Sirtuin Genes, Resveratrol and NMN - an interview with Dr Elena Seranova

 In this interview I discuss with moelcular biologist and founder of NMN Bio Dr Elena Seraova what sirtuin genes are, what NAD is, how Resveratrol works in synergy with NMN to upregulate the sirtuin genes and how this all affects the rate at which you age.

I first became aware of NMN and NAD precursors through an interview on Dr Rhonda Patricks podcast with Dr David Sinclair and subsequently I read his book "Lifespan", which I recommend everybody go out and buy. 

Dr David Sinclair is a very, prominent scientist at Harvard Medical School. And he runs his own lab.

He's been studying anti-aging and longevity for decades now. And he was actually one of the scientists who discovered resveratrol, which we're going to discuss later on and what resveratrol does.

His mindblowing book, really gave me a look into the near future as far as longevity and being able to turn back the clock on our aging biology.

Some parts of the book are so profound and astonishing it sounds almost like science fiction but it's not.

But one thing is for sure our lives and potential to live longer and healthier is about to change radically.

But it's not just about living longer in a decrepit state, it is about health span as well as lifespan.

We may not all want to live forever but we want to live a long and healthy live free from disease and degeneration.

So anything that I can do to help my friends, my followers, my family live healthier lifespans, I'm into.

So Doctor Sinclair is an expert on sirtuin genes.  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? 

Dr Elena: So sirtuins are enzymes, basically. And it's a group of genes that are very well conserved across multiple organisms, which means that they play a very important role in evolution and in our biology, when it's preserved over so many species you can bet it's an important set of genes that we should be paying attention to. 

What sirtuins basically do is they control the epigenetic regulation in our cells

Different sets of genes are being activated and deactivated all the time in all our cells according to external stimuli. If you for example go in to a freezer you will turn on specific genes that will make you shiver, when you go into a sauna other genes will turn on and make you sweat. Drink a cup of coffee and yet other genes are turned on. All these environmental stimuli, amino acids, even availability of nutrients, toxins, hormones and more affect what genes are being activated.  

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.