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Immunometabolic regulators of age-related inflammation
Vishwa D. Dixit, Yale School of Medicine, New Haven, USA
Thursday, Oct. 22, 2015 · 4:21 p.m. · 38m 29s
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Because I thought that maybe you guys
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would think that this is this this too
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much in new in this and maybe nobody's
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gonna show up and and I must say that
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I'm neither a nutritionist and nor and
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you're a scientist and just like
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Rebecca sex was saying that she was
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surprised I'm also extremely surprising
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actually flattered that I'm here among
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all you people to talk about some of
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the work that you're doing and so
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obviously have to thank Johannes and
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and the organisers for inviting me here
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is my first time here. And it's it's
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wonderful. So I think the first talking
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the session I was actually really
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intimidated because we are very simple
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minded people and we do simple
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experiments and luckily doctor dancing
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is start kind of you know back me up a
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little bit that in fact eight system
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exactly I don't exactly you system is
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is is actually not too far away and we
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really need innate immunity in fact and
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that's the the the thing that you're
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gonna discuss and which brings back you
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know this question that my colleague
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too much or about that that that much
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other too much knows very well. And he
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always say is that yes nuance brain
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controls the body but in fact body is
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very critical in controlling brain too.
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So I think this would attach a little
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bit upon those those issues. So I I I
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will not belabour this point because I
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think this is pretty clear to all of
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you that there is indeed a silver
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salami coming global And one is that of
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course there are lots of us there are
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no living longer. And and there are
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more of us that are gonna be living
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longer and this is a worldwide
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phenomenon so by twenty fifty you can
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see the predictions right here in both
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developing as well as develop the
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develop can please and if there are any
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japanese females in the audience you
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can see that they yeah the best hordes
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of living longer. And and what is
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stunning and I found this is actually
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from the congressional budget office in
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US which was a any kind of you know
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negative kind of a statement that every
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year of life expectancy "'cause" you
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social security approximately fifty
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billion. I mean that's pretty sad right
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I mean that that you would think about
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this in a totally unit in economic
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perspective that's not the only reason
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we should get about ageing because
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that's that you're gonna be a burden on
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the society but in fact these questions
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are not new and and that's this really
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brings me to the innate immunity and I
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think those of you who are interested
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in immunology and and and philosophy of
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science would recognise this guy yeah
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actually cough so of course he was the
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guy who discovered by the sides and
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macrophages and and hearing not very
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far from your boss to institute. And he
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is got the Nobel prize but but I like
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others I mean he was really the founder
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of innate immunity so this guy found it
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in community and you know this rather
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controversial book at that point of
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time if if you guys I'm not retired
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irish the read it it's actually quite
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interesting. And and I was talking
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about the location of life. But many of
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you probably would not know that yeah
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actually cough also was one of the
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first guys or discovered appointed
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tangent ecology and he said that
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teaching is like any other signs which
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can be started by exact method and so
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in this book he talks about EG and
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promulgation of life and and in fact he
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was you could call and also the one of
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the first nutritionists was interested
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in immunology of course with some can
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controversial ideas that like the bass
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solos and we'll get and bulgarian
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younger extends like spiral then and
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those experiments of or soon were
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completely would be and that he was
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proposing. But maybe there was some
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very interesting statements he made
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which I in fact coming to now as you
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know in twenty fifteen that he bait so
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many years ago he got a lot of things
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right and one of the things he said was
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that defined the side or macrophages in
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fact are critical to the biology of
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ageing but these are the cells that are
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critical for this and of course you
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could say that or maybe just because I
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discovered it so it's like you know is
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too biased for it but in fact I'll show
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you some data that would suggest that
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this what William actually got
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predicted could be fact we do to and of
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course you made this this product that
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that the pictures against infectious
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disease would benefit you only to
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reveal by madison's helplessly can read
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this much better than my an accent
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right and and this is in fact also very
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controversial in those days because
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people don't want to be in this this
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this and this can actually happen and
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in fact he's he's absolutely right and
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as a as we can see others have already
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shown you that and getting are the
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biggest incidents and and the because
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Burton it is really the chronic
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diseases and in fact the same
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degenerative diseases that India
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predicted that we wanna live long and
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that's what we're gonna have and it's
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instructions that you've actually done
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much better but you can see that these
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are the because of that data from
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institute of metrics an evaluation and
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can see the majority of these these
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chronic diseases and also I was of
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course is is is the big one right. So
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this this kind of brings this this
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question in in the field of ageing and
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of course which is a rather interesting
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is that in fact if you look at one of
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these chronic diseases of course is an
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article scale it's just a schematic
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representation that many of these
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chronic diseases of course I decided
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not one of them in this case selected
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what a cancer heart disease diabetes
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I'll sign on this this is a really
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related okay. So what this means is
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that in fact it is in fact every
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because risk factor for chronic
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diseases. And the argument or the
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philosophical argument in the field by
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some has been that the other biomedical
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enterprise basically that those each of
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this disease individually. So we spend
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billions of dollars and heart disease
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and billions on cancer and all that and
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a and some people in the field would
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like to argue or would like to state
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there is this something intrinsic in
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the biology of age she that needs to
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this onset of many of these chronic
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diseases and if we I understand that is
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before forestry fact tackle all of them
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in one goal of course is a is a big
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task and we all know how or likes magic
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about your event so so we have to all
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be sceptical about these things but
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that's one of the questions in the fee.
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And and obviously on it's very simple
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to know here that almost every one of
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these chronic disease has an
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inflammatory component right. So all of
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you guys know this is basically what
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happens that you know with ageing this
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chronic inflammation. And and oh the
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association between this chronic
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inflammation several of these diseases
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and the functional decline in
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production and the health plan that we
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see and In fact the the the cost of
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data between here and here is actually
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much less as as many of you or in
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pharmaceutical industry would know that
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our most of randy lemon is don't really
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work in in in in several of these
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chronic diseases in terms of the
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efficacy. So obviously there's a lot
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more going on what what we are
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interested in is to understand how this
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chronic inflammation is is happening in
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in in in ageing and in other diseases
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where there is no word infections and
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obviously this involves interplay of
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these several of these things
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potentially that is metabolic this
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balance where their emergence of what
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was holding signals that was more going
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by only massacre and these include like
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a box bodies cholesterol eureka said
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look my participation byproduct of
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course these things can emerge from
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mitochondria dysfunction these things
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can also we more some altered product
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microbiology just gotta be from your
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from your body that can impact your
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brain and of course the line infections
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there are latent infections and the
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billboard latent infections can in fact
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also need to to information. And then
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you know in this this the people
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discuss inflammation of course
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information imaging is actually very
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different than the classical signs of
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information on most of your already
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available you don't see this type of
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classical invited to the spot does that
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happen in in a in a more well response
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to infection. So what's actually going
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on this is a very simple schematic
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which is based on really Charlie Jane
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ways a hypothesis that really was
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developed that was one method of in our
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department which is that you have to
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have if you have to go to have
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information you gotta have these two or
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danger signals are dance dammit just so
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should molecular patterns so these are
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normally in case of immune system. you
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might draw we can also be general
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factors there are factors terrible
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means that the non material orange And
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these are things like unit crystals
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which we know the costs caused out a
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report about family there also
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mitochondria damage that can be used
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because the in and you want send and
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they're like a toxic fatty acids
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wendy's danger signals the present of
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course they have to be sense by
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something and union systems job is the
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first job is just since these no damage
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signals and try to repented enticement
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in terms of injustices. And this
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pattern recognition receptors you guys
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know a whole lot about like receptors
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and the red light receptors but I'm
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gonna tell you a little bit more about
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not like receptors or than five zones
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in the course of time. And of course
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their senses like antigen circus TC R.s
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and VC R.'s for adaptive immunity would
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not discuss that day these sensors
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sense these damage or danger signals
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well then you get the release of these
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effect was and is mainly come from a
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majority of them from the for lenient
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cells and I'll tell you a little more
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about the regulation of these two major
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effect the second. it you know I want
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be. So it's it is going to be lots on
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and and I must say that I'm a huge fan
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of your chocolate your job. And who
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seminal work really let the discovery
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of this complex and it was a huge loss
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to the feel of his untimely passing
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away what your shop was really the guy
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who establish the LRP three and several
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of these and a lot of Amazon every So
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this is basically a schematic from one
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of your review so here it basically
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shows. So that I don't also these not
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like receptors these sensors a very big
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family. And it took a while for these
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and large to come to be recognised
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"'cause" they're actually absent in in
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in in C elegance and sounds a lot. So
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which means most of you actually have
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it I think most of so but but that is
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sort of talk to you mainly about the
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analogue three because that's one of
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you know a whole lot about okay. So so
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based on work from your job in fact my
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cousin wish products that look and feel
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and several giants in the field you
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know a whole lot about the activation
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of this complex which is that this
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complex is composed of finality
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proteins and I'm not video one out
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three it has an adaptor on is yes the
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and of course the broadcast news ones I
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mentioned to the way this routine
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functions is that it needs to it's it's
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type of the molecular velcro and it
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samples by this up I didn't buy an
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interaction with the ask probing and
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this ask coding has a cast is
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activation recruitment domain which
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allows thing right but this broadcast
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there's ones I imagine and once the
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molecular velcro is a sample based on
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the sense and that is done by this the
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this uploading it causes the activation
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of this inactive system produce
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interactive system for oh that was one
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on on this guest is one basically
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control the post translational
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processing of these two key molecules
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on one data and I think you have you
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heard a little bit about I would be the
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probabilities talking one of these that
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CD thirty not tolerable belies also
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regulated in alzheimer's disease and
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I'll tell you a little bit more about
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it. So basically this in Flanders on is
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actually very unique is very very
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unique in the sense that you can sense
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very broad type of these so called
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bandage or danger signals which are
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structurally not related. So for
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example and always you request crystals
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there are obviously very different from
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fatty acids settlements and request one
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which we've shown that will gonna was
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on and and of course in I was on also
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senses microbial there's an associate
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molecular buttons that's the reason why
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it is there and and the consequences
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that that is activation of this gasp is
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one there's a non canonical casters
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haven't I don't have much time but most
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mostly negative data that I don't have
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time to show you but we can discuss
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later if use questions and the point of
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this light is that this activation of
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this cast is one which can in fact have
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multiple substrate controls that are
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impacted that ourselves and also the
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secretion of these two key from climate
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aside. So what I'm talking about with
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the blinders on activation. So these
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are data from macrophages and it's a
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readout of and by was on the division.
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just the activation of this cast is one
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problem Sistine pretty So I guess
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there's one is get in a cell in smiling
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itself so it is most almost all
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macrophages and and microbial. So here
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this is inactive gasp is when you
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provide and this for the activation you
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quite two signals in this case the poor
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signal list you are for activation and
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it does not cause the activation of the
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implant is also this is the active okay
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asp is one and then you provide the
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second signal this is extra cellular TP
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which comes from the dead cells what
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you get the cleavage of this activation
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and then more sodium you eight seven
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like unique myself on date. well these
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things in fact all these bands increase
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with age and many of them increase do
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several there's like a toxic fatty
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acids increase with age in in the brain
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itself and then you do not have an a
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Petri this activation is basically not
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there so it's a very specific but so so
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we looked into this in in in in the
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effort to understand what are the
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mechanisms of age related information
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and can we understand well I think
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enough I was on this one of the
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regulators and switching plan as long
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as the major one so here. What you're
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looking at Riley which is one of the
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side because that require cleavage of
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island beta it's easily measurable I
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want belies not easily measurable in
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this you know in in clean animals. So
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here are levels about would be at every
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age So the majority montel one type
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animals it all back six and you can see
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this yeah it is substantially age if
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your remote and I think this is this is
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reduced and if you remove the adaptor
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idiocy this is pretty much nonexistent
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so it means that probably other if
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lattice homes that are involved in this
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process. And then this non canonical
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and Panasonic asked as eleven which
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actually can sense LPS independently of
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power like receptive for so it was a
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lot of work but ms mainly negative data
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that non canonical blinders on this
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case is not required okay so these
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animals are protected from each
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selected information also having
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improvement into goes on this data so
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with ageing with inflammation these
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animals become insulin resistance so as
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to people and you could be the group
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was excursion colours in the white that
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animal and the enormity a code animals
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they're about pretty much or normal
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that so this is what's happening in the
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benefit. And so and like I said I'm I'm
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not and you're assigned is what we
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would really challenged by my
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colleagues in ageing fee and he said
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that if there are it if you're
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interested in information if
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information is really that important
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you have to look into the brain. So
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after a lot of prodding resistance we
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in fact did look into the brain and
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this is the data from people campus. So
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so this is broadcast is one in young
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and old and or gonna or twenty not of
00:14:47
animals and this is the active ghastly
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as you can clearly see that with ageing
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there is an increase in the activity
00:14:52
should be in files on in the
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hippocampus and in the absence of our
00:14:56
three this is substantially reduce this
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is just the the the the qualifications
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of cast as one and I below which is the
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major side and that is regulated by the
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involves some complex so so we looked
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into this to the elliptical campus it
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with the help of arguments where one of
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my colleagues in a my former colleagues
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in in Bennington whose studies the
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brain and and you did be standing and
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but you can look at is basically a
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strictly this is because it was one of
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the things that we were look at what
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happened age so this is why I age
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animals did you have a training and
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here I a lot between a lot of these
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animals have much more astral abuses
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the data these are all normal animals
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they're they're all back six something
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that obviously do not develop a angles
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and blacks like like the other all time
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or also this is normal ageing which is
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it we think is important in this
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context. And I would not have the the
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the basic premise of this is that the
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absence of our media Nancy in the
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hippocampus as well as cortex that is
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right option in this keep rolling
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planet we cited kind of age. So the
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question is to okay how to actually
00:16:05
assess what's what's going on in in
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these nice I mean people are a little
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bit easier but we still have to work
00:16:12
with animal more for this early
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discovery type of work and this right
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is from one of my colleagues don Ingram
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who in I developed this don't email and
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always has has really pushed this idea
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that if you have a study commissioned.
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nice it you have to really look at the
00:16:26
right test because if you use it Morris
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forum is for older animals majority of
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the black six myself cataracts and
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actually a blind. So so you're really
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not measuring cognitive function you
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just looking at blindness. So so So
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what is done is used about this very
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interesting amazed where myself
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basically have to we just go box I'll
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show you the video and there's just a
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lot more so that because the mice just
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need a little bit of post actually
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waddled through it otherwise it will
00:16:56
not move. So to see how this works or
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not the slightest that are quickly Al
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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
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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
Conference Program
Introduction to the 12th Nestlé International Nutrition Symposium
Thomas Beck, NRC Director
Oct. 22, 2015 · 8:57 a.m.
790 views
Introduction to Session I - Cognitive & Brain Development
Susan Gasser, Friedrich Miescher Institute, Basel, Switzerland
Oct. 22, 2015 · 9:04 a.m.
161 views
The development of a healthy brain
Michael Gazzaniga, University of California, Santa Barbara, USA
Oct. 22, 2015 · 9:16 a.m.
398 views
Q&A - The development of a healthy brain
Michael Gazzaniga, University of California, Santa Barbara, USA
Oct. 22, 2015 · 9:56 a.m.
Early influences on brain development and epigenetics
Stephen G. Matthews, University of Toronto, Canada
Oct. 22, 2015 · 10:49 a.m.
154 views
Q&A - Early influences on brain development and epigenetics
Stephen G. Matthews, University of Toronto, Canada
Oct. 22, 2015 · 11:29 a.m.
Building the physiology of thought
Rebecca Saxe, Massachusetts Institute of Technology, Cambridge, USA
Oct. 22, 2015 · 11:38 a.m.
226 views
Q&A - Building the physiology of thought
Rebecca Saxe, Massachusetts Institute of Technology, Cambridge, USA
Oct. 22, 2015 · 12:10 p.m.
Introduction to Session II - Cognitive Decline
Kathinka Evers
Oct. 22, 2015 · 2:02 p.m.
Brain health & brain diseases - future perspectives
Richard Frackowiak, CHUV University Hospital, Lausanne, Switzerland
Oct. 22, 2015 · 2:11 p.m.
120 views
Alzheimer's disease: genome-wide clues for novel therapies
Rudolph E. Tanzi, Massachusetts General Hospital, Charlestown, USA
Oct. 22, 2015 · 3:15 p.m.
Q&A - Alzheimer's disease: genome-wide clues for novel therapies
Rudolph E. Tanzi, Massachusetts General Hospital, Charlestown, USA
Oct. 22, 2015 · 3:59 p.m.
Immunometabolic regulators of age-related inflammation
Vishwa D. Dixit, Yale School of Medicine, New Haven, USA
Oct. 22, 2015 · 4:21 p.m.
160 views
Q&A - Immunometabolic regulators of age-related inflammation
Vishwa D. Dixit, Yale School of Medicine, New Haven, USA
Oct. 22, 2015 · 4:59 p.m.
Introduction to Session III - Nutrition & Cognitive Development
Pierre Magistretti, KAUST, Thuwal, Saudi Arabia and EPFL, Lausanne, Switzerland
Oct. 23, 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
Oct. 23, 2015 · 9:16 a.m.
413 views
Q&A - Energy metabolism in long-term memory formation and enhancement
Cristina M. Alberini, The Center for Neural Science, New York University, USA
Oct. 23, 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
Oct. 23, 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
Oct. 23, 2015 · 10:57 a.m.
Nutrition, growth and the developing brain
Prof. Maureen Black, University of Maryland, School of Medicine, Baltimore, USA
Oct. 23, 2015 · 11:09 a.m.
152 views
Q&A - Nutrition, growth and the developing brain
Prof. Maureen Black, University of Maryland, School of Medicine, Baltimore, USA
Oct. 23, 2015 · 11:49 a.m.
Introduction to Session IV - Decline & Nutritional Intervention
Tamas Bartfai, The Scripps Research Institute, La Jolla, USA
Oct. 23, 2015 · 12:48 p.m.
179 views
On multi-domain approaches for prevention trials
Miia Kivipelto, Karolinska Institutet, Stockholm, Sweden
Oct. 23, 2015 · 1:04 p.m.
216 views
Q&A - On multi-domain approaches for prevention trials
Miia Kivipelto, MD, PhD, Karolinska Institutet
Oct. 23, 2015 · 1:39 p.m.
Methodological challenges in Alzheimer clinical development
Lon S. Schneider, Keck School of Medicine of USC, Los Angeles, USA
Oct. 23, 2015 · 1:49 p.m.
124 views
Q&A - Methodological challenges in Alzheimer clinical development
Lon S. Schneider, Keck School of Medicine of USC, Los Angeles, USA
Oct. 23, 2015 · 2:32 p.m.
We are what we remember: memory and age related memory disorders
Eric R. Kandel, Columbia University, New York, USA
Oct. 23, 2015 · 3:03 p.m.
229 views
Concluding Remarks
Stefan Catsicas, Chief Technology Officer, Nestlé SA
Oct. 23, 2015 · 3:50 p.m.
168 views
Recommended talks
Gut hormones and nutrition
Sir Stephen Bloom, Imperial College London, England
Sept. 28, 2017 · 1:38 p.m.
1088 views