Prof Denis Noble and Prof Robin Choudhury - Can We Harness Epigenetics To Keep ‘Inflammation’ In Check? Implications For Ageing Well: Otter Voice Meeting Notes

Prof Denis Noble and Prof Robin Choudhury - Can We Harness Epigenetics To Keep ‘Inflammation’ In Check? Implications For Ageing Well

Leslie Kenny33min

Dr. Paul Ch’en

00:00

Professor Dennis noble here is one of the co founders of Oxford longevity project. His achievements, accolades, the list goes on. He's told me not to mention any of them, but he is one of the pioneers in systems biology, and he's known through lot of disciplines. Professor Robin Choudhury, equally big giant in the cardiovascular world. He's an honorary consultant cardiologist, an interventionalist. He's also professor of Cardiovascular Medicine at the University of Oxford, and both of them will actually have a bit of a chat about heart health. I'm going to leave the floor to both of you.

Professor Robin Choudhury

00:32

Thanks, Paul. Very much.

Prof. Denis Noble

00:37

Over to you, Robin, tell us about what you're doing.This man is just brilliant. Please carry on.

Professor Robin Choudhury

00:45

Well, I'm flattered. It is actually a great honor to share a session with Denis Noble, who's been a mentor and an inspiration meet for well over 30 years now. So I'll leave it at that to save his blushes, but I'm really delighted the chance to share this session, to share this session, and what I want to do, really, is to introduce some of our current work, which I hope is relevant to the things that we're thinking about today, and which is an area which Denis and I speak About from time to time, and it's the emerging area of epigenetics. And I want to give you a taster about how our lifestyles and how our metabolic health imprint to determine some important aspects of our longevity and well being. And the other thing I'll say is that I'm showing you pretty current data, and we do not have all the answers, and that's part of the the excitement. Does anybody know what this is? It's a blueprint. Can anybody recognize what it's a blueprint of? I Okay, so for fun. So it was, it is a blueprint, and it's a blueprint of the Guggenheim Museum. But I put up the blueprint really, because it's very relevant when we're thinking about genes. So the blueprint was developed as a mode of faithful reproduction using light sensitive sheets, and it allows for infinite copies to be made very accurately. What it doesn't do is allow for gray scaling and for nuance. And so it is in that sense, a set instruction. Now sometimes we talk about the DNA as being the genetic code or the blueprint for life, and indeed, in some important sense, I think that's a very good analogy. The DNA is the blueprint, and it encodes for the building materials, the proteins that go on to make the fixtures in the buildings, which we can think of as the cells. And they, of course, are configured to make functional organs, but it misses an important an important nuance, and that is that the blueprints themselves are not enough, and you need to have some marks, if you like, highlighters or bookmarks in the DNA blueprint that allow each cell to express the genes to make their characteristic function. And it's these epigenetic marks and their role in disease that we're going to think about today. So you heard from Leslie earlier that the major cause of death internationally--it starts to decline, it goes up (particularly in developing countries with lifestyle corruption), increase in diabetes--but acute myocardial infarction happens when one of the arteries that supplies the heart muscle with blood becomes blocked, and the muscle beyond that blockage dies, and that causes both infirmity and sometimes death. And this is my day job to spot this and to treat it. Here's an angiogram of a patient having a heart attack. Here the artery is blocked, and here we put some equipment into the artery to open it up and restore blood flow. And this is the stuff that blocked the artery in the first place. So this is so-called thrombus. It's rich in platelets. It's rich in cholesterol. It's got a lot of blood clotting proteins in there. And the red is, of course, from the red blood cells, but it reflects the combination of the processes that we're trying to address. And if you look into the walls of the arteries that get blocked up, they contain a number of different things, but amongst the cholesterol and the debris, there is an important cell type called a macrophage. And it turns out that patients with diabetes have more of these macrophages than patients that don't. And I'll tell you that patients with diabetes, a particular metabolic disorder, have much worse risk of myocardial infarction, heart disease in general, than to patients without. Now there's a paradox--so whilst the high glucose of diabetes seems to drive myocardial infarction very aggressively. Treating the blood glucose does not, in any simple or consistent way, reduce the risk of myocardial infarction. So whilst it's vital to treat the glucose for a bunch of reasons, it doesn't reduce the risk of heart attack. And that was the starting point for the work that I'm going to show you now. We started to question whether there could be some translation of metabolic disease, persistently high blood glucose, into some form of cellular memory, so that even after the glucose was corrected, something had been laid down, something had been remembered, which was not amenable to correction. And in very brief, the way this is done is that the DNA blueprint has attached to it a bunch of little marks that we call histones, and they determine the openness or not of the DNA and the ability of that DNA to be read. Okay, so what you need to remember from this is simply that there are marks, histone marks on the DNA, that determine which bits get read. And, in turn, the laying down and the removal of those marks is susceptible to metabolic influences, and in this case, it's driven, we think, by glucose, and I'll show you why we think that. So to test this hypothesis as to whether or not diabetes was remembered by the cells, we took some mice and we made them diabetic. We took the bone marrow from those mice, and then we stimulated that bone marrow, either to make inflammatory cells or to make reparative cells, m1 or m2. We rested the bone marrow in normal glucose for 10 days, and then we looked at some markers that would tell us about the inflammation or reparative status. And what these graphs are showing us is that, compared to the control, normal mice, the diabetic mice remember two important things: Firstly, they're switched on in terms of inflammation, but equally importantly, they're switched off in terms of the reparative mechanisms. So the glucose programs, it would seem, the bone marrow, in a way, that's a double whammy. To see if this was an important aspect of the disease that we're interested in, we then took some bone marrow from diabetic mice, and we put it, transplanted it, into mice with high cholesterol that tend to get this atherosclerotic disease, and we compared it, of course, to mice who didn't have diabetes. We waited for three months after the transplant, so complete normalization of the glucose, and then we looked in the place that we look to see if there was this development of the cholesterol-rich atherosclerosis in the arteries. And the long and short of it is, is that when, if you take the diabetic marrow, you put it into an entirely normal glucose environment, you get much more atherosclerosis than transplanting in the normal cells. So that's been remembered for a period of months in mice, which of course, have a very short lifespan. And the green coloration here is showing that the cells in the atherosclerotic plaque are derived from the bone marrow because we labeled them before we put them in. So that's the that's the key message. And I'll just skate over some human relevance quite quickly so we have time for discussion. But in essence, there are two couple of important things. Firstly, that whilst this laid down in the bone marrow, this experiment has shown that the memory, and these things are the histone marks, the bookmarks, the memory is transferred through the progeny. So it starts in the bone marrow stem cells, but it gets transmitted to the next generation of cells.

Professor Robin Choudhury

09:56

Those cells get released into the blood. And so one of the important things that we've shown in humans is that we can identify a similar process in the circulating blood of human patients with with diabetes. So we're in the process of exploring the clinical relevance of this, but it seems to be a real thing in humans. And then, just to finish, I want to expand the thinking about this, because whilst we've worked in diabetes approaching that paradox that I showed you at the beginning, it turns out that there are other important metabolic features that can also drive similar or analogous processes, and one very important one from colleagues in Germany, ikelapses group, shows that diet, Western style diet, also lays down these epigenetic changes in the bone marrow that result in the sorts of inflammatory upset that I've shown you. And then work just come out in the last couple of months from our group has also shown that surprise, surprise, because the glucose is everywhere. When we look at cells in multiple different organs, the liver, the kidney, the spleen, the heart, there's evidence that the sugar levels are reprogramming cells in multiple organs, and that the convergence of that reprogramming is on cells that drive fibrosis. So we think that might be important to a number of diseases. So I'll wrap up there so there's good chance for discussion. But just to emphasize the key messages: that there is an interaction between metabolic processes, diet and immune function. It's hardwired into the bone marrow stem cells, and the influences are multiple. So diet, glucose, probably smoking, possibly stress, and it's probably cumulative over time, and it quite probably starts in early life. The news isn't all bad, if we understand the mechanisms. Of course, there's an opportunity to intervene in them. We can identify patients who are affected. We have the opportunity to intervene in public health programs, not just in sophisticated drugs that modify the epigenome. One slightly scary prospect that I think Denis might pick up is is the possibility that if these epigenetic changes are not just in our own body cells, but are also in the germline that are transmitted to the next generation, there is at least the possibility that the way we live is transmitted to our to our own children. We don't know that we're investigating it, but it is plausible. Great. Thank you for your attention.

Prof. Denis Noble

12:52

Good, Robin, just to sort of get a feel for the audience, some of whom are not scientists, so my role is to somehow provoke you into making things even clearer than you've already done. Now, sounds to me a little bit like saying, well, if DNA is the hardware, epigenetics is the software, and we can, in various ways, rewrite the software. Am I getting it right?

Professor Robin Choudhury

13:49

I tend to use an even more simple analogy, which is of the book and the library, and to think in terms of the DNA as being a printed volume and the epigenetics has been the highlighting or the bookmarks in the volume that bring forward the passages that we ought to, ought to read. And each book is reproduced, it's published. And so each cell has the same copy, the same basic text, but the highlighting, the bookmarks, can be changed and are changed by the user.

Prof. Denis Noble

14:25

So it's open to what we do in our lives, and that's going to be the process by which, if we have enough knowledge to know what will control those marks, what will control the RNAs that tell the DNA what to do. We do find ways in which we can improve how we are managing and how we're managing as we get older. Now I hope that that's probably just broken the ice. I'm looking around now to see who, what, somebody over there, and is there a microphone going around, or do we rely on people shouting? You stay at that microphone, Robin, and I'll stay here, and she'll take it around over to you. Yes?

Speaker 1

15:18

I was going to ask, to what degree does methylation come into the study? And if you can predict someone's methylation status and then fix any nutrient deficiencies and ideally, then reduce homocysteine, does that then improve the outcome for patients or mice?

Professor Robin Choudhury

15:39

Okay, so there are a variety of different bookmarks laid down on the genetic code. One of them is direct methylation of the DNA, which I didn't really address, and there is some evidence that that's altered in in diabetes. It is tempting, and we're tempted as well to think that there's a really simple intervention, dietary or otherwise, that will get traction on some of these processes and allow us to make a very straightforward intervention. And we're tempted in that direction as well. So we've been, for instance, looking at a metabolite called beta hydroxybutyrate, which was released in fasted states, to see whether or not that would induce some reprogramming. And we haven't yet, at least had success with that. So I don't know about homocysteine specifically, but I would just say two things. One is that the interactions with metabolites are very complex and cell- and situation specific, and that we need to look at them one at a time, but in the context of systems considerations,

Prof. Denis Noble

16:58

Yes, in the middle here, and then two more over there, but first, this one.

Speaker 2

17:07

Firstly, thank you for the talk. It was really interesting, if not a little bit harrowing at times, but you spoke about kind of hyperglycemia as a possible cause of this increased atherosclerosis. Did you find, or would you hypothesize, any other specific dietary states, and you mentioned about the Western diet, or any other dietary states that one should look to avoid, or anything you guys are thinking about researching next in that regard.

Professor Robin Choudhury

17:33

So in terms of driving atherosclerosis? Yeah, I mean, the risk factors are very well, if not completely, but they're very well established, so you don't smoke, manage blood pressure, keep the bad LDL cholesterol down, and keep on top of blood glucose. There will be other factors that we haven't yet properly worked through, and there will be nuances to those particular factors that we don't fully understand. So at the moment, we're very interested in so we talk about diabetes in my laboratory. We now call it nominal diabetes because the definitions are arbitrary, and we're much more interested in the patterns of glucose excursion over the course of the day using continuous glucose monitoring. So I think we'll continue to refine our understanding of all of these factors.

Speaker 3

18:34

Thanks, Robin. So do you believe that in in mom and dad, if there is a methylation imprinting that it can be transmitted to the offspring, transgenerational inheritance. What's your view?

Professor Robin Choudhury

18:51

Well, so thanks, John. I mean, I'm the answer is, I don't have the data, so it's not a question of whether I believe it or not in that sense, which you'll understand, but I certainly understand that it is possible. And there are some data, for instance, not so much from overfeeding states, but from famines, imposed famines, that there are intergenerational transmission of metabolic disturbance. So it seems to me plausible and sufficiently important that we really ought to know the answer to it. So we're working with a group at the Karolinska now in gestation patients with gestational diabetes to see if their offspring have differently laid down epigenetic marks. Part of the problem is not only until now, we've not recognized this phenomenon, but we have not we still don't fully have the toolset that will allow us to analyze it. So we're doing a system, a systematic, mass spec based screen of the whole epigenome to try and get into this.

Prof. Denis Noble

20:01

Just to add to what Robin has said there, for those who want to go into the real scientific detail, I've just published an article in the Journal of Physiology called, "Bubbling beyond the barrier." The barrier is the barrier between our bodies and what we're doing and the germ line. And there's masses of evidence there, if you want to go into the detail, but these are early days, as Robin has also indicated, we need to know more about all of this. Anyway. Next one, yes, just over there, behind, behind the ones just asked the question, yes.

Speaker 4

20:36

Did you consider what consider or did you transfer good quality bone marrow into the diabetic mice to see whether that had a positive effect?

Professor Robin Choudhury

20:54

We didn't. But if you'd like a job, we'd love to do that experiment. So we, we think that's a great idea. So, so just to expand on where you've gone with that, thinking, if the problem here is that you reprogram the bone marrow, and those that reprogramming gets stuck, what are you going to do about it? So there are a number of different levels at which you could intervene, but one would be to restore healthy bone marrow, and that's a really intriguing prospect, particularly, although I've shown you the data for this epigenetic reprogramming, there's quite a lot of information now emerging, for instance, on something called CHIP along the lines of unhealthy aging of bone marrow. And it's not science fiction to imagine that we could replenish our own bone marrow in old age with stem cells that were taken from our young bone marrow with appropriate foresight and evidence. So I think that's really intriguing.

Speaker 4

21:58

Hasn't that also been done separate area with stored replacement from obese people, and that's where I was asking,

Professor Robin Choudhury

22:10

Yeah, so that's a different a different type of memory, because that's to do, we believe, with repopulating the gut microbiota. And if you want to do that experiment, please don't come to my lab.

Prof. Denis Noble

22:24

Can you take the microphone over there? But just before we bring you in, I just want to relate a little bit of history of my own development, health wise. I was born just before the Second World War, four years before it started. The end of the Second World War. If you saw a photograph of me at the age of about seven or eight, you would see almost no muscles. We were starved during the war because there was rationing. Everybody had to just receive enough to survive, more or less. What did I do for the next 10 to 20 years? I cycled everywhere. I can now move around with no difficulty. What was happening? Physiologists have shown what was happening, the RNAs that cause our muscles or the genes that code for the proteins in our muscles, the RNAs that activate those are what you increase when you exercise. That was shown by just taking mice, some exercising, some not, and observing the difference between the relevant RNA levels that are controlling the muscle protein. It works right over to you.

Speaker 5

23:39

Hi! Thank you for giving us an insight into your brain. I think we've done a pretty poor job about explaining what type two diabetes is to our our patients, and we've described it as a blood glucose disorder, rather than an insulin problem, hyperinsulinemia. And I was wondering where insulin comes into your hypothesis, and whether that might be having a function on the histones acting differently.

Professor Robin Choudhury

24:07

That's a very good question, and it speaks to the complexity of these systems, although I didn't spell it out in these experiments, both the in vitro ones and the ones that I've shown you in experimental mice, we used a type one model, so we took insulin away and left only the effects of high glucose to study. So we think what I've shown you today is related to the glucose. As you rightly say, in real life, there's a whole lot more biological complexity, including insulin and insulin sensitivity, and we need to feed that into the into the model, to get a better understanding. But you're you're right. I think that the obsession with blood glucose and treating the blood glucose and understanding the blood glucose with ever more complexity is missing the point. And it's trying. It's taking an actual diagnosis from tasting sugar in the urine and then applying effectively, and then applying the full weight of contemporaries of biological understanding to look at this very simple problem. But the problem is so much more complex than that,

Prof. Denis Noble

25:16

Robin one just before I come to you, but to take the microphone to her so that she could be ready. Is that over there? Yes. But before you come in, I'd like to ask you to elaborate, Robin, on something. You and Ghada before you made it very clear that one of the processes during aging is that our immune systems become weaker. Can we do anything about that?

Professor Robin Choudhury

25:43

Yeah, so there's a catch all term of inflammation. So from from a scientific point of view, I think that is a really unhelpful term. And in our work, we now talk about processes of inflammation because they're very complex. They vary according to situation, site. Some processes of inflammation are actually beneficial because they're resolving to infection or to early phase inflammation. So, in answer to your question, Denis, I think we just have to understand the specific processes, indeed, yes. And then intervene on them and try and get over this idea that there is this thing called inflammation and it's bad, or it's good, or that we can measure it with any single, simple measure, like the high sensitivity CRP. They're not without value, but they really skim the surface only, yeah.

Prof. Denis Noble

26:42

And it's one of the functions of this organization, the Oxford longevity project, to try and follow the way the science is developing, and then to be able to explain some of that to you. You've got a question,

Speaker 6

26:56

Yes. So I'm another non scientist. I am at the user end, and I was just you were saying about gaining the memory and potentially going rogue. Do you know a timeline for that? And how we can know what the timeline is, perhaps for unlearning that memory and relearning again? Is that the capacity? Would we have that capacity, and how long will that take?

Professor Robin Choudhury

27:19

So we don't know the answer, but let me just couch it in terms of how we might approach it. So one would imagine, from an evolution, an evolutionary perspective, that you don't lay these marks down lightly, because your DNA is the blueprint. So if you're going to alter the way you read it, you probably want to build those marks in slowly and in response to a consistent exposure. So you're not going to change the way you read your DNA based on a single Mars bar. So, probably, the writing takes months and years. Equally, unwriting, and you can unwrite it physiologically, is also probably not done in the short term, because the whole point of putting the marks in the code was to say, there is benefit to me, to my cell, from operating in this way. So I'm going to use the epigenetic marks to make that shift. So I suspect it will be like turning a ship, and it will go on quick, slowly, and it will come off slowly. If we want to intervene quickly, then the place to go is downstream in the processes. Because of what I didn't go into today in great detail, was the consequences of these marks. But the consequences, if you like, the proteins that get made, we can deal with those in the very short term. So whilst we're still correcting in the background, we can intervene in the short in the short term, in the foreground.

Prof. Denis Noble

28:51

Microphone goes to guardrail. Soleil, over to you.

Speaker 7

28:55

I just have two comments, actually, but one of them from your last question about what we do for our immune system, right? So I agree that inflammation is very important, and this what we now called it, like aged in a way, like a slow degree of inflammation. I'm totally agree with you need to learn more about it, but we already know that these coming was likely from cellular senescence, because they this is the signal they sent it that we are accumulated. And we know that fasting, inducing autophagy, exercise and sleep control all of that already. So we could do something from now we need, of course, to do more, you know, study more biomarker to be active in a way, to be able to treat and work better with people. Because, unfortunately, not everyone like doing this the right things. Just Just to mention that we could do it now, we could improve it in a way if we. Control, and it's easy, just like, if we have the determination and the knowledge, we can do that. I have the other comment from the question from Dr Todd about and your your theory, if it's coming from mother to, you know, to baby, there is a few study and one of them, I was like, I need, really to read the paper. But I was already shocked with the information that a pregnant woman, when they have circumstances, at difficult circumstances, and they have shortened of their tulim air, the baby have a shortened tulim air. So there is something happening definitely. We don't understand why or how, but it's definitely happening?

Speaker 8

30:43

Terrific question. Paul Ch'en? , I see one question. Oh, over here, yes, please,

Speaker 8

30:56

hello. Thank you very much. You mentioned the biomarkers of inflammation, apart from CRP, which is so inaccurate, what can we do in the community to measure abnormal inflammation? It came up with covid, and it was just impossible to

Professor Robin Choudhury

31:12

So CRP, for those are not aware, is a protein that's made by the liver in response to all manner of inflammatory stimuli. So it's very nonspecific. It changes over an enormous dynamic range. But it tends to be true that in whichever population you look at population, not individual level, there's quite a strong relationship between future cardiovascular risk and the level of CRP. So that's what I meant when I said it's not without use. There are clinical trials ongoing at the moment, and there are people in Oxford in these trials to look at instigating anti inflammatory treatments on the basis for that elevated CRP. So it's not useless, but it's not sufficiently granular for us to really understand what's going on in these complex processes, because it's such a nonspecific marker. And in answer to your question, not yet, but we're working on it because technology is moving so quickly, it's perfectly feasible that within the next decade, you'll have a chip a little bit like the covid test. You'll put a little bit of blood or plasma on it, and you'll run a series of polymerase chain reaction type things to multiply the DNA or the RNA, and you'll get a picture of what a person's inflammatory status is. So that that seems to me, with the rate of change of technology perfectly imaginable in my professional lifetime.

Dr. Paul Ch’en

32:47

Okay, and on that note, thank you to Dennis and Robin. I think next is a lot of food for thought in this lunchtime.

Prof. Denis Noble

32:58

Applause for Robin!

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