Health Longevity Secrets

Sex, Power, Suicide, and Mitochondria with Dr Natalie Yivgi-Ohana

• Robert Lufkin MD • Episode 226

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What if the secret to treating age-related diseases and extending healthy lifespan lies within tiny cellular structures that evolved from ancient bacteria? In this mind-expanding conversation, biochemist Dr. Natalie Yivgi-Ohana reveals how mitochondria—far more than mere cellular powerhouses—control everything from hormone production to programmed cell death.

Dr. Yivgi-Ohana, founder of Minovia Therapeutics, takes us on a fascinating journey through mitochondrial science, explaining how these organelles became integrated into our cells over evolutionary history. "Mitochondria used to be bacteria that entered into the cell and formed this symbiosis," she explains, describing how this evolutionary leap enabled life to thrive in oxygen-rich environments. This bacterial heritage gives mitochondria unique properties, including their own DNA separate from our nuclear genome, which makes them both vulnerable to damage and potentially replaceable.

The revolutionary approach Minovia has pioneered involves harvesting a patient's own stem cells, enriching them with young, healthy mitochondria from donor sources like placentas, and returning these energized cells to the patient. Unlike direct mitochondrial infusions, which pose risks of immune rejection, this method has shown remarkable safety and efficacy in clinical trials for both rare pediatric diseases and age-related conditions. "Seeing a child six and a half years old in a baby stroller and then two months later he's running in a shopping mall—it's unbelievable to see the impact," Dr. Yivgi-Ohana shares.

Perhaps most surprising is the current lack of clinical testing for mitochondrial function, despite its crucial role in health. "The strongest signal for health is how well mitochondria are doing," Dr. Yivgi-Ohana emphasizes, predicting that within a decade, mitochondrial function testing will become as routine as checking hemoglobin levels. This could transform preventive medicine by identifying mitochondrial dysfunction before symptoms appear.

Explore this frontier of cellular medicine that targets both mitochondrial and immune dysfunction—two major hallmarks of aging—simultaneously. Could rejuvenating our cellular batteries be the key to extending healthy lifespan? Listen now to discover how mitochondrial science is revolutionizing our understanding of aging and disease.

https://minoviatx.com/

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Speaker 2:

Hey.

Speaker 1:

Natalie, welcome to the program.

Speaker 2:

Hey, Rob, wonderful to be here. Thank you for inviting me.

Speaker 1:

I'm so excited again to talk about mitochondria one of my favorite topics and the cutting edge work you guys are doing at Minova. You know it's going to be a lot of fun, but before we get into that, let's just take a moment and maybe share with our audience a little bit about you and how you came to be interested in this fascinating area.

Speaker 2:

So I'm a biochemist by education. I did my PhD at the Hebrew University in Jerusalem and postdoctoral fellowship at the Weizmann Institute, and I've always focused on mitochondrial science. And when we studied biochemistry and we studied the role of oxygen consumption and the energy production, I actually didn't realize that while we breathe and we eat, the only thing that we are feeding is our mitochondria in our cells in our body. It took me a while, but when that click came I actually realized that I'm in the most important space of science that I could be, and that was for me, it was inspirational, and that was eventually led to the beginning of Minovia, this understanding of how important mitochondria are. So okay.

Speaker 1:

So we all back in biology class or even in med school, we learned that mitochondria were the power, the energy sources of the cell. Right, and that's still true, but they're much more so. What do mitochondria do and what is their role in the cell?

Speaker 2:

I actually started in my master's. I'm actually an embryologist, so I practiced in vitro fertilization and I studied the role of mitochondria in steroid hormone production in reproductive tissues. So did you know that mitochondria are actually responsible for the first step of steroid hormone production? All the sex hormones progesterone, testosterone, estrogen they are all dependent on these organelles to produce the first step in the production of these steroid hormones. Without it there is no life and there is no reason to live too right? Without sex hormones, who wants to live?

Speaker 2:

So mitochondria are responsible for steroid hormone production. They're responsible to monitor all the electrolytes inside the cell and the transition into the endoplasmic reticulum to provide all the energy required for protein synthesis, enzyme function, nucleotide synthesis, for the replication of the DNA, which is so important. So mitochondria have so many roles in the good and living cell. And then again we also learned that mitochondria actually harbor the proteins who are responsible for cell suicide. So if the cell has a damage that's beyond control of what can be fixed, mitochondria will trigger an event of apoptosis, which is the programmed cell death which is irreversible. So can you imagine? It's life and death in the hands of mitochondria? So so much more than just energy production, right. This is life and death itself.

Speaker 1:

Yeah, I love the book and I'm blanking on the author, but it's Power, sex and Suicide.

Speaker 2:

Nick Lane, exactly yes.

Speaker 1:

One of the great mitochondrial books and I still it's on my bookshelf right behind me. But I remember my wife would get annoyed when I'd leave the book laying out around because of the title. It said Power, sex and Suicide. What are you reading?

Speaker 2:

Sounds like a James Bond right.

Speaker 1:

And I love this story, how they said that even sexual differentiation is driven by mitochondria. The need for it is by mitochondria really.

Speaker 2:

Yeah, super interesting it was super, super fascinating.

Speaker 1:

There's so much we know and now it seems like mitochondria are really coming to the forefront in the metabolic health space and the longevity space. People are paying a lot of attention to mitochondria before, so what specifically is there? Why are they getting so much attention now in metabolic health and longevity? What's the role that they play in chronic diseases or longevity itself?

Speaker 2:

So it was known for a long time that mitochondria are part of. It used to be nine hallmarks of aging, or 12 hallmarks of aging, or 13 hallmarks of aging, but definitely mitochondrial dysfunction is one of the major hallmarks of aging. And when you look at metabolic diseases cardiovascular disorders, diabetes, kidney insufficiency there are so many chronic diseases where the dysfunctional of mitochondria is observed along the way and people did not know if it is a cause or a consequence of the disease. But definitely it plays a very significant role in the progression of those chronic diseases. So it was known and it's not surprising. I mean, we all feel the reduction in energy as we age, walk slower, we think slower, our movements are slower and our emotions and everything is so different and it was all connection connected to the lack of energy.

Speaker 2:

But, as I mentioned, mitochondria are responsible for protein synthesis.

Speaker 2:

You cannot live without producing your proteins and enzymes and everything, all the electrolytes and the channels that walk through the cells and signal the neurons to deliver the signal.

Speaker 2:

Everything is dependent on energy production and mitochondrial function. So it is not surprising that all the neurodegenerative diseases were also found to be associated with mitochondrial dysfunction. There is a need, a strong need, in movement of mitochondria across the neurons in order to deliver their signal into the tissue. You know, move your muscle now or you need to eat now. All of that is neurological sensing that is delivered by mitochondria moving into the throughout the neuron, throughout the path of the neuron, into the signaling pathway that eventually gives the signal to do the movement or to do the function. So it's not surprising that as we age and those mitochondria dysfunction accumulate, we feel this lack of energy in all sorts of different diseases. And some people do develop the chronic diseases as they age and some do not. And I think we should study and we should understand why some people are suffering chronic neurodegenerative dementia, metabolic disorders through aging and some are not, and maybe we can learn from there and then understand how to prevent them and some are not.

Speaker 1:

And maybe we can learn from there and then understand how to prevent them as we work. I want to come back and follow up on that, maybe before we do. Just mitochondria are unique, aren't they? And organelles? And the fact that they have this unusual history where we believe that they existed independently as an organism and then were integrated in a symbiotic relationship with us, so that they actually have their own mitochondrial DNA, which is transmitted, of course, just from the maternal line for the most part. And should we get our mitochondrial DNA tested? I mean, there's only 16,000 base pairs or so, right, as opposed to you know.

Speaker 2:

That's so important, right? So, indeed so, evolutionary mitochondria used to be bacteria. They entered into the cell and there was formed this symbiosis between the cell and the mitochondria, and they are the first form of life that was capable of living on this planet where there is such a high oxygen environment. So without this event of mitochondria being part of the cell, actually it wouldn't be able to live on such a high oxygen environment, because oxygen was toxic. It was actually a very toxic compound that caused cell death. And by the fact that mitochondria entered the cells and now is using the oxygen to produce the energy, it's life-saving, it's actually life-promoting. And this is why, when we want to talk about longevity and how to postpone death, we should think about this evolutionary path of mitochondria and maybe reverse that and think what if this is what happened when we started talking about mitochondrial transplantation? Think what if this is what happened when we started talking about mitochondrial transplantation? What if we can actually use this natural phenomenon of mitochondria entering cells? Can we reverse the aging process?

Speaker 2:

That was the initial thought, but indeed they preserved some of the DNA. Most of it actually was transferred to the nucleus. So the brilliant act of mitochondria they used to produce all the proteins themselves. That's a huge burden and if you know the Richard Dawkins selfish gene book talking about how selfish this DNA is, so bacterial being, you know, used to be bacteria. This mitochondria used to be bacteria that entered into the cell.

Speaker 2:

They thought, well, our DNA, bacterial DNA, is very exposed. It's like it has no protections and we are prone to many mutations and we will not survive. And what happened was they said, let's just transfer this DNA to the nucleus. Well, the nucleus is a very protective space for DNA. It has these three-dimensional structures and protein protecting and there is proofreading to fix mistakes in the DNA. So they transferred most of the DNA to the nucleus. More than 1,500 proteins are encoded for the mitochondria by the nucleus and transferred into the mitochondria and there were left only 16,000 base pairs encoding only 13 proteins of the respiratory chain that are still left in the mitochondria. But you know what? We already know that this is an ongoing process and there are already copies of this mitochondrial DNA integrated into our genome. Chromosome 1 carries all the mitochondrial copies, but it is under non-coding sequences. So not yet, but at some point maybe all these 16,000 will actually be transmitted to the nucleus and then we will be left with mitochondria without DNA.

Speaker 1:

So if I get my full genome sequence, I already, will in chromosome 1, have a sequence of my mitochondrial DNA. So if I get my full genome sequence, I already will, in chromosome one, have a sequence of my mitochondrial DNA.

Speaker 2:

Yes, you will see it there?

Speaker 1:

Back to the other question is there an advantage at this point in what we know clinically for kind of the longevity metabolic health space to get mitochondrial DNAs? I guess it's genotype? Do they actually sequence it really? It's so short, right, it's a ring. Is there any value? It's like $150. Is there a value for that now?

Speaker 2:

Yeah, so I definitely think there is, and this is the concept we're working for. So the fact that the mitochondrial DNA is exposed it's actually very much exposed for mutations and we do accumulate mutations with aging. However, when we go to a person who is 90 or 80 years old, who also have Alzheimer's, for example, he will have a higher mutation load of the mitochondrial DNA versus his age control that doesn't have Alzheimer's or myelodysplastic syndrome or all those diseases of aging. Those patients will have a higher mutation load than the common population who do not suffer these chronic diseases. And this is why, yes, it is important. It's a kind of a biomarker for, you know, predicting will you suffer a future disease or not. The more mutations you carry in the mitochondrial genome, that will actually predict if you will have a chronic disease of aging or not.

Speaker 1:

So it's almost like we talk about epigenetic methylation as a biological clock for the nuclear DNA. So what you're saying is mitochondrial DNA, since there's not really an epigenome there, it's more just the genes itself. The gene mutations themselves are essentially a biological clock that will predict aging and that sort of thing. And do companies read that out now on their results?

Speaker 2:

We're going to have them on the show here in a bit, but I just it was so funny to understand in all the scientific conferences that people actually throw away the mitochondrial sequences, because it's kind of a noise, there are so many copies of it, it's so noisy, so they throw it away from their analysis and you are left with only the genetic material.

Speaker 2:

But that is wrong and I think it is changing now. And I think this idea of a mitochondrial clock of aging is definitely something that we are trying to promote, and it's not only about the mutations, it's also about the function of the mitochondria, which again, very surprising to know, being involved in so many diseases that there are no methodologies to measure mitochondrial function or mitochondrial health in every individual. I mean, I would love to get my mitochondria tested, but there are no assays, and that's something that we're also investing in, because eventually it's not only about the DNA, it's the ability of the mitochondria to function, and there are so many mitochondrial functions, as we've just said. So what is it that you measure? So just a hint it's not a single measure.

Speaker 2:

It has to be a combined score of several biomarkers that also include the genetics, but includes also the function of the mitochondria and different functions.

Speaker 1:

So assessing mitochondrial dysfunction, which is so important in aging and metabolic disease? What is the state of the art for mitochondrial function? Given that there's nothing that directly measures that, can we indirectly measure with anything? There's the test from San Diego and the group Hamal's group down there and some other tests, but these are secondary. Is that right? What's available now, do you think?

Speaker 2:

So very few tests and people are trying to quantify mitochondrial content using specific enzymes that can tell them how many mitochondria are there. But it depends on which cell type you're measuring right. If you measure your swab, you will not get an answer what happens in your brain or what happens in your liver or your kidney. So it's very complex. Measuring mitochondrial function is very, very complex. There are a few biomarkers. For example, gdf-15 is a serum biomarker. You can measure it with a simple ELISA test in the serum of patients and that is strongly correlated with mitochondrial dysfunction systemically and you can find it in the blood. So very important biomarker and I think eventually it will become a diagnostic. But again, it's not a direct measure. What we do is actually we are taking blood samples from people and we are separating the blood cells, the white blood cells, where mitochondria are, and then we are measuring their function.

Speaker 2:

In this mitoscoring we are actually looking at three different parameters. We are looking at the ATP production, which is important, but you know it could come from glycolysis too. It doesn't have to come from mitochondrial function, and therefore the ratio between atp production and oxygen consumption, or, you know, respiratory chain complexes activity, is super important. So our second test is directed to complex one and complex two of the respiratory chain and we look at the ratio between ATP production, mitochondrial activity and then the number of mitochondria in the cells. The number of mitochondria is quantified by the number of copies of mitochondrial DNA. So those are the three tests that we are currently using to mito-score healthy people. To give a range, this is the healthy, normal range at this age, at this age and at this age, and now I will score you and I will tell you do you have mitochondrial dysfunction? And although it is in the blood, eventually the blood system does represent what happens in the body.

Speaker 1:

And back to the thinking about that and back to the DNA. If there are only 16,000 base pairs, is just calculating mutations and SNPs for mitochondrial DNA. Is that a valuable way to assess mitochondrial DNA aging, or is that not a good?

Speaker 2:

way to test function. I think it's not enough. I think the level of mutations is important, but there is something in our cells called heteroplasmy. Heteroplasmy is the coexistence of both healthy copies and mutated copies. So you might have a few copies that are mutated, but what matters is how many good copies do you have? This is why measuring the copy number of mitochondrial DNA versus the mutation load will give you a better answer whether you have a mitochondrial disease or not. That's what happens, by the way, in genetic mitochondrial diseases. So it is not something we are testing in pregnancies, because you cannot tell the mother whether a child will suffer a mitochondrial disease or not, because it really depends on the load of mutations. If you have enough copies of good mitochondria, it might just live great and never suffer a disease. This is why we're not doing this pre-diagnostic testing for mitochondrial DNA mutations.

Speaker 1:

So if I understand you right, then it's in assessing mitochondrial function and dysfunction, it's important to assess the overall numbers of each, because if you, if you, just if you sample and happen to get a, a bad mitochondria or a damaged one, it will appear damaged. Or if you happen to get one of the few good ones, it'll appear healthy.

Speaker 2:

So they have to have to do that all together then.

Speaker 1:

So it's, it's challenging and super challenging, and and with age and with chronic disease, but with aging itself, then this mitochondrial damage, this mitochondrial dysfunction increases over time. And that's the idea for mitochondrial transplantation is to somehow correct this or of course, correct, you know, childhood mitochondrial diseases, which is a whole nother thing. But the idea between my tell tell us about mitochondrial diseases, which is a whole nother thing, but the idea between my tell us about mitochondrial transplantation and what the thinking is there.

Speaker 2:

So for decades people have tried to improve mitochondrial function, but without really understanding what is wrong. What happens is that when there is dysfunction of mitochondria, sometimes the system is just working non-efficiently and you get more and more reactive oxygen species produced over the efficiency of ATP or energy production. So if this is the damage, once you're trying to increase mitochondrial activity, all you're doing is practically increasing the damage because your mitochondria who are already damaged, they will just produce more damaging factors. So the thought behind mitochondrial transplantation was if they are, you know, not working, let's just replace them right with healthy and functional ones. So that was the idea and again going back to evolution, the fact that there used to be bacteria and entered into the cell the machinery of uptake of mitochondria into the cell. The assumption was that it's still there, it exists. So let's try to isolate mitochondria from one healthy, very young source of mitochondria and then transplant them in diseased tissues or organs or cells. That was the concept. But to move from an idea into a product that you can actually use in the clinic, that's a big gap that you need to close and, as I mentioned, we started 13 years ago with the concept of let's just infuse people with young and healthy mitochondria and in my PhD I studied the role of mitochondria in placenta and in progesterone synthesis. You know that just before birth there is a huge increase in progesterone synthesis. That is the trigger of birth. And I, you know, I realized that this use and throw organ you know my mentor used to say this is the nature of garbage. It's just full of young, healthy, functional mitochondria and I said I just have to find something to do with it. So the initial idea was just let's take mitochondria from placenta and infuse them to people in need, and of course aging was the first indication we thought to people in need. And of course aging was the first indication we thought the biggest indication that could benefit from this therapy. But after three years we could really show that almost on every organ system that we tested improving angiogenesis, improving skin elasticity, improving hair growth, improving lipid metabolism Everything that we tried actually benefited from mitochondrial transplantation. It was amazing. We covered all different topics in patents. It was wonderful great IP portfolio.

Speaker 2:

But then we had to choose an indication and we started talking with regulatory advisors and with the regulatory authorities and we realized they have much concerns from two things. One, you cannot really isolate just clean mitochondria from cells. Okay, mitochondria are not like, they don't swim around, just mitochondria in the cells. They are bound to every possible other organelle in the cells. They are bound to the nucleus in some way, to the endoplasmic reticulum, to ribosomes, even to the membrane of the cells. They are bound to the nucleus in some way, to the endoplasmic reticulum, to ribosomes, even to the membrane of the cell. So they are bound all over.

Speaker 2:

When you isolate mitochondria, just bear in mind that you are isolating many other things. So the purity here is important when you're delivering a drug to people. And the second thing is, once you inject mitochondria, let's say to the blood, you have no control of what will happen to it after injection and where will it go. Most of the things that you inject will mostly go to the liver and the lungs. But we knew that the mitochondria are super sensitive and in the blood they will probably get ruptured and release the DNA. And we were afraid from just DNA flying around in the blood. That's not a good thing. And the immune system actually recognizes this DNA as bacterial because it is circular, just like you know the ancient bacteria that resulted in this mitochondria.

Speaker 2:

So we decided not to infuse mitochondria, just naked mitochondria, but to go through a cell therapy process, meaning we take stem cells from the patient outside into our labs, we load them with this healthy, young, functional mitochondria and then we infuse the stem cells back.

Speaker 2:

But when thinking about the multisystemic complexity of a person who is aging or a child with a mitochondrial disease, we wanted the stem cells that will have a multisystemic impact and we decided to focus on hematopoietic stem cells. Those stem cells can be easily retrieved from the patient outside the body and they know how to home back to the bone marrow and produce all the blood cells and the immune cells that can circulate through the blood and get to every organ system. And they are so important in tissue maintenance, removing dead cells and removing diseased cells from the tissues and then making the tissues work better, either the kidneys or the lungs or the brain. Everything requires a healthy and functioning immune system. So that was our leading idea behind developing mitochondrial augmentation technology in the form of an autologous hematopoietic stem cell transplant. Meaning we take your own stem cells, enrich them with you know donor young mitochondria and we deliver them back to the body. The cells know what to do after delivery by themselves.

Speaker 1:

So the let me, let me see if I understand this then. Well, first of all, a point I wanted to emphasize is that you, it seems like the mitochondria can move from cell to cell, right, and that's part of their old bacterial heritage, that they don't just stick in the heart cell or the nerve cell, they move around all over, which is an advantage. If you're going to be putting them in that way, and then you mentioned you're going to take autologous stem cells, so my own stem cells essentially, so it avoids all the immunological reaction, the foreign reaction essentially, but then you're going to take donor mitochondria from placentas or other things that are not mine, but put it into my stem cells. But is there a problem with foreign reaction to foreign mitochondria like that, even though they're my stem cells?

Speaker 2:

So that was the million dollar question. Right, I was thinking about it for 13 years. A year and a half ago, we started dosing patients with this allogeneic mitochondria from a foreign donor and you know what? There is no immune response. And even if we re and you know what, there is no immune response. And even if we re-dose patients, there is no immune response against the allogeneic mitochondria because they are hindered inside the cells. So as long as they're inside the stem cells and they are not just, you know, swimming in the blood, then there is no immune response. We do not observe. And we are testing in the clinical trials. We are testing anti-mitochondral antibodies none and we are testing whether there is an immune response against the mitochondria and we don't see any immune response. So it's actually very safe. As long as there are inside your own stem cells, there is no active rejection of this mitochondria.

Speaker 1:

And I mean I love stem cells and of course they, you know, for all the reasons you mentioned, they're you know, they're great and they do wonderful things. But there are challenges around about stem cells. It seems like you could take as an alternative maybe not as effectively, you could take these allergenic mitochondria from the placenta and just put them in my normal cells, just a blood transfusion, and stick them in the white blood cells or red blood cells, I don't know and infuse them that way and they would still get out. It wouldn't be the power of the stem cells going to the marrow and everything. But is that effective or it's just not worth it without doing the stem cells?

Speaker 2:

So it's not that easy and in order to infuse the mitochondria and get them into the cells, that requires very delicate processes and culturing conditions that allows them to go in. So, again naively thinking, we thought yes, just like you, yes, let's just infuse, they will go into the blood cells, they will be delivered. But that doesn't really what happens and I think thinking about an individual that needs to come every week or a month or two months to get these infusions that's actually the quality of life is not that good. But thinking about a therapeutic process I mean those steps of stays in the body for years. Afterwards, what if you come once a year and we get you tested? Okay, remember the biomarkers we spoke about. Let's get your blood tested. We'll see if you have a mitochondrial dysfunction. If you do, let's treat you with mitochondrial augmentation and you'll come back in six months. We'll tell you what's the efficacy of the treatment, how improvement you made with your mitochondrial function in the blood, and when you come after a year, if we see that there is drop of function, we will propose another treatment.

Speaker 2:

But it is all scientifically based. It's not just, you know, I feel weak or I don't feel very well. Oh, I took exosome therapy and it's wonderful, it's working on me, great. But how do you measure that? How do you really know what's the dose that you need? How frequent do you need the therapy? That all requires very rigid science that will tell you exactly what is it that you are doing.

Speaker 2:

We are all trying to improve our mitochondrial function. We know how good it is. We sometimes change our nutrition or we take supplements and we think we know what, what we are doing, but we don't know because no one is measuring it and no one shows us the results of all these dramatic changes that we are doing to our lifestyle, but how eventually it impacts our mitochondrial function. So I think it needs to be a combination and eventually, rather than just coming for infusion frequent infusions that you don't know what's going on inside the body, having a very controlled drug product, your cells enriched with mitochondria, qualified before you infuse them back, so you know exactly what you are infusing. And now you come back once a year you get another treatment. I think that's you know. It's maybe less scalable than just infusing everyone with everything and whenever they want, but perhaps more scientifically based and stronger.

Speaker 1:

Yeah, no, I love that approach is like you say with with exosomes or stem cells. You just, you know, infuse them. People feel better, or maybe they don't, or who knows. Or I mean, I take rapamycin, but how do I know if it's working? You know, autophagy, how?

Speaker 2:

do I know?

Speaker 1:

you know there's no measure, there's no test for it, and you know it's a leap of faith and I love that you're doing this. And, specifically, I guess there's a few things that need to be done. As we discussed already, the mitochondrial function test needs to be in place, and how far away are you from that? First of all, or is anybody from that? What do you think the future holds for that?

Speaker 2:

So first of all we developed the biomarkers alongside the therapy itself. And the therapy started with an ultra-rare pediatric disease called Pearson syndrome and then we moved into an age-related disease. So I do think we are making progress. So the Pearson syndrome is just 100 patients in the world. The regulatory path is very fast to get approval and it's very clear to see the impact on these patients because they are suffering multisystemic.

Speaker 2:

You know, seeing a child six and a half years old in a baby stroller and then two months later he's running in a shopping mall. I mean, this is it's unbelievable to see the impact of the therapy. But it's a child, right, you say. Well, his tissues are more generative. I don't know what the impact will be in an elderly individual. Could it be reversible? We don't know. So we went into an age-related disease. We went after myelodysplastic syndrome. We wanted to see a very clear outcome measure like anemia. So patients with hemoglobin 5, 6, 7, treated with every possible therapy and then there are no, really they are not responding. They are blood transfusion dependent. They are coming every week to get their blood transfusion and then you treat them and now you see the hemoglobin start to rise, the blood transfusions go down. But these patients are suffering other things. Right, they are 78 years old. Can you measure their kidney function? And all of a sudden you see some improvement in kidney function. Maybe they feel better, they have more energy, they're walking better. So this gets closer and closer into a therapy that will be widely available.

Speaker 2:

While we developed the biomarker, we said let's use them in our clinical trials and let's see now how the biomarker speaks with the clinical outcomes. So this is an ongoing process. While we are measuring the biomarkers before and after treatment at different time points, we are also measuring the biomarkers in healthy controls, different ages and in known genetic diseases. So now you have a threshold. This is a patient with a mitochondrial disease. This is a patient with a mitochondrial disease. This is a patient with a healthy mitochondria.

Speaker 2:

And now let's measure patients with Alzheimer's disease, let's measure patients with Parkinson's. And now we can extend our ranges and make them more personalized to specific therapies. So it will take a little bit more, but seeing the safety and efficacy of the treatment already in these very you know, very sick individuals gives us more and more confident that we can start treating elderly individuals. Where we measure the mitochondria, we know it is dysfunctional and now we can provide a treatment. I think we're ready for that. I think you know stem cell therapies have been widely used, but no one could really tell how effective they are. And this is the you know, the news that we bring to the world. We can really determine the efficacy.

Speaker 1:

That's great. So these two trials are ongoing with the pediatric disease and that one disease, and and and that one. That that's great. And then and then, and this is again with uh autologous stem cells and allergenic uh placental mitochondria that come in and everything. What is the, what is the cost for that? I mean that obviously come down. Um, what, what?

Speaker 2:

yeah, we believe it will be tens, tens of thousands of dollars.

Speaker 2:

So it's not a pill or not a simple injection just the process of, you know, collecting the stem cells from the patients, walking under good manufacturing production guidelines in clean rooms and GMP facilities, and doing all the analytics to make sure that the product eventually is very well characterized before infusion and then doing the biomarkers. That all will you know, eventually cost a few tens of thousands of dollars. This is currently something that we are working on to try to price, but again, it will be once a year, maybe once in two years, really depends on the impact and or when did you treat the patient.

Speaker 1:

Yeah, yeah, that's amazing. Well, just taking a magic wand, what do you think? Where do you see this field in five years? Or pick whatever goalpost you want. What does the future hold for this?

Speaker 2:

Oh, the future, and I don't know anywhere between five to 10 years, I think, with the cumulative clinical data that we have and we are still gaining. I think there will be a lab test, just like you test your hemoglobin and red blood cell count. There will be a blood test for mitochondrial function and people will do this as a screening just to know if a patient is going to suffer mitochondrial disease, and then mitochondrial augmentation will be proposed to anyone who goes below a certain threshold that we will determine for a healthy individual. When you go below that, you need to receive the therapy and that will be subscribed for anyone that does this test a healthy individual. When you go below that, you need to receive the therapy, and that will be subscribed for anyone that does this test, and it will be widely acceptable and everyone will do it at the home clinic. That's what will happen.

Speaker 2:

That's my dream and my vision for the field of mitochondria. For me, it is unbelievable that there are no mitotests in your clinic. I just don't get it. I mean, the strongest signal for health is how well mitochondria are doing.

Speaker 1:

Yeah, no, that's true. Are you familiar with the San Diego one, the Me Screen test, and that doesn't really answer the questions? Then right for you. I don't think it is direct Exactly.

Speaker 2:

You spoke about how to measure directly your mitochondrial function. So many things impact the metabolism, even your food. When did you eat? How did you sleep? So many things, but eventually you want to be able to clean out. This is just mitochondrial activity. This is what you should have. That's what you have today, and I think the diversity of looking indirectly at metabolites or different, you know, non-direct functional assays, I think it's good maybe for screening, initial screening, but that will not be a diagnostic tools, in my mind at least.

Speaker 1:

Yeah, yeah, no, that's there. On the studies that you're running right now, I wonder. It's not a perfect test, but more and more we're seeing epigenetic methylation clocks being applied to. Steve Horvath just published one on plasmapheresis, total plasma exchange and that effect. But of course you can see decrease in biological age just with vitamin d or with exercise or you know, it's not a perfect thing, but they are starting to apply it now with rapamycin and other things. Are you? Are you looking at that with your group at all?

Speaker 2:

so we definitely want to go there. This is why we also want to participate in the x price, because then we can share information and combine some technologies, because I think, when you are talking about mitochondrial function, if we improve mitochondrial function, it will probably impact also epigenetics, methylation, etc. Even telomere elongation is known to be dependent on mitochondrial function and and vice versa. Okay, if someone is impacting methylation, it will also impact mitochondrial function. So I think the combination will eventually become like a very wide clock that measures many things.

Speaker 2:

Aging is not a single element. It's very, very, very complex, and I do look forward. If you spoke about the vision and how, what will happen in five to 10 years, there will be several tests that can tell us really how to measure our health and how to influence our health, because it's all in our hands. I mean, we can really do it. We can really change the fate of what will happen to us.

Speaker 2:

There is the genetics, it's true, but there is more than that. There is the environmental. There is the food that we eat, the sports that we do, the supplements that we take. So there are many, many others, and they impact in multi-dimension. It's not a single thing, and this is what I love about mitochondria it's not one molecule that affects one pathway, it's a whole organelle that touches on every event that happens in the cell. When you do that now, you know, when you transplant this mitochondria, you know you're going to have a huge impact. Thousands of proteins, so much activity happening in there. You know, just a single mitochondria going into the cell, wow, what you get, it's a completely mind-blowing effect.

Speaker 1:

Well, I want to be sensitive to your time. I know you have a commitment here. Is there anything that we haven't talked about that you'd like to bring up before we wrap up?

Speaker 2:

So I really think that you should pay attention to the field. Be careful about just promises, whatever you know infusions of mitochondria, we should all be aware of how the regulatory agencies are looking into it. Sometimes people think about regulatory agencies like they're kind of the enemy, but no, they look after health eventually. And when we follow the guidelines into these diseases, of course we want to protect the patients and we want to make it as safe as possible. I will tell you a small story. Okay, when we went for the Pearson patients this is an otologist stem cell transplant, a hematopoietic stem cell transplant Every hematologist wants to condition the patients before you apply the stem cells. They say give some chemotherapy, clear some space in the bone marrow so the cells can engraft, Thinking safety of the patient and eventually, availability of this therapy to as many patients as possible. If you come to me and tell me treat your mother, I will never give her chemotherapy to get this treatment. So I said no, no way. Mitochondrial augmentation I will actually prove that the cells who are augmented with mitochondria have a benefit that makes them engraft and outcompete the other cells in the bone marrow because they are healthier, because they have stronger mitochondria, and we proved that and we actually prevented the need in chemotherapy that will come alongside this therapy. So, while you keep in mind all the safety issues, I mean, of course it's cheaper, it's faster, it's way more scalable to just infuse mitochondria to people.

Speaker 2:

I would actually be very careful. The benefit versus the risk could kill the product eventually. So I'm looking very far away and I'm saying one, make sure this therapy is safe. It is 23 patients treated. It's amazing. Two it's working. We see transformative effect in the patients. And three, we can actually measure it very clearly, very accurately, very reliably. We can tell you exactly what's the benefit that you're receiving from this. And I think I would ask this from every therapy that comes to me If it's rapamycin or if it's metformin or whatever differences we are making into our bodies, let's make sure we know what the impact is. Let's make sure it's safe and healthy for us to take it. So this is you know, whatever changing diet you are doing, let's make sure you know what the outcomes are and you have a way to measure it.

Speaker 1:

So let me unpack that a little. So the conventional medicine recommended the experts recommended in your trial with the pediatric patients that they undergo a chemotherapy to kind of deplete the bone marrow, open up space so that when you did the stem cells into the bone marrow they'd have space for them, sort of. But that was not necessary and you were able to show that it wasn't necessary. And that's obviously a big hurdle for mitochondrial transplantation. You don't want to have to go chemotherapy to do it in the first place. Then the second point was, as far as regulatory things, that we need to be careful about infusing mitochondria directly into the body because of the foreign protein and all sorts of all sorts of the DNA and everything, all sorts of things we have to do, so the using the autologous stem cells with the allergenic mitochondria.

Speaker 1:

That protects the mitochondria from their immunogenic effects because they're already in these cells, and so it's it's key to have something like that to avoid possible reactions and possible effects down the line with that.

Speaker 2:

Exactly. And, rob, you know what. We are killing two birds with one stone, because not only are we transplanting healthy, young and functional mitochondria, we are impacting the immune system. So when I thought about, you know how we can mostly impact aging, two of the major hallmarks of aging are mitochondrial dysfunction and immune dysfunction. So now we are targeting both of them through the hematopoietic system. So you know it's having two birds at once.

Speaker 1:

And just to play the devil's advocate, if I take my stem cells and I extract my stem cells and I rewind them using Yamanaka factors or other things and then inject them in, I won't get my stem cell mitochondria won't be rewound necessarily by those epigenetic rewinding factors. So I'll still have my old mitochondria but my young pluripotential stem cells. So that's a problem with stem cells right now is we need to address mitochondrial aging and if we just do stem cells alone without thinking of the mitochondria, that could be problematic, right?

Speaker 2:

Exactly exactly and I think maybe a combined therapy. So if you want to renew your stem cells with the aminococcal factors, bear in mind that you also need to renew your mitochondria. So maybe a combined therapy will be highly valuable, but just the bottom line, always mind your mitochondria In every therapy that you do always think about how the impact will be on the mitochondria and whether you're taking care of them. Yes, in general.

Speaker 1:

And there is no analogous epigenetic, partial epigenetic reprogramming for mitochondrial DNA, because there is no epigenome in mitochondrial DNA, unlike nuclear DNA, right. So there's no analogous thing to unwind. Instead we get younger mitochondria from the placentas or elsewhere that are even better perhaps.

Speaker 2:

Yes, exactly Better from the start.

Speaker 1:

Great, well, this has been so much fun, natalie. We'll link to your website for the company and the show notes and everything. Maybe tell them the name of the website also and how they can follow you on social media as well, for people that are listening to this just on audio.

Speaker 2:

So we are Minovia Therapeutics and our website is minoviatxcom, and you're welcome to follow us on LinkedIn as well and in the website, and thank you.

Speaker 1:

Yes, this has been great fun. Thanks, natalie, for spending time with us and thanks for all the great work you're doing, and hopefully I'll see you in Copenhagen, maybe by Zoom, but our paths will cross there.

Speaker 2:

Wonderful. Thank you so much, rob, it was a pleasure.