Welcome to Pushing the Limits, the show that helps you reach your full potential, with your host Lisa Tamati, brought to you by lisatamati.com.

Lisa Tamati: Well, hi everyone and welcome back to Pushing the Limits. This week I have Dr. Elena Seranova, who has already been a guest on the show. And today, we're talking about autophagy and NAD, and the interplay between these two. Now that might sound extremely boring, but it isn't. It's all about longevity and anti-aging. So, we're going to be talking about the science between about NAD precursors and the SIRTUIN genes, and how to upregulate the SIRTUIN genes, and all about autophagy, which is really the recycling of old and damaged parts and proteins of a cell that need to be gotten rid of. So, it's a bit like having a good garbage disposal unit happening. And there are many ways to activate autophagy, which we go into in this episode. We talk about intermittent fasting, we talk about cold and hot and hormetic stressors like exercise and yes, of course fasting. But also, mTOR independent pathways to activate autophagy, it'll all be revealed in this interview. 

Now this does get a little bit technical in the first 20 minutes or so. But hang in there and listen to this a couple of times. Because if you want to slow down aging, if you want to slow down the generative decline of your body and you want to have a long and healthy lifestyle, then this stuff is really, really worth paying attention to and trying to understand. 

We talk about NMN, which is nicotinamide mononucleotide, which is a supplement that is now available, is a longevity compound to upregulate the SIRTUIN genes. And we're really lucky to check that out. You can go and find that supplement, which has been made and produced by Dr. Elena Seranova and her company, NMN Bio. So if you head hop over to nmnbio.nz, we're now importing this into the country. So, this is one way that you can really fight aging and degenerative decline that we all fear and don't want. 

And when you listen to this episode and really listen to it a couple of times, you'll understand some of the incredible anti-aging things that are coming down. This is not pseudoscience. Dr. Elena is one of the most amazing neuroscientists out there. So please listen to this episode, enjoy it, get a lot out of it and get the takeaway. So, if you don't understand some of the terminology, don't worry, keep going. And by the end, you'll start to pick up certain bits and pieces. And if you listen to it again, you'll be able to pick up a little bit more and a little bit more. And at the end of the day, it's about the takeaways, what can you do to slow aging down and all that information is in there. So, I hope you enjoy this episode with Dr. Elena. 

Before we go over to that we are all about health optimisation, high performance, athletic performance. So, if you need any help with any of those areas of your life, please reach out to us, Support at lisatamati.com. Go and check out our website, lisatamati.com. You'll find all our programs, our Epigenetics Programs, our online run training system that's customised and personalised totally to you, and check out what we do. We love helping you be the best version of yourself that you can be. Now over to the show with Dr. Elena Servanova. 

Lisa: Well, hi everyone. Lisa Tamati here and very excited to have you hopefully join us this morning. It's 7:30am in the morning here in New Zealand. And where Dr. Elena Seranova is, it's very late at night. How are you doing, Dr. Elena?  

Dr Elena Seranova: Good, good. How are you? Happy to be here again.

Lisa: Yeah, very excited for today's topic. So, we're going to be doing a discussion around autophagy and NAD boosters and SIRTUIN genes. So it’s going to be a really interesting discussion that is really beneficial for you if you want to know how to live longer, live healthier, and optimise your body and your mind and your potential. So, Dr. Elena, can you just tell us briefly a little bit about yourself? 

Dr Elena: Sure. So, I started my journey as a psychologist. So I'm an interdisciplinary scientist. I majored in psychology at first and then I had my own private practise for five years which turned out to be a successful wellness centre. And I really got fascinated by neuroscience and the brain. And for this reason, at first I started studying the brain myself and then I found an amazing master's degree at the University of Sheffield in Translational Neuroscience, which basically combined the research and neurodegeneration with applications that could translate into therapeutics. So, this is what translational neuroscience means, is basically the combination and the outcome of the research—the hardcore biology research that can be utilised for therapeutic approaches and patients. 

I really enjoyed that. So that was quite cool, being in the lab and doing molecular biology experiments and so on. So, I kind of fell in love with the lab, and I decided to do a PhD as well. I continued my studies in autophagy and stem cell biology and it was quite challenging, but at the same time, I really enjoyed it. And I can definitely say that science is a big part of my life.

Lisa: Definitely your thing. Okay, so autophagy and stem cells. So in relation to neurodegenerative diseases in that case? Okay, but what is autophagy? Because a lot of people will be listening to it and go, ‘What the heck is that big word, autophagy’? It's sort of big word in biohacking circles, but perhaps not in the general public. Can you explain what autophagy is exactly? 

Dr Elena: Yes, sure. So, autophagy is a catabolic pathway that degrades dysfunctional organelles in the cell or protein pro aggregates. So, any material that is basically unwanted in the cell, autophagy can degrade. It's like the stomach of the cell. 

Lisa: So, it’s like eating it? It's eating, sort of... 

Dr Elena: Yeah, exactly. And what happens when autophagy is activated, we actually have the formation of the so-called phagophore, which is a membrane structure that basically engulfs different organelles and materials that need to be degraded to form the so called autophagosome, which is a round organelle that basically has this cargo that needs to be digested. That eventually fuses with lysosome. 

And lysosome is another acidic organelle that contains acidic hydrolases that are able to digest this cargo. And this process is very essential for the cell, it’s very vital. It's evolutionary conserved in all species, from yeast to models. And if it doesn't work well, the cell is basically in trouble because you have all this garbage...

Lisa: Floating around. 

Dr Elena: ...floating around and there is nothing to remove them. So, this is why autophagy is important. And we have different pathways that autophagy can be activated through as well. So, one of those pathways is mTOR, mechanistic target of rapamycin. And then we have other pathways that can activate this process such as AMPK, GSK3, and so on. 

Lisa: So is this like, sorry to interrupt, but like because I know that people out there might be like, ‘Wow, that's a lot of big words and a lot of information’. So, is it like that the cell has to do a housecleaning, and it's got stuff inside the cell that is not working optimally, and needs to be gotten rid of, or is it the whole cell? So, it's not apoptosis. So it's not where the host is disintegrating?

Dr Elena: No. Yeah, it's actually a—it's a pre-apoptotic pathway. So, before apoptosis is activated, we have autophagy. And if autophagy fails in what it needs to do, then we have activation of some apoptotic pathways. So, it's one step before that. And if everything goes well, and autophagy is functional—and by the way, in different diseases, we might be having different autophagy impairments at different stages of autophagy. So, it's either the initial phagophore formation, for instance, that it's not working well, and it can’t engulf the cargo, or it's insulator stages of autophagy, such as the acidic hydrolysis and the lysosomes that are actually not that acidic. So their pH is not acidic enough to digest the cargo. So, we might be having different defects in the autophagy pathway in different diseases.

Lisa: That leads to apoptosis. Am I right? 

Dr Elena: And yeah, if autophagy is not doing its work correctly, then eventually we will have apoptosis. And actually, this is what we're seeing in in vitro models of neurodegenerative diseases as well. So, for instance, if autophagy is not working well. 

And we have, let's say, dysfunctional organelles, such as mitochondria—dysfunctional mitochondria that are not working well. Let's say they are depolarised. And there is an excess production of reactive oxygen species going on. Now, if nothing can degrade these dysfunctional mitochondria, you'll keep on having this accumulation of reactive oxygen species, which eventually will lead to DNA damage and deactivation of PARPs. And it's basically a death spiral that will keep on leading the cell towards death. 

Lisa: Okay, so what is a PARP? You mentioned PARP there. And just for the listeners, too. So, apoptosis is basically cell death, programmed cell death. So, this is not—what's the other one necrotic or something? 

Dr Elena: Necrosis? 

Lisa: Yeah, necrosis, where the cell dies for—necrosis. But this is sort of a natural programmed cell death. But we only want that if we're actually renewing the cells and we are wanting new stuff. So, before that, the body tries to do this autophagy process, is that how it works? And then what so what is PARP? What is PARP, because that’s the word again...

Dr Elena: PARPs are a class of enzymes, and in order for them to function, they need a molecule called NAD, so nicotinamide adenine dinucleotide. And they're actually competing for NAD in the cell. And whenever we have increased DNA damage, we would have the PARP activation as well. And this would lead to NAD depletion, which kind of brings me to my next point about what other enzymes consume NAD. And one of those enzymes are SIRTUINS, which are the so-called longevity genes that are basically responsible for multiple processes in the cell, including epigenetic regulation of gene expression. 

So, they do—because SIRTUINS are a class of enzymes that are also dependent on NAD, and they're all the deacetylase enzymes, meaning that they remove acetyl groups from the DNA. And as a result, they control which genes will be expressed in which tissues, which is very crucial for the cellular identity and for the proper function of different cells. 

So, SIRTUINS in a healthy cell, so SIRTUIN should be upregulated and they should be having this housekeeping gene—housekeeping function where they basically control what's going on with the DNA repair and also with the gene expression as well. And if we do have—when we do start having impaired autophagy, and let's say there is increased reactive oxygen species, because there are increased dysfunctional mitochondria in the cell, you will have in more activation of PARPs, and all of the NAD will start being drained from... And SIRTUIN will not have enough energy to function. So, those are actually quite an elegant interplay between autophagy and NAD and SIRTUINS. 

Lisa: Okay. Okay, can I just want to like put that back to you, so that we can slow down because we are going technical quite fast. And I think a lot of people might be like, ‘What the heck are they talking about’? So, the SIRTUIN genes, basically longevity genes, and then one of the jobs is DNA repair. And another of the jobs is to say which genes are actually being activated right now. And these SIRTUIN genes are also responsible, I think, for cell replication, is that correct?

Dr Elena: The SIRTUINS are responsible for multiple functions, directly or indirectly. So, for instance, the SIRTUIN 3 gene is also responsible for mitochondrial biogenesis. And it's implicated in the amount of mitochondria that are being produced by the cell, which is related to cell replication eventually, because you do need to have enough ATP levels to replicate.

Lisa: Right. Yeah. So, this has definitely to do with ATP production as well and mitochondrial health. So, these are doing all of these jobs, the SIRTUIN genes, they're very, very crucial genes in our genome. And these are preserved across every species, I believe? Every species on the planet? 

Dr Elena: Yeah. Also from yeast to humans, it's also—SIRTUIN genes are preserved very well.

Lisa: And when things are preserved across species, then that gives a scientist an indication that this is probably a very important biological function and we need to have a look at this one because it's—from what I understand. 

Okay, so when you have activated PARP because you're not doing autophagy well and there's things going wrong, it's taking the NAD. So NAD is basically like a fuel source that both the SIRTUIN genes. And when PARP is activated, it's using to fuel its job. And so, this is competition for competing fuel sources. So, like if you imagine, you've only got one tank of fuel for your car, but you've got to go in two different directions and do two different jobs. You go, ‘How am I going to divide up my energy’? So, then it becomes important as to how much NAD we have in the body? So, what is NAD again? That says nicotinamide adenine dinucleotide? But what is that and how does it work? 

Dr Elena: Yeah, it does serve as a substrate for all of these enzymes, including SIRTUINS and PARPS and is basically a master regulator of metabolism. So, it's a very important molecule and it serves as—without NAD, the cell is not able to function properly just because this crucial molecule is implicated in so many different reactions. So, NAD is found in all living cells and organisms. This is also evolutionary conserved across species. And it exists in two forms, NADH and NAD+, which is the reduced and the oxidised form, respectively. And both of them are important. And both of them are implicated in multiple cellular reactions. 

Lisa: Is it going backwards and forwards in a cycle, NADH, NAD+, by donating electrons back and forth, sort of thing? 

Dr Elena: Yeah. Through electron transport chain in the mitochondria, yeah. So, this is why it's so important. And so, what we're seeing now in the latest advancements in longevity research is that we actually can supplement with different precursors of NAD, such as nicotinamide mononucleotide, for instance, NMN. And this is the supplement that my company... 

Lisa: See, you've now got that available on the market because this is such a crucial thing.

Dr Elena: Exactly. And I think that it's really interesting to also say that when it comes to the interaction between autophagy and SIRTUINS, there is also another regulation of autophagy there. So SIRTUIN 1 is actually responsible for activating some transcription factors such as TFEB and FOXO that have to do with initiation of the autophagy process. 

So, for this reason, when we do have dropping levels of NAD, decreasing levels of NAD, and there is not enough NAD for SIRTUINS to do their job. And let's say again—let's talk about that previous example in neurodegeneration when you have increased reactive oxygen species, and you have increased the level of stress and oxidative stress and decreased activity of SIRTUINS. 

And not only the situation is already bad, but because SIRTUIN 1 doesn't have enough energy to function and to activate the TFEB and the FOXO transcription factors to initiate autophagy, now you have all of this dysfunctional mitochondria floating around and autophagy starts being impaired as well because we activated enough. So, it's a negative feedback loop which actually accelerates the scenario where the cell is going towards cell death, basically.

Lisa: So that means like, if you don't have enough NAD, then your SIRTUIN 1 gene is not going to be able to initiate autophagy and clean up the cell and you're going to have dysfunctional mitochondria. Is that independent of the mTOR pathway? Or is that—am I getting confused? 

Dr Elena: So, okay. So, good question. So, what happens is there are some molecules that activates SIRTUINS. So, for instance, SIRTUIN 1 is activated by resveratrol, and this is something that has been demonstrated many years ago. So, when you have SIRTUIN 1 dependent activation of autophagy, you will be having it through an mTOR independent pathway.

Lisa: So it's a fasting mimetic resveratrol. 

Dr Elena: Yeah, yeah. Yeah, absolutely. So, because we now know that the mTOR activity is not affected by intake of resveratrol. And this is quite crucial because actually, even if we want to activate autophagy, we shouldn’t do it through the mTOR pathway, this is not the preferred way, because mTOR is also responsible for growth and translation in the cell. So, this is not—it's also quite a key player in the cell. So it's a serine threonine kinase, and you actually don't want it to be activated at all times because this may lead other conditions. So, what we're focusing on at the moment is to find molecules that can activate autophagy in an mTOR independent manner.

Lisa: Okay, so. So if the mTOR—cause mTOR is usually what's for growth it’s anabolic, it's causing growth. So for example, a bodybuilder goes to the gym, they're in an anabolic state, they are in an mTOR growth state. And when you have autophagy, that's sort of the opposite. So, it's a catabolic state where it's starting to eat itself. So, it’s mTOR, most people like do fasting for that reason to activate autophagy?

Dr Elena: Yeah, this is another good point there. So, when we're fasting, and there is actually conflicting evidence out there as to when autophagy is fully activated. Usually, people say that around 24 hours, you start having the autophagy activation. There are others that swear by the ketogenic diet, and say that if you don't consume any carbs, you will get autophagy activation anyway. However, from what other researchers have found is that, if you are in a ketogenic diet, and you do consume meat, it depends on what kind of meat you consume that will either activate autophagy or not. And it all has to do with levels of different amino acids in the cell because autophagy is quite sensitive to nutrients and to nutrient starvation to be activated. If you have an abundance of amino acids, again, it will not be activated. 

So, for instance, one amino acid that activates autophagy very well is leucine. And if you're eating certain meat that are rich in leucine, this is probably not good for your autophagic state. Something else to keep in mind, and I've heard, I think it was Dave Asprey saying that if you can manage to be on under 15 grams of protein per day, you will probably keep the autophagy going. 

Lisa: Because a lot of people on keto think I can eat a lot of protein, which is a mistake, really. It isn't about having—that's interesting, because I had Dr. David Minkoff on my podcast, Pushing the Limits a while ago, and he has a product called PerfectAmino, which is really a 99% usable form of amino acids and combination. And I was interested, ‘Well hang on, if I'm heading there, which is going a lot of good things in the body. But is that going to inhibit my mTOR, or autophagy’? Sorry, because I've got too much leucine in there?

Dr Elena: This is a very good point for all of this process food as well. So, for instance, there are some ready meals you can get or some protein bars that claim to have all the low carb and everything. And then they slam a badge on their pack saying that it's vegan as well. But then, why is it vegan if it has all the amino acids because that's one of the selling points when you're actually on a vegan diet, or you have some days where you are on a vegan diet. You want to get yourself in a state of partial amino acid depletion to get this beneficial effect of enhanced autophagy. And on intercellular toxins and so on. 

Lisa: Right, so for certain periods of time, you want to do this, and it's a cycling thing, you don't want to be completely deficient of aminos for too long because then your body will start to break down.

Dr Elena: This is what I do personally as well. So, during the week, so I am a fan of cattle/carnivore diet. So, this diet is quite comfortable for me and I enjoyed it quite a lot. But then during my week I try to have some days where I'm either vegetarian or vegan, just because I want to have those benefits. 

Lisa: Yeah. Up and down. And then this seems to be a theme in biology all the time is that it's not one thing. It's not staying on keto for ever and ever, amen. It's about doing cyclic keto or cyclic vegan and it’s cyclic. And our body loves this push and pull—when there’s recovery and there’s growth and then clean up phase, growth clean up. So autophagy can be activated through fasting. It can also be active through having resveratrol and upregulating the SIRTUIN 1 gene, how else can we activate autophagy?

Dr Elena: So there are different ways, there are different things you can really implement in order to activate autophagy. And I think that it all has to do with how you build your lifestyle in general. So, I think that in order for your body to function properly, you really need to have a kind of a healthy routine in general. And an analogy that I can give you there is that there are people that would buy a couple of supplements, and then they would be so proud of it. And then they would say, ‘Oh, yeah, but I'm taking those supplements now, and I'm so healthy’. And then their biorhythms are all off. They sleep at 5am every day. And they're eating crappy foods or super processed foods. 

Lisa: Yeah, it’s not going to work. 

Dr Elena: It’s all good. So, I think that when it comes to being healthy and activating your autophagy levels and having a healthy lifestyle in general, you need to start with the basics first. 

So, the intermittent fasting is definitely the first step to take in order to become a bit healthier. And from the research that I'm reading, and from the things that I'm implementing, I definitely believe that both anecdotal and scientific evidence point towards the fact that intermittent fasting is actually the way to go. I mean, there are conflicting opinions out there and there are pros and cons in every diet, and so on. And I get that. But I personally believe that with intermittent fasting, if you try to narrow down the window where you're uptaking food, this is very, very good for you. So, this is step number one. 

But then again, so either you're trying to raise your NAD levels, or you're trying to activate your autophagy, because those pathways are quite intertwined. And what you eventually want to do is you want to have increased levels of SIRTUIN, and SIRTUIN 1 in particular, and SIRTUIN 3, of course, and so on. And for this reason, in order to preserve this pool of NAD that is available for the SIRTUIN 1 to activate itself and activate the autophagy pathway. 

Another small tip that I can give is to actually avoid sunlight, which is something that people don't really consider. But what happens when we're exposed to sunlight, when our skin is exposed to sunlight for prolonged periods of time, we start getting the DNA damage. And when you get the DNA damage, you have PARP activation, and then again, you NAD pool...

Lisa: Wow. I never connected those dots. That's really interesting. So, because—I mean, we need sun. We need sun for vitamin D and for our mood and all that sort of stuff. So, you're not saying don't have any sun. 

Dr Elena: Yeah, sure. 

Lisa: But because the sun is causing DNA damage, it's going to cause more PARP activation, it’s going to have the SIRTUIN genes going to repair the DNA, that's going to use up the body's resources is what you're saying. 

Okay, wow, that makes sense. Makes sense. And then by the same token, like things like smoking that breaks DNA, like no tomorrow. This is why smoking ages you is because of all the DNA breaks. And this is why, when you're in the sun for hours every day, you get wrinkly skin and you get collagen lost and all the rest of the things that are happening. So, anything that's going to be causing DNA breaks is going to cause you to age quicker. 

Dr Elena: Exactly. 

Lisa: Using up the resources basically. Wow, okay.

Dr Elena: So it's obviously—you don't have to become a vampire and dissipate walk in the sun when you want to go somewhere. But sunbathing for hours is definitely not something you want to do with—to get your body go through, basically. So that's another tip. 

And then something else, really, really simple that can be implemented on a daily basis in order to maintain your SIRTUIN levels, and as a result, your autophagy levels, and your NAD levels is also to take a tablespoon of extra virgin olive oil, which contains oleic acid. And it basically does the same job as resveratrol. And it's interesting—I think that there's been a recent research article out that shows that like oleic acid might even be more efficient than resveratrol, in terms of activating SIRTUIN 1, which I think it's really, really cool. 

Lisa: So yeah. Well, combine the two. I do.

Dr Elena: Yeah, absolutely. You can do that. And then, you need to make sure that the extra virgin olive oil is actually of a very good quality because there is a bunch of... 

Lisa: There is a bunch of rubbish out there. So, make sure it's from an orchard that you know, it's cold pressed, it's all those extra virgin, it's all that sort of good stuff. And not—how do they do it with solvents and stuff? Or that it's come from multiple orchards and being cut with other oils. It's a really, really important point. And then oleic acid does so much good things in the body. But isn’t that fat, Elena? Like lots of people are like, in their minds are going, ‘But oil is fat. It’s the same with MCT oil. Isn’t that going to make you fat when you eat fat’? Just going to put that around. 

Dr Elena: There are good fats and there are bad fats. So, olive oil is good fat. MCT oil is a good fat. Avocado is a good fat. So, not all fats are made equal. So, this is definitely something important to keep in mind, especially with a good quality extra virgin olive oil. 

Lisa: Because each one of our cells is a membrane that has a phospholipid, isn't it? So we need that,  actually, this building of ourselves into the integrity.

Dr Elena: We have a phospholipid layer in the brain as well. And this is why we actually supplement with omega 3 fatty acids, because this is what it does. So, this is what omega 3 fatty acids do. They go into the phospholipid membrane, and then they basically...

Lisa: Make the integrity of that membrane better.

Dr Elena: Yeah, they contribute to the healthy phospholipid layer in the brain. 

Lisa: So that's why it's very important for neurodegeneration to have omega 3s going in and again, people get quality omega 3s. Not your cheap supermarket ones that are perhaps oxidised and have been sitting on the shelves for six months. So really important to get a reputable source here. And omega 3 is of course in fishes as well, and krill, and so on. 

Okay, so but is there a downside to fat? Because I studied epigenetics and a lot of people's profiles come back with don't have too many fats. And it's been one of those things in my head is like ‘Why would some people not come back with you shouldn't have too much fat’? I mean, there are things like gall bladders been removed. That's a pretty specific thing. But is there a genetic component? And probably not your wheelhouse, really, but is there a genetic component to your ability to process fat?

Dr Elena: There is a genetic component, and I've actually seen this with a family that has a history of very problematic digestion of fat, and so on. Absolutely. But yeah, again, not all fats are made the same. And when you cut off the bad fats from your life, things change and everything changes really.

Lisa: Yeah, it really is very satiating, too to have a little bit of fat and that can really help with cravings and blood sugar spikes—we're getting off topic. 

So you have a company, NMN Bio, which produces nicotinamide mononucleotide supplement. And you've got a whole range of other stuff coming as well. Why did you decide like, you need to get this out there on the market? Based on your research and your knowledge around this area, why is it important that people take NMN if they're serious about slowing aging?

Dr Elena: So first of all, I came across the biology of NAD and NMN during my PhD studies and my research kind of led me into this field because I was studying autophagy neurodegeneration. And actually, I still cannot disclose my research. 

Lisa: Yeah, it’s not published yet. 

Dr Elena: My research paper from my PhD is not published yet, but hopefully soon, so we're about to submit it quite soon actually. So for this reason, I started studying the biology of NAD and I actually saw how important and how crucial NAD is to the cell and what happens when we have a lack of NAD and depletion of NAD pools in the cell. And I've been supplementing with different kinds of vitamins and supplements my whole life really. So, I was watching closely this space for a while, and I was taking different supplements myself for a while. 

And so, when I came across NMN and I realised that actually there is this strategy where we can supplement with a precursor in order to increase our energy levels, I found it really, really interesting. And I thought to give it a go myself and try it out and see the results. And then what shocked me was that the immediate effect of the supplement—so within a few days, you can already feel a difference in your energy levels and your focus. And this comes from the fact that SIRTUINS are responsible for so many molecular processes in the cell. And this is why you have this effect, including the mitochondrial biogenesis, which gives you basically increased ATP, consequently. 

Lisa: You get actually more mitochondria. So, like, if you got heart disease... 

Dr Elena: The production of more mitochondria, and then they produce more ATP as a result. And then you have this magic energy, yeah. This is why I thought to bring this product into the market. And the other reason was that there was not enough reliable suppliers on the market, which is crazy, because it's actually quite a popular supplement. It's been on the rise, the interest was rising for the past couple of years, but what we're seeing is there is a lot of white labelling companies that don't offer any certificates of analysis and so on. And also, you have even big companies not offering proper certificates of analysis, which was me like, it was… 

Yeah, I don't understand. You have a big company, and you have just the purity report from like, 18 months ago, and you don't have any other analysis, such as heavy metals, or pH or microorganisms. So, the consumer is actually not confident in buying from you. And I wanted to deliver the best quality for myself and my family. And then I said, ‘Wait a minute. This is not done, right’. And this is why I launched the company because I wanted a company that was completely transparent. And I even say it on the website, that if you're interested in finding out who our suppliers are, and so on, and have any questions about our supply chain, just feel free to reach out to me. And I would be happy to disclose all of those things.

There are other companies that you can't find any registration number, or who the founder is, and so on. And it's quite confusing, really, because like you— you don't know who you deal with. 

Lisa: This is the same with the whole supplement industry. On the one hand, it's good that it's not regulated by the FDA, and whoever else, there are authorities around the world. Because like, then—they are turned into the pharmaceutical industry, which don't get me started. But on the other hand, there's not enough regulation around the quality control. 

And one of the things when I was searching for NMNs, searching the world for it, I had to go overseas and import it to friends in America and get it out of there. And this is why I like—was super excited to discover your work. And then, we've since now made it available down here. So, we're going to branch down here in New Zealand for New Zealand, Australia. And I wanted someone who I could trust, who has all the scientific knowledge behind it, there's all lab tests, etc. And that was really important for me for quality. 

Just on a side note. So I've been taking NMN now for—I think—so five, close to six months. I've had a massive weight loss and so as my mum. Why would that be? Like, I didn't take it for weight loss. I wasn't overweight, per se. But I had a couple of kilos that I was quite clear to get rid of. And what I've noticed—because I'm an athlete, that's my background—I haven't lost an ounce of muscle, which has been really awesome because most people are struggling to keep muscle mass, lose fat mass. My mum has lost 11 kilos. And she is of a genetic body type that really struggles with weight loss. She's conservation metabolism, from a genetic point of view, very, very hard for her to lose weight. So, I've never seen this in the history of her entire life, since I've been around. The weights just dropped off her. 

Is this some sort of upregulation in the metabolic pathways? Is it improving the insulin resistance? What's it doing there to cause such weight loss without muscle loss?

Dr Elena: Well, in my study so far, there's definitely evidence that it does improve insulin sensitivity, and it also improves the lipid metabolism profile. So those two are very important. And unfortunately, we don't have those studies in humans yet. But more clinical studies are on the way, and hopefully we'll have very good results this year with the NMN besides the safety studies that we already have in humans. 

So in mice, what we're seeing is that there is basically a reverse of type two diabetes, which is really impressive. And if you want to correlate this data into humans somehow, I would say that, obviously, I'm not a medical doctor, and this is not a medical advice, but I would say that it does have to do something with the metabolism, and it basically improves the way your body metabolises everything. 

Lisa: Worth trying and there's no downside to NMN. There's no, it's a vitamin B derivative, well then you will say to me, ‘Well, can I just take B3 and be done’? and it's like, no, it doesn't work like that, which should be a lot cheaper.

Dr Elena: That’s the other impressive thing about this compound is that it actually doesn't have, if any, side effects at all. So even in studies with mice, where the dosage that they use in mice is actually much higher than it is in the one that we usually have in humans. So, for instance, if someone would take 500 mg, or one gram of NMN per day in humans. And then in mice studies, they use something like 200 mg per kilogram of weight, which is much, much more, and it still doesn't have any side effects.

Lisa: Does it mean that we need higher dosages? Like in the human, or has it only been tested to one gram and why has it not been tested higher, if that's the case? 

Dr Elena: No, I think that there are studies underway for this as well. So eventually, we will find what is the ideal dosage for humans. I think that from anecdotal evidence, people can already see results from 500 mg or one gram and so on. There are people that take more. So, some biohackers say that they take two grams or four grams, and is still very well tolerated. But yeah, so far, it does not produce any side effects in terms of…

Lisa: Any downside.

Dr Elena: Basically. And, for instance, for myself, my stomach is quite sensitive. So, when I'm on an empty stomach, I can't take vitamin C or caffeine and I get nauseous and so on. And this is not the case with an NMN. So, I can take it first. It is very well tolerated on an empty stomach, very mild. I really love it. There’s so many reasons to love it. 

Lisa: Yeah, yeah, yeah, I have my morning and night. So, I'm on a gram a day. And is there any reason not to take it at night? So I split the dose—reasoning, thinking, keeping the levels up? 

Dr Elena: I mean, I would probably take it all in the morning, I think. There's been a study out that it can affect the circadian rhythms as well. And interestingly, it actually affects NMN—sorry—NAD levels affects the circadian rhythm. But it's not the other way around. So, NAD actually dictates the circadian rhythm in the body. So, for this reason, I would suggest to take it in the morning because then your whole body synchronise, then you wake up and you tell to your body that look, it's the morning now, and we're going to have increased NAD level.

Lisa: Increase. Ohh okay. So, okay, I got that wrong. I haven't noticed that I've had worse sleep or anything like that, or any rhythm has been out. But I would definitely swap to doing—my thinking process around that was keeping the tissue saturated over a 24-hour period, as opposed to all at once and then perhaps dropping, but I don't know. What is the half-life of it? Do you know? Is there any sort of evidence around that?

Dr Elena: I actually, not sure. No, no. 

Lisa: There’s no evidence yet. And so yeah, there's a ton of studies still being done that are currently, like this year, like going to be coming out, which is going to be really exciting. So that we're going to get more evidence. I mean, there's this stuff that I've been reading around fertility in animal studies, and they're starting to do human studies, which I personally am very interested in, in reversing aging of the ovaries and even with... I mean, the mice study was incredible around fertility, where the mice were postmenopausal, they actually knocked off any existing eggs with chemotherapy. And then gave them NMN and the mice went on to have babies. And there was a whole study.

Dr Elena: This is why I get so excited about NMN and this is why it's my first product because frankly speaking as a scientist, I've never seen results like that with a natural compound. 

Lisa: No?

Dr Elena: Because there is a bunch of natural compounds out there, there is a bunch of other supplements. And what we're talking about spermidine the other day... 

Lisa: Yeah, yeah, it's interesting. 

Dr Elena: ...another autophagy activator. Quite an interesting supplement, yes. By the way, it's also an mTOR, independent autophagy activator, which is good.

Lisa: Another very good reason to take that as well. And we were looking into that aren’t we, Elena about adding that? 

Dr Elena: Yeah, absolutely. We will look into this, but again, you don't see results, like the ones that you see with NMN in multiple studies from other compounds, it's really fascinating.

Lisa: Wow, so yeah, so there are other products that are going to... And this is a super exciting thing, like were our grandparents or our parents even didn't get the chance, like, with aging was aging, and there was nothing that you really could do to influence how fast you aged. They weren't aware of it. And later on, it's become well, if you eat better and you exercise a little bit more and you stop smoking and, and stuff, you’ll age slower. But now we're taking exponential leaps in our knowledge.

I mean, I fell into this realm when I was reading Dr David Sinclair's book, who is a very prominent scientist at Harvard Medical School, and made his book, Lifespan, which I totally recommend people reading. I was just like, ‘Oh my gosh, if I can stay healthy now’, because I'm 52, ‘if I can stay like, really, in top shape for another 10 years, by then we're going to have stuff that will help me live really long’. And that really excites me. And not just live long, but live healthier. 

Dr Elena: That’s the important part. The important part is not to just increase your age, it’s to increase your health span. So, the time that you're spending being healthy. And what you're referring to is actually called the aging escape velocity, where basically we’ll have more advanced research coming in every year of our lives. And this will eventually expand our lifespan, which is amazing. And I also think that if we preserve ourselves well, we might as well see this in our lifetimes, which will be amazing. 

Lisa: Absolutely. And I want another few decades, please. Listening to Dave Asprey, who by far, got...

Dr Elena: I want another like, few hundreds. 

Lisa: Yeah, well, I mean, I know it sounds ridiculous right now. But if you listen to Dave Asprey saying conservatively, and Dr. David Sinclair, too, like, conservatively, we could live to 150, 180, and beyond. Then once they crack the code, and they're actually able to turn the cells back to which they are working on right now. And which they can actually go in the petri dish, from what I understand like with skin cells and make them immortal. And they can't do it in humans because it's too risky, they could turn you into a tumour and stuff. But with the Yamanaka factors that were discovered a decade or so ago, they're actually able to turn the clock back to the point of you being a 20-year-old again. And this is like, ‘Wow, this is pretty exciting. Being able to regrow nerves, spinal injuries, people who have gone blind from macular degeneration’ — all of these things are coming down the line. This is very, very exciting. 

Dr Elena: There are several advancements in this field. So, as I said, my PhD is also in stem cell biology. So, I was working with human embryonic stem cells in the lab, and what they can do on a dish is just mind blowing. Because what I was able to do was to take human embryonic stem cells, and then dictate their fate, basically, with different growth factors, and then differentiate them into neural precursors at first. And then to push them further in order to become terminally differentiated neurons. And like four weeks later, you basically have a human brain in a dish and it's a primary human cells. And it's an amazing, physiological irrelevant human platform as well to study disease. And this is what I was doing during my PhD. 

So, I’ve seen it with my own eyes. And every time I would do, I would go through this process, I would differentiate the human embryonic stem cells into neurons. It would be as exciting as the first time because of what it represents, because it does represent the progress that we've made so far. And I personally started human embryonic stem cells for the sake of drug discovery. So, I wasn't interested—my project was not focusing on different therapeutic applications. However, I know that there are many advancements in this field as well. So, we do have clinics in America, where you can have a total body rejuvenation, stem cells, and so on. And this technology is definitely advancing. 

And I've been actually thinking about the application of this for myself. So as you know, I recently had a dental injury. This is something to keep in mind for the future. So perhaps in the near future, I can just inject myself with a bit of a stem cells there... 

Lisa: And that’s already happening to a degree. I mean, I've got a doctor friend up north, who's doing stem cell replacement for joints, and so on, for degenerative joints. Because stem cells, basically, for people who don't understand why this is important. The stem cell is the original like cell, but before it decides, ‘Am I going to become a skin cell, or a neuron or a liver cell’, it differentiates. So, it's a pluripotent stem cell, it can become anything. And so, in the lab setting, you're going to be able to say, ‘Well I want your cell to become a liver cell’. Will we eventually be able to grow organs that can be used for transplantation? Is that sort of one of the end goals? 

Dr Elena: Absolutely. And it's already been done with some organs. So for instance, I've heard that there is a research group that basically 3D-printed a functional thyroid gland from stem cells. 

Lisa: Wow. 3D-printed. So, the printer gets these differentiated cells somehow, and then makes it into a functioning organ that they will eventually—they're going to be able to actually transplant this into people and save the whole organ donation, horrific troubles that we have currently. 

Dr Elena: Yeah, exactly and I think that we're not too far away from this from whole organs being recreated in the lab. We already are able to actually do a 3D culture in the lab and create the so called organoids. So for instance, from stem cells, you can do a brain organoid, where you have a liposphere and it basically consists of different kinds of cells that you see in the brain. So it would have neurons, it would have glial, it will have astrocytes, and then it would have this brain organoid and then you can study it. 

So, we're already getting there. We’re close, we’re much closer than we thought we were 20 years ago. And I think that we're not far away from having different kinds of organs being grown in the lab for transplants and so on. 

Lisa: Hopefully not our brains because it's the seed of who we are. Honestly reading Dr Sinclair's book, I was like, ‘Am I in a Star Trek movie or something’? because it is pretty, pretty amazing. But when you do this, you also ask that to understand the whole process and how the whole thing functions, and then you can actually really slow down neurodegeneration and optimise things. 

And so the NMN that we're talking about right now is the beginning of this really exciting road, which we're going to be staying abreast of. And hopefully adding to what we have available to the consumer right now for prices that are not moon money, that it's out of anybody's reach, but actually what you can do today so that you can preserve your health. So that in 10 years’ time, when the real crazy stuff starts coming on line, you'll be able to live longer and healthier lives. And that's the whole goal of it. 

So before we just wrap up, I just wanted to reiterate again, so how is autophagy—can you just put that—how is autophagy related to NAD and SIRTUIN genes? Can you just put that two pieces together again, just repeat that a little bit?

Dr Elena: Sure. So basically, what happens is that you do need autophagy to recycle different damaged organelles in the cell when something goes wrong. So, and this is quite prominent in neurodegeneration because the reason we have—let's say, aggregate from proteins in neurons and dysfunctional mitochondria and so on is because neurons are terminally differentiated cells. This means that they don't divide anymore. So, they rely on autophagy in order to have their housekeeping function because they can't divide the junk away. Okay. So that's the reason why autophagy is important in terminally differentiated cells such as neurons. 

Lisa: So there's no hay flick limit for a neuron. There is just only one—when a neuron becomes a neuron, that's a neuron. Okay.

Dr Elena: Yeah, yeah. And then that's it. And what happens with the activation of autophagy, one of the signals is—comes through SIRTUIN 1, which basically can activate the transcription factors that are related to autophagy activation, which is the TFEB transcription factor, EB and FOXO, which are basically influenced the activation of autophagy. And more specifically, the mitophagy as well. So, mitophagy is the arm of autophagy that is responsible for the mitochondrial clearance in the cell.

Lisa: Yep, so mitochondria, just for people, are the powerhouses of the cell. This is where a lot of—so all of the energy is produced, if you like. And so, this is why mitophagy, as opposed to autophagy, so mitophagy is doing the same process, but within the mitochondria to keep your mitochondria healthy. And if your mitochondria are not healthy, and they're dying, and you're not having enough mitochondria in your cells, then you are going to be sick. And that could be heart disease, it could be neurodegeneration, that could be anything. So, keeping your mitochondria healthy is the basis of all bloody disease, blatantly. 

Dr Elena: Yeah, exactly. So then, if you have impaired autophagy in the cell, and then you also have some sort of DNA damage going on, such as the one from reactive oxygen species, for example. And then what you have is the activation of the PARP enzymes. And PARP enzymes heavily rely on NAD levels in the cell in order to function. And NAD is also a substrate for the SIRTUIN genes that are responsible for also regulating a bunch of very healthy, a bunch of processes in the healthy cell. And for this reason, if you do have increased activation of PARPS, you will eventually get this NAD drain out of the cell. And this will not be enough in order for the SIRTUINS to function properly. And this will also deplete your autophagy. So, both NAD levels and autophagy are important to the cell. And fortunately for us, we can actually replenish the levels of NAD by supplementing with an ad precursor such as an NMN.

Lisa: Okay, and so NMN has been proven to be by most of our bio available, because there's also like nicotinamide riboside which is used in a number of supplement companies that I know have nicotinamide riboside, but not many, there are some now, but have nicotinamide mononucleotide. Nicotinamide riboside is also a great molecule, but it's two steps away from becoming NAD. As long as it’s available. 

Dr Elena: Yeah, so nicotinamide riboside needs to be phosphorylated and fast converted to nicotinamide mononucleotide first. And then this will enter the cell and then this will increase the levels of NAD in the cell. And for this reason—so first, this area of research was focusing on the NR molecule, the nicotinamide riboside. But then when they started studying NMN, they actually saw that there is increased bioavailability and there is increased levels of energy that come after supplementation with NMN.

Lisa: Can you take—because NAD is a molecule, you cannot just take it as a capsule, and then it's all good to go. Can you take it as an infusion because I have heard of NAD infusions. I mean, it’s not available here. 

Dr Elena: Well, and I'm curious myself about this, and I haven't done it, I haven't tested it. And from what I've seen—so the concentration of NAD in those intravenous injections is quite low. And I think that the same way that we have many opportunistic companies in the supplement field, we also have many opportunistic clinics that offer this kind of treatments. So, again, this is not something that I have studied in depth, and I actually don't know how much will it help. But yeah, I mean, this is another way to boost NAD, I guess, and you can try it out. 

But with oral administration of NMN, we do have evidence that it can boost the levels of NAD in the tissue and in liver tissue and muscle tissue, and so on. And also, it's much easier to do and it's obviously much cheaper because those injections cost a lot.

Lisa: Yes, yeah. Just one last question in relation to antioxidants, because I mean 10 years ago or so we used to think our reactive oxygen species ,oxidative stress happens through the electron transport chain. When we're metabolising, and so on, we get all these oxidative stresses and free radicals running around. And if we take antioxidants, we're going to be counterbalancing that. Does supplementing with antioxidants, like vitamin D, like glutathione, like vitamin C, and so on, alpha lipoic acid, is that going to contribute, too, to the slowing of aging, because it's going to down regulate the PARP enzymes?

Dr Elena: People were very optimistic about antioxidants, something like 20 years ago. And everyone was talking about it and so on. But actually, the big studies that have been done, have shown that by taking antioxidants, you actually do not suppress aging. And there are some biomarkers that might have changed in those studies. But most of the biomarkers that they measure stay the same. Basically, saying that antioxidant is not the...

Lisa: Not the holy grail.

Dr Elena: ...that everyone was thinking about. 

Lisa: Was hoping, yeah. Not to say that antioxidants don't have their place because they definitely do. Especially if you have a lot of oxidative stress, and you need to, like with vitamin C, if you're infected, or—I've done a whole series on vitamin C. But then it's not the holy grail for stopping the aging process, but it probably does help with not having so much PARP activation. I don't know, as a non-scientific brain, I'm just connecting dots. 

Okay, so I think it's probably we've— so from a lifestyle intervention, apart from taking NMN and resveratrol, and oleic acid or olive oil, intermittent fasting, is there anything else that we can add to our anti-aging regime on a lifestyle intervention side? 

Dr Elena: Intermittent fasting, and then avoid exposure to sunlight, as we said. And SIRTUIN genes are being activated from any kind of stress. And what we can do is we can also induce some sort of an artificial stress, which could be done, let's say with cryotherapy. This is what cryotherapy does. When you're exposed to cold, you also have this stress signal that activates SIRTUINS, or the other way around, so you can try out a sauna. And this will also have the same effect. So, I think this is also something to keep in mind. 

Lisa: Breathing, breathing. So, sort of tumour breathing, or, like what one half does all of that sort of stuff. So, there’s hormetic stressors, there’s exercise obviously, that cause a cascade of changes and make you stronger. And yeah, it's sort of a balancing act. You don't want to be doing exercise for Africa or really freezing yourself to death, but you just want to have a little stress to cause a change in the body. So these hormetic stressors can be very, very helpful. 

Okay, well, I think we've covered a very, very, very complex topic and I hope we didn't lose everybody on the way. But at the end of the day, take NMN, take resveratrol, take olive oil, do your exercise, get in the sauna, if you have a chance to do cold therapy, do that as well. Get your exercise, get your antioxidants in there as well, to a certain degree and you're going to be able to live long enough but until other things come online, and you'll be able to improve everything. 

Dr Elena: Sounds good. 

Lisa: Brilliant. So Dr. Elena, thank you very much. Dr. Elena has been on the show, NMN Bio. So we have nmnbio.co.uk in UK and in Europe, and nmnbio.nz if you're down at this end of the world. We'd love to help you over the air. If you've got any other questions, please reach out to us. And thanks very much for being here today. It's been really exciting.

Dr Elena: Thank you, Lisa, thank you so much for having me.

That's it this week for Pushing the Limits. Be sure to rate review and share with your friends and head over and visit Lisa and her team at lisatamati.com