Revitalizing the immune system

This interview with Dr. Nicola Vannini was recorded on November 23, 2023 and transcribed using Sonix AI. Please check against audio recording for absolute accuracy.

Peter Bowes: In this episode, we continue our exploration of the gut metabolite urolithin A – we’ll do a quick recap in a second – and evidence that this natural compound plays a key role in the health of our immune system and our ability to fight infections. Now, the discussion we’re about to have is quite detailed, so I’m going to start with a few pointers that will hopefully explain a few of the terms we’re about to use. And a good place to start, if you didn’t catch it, would be our last episode, an interview with Dr. Anurag Singh, a long time researcher into the role of Urolithin A. In it we cover the background in some considerable detail, and you’ll find that interview in your podcast feed immediately before this one. In this conversation, we focus on a particular type of stem cells that are important for the health of our blood and immune systems. They’re called hematopoietic stem cells and as we age, we know their ability to do their job declines. The question and a subject of the new research we’re about to discuss is, can that decline be slowed down or even reversed through exposure to urolithin A? So let’s get into it. Dr. Nicola Vannini, welcome to the Live Long and Master Aging podcast.

Nicola Vannini: Thanks. It’s really a pleasure to be here. So urolithin A is a molecule that is metabolized by the gut microbiota, and the mother molecule is ellagitannic acid that derives from red berries. You can find it in pomegranate. And once is metabolized go in the organism. And urolithin eight has been shown to promote the metabolic fitness of the cells, especially by targeting mitochondria, because it’s known that during aging, what happens is that you have accumulation of defective mitochondria. Mitochondria are the horsepower of the cells, so they produce the energy of the cells. And you can understand that if this machinery are not working properly, it leads to accumulation of waste. This waste is damaging the cells and is inducing the aging process. So what Urolithin does is it has the capacity to target mitochondria to induce the recycling of mitochondria. So essentially you get rid of damaged mitochondria and they get replaced by new fully functional mitochondria. So you reduce the production of this waste. The metabolic fitness of the cells is ameliorated and you have rejuvenation of the cells.

Peter Bowes: What I’d like to dive into all of that in some detail and look at your new research. Maybe you could just tell us a little bit about your own career and how you came to this area of specialty.

Nicola Vannini: I start my study in Italy. I did my master’s and PhD in Italy, and then I moved for a couple of years in US in San Diego, the Burnham Institute, and afterwards I went to Switzerland, where I did my postdoc. And then a few years ago, like in 2016, I started my own lab at University of Lausanne. And there I’m really focusing on the effect of aging on the hematopoietic and immune system. So I’m as a background, I’m a stem cell biologist, so I’m really interested to see the effect of aging on hematopoietic stem cell. Because hematopoietic stem cell are the mother of all the immune and blood cells. So if you have a healthy hematopoietic stem cell that will reflect in a more healthy immune system. So essentially what we are doing in my lab is really to try to understand some of the metabolic features that are leading to the aging of hematopoietic system. Also, how we can target it in order to rejuvenate the hematopoietic and immune system.

Peter Bowes: Which is our special interest in this interview and some research that you published recently in Nature Aging. And this really does focus in on immunity. And as I mentioned, our ability to fight diseases. Can you maybe just take us back to the beginning, what you set out to try to achieve, what your thesis was, what your idea was? Essentially, this was a study in two parts with mice. 

Nicola Vannini: Yes. So essentially what happened during aging in all tissues you have this accumulation of defective mitochondria. And indeed we found that in hematopoietic stem cell it happened the same. So all the hematopoietic stem cells they accumulate these defective mitochondria. And during aging,hematopoietic stem cell they first they lose their capacity to to give rise to all the blood lineage. They give rise preferentially to myeloid lineage. And that is associated to immune depression and so higher susceptibility to infection and cancer development. And the other thing that is happening, you know, hematopoietic stem cell are really important in the context of bone marrow transplantation. So during aging they reduce also their capacity to reconstitute the blood system of a recipient individual. So essentially we saw that in hematopoietic stem cell there was this defect in mitochondrial metabolism. So essentially what we did we screened different molecules for their capacity to modulate the metabolism in hematopoietic stem cell. And the best performing one was Urolithin A.

Peter Bowes: And how did it affect the mice you treated old mice. How did they change?

Nicola Vannini: So essentially we did two sets of experiments. One Ex-vivo. So essentially where we took hematopoietic stem cell from old mice, and we cultured in a dish in the presence of Urolithin A. And another set of experiments where we fed the mice. And then we checked the immune functionality. So in the first set of experiment, we took a hematopoietic stem cell from young old mice and the one from old mice, they were treated with urolithin A. Afterwards they were transplanted in recipient mice. And the results were quite astonishing because all the hematopoietic stem cell treated with urolithin A they perform as well as the young hematopoietic stem cell. So the same capacity to reconstitute the blood and immune system of little irradiated mouse. In the second set of experiment, we supplemented urolithin A in the food, and we tested the capacity of these mice to respond to a virus. So essentially we infected the mice after a feeding period of three, four months. And we measured the quantity of the virus in the mouse and the mice that were fed with urolithin A they were much better in clearing the virus. So they had much better response to the virus, not as well as the young mice, but they perform much better than old mice that didn’t receive urolithin A.

Peter Bowes: This was a synthetic form of urolithin A that you were using. And just for clarity, urolithin A it comes in one form. Whether we’re talking about mice or humans, it is the same. It is produced in our gut. But we’re talking about the same compound. 

Nicola Vannini: Yeah, exactly. It’s the same compound. And it was chemically synthesized. Essentially we use a compound that is chemically synthesized and we provide both or in the dish when we cultured the hematopoietic stem cell for transplantation, or we provide it in the food of mice. But the molecule is the same, the one that you have in mouse and the one that you have in human.

Peter Bowes: And you describe the results as “astonishing.” To what extent were you astonished? And what are the do you think the implications of this?

Nicola Vannini: So the the results were quite surprising because it’s for me, it’s several years that I’m working on different molecules that are known to modulate the metaplastic immune function. But this the first time for me that I found a molecule that has such a strong effect. Obviously the impact is is quite wide, because you can imagine that improving the immune function of older adults has a really big impact, because we know that elderly population are more susceptible to infection and cancer development. And we can imagine that by boosting their immune system with this, with urolithin A, we can prevent infection, but also we can delay the onset of cancer.

Peter Bowes: Which is really quite striking, isn’t it? Now, what is the next stage? There have been some human studies, presumably more clinical trials involving people are needed. 

Nicola Vannini: Yes. So we are now trying to set up our own trial with the specific category of patients that have similar feature of immunosenescence that you can find in elderly population. And this category of patients are cancer free patients that receive chemotherapy because it’s known that chemotherapy is used, is inducing premature aging of the immune system. So now the and this effect is permanent. So people that have received chemotherapy even they are cancer free. They are cured. But the damage of immune system will persist. So the idea is to see whether Urolithin A can revert these immunosenescence features. Also in this category of patients. And the other direct application that we can see for Urolithin A is also in the context of elderly vaccination because it is known that elderly, they respond much less to vaccine immunization. So we can think to supplement urolithin A to this category of patients before receiving vaccine to have a more long lasting response.

Peter Bowes: So in addition to and I frame it like this, reversing aging or at least reducing the biological age of an individual animal, the applications as you’ve just described are quite wide in terms of not only preventing disease, but treating disease as well.  

Nicola Vannini: Yes. So I can see both the things, because you can imagine that if you boost the immune system, you can in an elderly population, you can prevent infection, the onset of cancer development and but at the same time, being a molecule that restore the mitochondrial function, there are many diseases that carry mitochondrial mutation. So we can also think to apply this kind of supplementation in the category of people that have this mutation in mitochondrial machinery. So in a way to restore the metabolic fitness of the cell.

Peter Bowes: And one other thing I wanted to ask you about, you kind of hinted at it earlier. The way that we get urolithin A without any supplementation is that we generated ourselves, and a healthy gut is important to do that. And we know this from other research that we as individuals, to differing extents, are able to produce urolithin A some of us are a good prolific producers and others not so much. Now, in terms of your research and what it tells us, how do you think that is going to help us decide whether we actually need urolithin A supplementation? Because there’s always this question, I think, in people’s minds when we’re talking about any form of supplementation is, do I actually need it?

Nicola Vannini: So essentially, the only way to know that will be to analyze their own gut microbiota. But since Urolithin A doesn’t have any side effect, I think, you know, the supplementation would be a good strategy both for people that has the right gut microbiota and for people that doesn’t have it. Because if you get directly urolithin A, you have compounds that you know that will be absorbed and you will have it in your, in the body. So in both cases, I think it’s well known that Urolithin A doesn’t have any side effects. So I would I would go for it.

Peter Bowes: And looking at more broadly, you say you were, you didn’t expect the results to be quite as strident as you’ve seen. In terms of longevity, science and moving forward, how big a impact do you think this better understanding of urolithin A and the process is going to have on us? Because clearly we’ve been talking in the past mostly about urolithin A mitochondrial health, muscle strength. There’s a lot of good research that shows that in human beings, supplementation with urolithin A can help us from a physical standpoint in terms of our strength, our our stability, our perhaps preventing frailty in old age. But what you’re talking about is going much broader in terms of the really killer diseases that can potentially shorten our lives. 

Nicola Vannini: Yeah. Because there were several work that came out a few years ago now. Essentially, I think the impact of urolithin is so strong because it has been shown that if you rejuvenate the immune system, the impact that you have is in the whole body. So the effect that you you have on the on the muscle, for example, yes, forcibly is, is because of urolithin A is affecting the muscle. But part of it is also coming because urolithin A has an effect on the immune system. So the effect on immune system has a broad effect and it can impact different organ. And as I mentioned before, also different disease. Because if you have it’s the the immune system is the first barrier for infection but also for, for diseases kind of housekeeper to check that everything is is working correctly. One of the aim of my lab is really to find strategy that can improve or revert immunosenescence, because if you do that, it is not just the impact on the immune system, but you have a broad impact on all organisms.

Peter Bowes: I want to ask you more of a general question. This is a podcast about human longevity. It is about healthy aging. It’s about trying to maximize our health span. The number of years that we can live without chronic diseases. Is this something that you spend a lot of time thinking about, of the kind of lifestyle using science that we could be living in the decades to come.

Nicola Vannini: Yeah, for sure there are. One of the things is for sure the physical activity and nutrition for sure, but the two things are going quite together because physical activity is improving the metabolism of cellular metabolism. So if you do physical activity, you improve your mitochondrial fitness. And with specific supplementation of specific nutrients, you can achieve similar results. For example, with the urolithin A or it has been shown also for, for example, NAD booster that can somehow improve mitochondrial fitness and the metabolism of the cell. When you have these improvement of metabolism, then it will reflect on the general capacity of the cells because as I mentioned before, if you have a metabolism that is not working correctly, you have an accumulation of a lot of waste that is going to damage the cells and push toward aging. But if you have a metabolic system that is working properly, you will reduce strongly the accumulation of this waste. And you can prevent or like in the case of Urolithin A, you can even revert some aging features. 

Peter Bowes: But you make an important point, and that is that we’re probably looking at a future where, yes, supplementation to an extent is going to be part of our lives, but still, crucially, will be a good balanced diet and a lot of exercise.

Nicola Vannini: Exactly. Exercise for sure is is key I think is is the two things are going together, you know, the nutrition and the exercise. Because if you want to keep a good metabolic health, you need both of them. You know, you need to stay active. You need to have a balance and nutrition. And you can also implement it with the specific supplements like Urolithin a. So I think the combination of all these things are really meant to improve the quality of life in the elderly.

Peter Bowes: Just one final thought. What kind of response have you had from the scientific community and especially researchers involved in this particular field, outside of your own laboratory? What has the response been to this study?

Nicola Vannini: So they actually the effect was quite as I say, was quite astonishing. And also colleagues all over the world when when they saw the results, they were quite, quite surprised because it’s for me and also for many of my colleagues, was the first time that they see a molecule that was able, especially in the context of transplantation, to restore completely the blood reconstitution capability. And these results that were presented also at ASH meeting at the American Association [Society] of Hematology last year and had a really nice feedback from many colleagues. So I think the story is, is quite well received from the community.

Peter Bowes: Well, it is a story that we are going to continue on this podcast, that we are going to continue to watch closely. It is really fascinating research. Nicola Vannini, thank you very much indeed.

Nicola Vannini: Thanks to you.

Peter Bowes: And if you’d like to delve into more details to read the original paper, I will put some links into the show notes for this episode. You can find them at the Live Long and Master Aging website LLAMApodcast.com. This has been a Healthspan Media production. We’ll be back soon with another conversation. In the meantime, thank you so much for listening.