Pomegranates, cancer and immunity

This interview with Dr. Dominic Denk was recorded on March 22, 2023 and transcribed using Sonix AI. Please check against audio recording for absolute accuracy.

Peter Bowes:  We’re going to delve deeper into the latest research around a natural compound called Urolithin A, which we’ve discussed at length on previous episodes. And if you go to the index on our website, LLAMApodcast.com search for Urolithin. A, you’ll be able to catch up on our previous conversations about this metabolite, which is derived from our diet. Certain foods like pomegranates, are particularly rich in the essential components. They’re called ellagitannins, which we need to produce Urolithin A which is hugely important for our mitochondrial health, the energy centers of our cells. Well, today we’re going to talk about some new research that suggests it could also be important in fighting cancer. I’m joined by Dr. Dominic Denk, a physician at Frankfurt University Hospital and one of the authors of a recent study carried out with the Frankfurt Cancer Institute. Dominic Denk, welcome to the Live Long and Master Aging podcast.

Dominic Denk: Well, thank you very much, Peter.

Peter Bowes: The findings of this study are indeed very interesting and we’re going to delve into them in some depth in a moment. I thought it might be useful, just first of all, for you just to tell us a little bit about yourself, the work that you do in Frankfurt and your particular interests.

Dominic Denk: Well, I guess you summarize it brilliantly. So I’m a physician at a hospital in Germany, large university hospital, and actually act as a clinician scientist, meaning I work in the hospital with patients at the bed every day treating internal medicine diseases, gastroenterology diseases. But on the other hand, I also work in the lab at the bench trying to explore cancer and trying to find out what drives cancer and how to treat it. So pretty much taking what I see in the hospital and then moving it into the bench and then back to the patient, hopefully at least.

Peter Bowes: And does that sort of dual purpose in terms of being a hands on physician and a researcher as well. Does that broaden your, I would say broaden your horizons, but perhaps broadens your perspective as well in terms of what the ultimate goals are?

Dominic Denk: I do think so. I think it actually improves both both sides of the coin, actually. So being a physician working in a lab, it means that I understand what drives disease and what patients need for their therapy. I know which approaches are realistic, for example. And on the other hand, I can also understand new developments from the lab if they actually make sense in the hospital as well. And I understand the techniques that go into research and how long certain things take that we can’t just treat cancer as it is that quickly. Cancer is a very diverse disease. Every type of cancer is different. And even the same type of cancer in a different patient is widely different. And it is so complex that it really makes sense to see both sides of the coin to, in an ideal case and hopefully in the future, have some individualized treatments for patients so we can treat everybody specifically to their needs.

Peter Bowes: And of course, one of the complexities is that not all cancers are equal. The science behind how certain types of cancer evolve can in many cases be very different.

Dominic Denk: That is indeed the case. And then the big complexity comes from the fact that cancer is not just only the cancer cell, right? So back in the day, many decades ago, we figured out, okay, we have our cells in the body, they change, they undergo mutagenesis, meaning the genes change. And that means that the cell then becomes malignant and we have cancer. And if we just nuke these cells, we treat them with chemotherapy, for example, we’ll keep this growth in check and cancer is cured. But what we see now these days is that cancer is actually quite a generous disease and we have many cells inside the cancer, not just the cancer cell. We have immune cells, we have fibroblasts or stromal cells, and they all actually interact with the cancer cells and they can drive disease progression. So to really understand what’s going on, even if two patients have the same type of cancer, you really have to deconstruct that cancer itself. Which cells are inside that cancer and how do they interact to then actually target it specifically? So not going for the cancer cell alone because that will not be enough, unfortunately. 

Peter Bowes: So we’re going to talk about Urolithin A. Perhaps we could go back to basics to start with and you could explain to us, as we have discussed this on the podcast quite a few times before, but I think it is worth explaining again what Urolithin A is. I mentioned it’s a metabolite, but what is it and why do we need it?

Dominic Denk: So it’s actually quite an interesting compound. So there’s certain fruits, pomegranates, berries or nuts, for example, that are very rich in natural compounds called ellagitannins. And the thing is. Those are actually metabolized inside the gut by the local gut material into something called urolithin A. And urolithin A is something that has been shown to induce mitophagy. So now you have to kind of go back and explain mitophagy and understand that mitochondria, as we all know from school, I guess, are the powerhouses of the cell. So Mitophagy is a program that leads to degradation of mitochondria to renew them. So if you have aged mitochondria, they get replenished and get made better. So that’s what evolution does. And the main issue usually is that you need an appropriate gut microbiome, meaning not everybody can produce urolithin A. Otherwise I could just recommend you eat tons of pomegranates, but only just about a third of all age people actually can produce urolithin A and as we age and now we come back into aging, actually that proportion of material gets lower and lower. So we have to find a way to actually get Urolithin A into our body as it has many diverse, important effects on us, on aging and on cancer importantly. So taking urolithin A directly, it seems to be a very nice approach to kind of circumvent this issue of taking it up. And there’s this group in Switzerland, which I guess you discussed in previous podcasts by Professor Auwerx that actually deconstructed the pomegranate. Having seen that there are certain diseases that are associated with better outcome. People consume pomegranate and just looking at this fruit, they looked at all the molecules inside it and then they actually found out that Urolithin A is one of those compounds. Actually the one compound inside the fruit that drives all this? And this is how they started to isolate that compound, to synthesize it themselves. And this is what really started all this biomedical research on this compound and ultimately drove us to study euphony in cancer.

Peter Bowes: And so we are able to varying extents, to produce urolithin A ourselves. And that ability oftentimes deteriorates as we get older. There’s no way of knowing, is there, unless we have a very specific test. There’s really no way of knowing where we stand individually. There isn’t a simple test and it isn’t a regular blood test that your local doctor would likely give.

Dominic Denk: You know, there’s no simple test companies that actually commercially sell urolithin A they have such tests where you can, for example, drink pomegranate juice and then send them your dry blood before and after to see if we actually did produce urolithin. A But there’s no test by your local doctor that can actually assess this adequately, and we’re not entirely sure how to really look at the gut microbiome in a very feasible manner to actually see if you and me, if we actually have the adequate gut microbiome, just also knowing that it’s very complicated, very expensive. So it’s not that simple. But you can probably assume that if you are over 40 or 50, there’s less than half of a chance that you can actually produce it. And even then you would need to use tons of urolithin A containing fruits or pomegranates like multiple liters of juice per day to actually get the same amount. So it’s not that easy.

Peter Bowes: And you mentioned pomegranates several times. Indeed, I mentioned pomegranates in the introduction and pomegranates are very closely associated with urolithin A. I think we should probably also stress that they’re not the only foods. There are other fruits, indeed foods that are not fruits that can help us produce urolithin. A And people might be watching or listening to this saying, well, I actually never eat pomegranates. That doesn’t necessarily mean that they are unable to produce urolithin A as they need it.

Dominic Denk: That is correct. Of course. I mean, it’s also in other fruits and raspberries. It’s the nuts, for example. So if you are having a somewhat balanced, so to say, healthy diet, you will produce probably Urolithin A just not in the amounts you would really need to get these beneficial effects that we have seen in our study that people have seen for muscle studies, for example. But yes, if you have a balanced diet, you have plenty of other sources of urolithin A, pomegranate is very rich in urethane a and this is why they’re, so to speak, the poster child of urolithin A because this is where you get the most from.  

Peter Bowes: So let’s talk about the study and I’ll let you explain the basis for the study. But essentially the finding is that urolithin A could indeed help us improve the function of immune cells and there could be implications there for fighting cancer.

Dominic Denk: Exactly. So to kind of get into this, you have to look a little bit broader spectrum. What drives cancer and how the body actually treats cancer. So usually we have an immune system that’s actually built to recognize malignant cells, right? And the way this is usually done is that each and every cell presents so-called antigens. So pretty much a little sign, this is me, this is what’s inside of me. I’m a healthy cell or even if I’m an infected cell. So, for example, this is the normal pathway an infected cell could show to the outside. Look, I’m infected by a virus. The antigen gets recognized by an immune cell. And this is then the signal for the immune cell to kill that cell. And this is how we usually limit infections in cancer, for example. So that’s the one thing you need an antigen that needs to be recognized by the. And so and we’re wondering about the question how we can improve this interaction, because in many cancers, antigens are down regulated by the tumor. The immune cells get exhausted, which is pretty much just a fancy way of saying they get tired, they don’t function as well. We wanted to kind of improve this. So basically the work in the lab that I work in, they’ve seen recently that you can improve antigen presentation. So this little signature here, I’m infected, I’m a cancer cell by inducing mitophagy. So by induction of mitochondrial replenishment. The thing is, in that study they used a mouse model genetically ablated some genes, which is something you cannot do in human beings, right? If you’re in the hospital. And here comes once again the idea how can this improve our daily care? You need to find some sort of dietary supplement or medication that does just this that the patient can take so you can help with the cancer treatment. So quite innocently, actually, we just wanted to induce this antigen presentation by inducing mitophagy and we looked on the web, looked at the recent literature, as you do as a scientist. And we found this this compound urolithin A that has been studied in muscle models, actually. And this group in Switzerland, they have seen that it’s an inductor of mitophagy and it improves muscle strength and endurance in worms and rodents. So we figured, wait a minute, if this is something that’s already tested in animal models, it’s safe to consume in humans and it does what we want to see. Why don’t we try this in our cancer models just to once again see antigen presentations upregulated. So we did this and we tested this on mouse models of cancer. And quite surprisingly, we saw that the tumors were not even surprisingly at this point, but we saw that the tumors were smaller in the mice that had very aggressive tumor forms, and they were actually treated quite nicely. And when we then looked more into the detail, into the tumor microenvironment, so seeing which cells are actually inside the tumor, we could see that were actually more T cells. So immune cells that are there to fight the cancer inside the tumor. And we figured this cannot be the effect of antigen presentation alone. It must be also that, yes, there’s more signal that there is cancer, but the immune cells recognize this. They must also function better one way or another. And this is what really kicks this off, because then we went into studying the immune cells more into detail. We exposed them to urolithin A. And long story short, we found out that urolithin A yes, it acts on the cancer cells, but more specifically actually acts on the immune cells and it rejuvenates immune cells in a way they become more potent, they last longer, and they constantly replenish the immune system so that we always have fresh pools inside the tumor, which is one of the main issues in cancer. Because T cells enter the tumor, they become tired, they don’t function as well. And this were many therapies fail. So we think it’s a very interesting and novel approach to not necessarily treat the cancerous cell, but treat the immune system, which then in turns treats the cancer, which is actually what our body is built to do.

Peter Bowes: You’re listening to the Live Long and Master Aging podcast. Our guest is Dr. Dominic Denk from Frankfurt University Hospital. We are talking about Urolithin. A And really, Dominic, this is quite exciting the way you’ve just laid out the study and the findings. Where do you go next with these really promising findings?

Dominic Denk: Well, of course the first answer would be, ‘well off to the clinic, you go, let’s treat some cancer patients.’ There’s two limitations of this or one major limitation. Of course, the studies we performed their mouse studies. We also used human T cells to show the switch, to show that these T cells actually become more or they change their phenotype, at least we don’t know if they’re more potent yet. And as I said, we want to use this in the clinically feasible manner. So ideally you take a pill, you take these supplements that are already approved and already deemed safe and then treat patients with this. And to really fairly approach this, I think, and to really to be able to tell patients, hey, this is what might help you. You want to see if the same stuff happens when you take these compounds. So what we want to do is we want to take urolithin A, these already approved supplements and take healthy volunteers, aged adults, between 45 and 70, for example, and have them take these compounds for just a month and to see if we see the same T cell switch, because you can assess this in the lab, you can just see what are the transcriptomic programs of these cells, what receptors do they express? And then we actually know if this is the same thing we see in our mouse models and we saw in the lab before, we know, hey, something is going on and something is happening here. And then the next step, I think then it’s really fair to go to cancer patients and then really maybe even have some promise of that, hey, this is what might be working. So we’re getting closer and closer. We’re starting off this this first clinical trial that is outlaid actually this week. And I think within the next 1 or 2 years we can hopefully, if the results are positive, go into actual disease application, try to treat patients with this.

Peter Bowes: Which really just prompts what was going to be my next question, that I’m very conscious often doing interviews like this that I don’t want to give. We don’t want to give people false hope that there is something that is immediately around the corner that is going to help them with a condition that there is more research to be done, there are more clinical trials to be done. But you outline the possible timeline there. And to me it sounds as if we’re on the brink. We’re getting quite close to some findings that could be of real practical use to people.

Dominic Denk: Indeed, of course it’s something you have to be careful as a physician, as a scientist, to say, yes, this might work. It might also not work. But we have very strong data and the strong point in these findings – and the study – is that there is already a supplement that has been approved and tested in human beings. The thing how it usually works when you when you treat cancer in the lab and you find something new, it’s usually it’s a new medication, right? It’s a new approach. So this usually has to be validated in further studies. You have to show it’s not toxic to diverse animal models, and then you have to go to multiple stages of trials to see phase one, phase two, phase three. So the compound is not toxic. It actually doesn’t harm the patient. And only then at the very stage, which usually takes 7 to 10 years, you can go towards the final step, the exciting step to see in a double blinded manner, does this actually work? But now that we skip all these steps and we know it’s it’s relatively safe or it is safe to consume at this point in the doses we’re trying to test, the only we could actually start right now, but the only thing we’re doing now is this fairness approach of actually knowing that something might be happening. So I think we are close. That, of course, doesn’t mean we’re going to cure all cancers immediately. Of course not. But I think for certain subsets of people with a dysfunctional immune system, with an aging immune system that get or receive certain types of therapies that are built on the immune system, we could probably help here. And it’s as easy as just adding it to the therapy. That’s, of course, the idea and the hope that we would have.

Peter Bowes: Now you’ve just used the word cure, which obviously is what a lot of people would be looking for. But is there also potentially a preventative element to this as well with these new therapies? And we’re not talking about eating lots and lots of fruits and pomegranates. We’re talking about supplementation, as you’ve described that supplementation already exists. But is there a preventative measure, in other words, supplementation for healthy people with an eye on what could occur in the future?

Dominic Denk: So, of course, once again, cautious answer. Likely. Possibly. So what we have seen in mouse models, we actually did kind of this that you outlined. We we had mice that we fed this urolithin A rich diet for over a week. And then we started the tumor induction. And so as a preventive measure, indeed, and we could actually see that the tumors then, although every mouse develops a tumor, it’s a very aggressive model. The tumor is smaller and gets onset much later. And knowing that cancer often arises on a background of a dysfunctional immune system. So the immune system doesn’t recognize the first cancerous cells. The idea that you can probably rejuvenate the immune system or help it function better might lead to the conclusion that this actually would be something you could take preventatively. That’s the concept behind it. It could work. We don’t have, of course, enough data if such interventions on the immune system on a long term scale. Now I’m speaking 20, 30 years and hundreds of thousands of people actually has an effect. But the idea of it and the main idea and concept we have of the immune system and cancer would lead us to the conclusion that this could be something that might be working. But for how long you would have to take this, I do not know and I wouldn’t recommend this yet to to go that far. Of course.

Peter Bowes: I just want to delve into and again, we’ve talked about this before. You’ve mentioned mitophagy several times, autophagy, mitophagy referring to mitochondria, which really is right at the heart of, of everything you’re talking about, that essential process of renewal or kicking out of cells that don’t work properly and replacing them with cells that are new and vital. I was wondering if you could just encapsulate the importance of that, that basic biological principle.  

Dominic Denk: Yes. So what you need to know and I guess you dropped into this before in your previous podcast that every cell consists of mitochondria, right? They’re tiny guys, tiny organelles that are inside every single cell, and they drive the metabolism of the cell. They drive what the cell consumes, how it works functionally, which nutrients it consumes, and ultimately the Transcriptomic program and what we have seen and also people in aging disease and cancer disease have seen that mitochondria are quite important to healthy medical functions. Quite important to treat disease and to prevent disease, because if mitochondria don’t function as well, they accumulate. They have this tendency to accumulate and then the cell usually goes into programs that rendered less functional, render it to the point where it doesn’t fulfill its function for the immune system. For example, the cell ages faster. It means the cell, even if it recognizes the cancer cell, it will not fight it because there’s just not the playground there. The base work there because the metabolic features of the cell to really upregulate these programs, it means are not there. So really keeping mitochondria fresh means keeping all cellular functions fresh. And the issue with aging, of course, is then that usually these mitochondria they accumulate.

Peter Bowes: And Dominic, a broader question. As we look at longevity, there are many tools in the box, if you like, that we can use in terms of interventions to pursue a longer lifespan or a longer health span, as I prefer to talk about it. And we can be talking about exercise, we can be talking dietary interventions, sleep, mental health, they all in terms of the whole body, they all play a role. And then of course, there is supplementation and that’s what you’re talking about here. And we’re learning a lot more about the kind of supplements that are really effective in pursuing a long healthspan I’m just curious, maybe just looking to the future where you stand on supplementation, to what extent is it going to play a major role in how we live and how we pursue a longer lifespan?

Dominic Denk: So I think at the current state right now, 2023, we don’t have yet enough data to to postulate. Now, speaking as a cancer scientist to take supplements to prevent cancer, of course. But I think there will be a time and we’re actually actively studying this these days where we can actually say, yes, there are certain supplements that are safe that we can take that actually have an effect. You were you were speaking of basic measures such as lots of sleep, exercise. Those are actually proven to work. We know those are things they reduce inflammasome activity. So inflammatory signaling inside the body, which is one of the main drivers that actually drives immune dysfunction and drives mutagenesis and cancer cells. So it drives cancer cells to become more malignant and it drives the immune system to be dysfunctional. So reducing stress, getting healthy amounts of sleep and exercise are very important. Then nutrition, of course, such things as reducing whole body fat composition. Those are all things you can do. Yes. Speaking as a immunologist and cancer scientist, now, I guess you’re thinking of some supplements that are actually studied in anti-aging, metformin, rapamycin, those kind of things. There’s actually very similar pathways that regulate immune function that are also affected by these kind of let’s call them drugs or supplements. So T cell stemness – so the, the functional properties of an immune cell attacks cancer are most likely, judging by the current literature affected positively affected by metformin but rapamycin as well. Those are actually the same, the same pathways. They all converge at the same level, but we just don’t know how long you have to take them in which doses you have to take them and when is the right time point? Because once again, cancer is a very diverse disease, right? So even if we know and I think the the data is quite convincing at this point that these things work for anti-aging. They work at reducing inflammation, inflammation activity. They work at helping the immune system. We’re not entirely sure how they act on other components of the tumor per se, because sometimes you might even need inflammation to activate the immune system. So long story short, I think it is coming. I think science is making great advances and one of these things are currently staying already available right now will be one of the keys that we can probably supplement, not just with a therapeutic intervention, but also preventative.

Peter Bowes: And again, this is a broader question. Is there, do you think, enough support from the the scientific and broader community for this kind of research? We’ve heard recently a lot of high profile politicians talking about pursuing a cure for cancer, which is great. I mean, if that were to happen, obviously fantastic, but it’s often very simplistic language. And you’ve spelled out very well for me and for us that this thing, this sort of thing doesn’t happen overnight. And there are trial after trial after trial. And the last thing we can or should do is create any kind of false hope that we’re talking about decades. And with so many different diverse kinds of cancer, there is a tremendous amount of work still to be done.

Dominic Denk: That is true. So once again, as you mentioned briefly before as well, cure is a very dangerous word. Cure implicates that the entire disease is gone forever, which is often not what happens when we treat cancer. Importantly, metastatic disease we achieve to get stable disease, stable conditions, meaning you might have a lump in your liver in your brain. But you don’t feel it. It doesn’t get bigger. It’s. It’s all good. And that’s what you’re mostly scared when you hear of cancer, of metastasis, of course. So we don’t necessarily look for cure, but we want to keep stable disease and now going towards preventing cancer, I think it’s even more so important than treating it because there this is what. Having having cancer in the first place is what drives all the issues of having to find a cure. So if we can identify basic measures, but also medications that might help us decrease the cancer risk, we avoid running into many other issues that we have in the first place. And one of these things, for example, can just be having a somewhat healthy immune system that detects cancer in the early stages that will not avoid all cancers. Of course, we just know that most people in their life will have a cancer diagnosis. About one third of all people throughout their lifetime can be any kind of cancer. But it is something that I’m very confident we can reduce. And with things like early screening or even just preventing the onset by itself, those are very important measures.

Peter Bowes: I think it is hugely important research. I just wanted to ask you in closing more generally, I’m always interested in talking to people like yourself in terms of your own personal ambitions and goals, in terms of longevity and perhaps your lifestyle. What do you do on a daily basis knowing what you know in terms of digging deep into the science? But what do you do on a daily basis to nurture your own healthspan.

Dominic Denk: Well, I would do everything wrong. In that case, actually – being a physician means long working hours. It means lack of sleep and doing this dual lifestyle of being a clinician and a scientist. You don’t actually do the right things. But what I try to achieve and that’s what I actually prioritize as much as I can, is getting healthy amounts of sleep and exercising regularly. Just knowing that we’ve increased age 30 plus your your muscle function decreases, your immune function decreases. So getting healthy amounts of sleep, exercising and watching your diet in a way that you keep high amounts of protein, low amounts of carbohydrates and fat, those are the main basic things you can do. I don’t take any supplements myself at this point, just knowing that the science might not be yet, But I’m keeping very close eye on that and actually working on this myself. So as soon as we have convincing data, I think that’s something we could postulate.

Peter Bowes: Well, Dominic I think you’re doing fascinating work. I intend to follow it with a huge amount of interest. Thank you very much indeed.

Dominic Denk: Well, thank you. Thank you for having me.

Peter Bowes: And if you’d like to dig a little deeper into the study that we’ve just been talking about, there’s a link to it in the show notes for this episode, along with a full transcript of this conversation. You’ll find them at our website, which is LLAMApodcast.com. That’s LLAMAPodcast.com. The Live Long and Master Aging podcast is a Healthspan Media production. We’ll be back soon with another episode. Thank you so much for listening.