Sirtuins and NAD Supplements for Longevity

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, hello everyone and welcome back to Pushing the Limits. Super excited to have you again with me. Today I have Dr Elena Seranova, who is a molecular biologist to guest on the show. And really exciting. We’re going to be having Dr Elena on regularly to talk different aspects of longevity and anti-aging. And today we're talking about longevity. We're talking about sirtuin genes. You might be thinking, ‘What the hell are sirtuin genes’? but you're about to find out. And why it's important and what you can do to upregulate and support these genes, these anti-aging genes or longevity genes. 

So before we get over to the show, just want to remind you. If you are wanting help with any sort of health journey that you're on, if you want some one on one coaching and please reach out to me at lisa@lisatamati.com. If you're looking for help with gene testing, epigenetics, anything of that nature as we've spoken about before on this podcast, you can also reach out to me there, or check out the programme via our website, at lisatamati.com. Everything in health now is about personalizing everything to your genetics. So that's the nutrition, your timings of the day when you eat when you exercise, what parts of your brain you use the most, what your dominant hormones, your personality traits, because of your genetics, all of these aspects are covered in our epigenetics programme. So I'd love you to go and get that. 

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I am really stoked to have you back. I hope that 2021 is going well for you, that you've had a good break over the last few weeks. And if you're in the southern hemisphere, you're enjoying our beautiful summer. So without further ado, Dr Elena Seranova over in Dubai. 

Well, hi everyone and welcome back to Pushing The Limits. I'm super excited. I'm jumping out of my skin. I have an amazing lady with me, Dr Elena Seranova. Hello Dr Elena, how are you doing?

Dr Elena Seranova: Hello, hello, it's really nice to be here today. Thank you for the invitation! 

Lisa: It is super exciting. So Dr Elena is sitting in Dubai, and we're going to be having a really in depth conversation today. And it will get a little bit scientific but hang in there with us people because this is all about longevity and anti-aging and who isn't into that? 

So Dr Elena is a molecular biologist. And she's going to be sharing today some really critical information about the sirtuin genes. you’d be going, ‘What the heck is a sirtuin genes and what do they do? And why do I need to know about them?’ But these are really important things. 

But before we get into that, the nitty gritty of the science, Dr Elena, can you give us a little bit of background on you and where you've come from? And what you've done in a nutshell, so to speak? 

Dr Elena: Absolutely, yes, so I'm actually an interdisciplinary scientist. So I started my studies in the field of psychology. And then I opened my private practice. So that was my first business that grew into a wellness centre and was in operation for five years. I had two branches. That was back in my home country in Greece. 

And I ended up working with a neurofeedback device that was basically retraining the nervous system of different patients with psychological and neurological diseases. And this is how I got interested in neuroscience. And I started studying it myself. I took a couple of those online courses. And I realized that this is such an amazing field. 
And in order to understand the symptoms that I see my patients, I actually need to understand the proper science behind it. 

And when I started digging deeper, I realized that it's actually the genetic component that is the crucial part that produces all the symptoms. So then I found this amazing master's degree in neuroscience and genetics, and specifically in translational neuroscience in the UK. And back in the days, in 2015, the Greek crisis was bad. So I couldn't grow my business as much as I'd like. 
So I decided to move to the UK to do this master's degree. And after this, I ended up, co-founded a biotech start-up that also had to do with the biochemical assays that were aimed at elucidating gene to gene regulatory networks. 

And with that, I also realized that I'm even more fascinated by the science, and I really want to stay in biotech. And my co-founders were making fun of me because I was the only person in the office not having a PhD. Yes, that was a traumatic experience. And at the same time, they were surprised when I said that I'm leaving the start-up to do my PhD. 

Lisa: They shouldn’t have said so. 

Dr Elena: Yes, exactly. So yes, this is how I continued my studies. And my research was focused on the molecular pathway of autophagy. And I was using human physiological cellular platforms of neurodegeneration, utilizing human embryonic stem cells and induced pluripotent stem cells to model neurodegeneration, which was very, very interesting. 

And I actually have a review in the Journal of molecular biology that got out a few months ago, in April 2020, on the modelling of neurodegenerative diseases and studying autophagy in those models in human pluripotent stem cells. For anyone interested, you can go check it out. It has an open access. 

Lisa: We’ll put the link in. Well done. Congratulations, that’s pretty amazing. And that brings me to a point I'll have to have a separate conversation with you about neurodegeneration and what we can do for the elderly. I've got a vested interest in that one. So we'll definitely put that on our calendar because Dr Elena is going to be coming on the show actually quite regularly in the next few months. So we're going to be doing a bit of a series because I think the information that Dr Elena has is just going to be crucial for you guys out there listening. So really, really excited.

But today's subject is all around sirtuin genes. Now these are—I'm going to try and explain it because I've been deep in this research too. So what tipped me down to this path and longevity and anti-aging, obviously, I've been in that space for a while. I listened to Dr David Sinclair on a podcast and subsequently read his book Lifespan, which I recommend everybody go out and buy. It's called Lifespan: How We Age—And Why We Don't Need To. 

And Dr David Sinclair is a very, very prominent scientist at Harvard Medical School. And he has his own lab and he’s been studying anti-aging and longevity for decades now. And he was actually the one of the scientists who discovered resveratrol, which we're going to get into today and what resveratrol does, and it's very pertinent to the conversation. But it is also in this book, really giving me an eye opener into what's coming down the pipeline as far as longevity and being able to turn the clock, actually literally back to when you—so, our cells become young. 

It sounds almost science fiction-y, some of the stuff that he's talking about that is just around the corner. It is like absolutely amazing stuff that we are going to be able to live longer, healthier lives. And for me, it is about health span, as well as like I obviously want to live long, but most importantly, I want to live healthy till the end. And I think that's probably the priority for everybody. Rather than having the typical degenerative, long, slow, drawn out process. 

So anything that I can do to help my friends, my followers, my family live healthier lifespans, I'm into that research. So Doctor Sinclair is an expert on sirtuin genes, this is an area that he studied. And Dr Elena knows all about this. So Dr Elena, can you just tell us, for starters, where do we start on this big subject of longevity genes? And what they do in the body? That might be a good place to start. 

Dr Elena: Yes, sure. So sirtuins are enzymes, basically. And it's a group of genes that is quite well conserved across multiple organisms, which means that they play a very important role in evolution and in our biology. And what they basically do is they control the epigenetic regulation in ourselves. And this means that when—in different tissues, there are different genes being activated at a different time. So we'll be having different sets of genes being activated, and this will be in response to different external stimuli, environmental stimuli, amino acids, even availability of nutrients, things like that. And what they really do is they control that all of the important regulatory pathways in the cell are functioning as needed, and they are quite responsive to external stimuli. 

So for instance, you mentioned resveratrol, which is a molecule that is found in grapes and in other berries and different plant sources. So, resveratrol is actually found when the plants are stressed. So when there is some sort of either fungal infection in the plants, or there is no water and so on, resveratrol is the molecule that is being secreted. And what's happening is that sirtuins can sense this molecule, and as a result they do get upregulated. 

And the reason for this — I guess this evolved from a revolutionary stand point of view is that, so you would have let's say, some small animals running around and consuming different plants, things like that. So the small animals cannot really distinguish consciously between danger, different dangers or lack of foods and things like that. So this process had to somehow be automated. So for this reason, again, resveratrol is like a signal that says to the little animal that there is some sort of danger in the environment. And then what's sirtuins do is they upregulate many physiological processes in order to deal with potential danger. 

And there are different stimuli like that in our environment, and we can actually artificially activate sirtuins. So for example, with the use of sauna. We do have this heat shock response, where there is a stress signal from the environment, and then again sirtuins get activated because there is some sort of stressor coming into the body. Another one is exercise. So what happens? And actually not any kind of exercise. But let's say if you're just going for a walk for 20 minutes, you won’t get sirtuin activation. But if you're going for a run, and you start being out of breath, so that your body goes into slight hypoxia. And this is the signal that activates the sirtuin. So for all of the healthy living enthusiasts, don’t just go for a run. Absolutely. 

Lisa: So just to recap on that, so this sirtuin genes which code for this enzyme. This enzyme is really important, and we'll get into a little bit more than nuts and bolts of this enzyme, but it does some very important activations on the genome, which is what we want. 

Dr Elena: It basically regulates which genes will be switched on and which genes will be switched off. So it allows for a very tight control, for a very tight regulation of the functionality of different genes in the cell.

Lisa: Right. And then so sauna, which produces heat shock proteins, I've just bought a sauna recently for that reason. Yes, yes. Well, I heard about heat shock proteins, what sauna can do, how beneficial it is for so many things. I didn't make the connection to that and sirtuin genes. So that's really something I've learned today. 

I did know about the exercise, and this is why like high intensity interval training, in moderation people — not like go and do this every day, please, but in moderation. It has a longevity benefit, has an improved actual VO2 max and endurance. And all of these great cardiovascular benefits is partly in relation to the sirtuin genes. 

And just going back to the resveratrol, this is a xenohormesis, isn't it? So a stressor that the body goes, ‘Oh, where our environment—is there's something wrong in our environment. So we need to hunker down and get ready for battle’, rather than going forth and multiplying and everything's easy and happy. 

So we want to push and pull in regards to all of these things like exercise, like sauna, like resveratrol, you want times of actually pushing things and in times of recovery, so it's not just going in one direction, is it? It is like balance. 

Dr Elena: Definitely. Definitely. And then yes. And then another trigger for the sirtuins phase, caloric restriction. And this again comes from what we just described about the animal being hungry, potentially in the near future. So the sirtuins get activated. So it’s the same when you're on a calorie restriction and you're doing intermittent fasting, you will get this reaction again. 

And this is tied up to autophagy as well, which has been activated. So you actually need to be fasted for several hours for autophagy to be activated. And research suggests it could be around 18 to 20 hours or more in humans. So I'm personally trying to do this on a daily basis. I'm having a very narrow window where I consume food probably three, four hours a day. I mean, it's not possible, always, especially when you're traveling around like I do at the moment. It might be challenging because I also want to eat high quality food. So I don’t want to be eating junk at the airport.

Lisa: Pretty hard, isn’t it? 

Dr Elena: Yes. I mean, sometimes this actually pushes me to fasting even longer.

Lisa: Great discipline. I can't—I struggle to go over the 16 hour. And I think partly with autophagy—so autophagy, people, this is when the body basically, there is a pathway called mTOR, which we're going to probably do another episode on. And this is a growth regulation pathway where we are actually—if we are activating there's a lot of amino acids, a lot of proteins in the body and a lot of nutrients in the body sort of goes into growth mode. So like bodybuilders want  this growth mode for example. 

And when you go hypocaloric for a while and you restrict the calorie intake, then the body goes into a state of autophagy, which is where it's basically eating and recycling it's old cells that actually need to be gotten rid of. And these cells are called senescent cells. So these cells are alive, and they're putting out inflammatory chemicals or cytokines, and then not actually replicating, and that causes problems in the body. And as we get older, we eat more senescent cells. 

So you don't want to be in a state of starving all the time. That's not what we're saying here. This is why it's intermittent fasting. And you don't have to do this every day, people. I know, I don't. I'm not as disciplined as Elena. But doing this on, I think something like five days may be normal and a couple of days, where it's sort of a longer fasting period. And just giving your body that change. If you go hypocaloric for weeks on end, you're going to down regulate your metabolism. So that's not where we want to go. And then you're going to have nutrient deficiencies and so on from that point of view. What we're trying to get is this seesaw, the body seems to—like in all of the studies that I've done, it seems to like the seesaw, like cycling. It likes going up and down, up and down. And that actually helps it keep its ideal balance, putting it very bluntly and simply. 

So autophagy is something that we want. So fasting, mimicking sauna, exercise, all of these things are going to upregulate the sirtuin genes and these sirtuin genes. Now can you tell us—there are seven sirtuin genes in the human genome, can you just go briefly over what one up to seven does?

Dr Elena: Yes, I mean, there are quite a few functions that those genes have. So I don't think we'll have time to go through all of them. The important ones for our subject today for sports and longevity, and so on, is sirtuin 1 for sure, which is a very important protein that can be found both in the nucleus and the cytoplasm. And actually, its expression is different in different kinds of tissues and it also depends on its necessity and its function. And it's actually what we’ve seen is that sirtuin 1 is one of the first genes that would go onto the side of a double stranded DNA break to recover it. So it is heavily involved with DNA repair, very important gene. 

And then sirtuin 3 would be the other very important for longevity, which has to do with mitochondrial health and mitochondrial function. So those two, they both are enzymes that in order to function, they do need a molecule called NAD, nicotinamide adenine dinucleotide. And without this molecule, they cannot perform its functions. And what's happening, when we age is unfortunately we do have a reduced levels of this molecule as we age, of NAD. And it just keeps on decreasing and decreasing, basically leading into death but a literal death spiral, where you don't have this beneficial effect of the sirtuin genes repairing your genome, repairing your DNA. And the epigenetic regulation becomes basically loose. So this is what is directing the loss of cellular identity as well. So this is one of the hallmarks of aging, where the cells are losing their identity. And then everything that is happening in the cell, all of the functions, they’re being so tightly regulated. So this is what's happening there. 

And then NAD, it's worth mentioning that it exists in two forms and both forms are important. So NAD+, which is the oxidized form and NADH, which is the reduced form. So the reduced form, it's actually something that not many people talk about in the aging space and the supplement space, so they barely know NADH and NAD+. And NADH is actually important for the maintenance of mitochondrial membrane potential. So if you don't have enough NADH, your mitochondrial membrane potential will not be preserved as needed. And this would also lead to decreased mitochondrial function. And decreased mitochondrial function means that you will have a less ATP production and less energy as a result. 

And the reason why this is so important for neurodegeneration, as you mentioned previously, because actually, the central nervous system is perhaps the first one that is being affected as we age. So it's very important. And the reason for this is that the postmitotic neurons that we have in the brain, they are heavily relying on massive ATP production in order to function.

Lisa: So let's stop there, Elena because your brain is so big. We might have lost a few people on the way there, we might have to backtrack a little bit. So NAD, nicotinamide adenine dinucleotide plus or NADH. So is this a little bit like oxidized, like vitamin C oxidizes and then reduces, oxidizes and reduces. And electrons can be donated backwards and forwards. Is that the same thing, sort of pathways? 

Dr Elena: Yes, yes. Yes. That’s right. So NADH gains two electrons. 

Lisa: And that is recycled through?

Dr Elena: Yes, this is happening through electron transport chain in the mitochondria. And we need both of those molecules in order to maintain proper cellular function. And so this would bring us to our next subject, which is what we can do in order to fix this decline of NAD.  

Lisa: Before we go there, let’s just hang on a tiny bit on this NAD, because — so NAD, I know Dr David Sinclair said, arguably the most important molecule. So people, note this name, NAD, NAD+, or NADH. This is the most important molecule in our body next to ATP, and ATP is our energy production. So without energy we’re dead in 30 seconds, and without NAD, we're dead in 30 seconds as well. So either or we're both pretty much up the creek if we don't have either.

As we age, the NAD levels go down. And one of the things that regulates the NAD, or needs NAD sorry, is the sirtuin genes to do their job of DNA repair, is one of their jobs. There are many jobs that it does. And if the NAD is being used by the sirtuin genes to repair DNA, then it's not doing its other jobs. And as we get older, like we have something like 2 trillion DNA breaks, it can be wrong, per minute or something ridiculous. Dr Sinclair said, every minute in our body — so, these enzymes are running around trillions of times in our body doing the DNA repair. And also we need to replicate ourselves and do all of this sort of work. 

So if the sirtuin enzymes are busy doing one thing, they're not doing another thing. So we want to have more of these enzymes available for all of these jobs. And especially as we get older, and we need more support. So that's just a bit of  how that sort of explained what the NAD is. 

Now, we should go on to the next part of the equation. So like there was an NAD salvage pathway, the body needs grams of it every day and we don't necessarily just get it by our food. But there is NAD boosters. What can we do to increase our NAD levels in the body?

Dr Elena: Yes, so yes, this is exactly where energy booster supplements come in. And there are various supplements out there. and recent evidence points towards two particular molecules that are being researched. One is an NR, nicotinamide riboside and then the second one is NMN, which is nicotinamide mononucleotide. 

So now the NR molecule, in order to boost the NAD levels it needs to be converted into NMN first. And for this reason, scientists are focusing predominantly on NM. And I would say now there is increased interest in the NMN molecule at the moment because it looks like it has increased bioavailability, is being absorbed better. And in tests in mice, it does have a better effect on NR in terms of boosting NAD, but also in terms of the—in terms of improving the phenotype of aging mice with different studies that we've seen that have come out in the past couple of years, from gene expression to energy metabolism, lipid metabolism, insulin sensitivity. A bunch of other markers being improved in my supplemented with NMN. And I have to be honest with you I haven't looked in depth into the research for NR, however the evidence from NMN studies so far is quite overwhelming for me.

Lisa: Exactly, wonderful with all the research, too. 

Dr Elena: Yes. I mean we would need to have more comparisons but from anecdotal evidence from myself and people that I know that have supplemented themselves with both, everyone just pretty much mentions to me that they do like NMN much more than NR, and they can see the effect. And this is the reason why I ended up supplementing with NMN myself. 

So basically, I started studying NAD biology in block during my PhD. And unfortunately, my research paper is not published yet, so I won't be able to share that out. Perhaps next year hopefully I'll be able to share my data with you. 

There is a paper from our collaborators lab though that is on bio archive already. And it's from Viktor Korolchuk in Newcastle. And they showed there how basically functional autophagy can maintain NADH pools, which is quite an interesting paper. And it does intertwine a bit with my work. But unfortunately, I can't share right now. 

Lisa: Yes, you have to keep zip right now until it's published. So we can link to the bio archive, the one you mentioned there, at least, do some research and also I’ll also link to Dr David Sinclair's work, in his book, obviously. Because it does put it in in a way that people can understand, which is really, really important. 

Okay, so NMN, nicotinamide mononucleotide is one of the in NAD boosters, and we need the in NAD to...

Dr Elena: Yes. And it's the only direct precursor of NAD. So this is the beauty of it. So from NMN, it converts straight away to NAD. So this is why it has such an enhanced bioavailability. This is why it has those effects because NAD is quite a large molecule by itself. So it's actually hard to—if you supplement orally with NAD. The absorption of the—it will not be high, because of how big the molecule is. So this is why it's called dinucleotide because it has two nucleotides that would need to penetrate the cell. But NMN is a mono nucleotide. And this is why it absorbs better

Lisa: It's actually made there—it's put together in the cell. So the nicotinamide mononucleotide enters through the membrane into the cell, from what I'm understanding, and then it becomes a dinucleotide. So it's a phosphorus molecule, I think or something that's added to the NMN. And then it's an NAD. 

Dr Elena: So yes, so basically it's NMN is a phosphorylated NR molecule basically. 

Lisa: Okay, phosphorylated NR molecule, okay, and then when it goes to NAD...

Dr Elena: And that’s the reason why NMN is actually a bit more expensive than other supplements. Because in comparison to other supplements that are just, let's say, plant extracts or something like this, there is quite a lot of biology implicated in the production of NMN. So there are several steps it would need to go through. And it's quite complex and laborious to produce. And this is why it's a bit higher in terms of price. 

But from my personal experience again, so I started supplementing with NMN over a year ago, while I was still doing my PhD. And at that point—when I found NMN, I already had a burnout. So, which is something that a lot of PhD students experience and my project was quite, quite challenging. And human embryonic stem cells require quite a lot of cell culture in order to just survive, let alone to expand them and do experiments on them. 

So yes, at some point during my PhD, I literally was doing 18 hours, from 6am till midnight. With eight or ten hours of cell culture during that day, let alone the experiments I had to do. So yes, quite challenging. However, it was a priceless experience. I learned a lot. And I think that it was definitely worth it. 

So yes, back in the day, so while I was experiencing this burnout, I found out about NMN. And I thought to give it a go. And it was basically amazing the fact because I've been supplementing with different supplements for the past 15 years or so. And I'm a biohacker myself. 

Lisa: Yes, yes. Like me.

Dr Elena: I transfer with different supplements and stuff. And this was the supplement that I felt the effect of within a few days of taking it and I've never experienced that before with any other supplements. So within three, four days, I actually felt different. I felt the different energy levels. I felt an increase in my energy levels and I felt an increase in my focus. And I remember my partner calling me at some point in the evening at 8 or 9pm, something like that. And we were talking on the phone and he just said ‘Oh, so you're not tired yet’. And I’m like, ‘No, I'm not tired. I actually feel great’.

Lisa: ‘This stuff's working’.

Dr Elena: Absolutely. Yes. And this is how my current business was born. And this is how NMN Bio was born. And I was so excited to actually have a product in the market that is pure, potent and I know that it is what it is. And because I have been struggling to find a good supplier of NMN for quite some time. 

Lisa: Tell me about it. 

Dr Elena: Yes, because of its price, I think that there are quite a lot of opportunistic companies out there that just white label the NMN powder, and they don't even have a certificate of analysis and you don't even know what's in there and things like that. And they just totally diluted with niacin or something else.

Lisa: Exactly. Yes, this is a danger and this is why having a significant analysis and having it scientifically backed in every batch tested and stuff is really important. I've been on—prior to meeting Dr Elena—I've been on in NMN for maybe five, six months now. And I've had my mom and my brother on it and my husband on it. But I had to go through, jump through all of these loops to get it out of America. Get it sent to someone there. Get it shipped over here and it's not been available down the scene of the world. And finding a reputable source is absolutely key with this molecule. 

I remember David Sinclair saying, when you do get your NMN do keep it in a cool, dry place. So don't stick it in a hot place under the sun somewhere. Ideally, probably in the fridge if you can, to give it an extended shelf life and for it to do its job properly. 

So you've founded a company NMN Bio, at the UK, and I'm really excited to be working with Dr Elena and I'm going to be importing it down to Australasia.

Dr Elena: I'm super excited about this too.

Lisa: Yes, me too. Like it's just super exciting for me. Because I'm spending a fortune a month, giving this to my family anyway. And I could never test what I was doing. And now I have a place where I can trust that it's coming from a good source. 

So nicotinamide mononucleotide is the one aspect but that's not the end of it all. Is it though? That's not—so resveratrol we mentioned before. This work in combination—and on that point, it should be trans-resveratrol that you take, if you're taking resveratrol with it.

Dr Elena: Yes, absolutely.

Lisa: And we don't have this yet in the cater of products. But this is in the pipeline, isn't it, Dr Elena? 

Dr Elena: Absolutely. Yes, this is coming in 2021. Super excited about it. Hopefully we'll have it on the market in the next few months.

Lisa: In the next months. 

And but resveratrol, trans-resveratrol you want to be taking that in combination with nicotinamide mononucleotide. So an analogy that Dr Sinclair said was resveratrol is like the accelerator pedal and nicotinamide is the fuel. I think that’s the way around. 

Dr Elena: Yes, absolutely. That's correct, because basically what activates the sirtuin is the resveratrol molecule. But in order for them to function properly, you do need the NMN because this is what they consume in order to function. And so this is why it's such a good synergy. And as you said, trans-resveratrol is absorbed much more. And also in order to increase the bioavailability of resveratrol, it's good to take it with some sort of full fat dairy. So for instance, a yogurt. David Sinclair says that he does take it in the morning with a full fat yogurt.

Lisa: With some fat, yes..

Dr Elena: In fats, or you could you could do some cheese, probably. I do yogurt as well. 

Lisa: Does it have to be dairy? I've been taking it with oil, is that okay? 

Dr Elena: Yes, this could work as well. So yes, absolutely. There are a few people doing olive oil for this type.

Lisa: So it just needs a fat in order for it to be bioavailable, because it’s a dry powder. And so the oil in the fat helps. Because it's a very insoluble molecule.

Dr Elena: And then what I do for my personal anti-aging cocktail...

Lisa: Which is obviously working, because Dr Elena is actually 110 years old. 

Dr Elena: No, just 32. 

Lisa: She’s just 32 but looks like—honestly, I thought, seriously 32? I would have thought you were 22. So something's working. The good diet. It can't be that overworked because you've been definitely overworking for the past few years. And this is obviously helping. 

And I'm 52. So I'm old enough to be your mom. And I'm definitely super excited about anything that's coming down the pathway that's going to slow down the degeneration. Because over the years, and after smashing the crap out of my body, I've definitely got some repair work to do. And my mom is 79 years old, she's in the corner over there, taking her NMN as we speak, and her resveratrol, along with their hemp seed oil and all the other supplements and a big green smoothie of broccoli juice. So she's like going, ‘ugh’, it'd be quite funny for you to see her face right now. 

Dr Elena: You should also add apigenin to her cocktails. So, this is another molecule which is very interesting. And perhaps in a later podcast, we can also talk about a couple of different things that have to do with raising your NAD levels in different ways. So, basically, what happens, besides sirtuins, there are different other enzymes called NADases that also consume NAD. And if they do that, consistently, there is not enough NAD for sirtuins to do their job.

So such enzymes are called parks, which are activated when there are some stress signals in the body. So, for instance, one such signals when let's say your mitochondria are going bad and there is some sort of stress related to mitochondrial function, you will get a secretion of cytochrome c from mitochondria. And then as a result, you will get some sort of activation of the park enzymes and they also consume NAD.

Another NADase is CD38. So, this is an enzyme that is activated when there is increased inflammation in the body. So, as we age, CD38 levels increase. And what has been demonstrated very beautifully in a recent study in mice was that CD38 actually controls the functions of sirtuin 3 in an NAD dependent manner. Because they did quite an elegant experiment, where they did have CD38 knockout mice, and the wild type mice or regular mice. And in the CD38 knockout mice the levels of sirtuin are two and a half times higher. And then when they put a saturating amount of NAD in the wild type mice, what happened is basically the function of sirtuin is also increased. And it was similar with the function of surgeries in CD38 knockout mice. So this means that if CD38 is absent, then sirtuin3 in this instance is upregulated and is working much more. But when CD38 is present, it consumes all of NAD and then there is not enough NAD for sirtuins. 

Lisa: And this is so this is why we need a bigger pool of NAD, basically for all of these problems as we age. 

Dr Elena: So this is one point and then the second point I was going to do there is that apigenin, so the supplement that I mentioned to you, which is actually present in parsley and predominantly in dried parsley. So you can actually get it for cheap. 

Lisa: Yes. 

Dr Elena: Have a teaspoon of dried parsley every day. So apigenin is a molecule that actually blocks CD38. So this means that it can also increase the levels of your NAD and make it available for your sirtuins.

Lisa: Wow. I'm off to get some parsley. I just ripped my parsley plants out of the garden. Bugger. I will get seeds, so I'll have to plant some more. And you do need to dry it in order for it to intensify.

Dr Elena: If you dry it, it will have even apigenin. So, the bioavailability increases somehow, I'm not entirely sure of the mechanism. But yes, dried parsley. 

Lisa: Yes. Sorry. There's a noise in the background with my mum washing out a broccoli.

Dr Elena: No worries.

Lisa: Yes, yes, yes, this is my podcast life. Real. 

So activated immune cells. So like I've had an infection for the last couple of weeks. So I've been under a hell of a lot of stress in the last year, like really—losing my father and so on, a hell of a lot of stress. And the day before Christmas, I stopped working and I started to relax and my immune system then went, ‘Okay, cortisol levels are now going down. We're going to make you sick. We’re going to do some repair work’. 

Dr Elena: That’s how it’s usually done. 

Lisa: Yes, yes. That's what happens when you relax. So my whole Christmas period was spent with a head cold and a chest cold. Now, when my immune system is activated like that, I'm going to need a lot more NAD because of this in NADases. You call them, NADases? And the CD38 would have been one of those things that was probably more active when I was sick. Would that be right? Okay, so we need to increase that in order to help our immune system. 

So does this—random thought—does this help with other autoimmune diseases as well? Like, does it help deep down regulate some of the inflammatory pathways? 

Dr Elena: I don't know, this is not my area of expertise. Wouldn’t be able to comment on top of my head on this.

Lisa: Yes, just me connecting the dots going—that would make sense but okay. So all right, so we've covered quite a lot of ground today. And I think we'll probably wrap it up there, Dr Elena. And we'll go on to mTOR and autophagy and other things in subsequent podcasts, and so on. 

So we're going to put all the links. If you guys want to get some NMN, and in a few months, we will have resveratrol as well. I'm going to put the links in the show notes to the new website. And we're going to be importing it down to here to New Zealand and Australasia. And I'm really excited about that. Because there is one other company that has it here and it's not got any certificate of analysis, there's no sort of thing. So you want to make sure that you know where you're getting this information from all your supplements from, and you want to know who's behind it. 

So I'm really, really excited about working with your Dr Elena. I think this is brilliant. I know we've got a whole lot of products that are in the pipeline that are going to be coming down in the next year or so. Other things—so we will be covering those in future episodes. Things like, I don't know epistane... 

Dr Elena: We should definitely talk about senescent cells and what we can do in order to combat them. And then of course, the subject of my PhD, which was around autophagy. So, this is definitely a very nice subject for discussion, because as you mentioned, mTOR is not something that you want to mess with on a regular basis. And actually, the good news are that there is the mTOR- dependent activation of autophagy and mTOR independent activation of autophagy. So my PhD supervisor was the one that discovered during his PhD probably 20 years ago, 15 years ago, the mTOR- independent regulation of autophagy and different molecules that value also can work and activate autophagy in an mTOR-independent manner. So one such molecule is already on the market as a natural sweetener. It's called trehalose. 

Lisa: Trehalose. 

Dr Elena: If you want to supplement your...

Lisa: How do you spell that? 

Dr Elena: Trehalose. T-R-E-H-A-L-O-S-E. This is what I use for my coffee.

Lisa: Oh, trehalose. So that will help you increase your autophagy? 

Dr Elena: Trehalose has been shown to activate autophagy in an mTOR-independent manner. Yes.

Lisa: Wow. So I don't need to starve myself in order to activate... 

Dr Elena: I mean, there is not that much data in humans yet on this particular molecule, to be honest. I actually don't know what is the dose that you would need to have this effect, but I still prefer it over sugar.

Lisa: Yes, absolutely. And anything that supports that pathway anyway and getting rid of these senescent cells. So senescent cells just for those wondering what the hell we're talking about. Senescent cells are basically cells that are still alive, but they're no longer replicating. They're not doing the job properly. And they're sending out inflammatory signals into the body. So they attract cytokines that cause inflammatory responses. 

And so what we want to do is we want to knock these cells off them to have their autophagy, meaning their cell death. And when we recycle the parts of the cells for the new job, and that's what we want to happen. As we get older, we get more and more senescent cells and there's actually literally ways our body down and stops and increases inflammation and causes a lot of the effects of aging, if you like. So that's definitely a subject for next time.

But Dr Elena, you've been fabulous today. Thank you so much for the work you do, for the patient you bring to the project. I'm super excited about our collaboration and helping lots of people stay younger for longer. I think that will be.

Dr Elena: Absolutely, that’s the goal.

Lisa: Yes, absolutely. Have a wonderful evening because it’s around midnight in Dubai. So thank you very much for staying up late for me over in Dubai. It's probably too much. 

Dr Elena: My pleasure.

Lisa: And we'll see you again soon. Thanks Dr Elena.

Dr Elena: Okay, thank you. Bye bye.

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.