49
legislation little about it was very
00:30:51
surprising. And made our task actually
00:30:53
much harder than men we've so here is
00:30:55
again the same gasp as one active
00:30:56
should analysis here you're looking at
00:30:58
on the data activation is upon the it
00:31:00
causing the activation of you know
00:31:01
between classes all it's reduced by the
00:31:03
HBO this is probably more relevant to
00:31:06
the to those of you who are interested
00:31:08
in in your crystals and out which was
00:31:10
actually discovered here by by your job
00:31:13
and you can see that in even in the in
00:31:14
the we're still in use in front of of
00:31:16
activation present the bitch produces
00:31:17
this and so does a bit with the
00:31:19
sediment. So I'll get to the mechanism
00:31:23
but the key point here is is that you
00:31:25
know there's a lot of talk about this
00:31:27
this could potentially worked so this
00:31:28
GPR one of the GPC R.s and so we tested
00:31:33
this and the answer is actually no it
00:31:35
so beauty does not require GPR one
00:31:38
aligning to elicit it's effects on you
00:31:40
know and or it imply wasn't. So do the
00:31:42
GPR one nine in a court cells and these
00:31:44
are the white blood cells and and this
00:31:46
is you to be blocking inclines wood
00:31:49
blocks and in both the situations here
00:31:51
it has no effect. And of course between
00:31:53
comes in a concern financial more so it
00:31:55
also comes in this biologically
00:31:57
inactive you will form so we just have
00:32:00
a experiment as a sort of a controlled
00:32:02
experiment it shouldn't work right. And
00:32:04
that's all it works fantastically
00:32:05
actually and which is great anyway
00:32:08
because this this elephant has a longer
00:32:10
half like it doesn't going to DCA it
00:32:12
still by GPR one O nine a what the but
00:32:15
the data is pretty clear it is it
00:32:17
doesn't it does is very effective. So
00:32:20
what's going on what's the mechanism
00:32:22
because about five years we're gonna
00:32:24
slow people and and the announcers
00:32:27
mostly negative so it listed about the
00:32:30
starvation response you get all these
00:32:33
these phenomena well all these isn't
00:32:35
activity all all this like bass
00:32:36
reduction one contrast is activation of
00:32:38
implicated deductions that causes a
00:32:40
offered you a possible like each one of
00:32:43
them actually controls inflows of
00:32:44
activation beach be continues all of
00:32:47
that and then able to be but ahead a
00:32:49
few period is also class at last one
00:32:51
edge that inhibitor. So it can affect
00:32:53
transcription to that mechanisms it can
00:32:56
like you to peer one nine a and of
00:32:58
course my favourite was that it goes
00:33:00
into DC yeah generates this it'd be
00:33:02
really metabolites would can all this
00:33:04
post start specially modified several
00:33:05
proteins and hence little I was all on
00:33:09
it turns out is actually very simple
00:33:12
not these pathways are involved and the
00:33:14
way it really works as to its by
00:33:16
physical effects. So here is the data
00:33:18
shows. So so like I mentioned the RP
00:33:21
indian clothes on for it to be a sample
00:33:23
it requires the legalisation or the
00:33:25
privatisation of this adaptor or that's
00:33:28
ask okay this is absolutely critical
00:33:29
for this project putting sample. And
00:33:32
you can study that informs the spec and
00:33:33
you can study then yeah by actually
00:33:36
looking biochemical into legalisation
00:33:37
of this adaptor and this was the data
00:33:40
that was that in collaboration with
00:33:42
them all you mother maybe so many and
00:33:44
in Philadelphia and what his lab here
00:33:46
to recycle this compound and he did and
00:33:49
what you basically shows is that then
00:33:51
you probably have lots of you. right in
00:33:53
the macrophages they're really blessed
00:33:55
like the activation is basically you
00:33:57
don't get a organisation of this
00:33:59
adaptor. So what would be lost I mean
00:34:02
we we got these one So these are
00:34:11
macrophages and design and beans solid
00:34:12
yeah see in the cell pellet a basically
00:34:14
what happens is that it gets it gets
00:34:16
like a motorised and and you can study
00:34:19
the legalisation by the time are and
00:34:21
the more more formation is like a
00:34:22
standard the classical legalisation as
00:34:25
it it's not the best way to look at the
00:34:27
finalisation for finalisation yeah look
00:34:28
into this you know it and you might
00:34:30
just with the my cost of it actually
00:34:32
wanted that but by chemically this is
00:34:34
basically how it is done. And projected
00:34:37
a little bit more detail. So in fact
00:34:39
there are diseases like you know
00:34:41
several diseases called the guy by a
00:34:44
lot of these and there and used by
00:34:46
again function mutation of analogue
00:34:48
three and this is not by how often and
00:34:50
so basically in these in these lies and
00:34:52
in these cells you can get yeah
00:34:54
division of you know and or between in
00:34:55
files on without any presents a penny
00:34:58
damn circus considerably active. So
00:35:00
here is basically the data show that
00:35:02
many complete with hydroxide a banana
00:35:05
like the jails what it does is block
00:35:07
legalisation or there's yes see a
00:35:09
doctor. And then these guys or that I'd
00:35:12
I'd which contains wanted you didn't
00:35:14
buy all people Masters because my store
00:35:16
really become very cute agenda guys as
00:35:18
you guys all know so you you require at
00:35:20
least you don't has retired and then
00:35:22
you provide this you don't extradite
00:35:23
fee is you don't ask buy these animals
00:35:25
these animals which is actually suffer
00:35:27
from a very nasty point slightly these
00:35:30
and right now these kids are basically
00:35:32
treated by I want inhibitors and a one
00:35:34
one upon anybody but a huge and died in
00:35:36
at least in animals is very effective.
00:35:40
So close it actually working so this is
00:35:41
of course very simplistic. But that's
00:35:44
what we think is going on in this case
00:35:46
that of course energy metabolism any
00:35:47
need maybe is like and during the state
00:35:51
of negative energy balance or perhaps a
00:35:52
little card that's what you get is
00:35:54
fairly acid oxidation and keep the
00:35:56
genesis and keep our system going to
00:35:58
this year and the host too so why
00:36:00
that's the main function at that point
00:36:01
of time is to have these energy after
00:36:03
the break but we still have an immune
00:36:05
system to handle and what we actually
00:36:08
does is it actually happens the meeting
00:36:10
system and it down wasn't definitely
00:36:12
needed needed E immune system by
00:36:15
specifically acting on the in a
00:36:16
marketing plan as all it does not block
00:36:18
the other one was on for reasons
00:36:20
actually still do not understand
00:36:21
gleefully but it and it does so in
00:36:23
response to actually very divers and
00:36:25
all the active ages and the way he does
00:36:28
or is it fox TV flux of compassion from
00:36:31
the back of his use of this was
00:36:32
discovered but their balloon as
00:36:33
continuous your Michigan but this is a
00:36:35
lucky signals and the stars all these
00:36:37
diapers danced across the activation.
00:36:39
And once that would actually busy flux
00:36:41
then you get the legalisation of this
00:36:43
complex and that's how it is working.
00:36:45
And in fact we need to be does not
00:36:46
require any of these these fancy you
00:36:49
know about ways in which are this
00:36:51
regulated eight so it does not require
00:36:53
completely wood yesterday maybe is not
00:36:55
out the mitochondria on coupling it
00:36:57
actually does not even that why
00:36:59
oxidation in the PC in the macrophages.
00:37:01
So that's basically how it works I'm
00:37:04
almost done. And so that's the point I
00:37:07
think it's quite quite interesting in
00:37:09
this case because we think that you
00:37:12
don't buttons are perhaps one of the
00:37:13
mediators of adaptive starvation
00:37:15
response and that it is signals to and
00:37:18
the signals the state of negative
00:37:19
energy balance related your system like
00:37:21
the activity and or between plan as
00:37:22
well and we also think that the HB just
00:37:26
like the regulatory cells in the body
00:37:27
this we think that the record pretty
00:37:29
without like an that it it blocks the
00:37:31
alacrity and lands on like this.
00:37:33
something we ask legalisation. And
00:37:35
actually does it to its by physically
00:37:36
factor which which we think is actually
00:37:38
quite promising in in potential And
00:37:42
that is the key to metabolite or
00:37:44
potential by its could potentially used
00:37:46
and this is something that you
00:37:48
interested in again several of the
00:37:51
enormity needed diseases so that we
00:37:53
need to be tested there is some data
00:37:55
from from from Richard region mark
00:37:57
Madsen that it could potentially be
00:37:59
slightly effective in alzheimer's I'll
00:38:01
start piranha college all my colleagues
00:38:03
that were responsible for for helping
00:38:06
me out that this work my colleague but
00:38:08
on recordings in Barrington country
00:38:10
work was done in collaboration data
00:38:12
grabbers that at at bennington. And a
00:38:16
majority of the data that I showed you
00:38:18
have been produced by right grant my
00:38:21
former we'll start and you neon was the
00:38:23
junior faculty at appealing and the

Share this talk: 


Conference Program

Introduction to the 12th Nestlé International Nutrition Symposium
Thomas Beck, NRC Director
22 Oct. 2015 · 8:57 a.m.
416 views
Introduction to Session I - Cognitive & Brain Development
Susan Gasser, Friedrich Miescher Institute, Basel, Switzerland
22 Oct. 2015 · 9:04 a.m.
The development of a healthy brain
Michael Gazzaniga, University of California, Santa Barbara, USA
22 Oct. 2015 · 9:16 a.m.
219 views
Q&A - The development of a healthy brain
Michael Gazzaniga, University of California, Santa Barbara, USA
22 Oct. 2015 · 9:56 a.m.
Early influences on brain development and epigenetics
Stephen G. Matthews, University of Toronto, Canada
22 Oct. 2015 · 10:49 a.m.
Q&A - Early influences on brain development and epigenetics
Stephen G. Matthews, University of Toronto, Canada
22 Oct. 2015 · 11:29 a.m.
Building the physiology of thought
Rebecca Saxe, Massachusetts Institute of Technology, Cambridge, USA
22 Oct. 2015 · 11:38 a.m.
152 views
Q&A - Building the physiology of thought
Rebecca Saxe, Massachusetts Institute of Technology, Cambridge, USA
22 Oct. 2015 · 12:10 p.m.
Introduction to Session II - Cognitive Decline
Kathinka Evers
22 Oct. 2015 · 2:02 p.m.
Brain health & brain diseases - future perspectives
Richard Frackowiak, CHUV University Hospital, Lausanne, Switzerland
22 Oct. 2015 · 2:11 p.m.
Alzheimer's disease: genome-wide clues for novel therapies
Rudolph E. Tanzi, Massachusetts General Hospital, Charlestown, USA
22 Oct. 2015 · 3:15 p.m.
Q&A - Alzheimer's disease: genome-wide clues for novel therapies
Rudolph E. Tanzi, Massachusetts General Hospital, Charlestown, USA
22 Oct. 2015 · 3:59 p.m.
Immunometabolic regulators of age-related inflammation
Vishwa D. Dixit, Yale School of Medicine, New Haven, USA
22 Oct. 2015 · 4:21 p.m.
Q&A - Immunometabolic regulators of age-related inflammation
Vishwa D. Dixit, Yale School of Medicine, New Haven, USA
22 Oct. 2015 · 4:59 p.m.
Introduction to Session III - Nutrition & Cognitive Development
Pierre Magistretti, KAUST, Thuwal, Saudi Arabia and EPFL, Lausanne, Switzerland
23 Oct. 2015 · 9 a.m.
Energy metabolism in long-term memory formation and enhancement
Cristina M. Alberini, The Center for Neural Science, New York University, USA
23 Oct. 2015 · 9:16 a.m.
126 views
Q&A - Energy metabolism in long-term memory formation and enhancement
Cristina M. Alberini, The Center for Neural Science, New York University, USA
23 Oct. 2015 · 9:53 a.m.
Building the costly human brain: implications for the evolution of slow childhood growth and the origins of diabetes
Christopher Kuzawa, Northwestern University, Evanston, USA
23 Oct. 2015 · 10:29 a.m.
Q&A - Building the costly human brain: implications for the evolution of slow childhood growth and the origins of diabetes
Christopher Kuzawa, Northwestern University, Evanston, USA
23 Oct. 2015 · 10:57 a.m.
Nutrition, growth and the developing brain
Prof. Maureen Black, University of Maryland, School of Medicine, Baltimore, USA
23 Oct. 2015 · 11:09 a.m.
Q&A - Nutrition, growth and the developing brain
Prof. Maureen Black, University of Maryland, School of Medicine, Baltimore, USA
23 Oct. 2015 · 11:49 a.m.
Introduction to Session IV - Decline & Nutritional Intervention
Tamas Bartfai, The Scripps Research Institute, La Jolla, USA
23 Oct. 2015 · 12:48 p.m.
On multi-domain approaches for prevention trials
Miia Kivipelto, Karolinska Institutet, Stockholm, Sweden
23 Oct. 2015 · 1:04 p.m.
Q&A - On multi-domain approaches for prevention trials
Miia Kivipelto, MD, PhD, Karolinska Institutet
23 Oct. 2015 · 1:39 p.m.
Methodological challenges in Alzheimer clinical development
Lon S. Schneider, Keck School of Medicine of USC, Los Angeles, USA
23 Oct. 2015 · 1:49 p.m.
Q&A - Methodological challenges in Alzheimer clinical development
Lon S. Schneider, Keck School of Medicine of USC, Los Angeles, USA
23 Oct. 2015 · 2:32 p.m.
We are what we remember: memory and age related memory disorders
Eric R. Kandel, Columbia University, New York, USA
23 Oct. 2015 · 3:03 p.m.
137 views
Concluding Remarks
Stefan Catsicas, Chief Technology Officer, Nestlé SA
23 Oct. 2015 · 3:50 p.m.

Recommended talks

The future for food and health
Susan Jebb, University of Oxford, England
28 Oct. 2016 · 2:01 p.m.