Gladden longevity — Episode #34

Speaker 1: Welcome to the Gladden Longevity Podcast with Dr. Jeffrey Gladden, MD, FACC, founder and CEO of Gladden Longevity. On this show we want to answer three questions for you. How good can we be? How do we make 100 the new 30? And how do we live well beyond 120? We want to help you optimize your longevity, health and human performance with impactful and actionable information. Now, here's today's episode of the Gladden Longevity podcast.

The Gladden Longevity Podcast is provided for informational purposes only. It does not constitute medical advice. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of a physician or other qualified health provider with any questions you may have regarding a medical condition. The use of any information and materials linked to this podcast is at the listener's own risk.

Dr. Jeffrey Gladden: On today's Gladden Longevity Podcast, I'm going to be talking with Chris Mirabile. Chris is a fascinating individual who at a young age came to grips with his own mortality, and from that, even though he is only 38 now, has really dived into the whole longevity space, biohacking space, and has developed an interesting company with a product that's designed to address all nine hallmarks of aging simultaneously. I think you're going to love this podcast. It's a very interesting conversation. We talk a lot about a lot of different really important things for you to understand. I hope you enjoy it as much as I did making it.

Welcome, everybody, to this edition of the Gladden Longevity Podcast. I'm your host, Dr. Jeffrey Gladden, and I'm here today with Chris Mirabile. Chris is a very interesting guy and you're going to learn a lot from him in terms of how he's hacked into his own longevity. He's started a company around this and I think you're going to be very interested in his products as well. Chris, welcome to the podcast. It's great to have you today.

Chris Mirabile: Thank you. It's a pleasure to be here.

Dr. Jeffrey Gladden: The audience doesn't realize this, but this is probably about the third or fourth time we've attempted to record this but having some technical difficulties here. So, appreciate Chris's patience in that regard. Bring the audience up to speed a little bit. What is it that got you really interested in your whole health journey, your whole longevity journey?

Chris Mirabile: Sure, I'd be happy to. When I was 12 years old I started to get interested in health and exercise. I had seen an issue of Men's Health magazine on the newsstand, and I was inspired by the people in the magazine. I started to exercise and watch what I ate, all with the superficial intention of being attractive to the girls I had a secret crush on.

Dr. Jeffrey Gladden: Well, that's a good reason. What else do you need?

Chris Mirabile: I thought so. Well, ultimately when I was 16 years old, I had a sudden seizure while on a school trip in New York City, and it turned out that it was caused by a brain tumor. And so, at that point my interest in health, it evolved rapidly from being superficially focused to biologically focused. I wanted to understand why despite me exercising more and eating healthier than my classmates, why did I get the brain tumor? And that was a question that nagged at me for years.

Dr. Jeffrey Gladden: This is a big deal because you were only 16, you were probably on the verge of getting a driver's license and then starting to think about dating and all these things, and all of a sudden you're hit with a seizure and a brain tumor. This is a massive shift in your life. It must have been a huge impact on you.

Chris Mirabile: Yes, it was. I went from playing on the football team and having some parties with friends over the weekends to suddenly spending my weekends writing poetry in the woods and journal entries and thinking about existential questions and what I wanted to make of my life and so on. It was a radical transformation that took place.

Dr. Jeffrey Gladden: Right. It's interesting because we find that for many people it's when they face their own mortality that they have a shift in their thinking, and that could happen in their 50s or 60s. Somebody has a heart attack, somebody even develops diabetes or high blood pressure, and all of a sudden it's like: “wow, okay, my physiology is failing me.” And here you are at 16, on one hand being hit by this, but on the other hand, being given the gift of actually understanding that your physiology is fragile and that it does have mechanisms behind it, and when they go awry, all of a sudden it has a massive impact on your life. On one hand, I can see that that almost was a gift for you. You're out there asking these existential questions. That's pretty interesting for a 16 year old.

Chris Mirabile: It was definitely a gift. That's how I have made a conscious decision to characterize the experience, as a gift. It transformed my perspective on so many different things in life, and it also implanted the seed of what is now the company I've started, NOVOS, and the direction that I'm going in my life and many, many other things over the course of the years since then. So, yes, it was definitely a gift.

Dr. Jeffrey Gladden: What did you figure out? Obviously, you're coming to grisp with your own mortality, you're moving into: what is the meaning of my life? How am I going to spend it? You're probably asking questions, how much time do I have? All these kinds of things. What were you able to figure out about the tumor itself? Were you able to lay it to rest, so to speak, or where were you with that?

Chris Mirabile: Not entirely, but enough for me to move on. What particularly bothered me was the neurosurgeon had told me that the chances of me having a recurrence of the tumor was the same as for anyone else to get the tumor in the first place. That it was a very random chance mutation that led to the tumor in the first place, and that I should not be worried about it coming back. And, of course, I'd love to not be worried about it coming back. But naturally, when you go through an experience like that, it is in your mind. How can I prevent this from happening? Why did it happen in the first place? I started to dig into my genetics. At the time, it wasn't a full genome sequencing, it was just the 23 and me subset of genes. But enough for me to then be able to export that data into other genetic tool sets to be able to dig deeper into what my genes say about me.

And I did find that there were a couple of genes that could increase the likelihood of a brain tumor, not by an enormous amount, let's just say it's one in a thousand approximately, the chances of getting a brain tumor, my odds were maybe more like one in seven or 800. But that was enough for me to feel a little bit more, I wouldn't say at ease, but that I was comprehending the rationale, the reason for it, that it could be slightly genetic combined with the transmutation, maybe even environmental reasons that I didn't know of at the time, like high sugar diet for most of my childhood, for example. That was enough for me to be able to start to move on, but it also then opened up the world of genetics and the fascination for that.

Dr. Jeffrey Gladden: Absolutely. You basically were trying to unravel or nod around what caused the seizure and the tumor, and then that opened up the whole spectrum of genetics that can tell us a lot about ourselves. What was the transition from there into a more broad interest, if you will? Was it like, I've had this problem, now I want to go out and protect all the other assets of my life that I can to ensure or minimize the risk of this coming back and also minimize some other untoward thing coming? Was that sort of the thinking, or was there just a general other reason for it?

Chris Mirabile: I wish I had that foresight and from the beginning had this vision for focusing on longevity. It wasn't that immediate. I went from there to understanding my genes better. And so, learning, for example, that I was homozygous for a genetic polymorphism called MTHFR C677T, which I'm sure you've come across before. And that homozygous mutation led to me not methylating properly. And so, digging into the research of, what are the things I can do to improve my methylation and detoxification, methylation is something that we can talk about in terms of its relevance to longevity if you'd like to at some point during this conversation.

But I started to, for example, supplement with methylated forms of B vitamins to get more methyl donors in my diet. I experimented with trimethylglycine, that was too intense for me, and I settled with choline and trying to get it from food sources, for example. And that's just one example of the steps that I was taking towards optimizing my health. I saw step function improvements in my performance, my clarity of thought, my lucidness in terms of just perceiving what was happening around me, energy levels and so on. All the while I was also, I had met a very famous biohacker, so to speak. I had a one-on-one sit down with this person and was drawn to the concept of biohacking.

I started to experiment with that as well and do my own research to try to find things that would be beneficial to me. All the while I stumbled upon this concept, which I didn't know at the time, but I've since learned, there is a scientific concept behind it called antagonistic pleiotropy. And this is where there is a turning point for me and the realization of the importance of looking at health through the lens of longevity. Because what I was questioning was, is what is being recommended to me today good for me, not only today, but also in the long term? With that experience of having had a brain tumor in mind, I wanted to make sure that what I was doing today would be good for me in the long term.

And antagonistic pleiotropy is the idea that what is good for you today can actually come back to harm you in the future. An example of that could be, I'll just give a very simple one. If you get a lot of sun exposure, UV rays, in the short term it could be good for the sake of vitamin D production, nitric oxide production, which is a vasodilator, so it improves your heart health, your cardiovascular function, but in the long term it could come back to haunt you in the form of melanomas or skin cancer. And so, with that in mind, I started to ask, are the things I'm doing today good for me not only in the short term, for my short term health or performance, but also in the long term? Is this going to actually come back to haunt me in the future?

And when looking at things through that lens, I then realized that there was a lot more to health than what was being presented to me, and that drove me towards longevity.

Dr. Jeffrey Gladden: That's a really, really wise statement right there, because I think you see a lot of people in the longevity space focused on a particular outcome like, it's all about muscle mass. If we have muscle mass that's a really good longevity benefit. We're going to step on the mTOR gas pedal all the time to try to build muscle mass and bone density. That's a currency of longevity. I've heard that said so many times, muscle mass. And yet really biology is this economy of balance is the way I describe it. And so, to your point, it's really about sunlight is good, but too much sunlight is bad, and maybe you're increasing your risk for melanoma.

I think this antagonistic pleiotropy, really the way to play that game is through a thought process that focuses on balance, right? Where you're paying homage to what's needed today but you're also doing it in a very conscientious way to pay homage to what's going to be needed in the future. And there's some other interesting genes around there, like the APOE4 gene, I'm sure you're familiar with, provided a survival benefit in terms of increased inflammation and accelerated inflammatory response. And so, a thousand years ago, that was advantageous if you got cut, if you got bit, if you got whatever else. But now, it's associated with increased neuroinflammation and a higher risk for Alzheimer's or dementia or cognitive decline.

So, learning how to play the genes actually to the optimal benefit is really a big part of this whole thing. And just to circle back to the methylation question, talk to us a little bit about some of the insights that you've garnered there. I have some methylation issues as well, and my father actually died with dementia, and I don't have any of the APOE4, I'm APOE 33. I don't have epoxy one. My TOM40 is normal, but I have an MTHFD1 gene that increases the risk for depression and dementia. And then I have an MTHFR mutation as well and some other ones. It's important for people to understand that these mutations can have an impact not only on longevity, but also on the quality of your life.

You're talking about being more cognitively alert, feeling brighter, a little bit of increased energy, things like that. So, really understanding your genetics and going after it in this balanced approach is really key, not only for the short term, but the long term from my perspective, I would say.

Chris Mirabile: A couple of things came to mind while you were speaking. One is just rewinding a little bit, is the point about when you mentioned APOE, evolution only needs us to be able to procreate. Right? It is really for us to get to maybe 30 years old or so. And by then, we've had a few children and then evolution doesn't really care what happens to us anymore. And throughout history that was the average life expectancy up until recent times. For us to be able to go much longer to reach 90, 100, 110, 120, and to be in really good health in the process, we need to really rethink things. And so, taking a historical perspective, let's just say a paleolithic perspective of maximizing protein intake and mTOR activation like you mentioned, build muscle, feel really viral, and energized and so on.

That might not necessarily be what's best for you in the long term for you to avoid disease and for you to have very good health lasting into 90s or 100 plus. But there are things that you can do where if you are mindful of antagonistic pleiotropy, like I mentioned earlier, where you can to your point, balance things and you can optimize your health here and now you can optimize your performance in all senses of the word, whether it's psychological performance, physical performance, and so on. And you can also maximize your longevity. And that's something that we as a company, the company I started, NOVOS, we really try to position ourselves based on the latest research in the middle of the three of those.

So, if it was a Venn diagram where all of those three concepts intersect, what can we do to maximize all of those? And that's what we focus on. To your question about methylation specifically, some of the insights I've come to is that, first of all, there is such thing as over methylating. I alluded to that when I mentioned I experimented with the supplement, trimethylglycine. Trimethyl has three methyl groups attached to a glycem molecule. So, it's a lot of methyl donors. And it's not as rate limited as something like choline, which also provides methyl donors, but not as aggressively. There is a balance, again, to your point of you can go too far with methylation, you can also do too little methylation. And if you're not methylating enough, maybe we can give a better context to the audience.

Methylation is basically activating and inactivating genes. You've got your genome that is like the piano keys, and then the piano player is like your epigenome, your epigenome being the layer above your genome, which genes are turned on and off. And the way genes are turned on and off is through the process called methylation. So, a methyl group will be attached, and typically that is inactivating a gene, not always, but typically it's inactivating a gene, preventing it from being able to exert its effects, so to speak. And so, why and when are we going to need to turn genes on and off? It's based on environmental signals, environmental cues. So, if you're exercising a lot, you're going to turn on certain repair genes, whereas if you're sitting on a couch and you're not exercising, you don't need those genes to be turned on.

So, for your body to have the ability to respond to the environment, it's critical that you can properly methylate. And if you don't properly methylate, you might not repair your body in the ways that you're supposed to, or you might not produce, to your point about depression, you might not produce the neurotransmitters that you need to be able to feel happy or alert or content with life or motivated to achieve something. There's a lot of different things that methylation really impacts, practically everything when it comes to our physiology.

Dr. Jeffrey Gladden: It's interesting. There is the methylation of the DNA itself, which is as you say, modulating gene expression. And then there's the methylation pathways, which are also responsible for making certain neurotransmitters like dopamine and serotonin and things like that. Things like glutathione and other molecules that your body needs. The methylation is both modulating, just so the audience understands, it's both modulating DNA expression and then also modulating cellular metabolism in terms of how it's making certain molecules that you actually need to function optimally. It's really a fascinating area because it crosses over into both sides of that equation.

It makes it a very, very critical area for people to understand their own genetics, around methylation, if you will. I think it's fascinating that you taking the TMG, the trimethylglycine, that you found that that was too much. What did you experience with that when you felt it was too much?

Chris Mirabile: Surprisingly, I felt a little bit foggy brained and tired, sleepy. It isn't immediate, it takes place hours later, but by the end of the day or a couple of days into it, I look back and I say, I haven't been feeling my best in the last few days. And when I pull it out, then I'm feeling back to normal again.

Dr. Jeffrey Gladden: Cool. I think that's a good takeaway for the audience too, is that just because something looks good on paper, you have to feel into it. You have to play with it and see what's going to work best for you. So, with all this, you then became fascinated with, how do I optimize my longevity? And from there you decided to start a company. Now, I think you're a serial entrepreneur if I'm not mistaken, right? You've started a number of different things, kudos to that. That's always a great thing, and I love people that have that mentality. Tell us a little bit about how you moved into starting NOVOS and how you pulled it together, what the vision was, and then what you've created there.

Chris Mirabile: Sure. To your point about being a serial entrepreneur, that was partly motivated by my experience with the brain tumor and the existential questions of, what do I want to do on this planet, my brief time here? One of the answers was, I want to have an outsized influence, a positive influence on the world. I felt like if I was just working for someone else, I would not be able to bring my creative visions to manifest them nearly as effectively as if I was an entrepreneur. In terms of my decision to start NOVOS, I had come across the seminal paper called The 9 Hallmarks of Aging. It was published in, I believe, 2014. And that really got me interested in longevity, understanding that there are biological causes of aging, and that we've identified them and that there are ways to potentially offset them or slow them down to therefore slow down the progression of diseases of aging or the aging process in general.

But I didn't know what I could do in the space. My experience as an entrepreneur was on the technology side of things. I had started tech ventures, but as I hope is becoming apparent, I've always had this passion about health and going to the science side of health rather than just mainstream health. I was volunteering at NYU Medical Center, the hospital where my brain tumor was removed, in the pediatric ward because I had promised myself when my life was spared that I would one day give back. I was doing this in my early 30s. One day when I was leaving, I saw a poster on the wall for the mitochondrial summit, which most people would just walk right past it. But that was something that excited me. And I saw some of the scientists who were presenting were scientists who I was familiar with their work.

For example, Dr. David Sabatini was there, he is at MIT, famous for his work with mTOR and rapamycin, for example. And so, I wanted to go there, first of all to learn, but more importantly to actually corner them and ask them some questions related to ideas I have been playing with in my mind, essentially to find out what their perspective was on natural substances and their ability to impact the hallmarks of aging or these pathways that can impact the hallmarks of aging like mTOR or AMP kinase and so on. And when I spoke to them, I was actually pleasantly surprised that they were very optimistic about the potential of the ingredients that I had brought up to them.

And I was surprised because as I'm sure you're familiar, most medical doctors are very pessimistic about supplements. They think that you're creating expensive urine, is the common phrase that I hear, and that you just eat healthy and exercise a little, and that's enough. But we know that that's not the case. There's plenty of science. There's plenty of snake oil out there as well, but there's plenty of science for very powerful substances. And, in fact, some of the most powerful prescription drugs were derived from nature on the topic of longevity, metformin and rapamycin were both derived from nature, aspirin as well. There's a lot of power in nature. And so, I was pleasantly surprised as I mentioned, and that was enough of a validation point for me to say, there is something here, some potential to take advantage of and to try to improve my health and those of my loved ones and then in the community at large.

Because everything that had been done at that point in the field of longevity medicine was being done on the biotech side, very advanced therapies, everything from DNA modification to inventing new molecules. And we're looking at 10, 20, 30 years before these come to market, they might fail. There's much higher risk for these approaches. They have to be for a specific medical indication for the FDA to approve them, because the FDA doesn't treat aging as a disease, at least they don't yet. There's a lot of roadblocks for me, or my loved ones to be able to integrate this into our lives.

Dr. Jeffrey Gladden: I'll just intersect that also the whole pharma model of intervention for aging, I think is inherently flawed, because in the pharma model there's a pathway will go in and interrupt it or will go in and push on something, but then molecules get shunted around that blockade or whatever it is. And so, you end up with side effects and other things. It's really not a very biologically simpatico kind of approach. We're just going to go in and throw up a dam here and stop inflammation. That's why we've become so enamored with peptides as a way to actually set off a healing cascade of aids within the body. I think natural molecules as well are part of that, particularly if you get them in a good way and their bioavailable and all these kinds of things.

If you check all those boxes, I think they can also have not just a singular effect, but really help create a cascade of effects within you, that actually push you into a more healthy state. I think that's a much better approach. That being said, supplements can act like medicines. Berberine is very much like metformin, things like that. We have things that are very similar, but even metformin has a number of therapeutic things that it does. It doesn't just do one thing. I like the approach of using the supplements, and it is interesting that when I look at journals like JAMA or something like that, well, here's a study on the use of something for an indication. It could be chondroitin sulfate for osteoarthritis, let's say.

And inevitably, they give the wrong dose to the wrong people, for the wrong period of time, and then they conclude, well, this is useless. It's worthless. Right? And you see that over and over and over again, and it's almost like pharma/the medical industry has a vest in interest in disproving that supplements can actually be helpful, is really when you read the articles, that's almost the mindset that you come away with. It's like they're really not interested in seeing this work.

Chris Mirabile: I agree with you. There's a tremendous amount of potential with these ingredients, and you make a great point in terms of the dosage, the time duration, the types of people who are being studied, so on and so forth. Oftentimes the studies are too short, they're not getting the dosage right, or it's not a large enough sample set, so they don't have the statistical power to conclude that it had an improvement. But meanwhile, you look at the results and you're like, yeah, there's pretty good indication here that it is working, even if not to the statistical confidence interval that one would ideally have.

Dr. Jeffrey Gladden: With the people that are so sick that it would be a miracle if it could reverse it. And so, then it's counted as well to see it obviously doesn't work, whereas if it was used earlier in the disease course, it might have a dramatic impact. It's interesting. Anyway, and when the audience is hearing things like that supplements don't work, this and the other thing, yes, always look at things through a critical lens, but also understand that there seems to be a lot of bias on the medical community side to point out that these things are not helpful. They almost seem to have that bias. They want to see them fail almost.

Chris Mirabile: I once heard the statistic, I haven't looked up how accurate this is, but that approximately 50% of the medical doctor curriculum in terms of the studies that are cited during your coursework is actually studies funded by the pharmaceutical industry. And then, approximately half more or less might be from public funded studies like NIH and so on.

Dr. Jeffrey Gladden: That's right. Pharma funds a great deal of research. And then the other interesting thing is that there's a lot of, what shall I say? There's bias in the editorial groups that basically are running the journals. They also have a bias. Well, they'll discount articles that are very publishable, have good data, but they just don't like what the outcome is. There's been a lot of that with a whole recent viral illnesses where therapies have been shown to be effective, but nobody can get them published in a reputable journal, even though it's reputable research because of the bias of the editorial board.

The more I look into it and the more I experience it as we go through different challenges, community challenges with health, et cetera, it's really stunning that there is this fairly strong bias towards “this is how it is and everything else is going to fail”, anyway. You're working obviously on the side of no, we think we can create something that actually is helpful. Tell us a little bit about that. Tell us what you've actually created and how you think it's helpful.

Chris Mirabile: Sure. I started the company NOVOS, which you can find at novoslabs.com. The vision when I started the company was to be the first company to address all of the hallmarks of aging simultaneously. The perspective being that if you're only addressing one of the hallmarks of aging, say mitochondrial dysfunction or genomic instability, that you're only addressing one small piece of the puzzle. If you take an analogy of a car, you might only be repairing a flat tire or replacing the muffler in that scenario, when you really need to maintain the entire car for it to be running optimally for the long term. And so, we were the first company, and to my knowledge, the only company to this day that addresses all of the hallmarks of aging simultaneously.

And in fact, we added one hallmark to the nine, based on scientific research, which is crosslinking. A lot of scientists that we work with and advise us, agree that crosslinking should also be included in the hallmarks of aging. The very first formula that we brought to market is called NOVOS Core. It's the foundational supplement in the NOVOS lineup, and it consists of 12 ingredients that address all 10 of these hallmarks of aging. Each of the ingredients needs to have research supporting it to extend healthspan and or lifespan in ideally multiple species. By seeing the ingredients improve healthspan and lifespan in multiple species indicates that it is most likely an evolutionarily conserved pathway.

In other words that if it works for worms and flies and mice as well, it is most likely something that will also extend itself into humans, like the mTOR pathway, for example. And the reason that we look at it in that perspective is because, as you know, it is incredibly difficult in terms of cost and time to be able to do human lifespan studies. It is practically impossible. You need decades and thousands and thousands of people to have a large enough sample size and it costs tens and tens of millions of dollars or more than a hundred million dollars. So, for us that's not realistic. So, we have to look at other markers and indications. In fact, if you go to our website, novoslabs.com/evidence, we have 10 different rules or filters that we put ingredients through before we decide if it is adequate to be considered for a formulation.

And then, of course, after we get through those filters, we then look at the formulation holistically and make sure that there are no counter indications or that any of the ingredients are overdoing something. For example, hormesis. We don't want to overdo the hormetic stress because that's going to end up being an inverted U in terms of the value of it. We want to be at the peak of that U shape chart. So, those are the filters that we put everything through, but we don't stop there. Even though we have more than 190 scientific studies to port the inclusion of the ingredients, and we have a team of six world class longevity researchers out of Harvard, MIT, and the Salk Institute, people like Dr. George Church who's at Harvard then MIT, he invented the first direct genome sequencing method in 1984.

These are world class scientists that have been part of the journey with us in formulation and scientific studies. We are also running to that point, scientific studies. The first two that we published, you can also find on that evidence page towards the bottom in section five. And one of those studies was looking at DNA damage. This was an in vitro human cell study, where we irradiated these human cells with NOVOS, without NOVOS, and then also had the control of NOAA radiation. We found that we were able to reduce DNA damage by as much as 77%. And, on average, I believe it was 68% reduction in DNA damage. The lab, it was a third party lab we worked with, was so surprised by this result that they called their CEO to tell them, because they had done $7 million worth of studies prior to us, and they had told us before we started the study, to not expect any significant results, because they had done so many studies with individual molecules and pharmaceutical drugs and so on, and they didn't see any significant results. And for us, they did.

That was the first study. The second study we ran was looking at cellular senescence, which is another hallmark of aging. Senescent cells are like zombie cells, so the cell is no longer able to function and it secretes inflammatory molecules called a SASP, S-A-S-P, that can then cause other additional damage to nearby cells and inflammation and so on. And so, the body should rid itself of these cells, but it doesn't. They fly under the radar. And so, this study was done at Newcastle University by an academic who is a world authority on senescent cells, and he was able to show that NOVOS was able to have a senomorphic effect on senescent cells, specifically senostatic effects. So, we were able to prevent those-

Dr. Jeffrey Gladden: Let's explain senomorphic and senostatic and senolytic for the audience, just so they're clear.

Chris Mirabile: Sure. Happy to.

Dr. Jeffrey Gladden: Senolytic in senescent cell, right? Senomorphic will take us a senescent cell and actually make it functional again, technically. And a senostatic would keep it from becoming SASP is what I'm assuming that you're going to say. Is that correct or close?

Chris Mirabile: Right. Yes. Exactly. Senolytic is where there's a lot of research money going right now in an attempt to destroy senescent cells selectively without damaging nearby tissue. Now, that has proven itself very difficult to not damage nearby tissue. Senolytic are something that you got to be careful with. Also, there are researchers like Dr. Judith Campisi, who's an authority on the subject matter, where she was able to show if she destroyed too many of the senescent cells, it actually had a negative effect on the mice that she was studying. There's a sweet spot. And so, our perspective as a company is that until more is known, first do no harm. And what is safer is to prevent the senescent cell from spreading, and ideally also try to reduce its footprint, its physical size.

And so, we were able to reduce the size of senescent cells by more than 40%. And equally as important, the nearby healthy cells were not damaged at all by the NOVOS formulation.

Dr. Jeffrey Gladden: [inaudible 00:36:15] status. The senescent associated secretory phenotype, the SASP cells, were you able to show a reduction in SASP cells or reduction?

Chris Mirabile: That's a follow-up study, is for us to look at the specific SASP, the phenotype of the senescent cells. But what's also very important to note is that the same study was done to the gold standard longevity pharmaceutical drug rapamycin, and our effects were comparable. It was almost equal to rapamycin effect on senescent cells. So, within a couple of percentage points. That was really exciting result. And then, there's a third study, which we haven't published yet, but I can speak about, which was done at the University of Bologna by somebody who studies DNA damage, Professor Lorenzini. And he was able to find that when administering chemotherapeutics to human keratinocytes. So, these are skin cells, that NOVOS was able to reduce single strand and double strand DNA brakes.

I mentioned DNA damage earlier, that was more like oxidated damage, almost like rust on a car. But single strand or double strand break is like splitting the car in half at its axle, right? It's much, much more extreme. It basically makes the cell dysfunctional. And looking at the nuclei of the cells, the marker was looking at foci, how many foci, the more foci the more strand breaks there are. And administration of the chemotherapeutic, one was a strong one, one was an incredibly strong chemotherapeutic. The incredibly strong one causes practically every single healthy cell or DNA strand to have a double strand break. More than 20 foci per sample as opposed to it being less than five as being the ideal.

And then when administering NOVOS, about 25% of the cells stayed within the healthy range as opposed to 0% staying within the healthy range. And then, with the less aggressive chemotherapeutic, the results were even better.

Dr. Jeffrey Gladden: Is that a function of blocking damage or augmenting repair? Because when I look at the ingredients in NOVOS, I see that there's some things there that could activate sirtuins, which can activate DNA repair. And so, do you have a feeling for whether or not you're actually repairing the damage or actually preventing the damage or both?

Chris Mirabile: It's a great question. It's most likely, I would expect, especially in vivo that it would be both. We don't know for sure yet, but based on the research that we did to formulate the product in the first place, it is most likely both. In vitro scenario, I wouldn't be surprised if it's more heavily influenced by protecting and preventing damage, but it's just a guess at this point. We'll have to do additional research to have answers from that.

Dr. Jeffrey Gladden: So, then have you had the opportunity to measure other metrics with NOVOS, like telomere lengths and epigenetic ages? And are you doing anything for mitophagy and autophagy and things like that? Actually, as you go through the nine hallmarks of aging, balancing mTOR and AMPK and some of these things that we know are critical, have you had a chance to measure some of those things or do you have any human studies that have shown? I know that you've done some work on yourself, maybe you can speak to that too. And [inaudible 00:39:44] in the product

Chris Mirabile: Happy to answer those questions. Essentially, you're asking if we have clinical studies, and those are starting soon. So, yes, we do intend to prove this out, clinically, but I can't give more detail in terms of timelines and so on because clinical studies are very time intensive, expensive studies. And so, I don't have any definitive information. We-

Dr. Jeffrey Gladden: We have people that would be very interested to participate. So, anyway, we can be-

Chris Mirabile: Okay. Right up. We can follow up after the call about that. What I can speak of are some anecdotes, which anecdotes, a lot of people critique them, but don't forget when you have enough anecdotes then it turns into statistics, right? It's just an N equals one sample. And so, I can speak about an anecdote of my own as well as a family member who was one of the beta testers for NOVOS. I'll start with the family member. This person was in their early 70s, and prior to taking NOVOS, took an epigenetic test to find what their biological age was, and the result came back as minus one year from their chronological age, which is well within the range of margin of error. It's essentially equal to their chronological age.

After taking NOVOS Core and Boost, our two products for six months, they took the same test again and the result came back as minus 10 years. It was a tenfold increase from what it had been prior, and that is well beyond the margin of error. The only thing that had changed over that time was taking NOVOS Core and Boost, we made sure that this person wasn't changing their diet, adding or removing any supplements or adding or removing any prescription drugs. And their lifestyle didn't change significantly in terms of exercise or time outdoors or alcohol consumption.

Dr. Jeffrey Gladden: So the audience is clear, I think NOVOS Boost is NMN, is that correct, in addition?

Chris Mirabile: NOVOS Boost is NMN correct, which is a precursor to NAD. Yep.

Dr. Jeffrey Gladden: Right. And NAD is obviously important, so two in activation, which is important for DNA repair and modulates methylation also in epigenetic age. It's nice. You're coming at it through a logical biochemical pathway. And then what about for yourself, what have you seen in yourself?

Chris Mirabile: Right. I launched the blog not too long ago, about a month and a half ago called slowmyage.com. The reason I started that blog was because I got a number of biological age tests done, and the laboratory, which is a renowned lab in this specialty, told me that they hadn't ever seen results like mine before. They were so surprised by my results that they reran the DNA two additional times and then they reran the analysis of that DNA three times. And they said, definitively, that they are sure that the results are accurate. And so, part of the reason why they couldn't believe it was that, for example, my telomere age was the equivalent of, I think it was 7.6 year old, basically under eight years old. That's more extreme.

Telomeres, we can't read too deep into telomeres, although once were considered to be maybe a marker of biological age, we've since learned that although they do decline with age, the spread between the longer telomeres and the shorter per any given age is too wide to really be able to use it as a reliable measure of biological age. Nonetheless, it's important that you don't have short telomeres.

Dr. Jeffrey Gladden: That's right. You don't have short telomeres. That's true. Just so the audience understands, telomeres get shortened with cell division, that's one way they're shortened and they're relengthened by telomerase, which is the enzyme that lengthens them. But they all are alternative pathways for both shortening and lengthening, which sort of confounds the numbers in a sense, so that somebody that's 90, even though their telomeres are shorter, they may be activating alternative pathways to relengthen them, that does not depend on telomerase. So, it's no longer as clear of an indicator as say DNA methylation as to what their chronological age might be.

All that being said, even though it's not as accurate of a clock, it's still a critically important thing that you not have a population of telomeres that are predominantly short, because that is a problem. And the reason is because those short telomeres lead to cellular senescence, which is something that we were just talking about. There's been some talk that, I've talked to people at Berkeley and things like different researchers, and it's like, well, telomeres no longer matter. Well, actually they do matter. They're just not the ruler that you thought they were, but they still matter greatly. So, anyway.

Chris Mirabile: Exactly. I completely agree. And to your point about the short telomeres then leading to senescent cells, by extension telomeres can become short from excess DNA damage. And so, to that point about the effects that NOVOS can have, that is one hypothetical reason or explanation for me having the telomere length that I do have.

Dr. Jeffrey Gladden: Do you feel like you're activating telomerase with your product? Do you have any data to show that you might be, or is that in the works too?

Chris Mirabile: I don't personally know. The medical and scientific team at NOVOS probably has an answer for that based on the research during the formulation process. I don't know personally any of the ingredients.

Dr. Jeffrey Gladden: It would be interesting to know if there is, because none of the products that are in it, then we can rattle them off with the audience here, we've got them pulled up. But none of the products per se is a known major telomerase activator if you will. And yet sometimes things are working through different pathways and alternative pathways to do things. That's rather interesting. So, just so people know, it's fisetin, it's glycine, it's pterostilbene, it's rhodiola, it's micro-dosed lithium, it's Calcium Alpha-Ketoglutarate, malate, glucosamine sulfate, magnesium, hyaluronic acid. Those seem to be the primary.

And vitamin C, L-Theanine and ginger are the primary ingredients. And then, the Boost is NMN, nicotinamide mononucleotide. That's what we're talking about in case anybody's wondering what we're referring to here. So, you have the telomeres of a seven-year-old, and what about your epigenetic age?