One fascinating and incredibly important molecule to pay attention to in the field of healthy longevity is nicotinamide adenine dinucleotide (NAD+). It’s literally in every cell and contributes to over 300 different reactions in the body as a coenzyme substrate. Dr. Nichola Conlon, PhD, is an expert on NAD+ and launched Nuchido Laboratories to rigorously test and develop a NAD+ booster supplement packed with epinutrients. She joins me in this ridiculously interesting conversation where she explains the role of NAD+ as a signaling molecule, its relationship with longevity proteins sirtuins, its impact on multiple hallmarks of aging, its relationship to the salvage pathway, NNMT and CD38. And that just touches the surface of all we discuss in today’s talk! I’m thrilled to have her with me and hope you enjoy listening. ~DrKF
We know that age is the biggest risk factor for major diseases such as cancer, heart disease and Alzheimer’s. The big question is, how can we slow cellular aging in a way that actually reduces the risk of age-related chronic diseases and positively affects biomarkers of longevity? This is exactly what our guest on today’s show has passionately focused on in order to develop a carefully crafted nicotinamide adenine dinucleotide (NAD+) booster using her background as a molecular biologist. Dr. Nichola Conlon, PhD, joins us to set the stage for understanding why NAD+ is the most important molecule you may have never heard of, why it’s linked to aging, and the importance of supporting optimal NAD+ levels for longevity.
In this episode of New Frontiers, learn about:
- Why NAD+ is critical for longevity and healthy aging
- NAD+’s role as a signaling molecule and in DNA repair
- The relationship between longevity proteins sirtuins and NAD+
- The latest science on why NAD+ declines with age
- How to address the root cause of NAD+ decline
- How NAD+ is produced and the role of the salvage pathway in recycling NAD+
- How aging affects the key enzyme of the salvage pathway, NAMPT
- Nicotinamide’s (vitamin B3) impact on NAD+ function
- The impact of CD38 enzyme on NAD+
- How aging, NAD+ recycling, and methylation intersect
- How to address intracellular accumulation of nicotinamide
- Why methyl donor depletion is of concern with reduced NAD+ production and aging
- Nuchido TIME+’s whole systems approach to boosting NAD+
- The importance of combining epinutrients to stimulate various pathways
- Potential benefits of NAD+ IV infusions
- Using an NAD+ booster as a fasting mimetic to prolong activation of pathways
Dr. Kara Fitzgerald: Hi everybody. Welcome to a New Frontiers in Functional Medicine where we are interviewing the best minds in functional medicine. Of course, today is no exception. I am really excited, actually, as always, to be talking to the brilliant minds in science and in functional medicine and systems medicine and longevity science. Today I’m going to be chatting with Dr. Nichola Conlon. Nichola is a molecular biologist by training. She’s specializing in the study of aging as a biologically complex disorder. After years focused on the early stage drug discovery with a leading biotech firm, Dr. Nichola founded Nuchido Laboratories to deliver disruptive innovation in the field of anti-aging, rejuvenation, and health span. Driven by her belief that cutting-edge science should not lie hidden. Go Nichola.
Dr. Nichola is on a mission to democratize science and has a skill for translating and presenting advanced science in a way that helps to educate and support people to take care of themselves, to take control of their health. Along with other leading scientists at Nuchido, Dr. Nichola has identified the right combination of targets to restore cellular NAD+ production back to youthful levels leading to the development of a second generation NAD+ booster called Nuchido TIME+. Dr. Nichola, welcome to New Frontiers.
Dr. Nichola Conlon: Hello. Thank you so much for having me, Kara. I’m really excited to have a chat with you today.
Dr. Kara Fitzgerald: I’m excited because you’re bringing really a great scientific background to longevity science, to the natural products industry, to continuing researching natural products and looking at things that are really important to us here in functional longevity, if you will. You are bringing together many, many different areas that I’m particularly enthusiastic about. You’ve launched this extraordinary NAD+ booster product that we’re going to speak about today in careful detail. You’re just perfect to join me on my podcast. I want to get into understanding you, your background, your company, maybe a little more detail, a little more blowout of what brought you here. Let’s start with a big overview picture, and then we’ll move into the nitty-gritty.
Dr. Nichola Conlon: Yeah, of course. I’m not a medic, I am a scientist, and my area of specialty is the science behind why we age at a cellular level. Obviously, everything that we’re experiencing in terms of aging is really starting deep within inside ourselves, in our cells and all the pathways and different compartments within there. Although we tend to recognize aging on the outside. My background is to be really understanding what is going wrong at the cellular level to cause what we recognize as aging. I’ve been really fortunate to have quite an interesting background. I actually worked in drug development, but I was developing drugs to slow cellular aging. Now to the average person, when you say you’re developing drugs to slow aging, they’re like, “What? That’s crazy. You can’t do that.” It’s a huge area now within drug development because as you and I both know, age is your biggest risk factor for all of the major diseases that drug companies are trying to treat.
Cancer, heart disease, Alzheimer’s, everything. Your biggest risk factor is your age. The idea is, is there a way that we can slow aging at a cellular level and if we can, will that have an impact on actually reducing our risk of age-related chronic disease? The idea is that we would be looking to extend our period of healthy lifespan, extend our health span so that we’re not getting chronic age-related diseases as we get older. I was fortunate enough to enter that world as it was just beginning within the world of pharma. This was back in around 2013, 2014, and it was a really interesting time because I spent a lot of time really understanding the biology at a cellular level behind aging. What were the best things to target? Meeting all the key players within the aging and the longevity community.
Then the ultimate goal was how can we take all this knowledge and look at targets within ourselves? There were two main things that really bothered me in the world of pharma or drug development. The first was how long it takes. Going from where I was in a lab looking at the latest cutting-edge science to then actually getting that science out to people that will actually benefit from it, you’re looking at least 10 years, more like 15.
Dr. Kara Fitzgerald: Right.
Dr. Nichola Conlon: That was just, “Oh.” You see this really amazing science and think this isn’t going to get to anyone anytime soon. The second thing that really bothered me and was part of my job, we would send a load of molecules for screening in the labs. We’d then get the data back and we’d literally have a list of these molecules work exceptionally well to at the bottom of the list, these just don’t work at all and everything in between. Part of my role was I had to look at which molecules were patentable. Which molecules could the drug company own? Therefore, they would be the ones that they would take forward in development. What I’d often see was that the things that worked really, really, really well were not drug molecules. They were things that were naturally found in foods. They were things that were approved as supplements. They were not what a company could patent and take forward. These things would just get pushed to one side and then the things that would go into development were half is good, and it was like, “Wow, they’re actually going to put all this money into development in something that just works half as well.” I get it commercially, but ethically, I was like, “This is crazy.” Because I just saw that time and time again.
Dr. Kara Fitzgerald: It’s just ridiculously interesting. I want to just take a minute and say, that is so interesting. Yeah, I was going to ask you, were there any drugs in the pipeline that we might have heard about? I think you’ve answered that. I’m sure that anything that you guys have discovered so far is still hanging around in the lab, going through many, many, many hoops and not even close to being ready for prime time. Is that true?
Dr. Nichola Conlon: Exactly that. There was a situation that I could see where it was like, “We have amazing science that could benefit people, and we have molecules that can do this that are already known to be safe and well tolerated and have hundreds of millions of exposures.” Because they’re in our food and things like that, and they’re just not getting the research that they deserve. I decided that I was going to leave that world. I left in 2017 and I found Nuchido Laboratories and my whole mission was how do we do something with those molecules? How do we get them their research and all of their evidence base and the testing that they actually deserve? I’m sure you can imagine what people said. They thought I was crazy when I was leaving my really credible job in drug development to start a supplement company.
Dr. Kara Fitzgerald: Yeah. Oh my God, that had to be pretty hard. Was it? You had some good support behind you, I hope. I can only imagine the kind of flack that you received.
Dr. Nichola Conlon: Obviously, supplements have a bad name. There are a lot of things out there that don’t work as advertised and don’t have much science behind them. From my perspective, I was like, “The way that you identify molecules is exactly the same, whether you’re looking for a drug or something that’s not a drug.” Actually, our bodies have no idea what the heck a drug is, or a supplement or a nutrient. Like our body doesn’t go, “Oh, that’s a drug, so it must work. That’s a nutrient, so it can’t possibly do anything.” Our bodies have no idea. They all have an equally strong physiological effect. It’s just that I wanted to bring the more credible side of testing and the scientific credibility out of the drugs world, but bring it into the supplements world.
Dr. Kara Fitzgerald: Very interesting. We saw this a lot in the fervent COVID research happening where there was a lot of exploration into molecules that might be effective before we had any grip on how to address this virus. They were all coming out in preprint at the time, but as often as not, it was a natural product that appeared to be as potent or more so than some of the drug molecules that they were exploring for efficacy with COVID. Very, very interesting.
You just took this huge risk in leaving a credible, probably an interesting career. I think you’ve explained it well and it’ll be interesting to a lot of our listeners that you were seeing all these molecules that were fabulous. It’s kind of cool to get a behind the scenes look from a scientist who’s there… These are natural molecules. Let’s just sweep them off to the side. I could see that would be an ethical tug for a lot of us listening. You decided to make this leap. What molecules grabbed you? Let’s move over to talking about that stage in your career and what you’ve decided to focus on.
Dr. Nichola Conlon: Yeah, I think, one thing I did learn from drug development was that… Again, I was fortunate to work for a very forward-thinking company that was investigating new drug development techniques, and they specialize in something called systems pharmacology. Conventional drug development, basically we’ll go, “Okay, we have a disease. We have a gene or a protein or an enzyme or something that goes wrong. We’ll just get a drug and we’ll stick it to that particular pathway or protein or whatever, and that’ll fix it.” As we know, 9 times out of 10 it doesn’t, because biology is incredibly complex and often there’s not just one thing that’s going on. Also, molecules and drugs don’t stick to just one thing in the body. They have footprints and they affect many different things. I specialized in something called systems pharmacology, which actually was a more advanced discovery technique that took into account all of this.
Basically, it addressed the fact that there was complexity. It addressed the fact that if you’re going to have any real physiological effect in the body, that probably just doing one thing or looking at one target or one molecule, probably wasn’t going to cut it, and if you want to have real efficacy and real impact, then the best way is actually to look at multiple targets at the same time and use combinations of different molecules at the same time. There you would get a much bigger effect. The hit rate using that approach was way higher. Not only did I want to look at how can we bring some of these more natural molecules out of that world and test them, but actually the way that you could be putting combinations of different molecules together so they actually work in a slightly different way, or they’re synergistic and have the more powerful effect.
A huge part of what we focused on at Nuchido Laboratories was how are we going to take some area of aging science? How are we going to understand the physiology? And then how are we going to take combinations of molecules, use that system’s approach to identify potent combinations in molecules that will then be regulated and approved as a supplement so we can get it out to people very quickly rather than waiting 10 to 15 years? One of the first things that I really wanted to look at was NAD+, because this back in 2017 had become a lot more popular. There were a lot more people talking about NAD+ within the aging space. For me, looking at all the research behind it, there was good promise. We now had a good idea of what was the underlying physiology surrounding it. I really wanted to look at developing our first product as an NAD+ booster that worked better than the ones that were already out there.
Dr. Kara Fitzgerald: Awesome. Did you have some notion on the natural products you were going to really hone in on? You must have.
Dr. Nichola Conlon: At the time. No. It was actually the targets. We knew what targets we were going to be looking at based on the latest science around NAD+. Would it be helpful to do a bit of a NAD+ 101?
Dr. Kara Fitzgerald: Yeah.
Dr. Nichola Conlon: I’m sure everyone’s familiar with it. We know the reason NAD+s… It’s just an incredibly important molecule in the body. Anyone that’s done any biology or medical training will have heard of it because it’s important for over 300 different reactions in the body as a coenzyme substrate.
Dr. Kara Fitzgerald: I just want to underscore that. We’re using NAD+ in different structures all of the time.
Dr. Nichola Conlon: Yeah.
Dr. Kara Fitzgerald: I think in literally every cell, if I’m not mistaken. It’s just…
Dr. Nichola Conlon: It’s every cell. I quite often say it’s probably… If you haven’t heard of NAD+, it will be the most important molecule that you’ve never heard of because if you didn’t have it, you would literally be dead in 30 seconds. It’s that critical for our physiology. It’s most famous for its role in energy production. In the Krebs cycle, which occurs in our mitochondria, which literally takes the food that we eat and converts it into ATP, which is the energy that all our cells need to survive and do all of the functions. Incredibly important for that. The other thing that it’s been becoming more famous for now is its role in cellular maintenance and repair. NAD+ is now known to basically act as a bit of a signaling molecule in the cell where it tells the cell to switch on and off maintenance and repair pathways such as DNA repair enzymes. The things that are going to make sure our cells stay in good health.
As a general rule of thumb, if you have high levels of NAD+, you have good levels of energy production and good levels of cellular maintenance and repair. If you have low NAD+, energy goes down, maintenance and repair go down. The main reason why NAD+ can seem to regulate all these different functions is that it works in tandem with a group of proteins known as the sirtuins. Some people might have heard them referred to as longevity proteins. This is because these sirtuins are known to actually switch on a whole host of downstream pathways and processes that are beneficial for cellular health, that switch on recycling, switch on repair, switch on DNA repair. The sirtuins basically switch all of these things on. The link with NAD+ is that they are absolutely critically dependent on NAD+. NAD+ basically acts as a fuel to power the sirtuins. Without NAD+, they don’t work.
Dr. Kara Fitzgerald: That’s interesting about that, just to link it back to aging is… You’re going to do it anyway, but just off the top of my head, there was a paper that we’ve been interested in my group. The most recent hallmarks of aging paper. This is teasing out all the mechanisms that really seem to drive aging and NAD+ seems to have a finger in a lot of them. They’ve expanded to 12 hallmarks. I think that originally there were nine, and this group has just recently expanded them. NAD+ is right in the middle.
Dr. Nichola Conlon: Yeah, it is. That is one of the reasons why I… Of all the things we could have chose out… Well, at the time there was nine hallmarks of age, and now there’s obviously 12. We have done a lot of research in areas like senescence, but for me, NAD+, everything seemed to come back to NAD+. If it was an NAD+ decline, it was linked to some of the hallmarks being established. If you restored NAD+, it seemed to get rid of some of the hallmarks of aging. It’s very intertwined. I guess it’s not surprising because it’s in every cell. It performs so many different functions that it’s unsurprising that it’s going to impact multiple hallmarks. Yeah, the reason that NAD+ is linked to aging is because it’s being found to decline exponentially in our cells as we get older.
Dr. Kara Fitzgerald: Why though? Why does it drop like a ton?
Dr. Nichola Conlon: Well, it’s estimated actually to drop by about 50% every 20 years. That’s from birth, in the tissues that had been studied, that’s actually from birth. You can see that even by the time you’re 20, it’s halved. Then that halves again. Then that halves again. By the time we’re in more advanced ages, there’s really not very much NAD+ left in our cells at all, which is pretty scary because it’s so important to think that this molecule that we really rely on is becoming critically low. For a long time people didn’t really understand what was happening to NAD+. They didn’t really understand the underlying mechanisms that were causing NAD+ decline. It is now become well established what is causing this. I think, first of all, a key thing to point out is that our cells are actually really good at making their own NAD+.
When we’re young, all of our NAD+ is actually just produced internally. I think a lot of people think it comes from our diet or it comes from some external source, but it doesn’t. In young youthful cells, we actually have a pathway called the salvage pathway, and what this does is it basically recycles NAD+ continuously. When NAD+ is used by cellular processes such as the DNA repair enzymes or the sirtuins, they actually split it apart back down into some of its building blocks. One of these building blocks is nicotinamide vitamin B3. This nicotinamide is then actually recycled back into fresh NAD+ again. That makes sense because NAD+ is so critically important that ourselves almost have to have this fail-safe way to have a continuous supply. We wouldn’t really want to rely on it coming from our diet, for example. That’s how it’s produced in young cells. We now know that the main reason why it’s declining is actually this process becomes dysfunctional as we get older. We start to see… Sorry. Yeah.
Dr. Kara Fitzgerald: I don’t want to ask you a question about that process, but I just want to say we had an interruption from my newly minted five year old. She just turned five and she’s an insane bundle of energy, right? Kids, you can see NAD+ just busting out. It’s interesting to think about it. The more exhausted she gets, the more energy she gets, which is such a paradox. It’s funny that likely NAD+ is playing a big role in that. And by the time she’s 20, she’s going to have a very different… She’s still going to have a lot of energy, but it’ll be different. It’s fascinating for me to think about that pearl that you just gave about NAD+ being so high at birth and then halving and halving and halving over time. Why is the salvage pathway breaking down because we age?
Dr. Nichola Conlon: Yeah, what we see is that there’s a key enzyme within the salvage pathway. It’s got a very long name, but we abbreviate it to NAMPT. This NAMPT enzyme is what we would describe as a rate-limiting enzyme. Out of the whole pathway, it’s the really, really critical one. It’s levels of activity are directly correlated to the amount of NAD+ that will be produced. What we see in older cells is that NAMPT starts to get turned down. This means that the key enzyme that’s powering this recycling pathway just starts to go down with age. It means our cells just simply can’t make and recycle as much NAD+ as they did when they were young. That’s one key reason.
What we also now know is that the demand for NAD+ in older cells actually goes up as well. Right at a time when your cells actually need more NAD+, you actually see a reduction in the ability of the cell to make it. This causes a lot of other downstream knock-on effects because what happens is, for example, we have a lot of inflammatory processes in older cells. There’s a really famous one called CD38. It’s an enzyme that seems to become upregulated with chronic low-grade inflammation as we get older. Now, CD38 just eats up NAD+. It uses so much of it. When it uses NAD+, it gets broken down. This is broken down in nicotinamide. Now in young cells, this nicotinamide would just be flipped straight back into NAD+ again via the salvage pathway.
But, we know that enzyme isn’t working as efficiently. Therefore, what happens in the cells is that older cells start to build up this nicotinamide because it’s not getting recycled. Then the cells are like, “Oh my goodness, we need to maintain homeostasis. We don’t like it when things build up. How do we get rid of it?” What it does is it increases expression of another enzyme called NNMT, which is a key methylation enzyme. This enzyme sticks a methyl group on nicotinamide to signal its excretion from the cell. Then what you see is then further dysregulation because you start getting methyl donor depletion because it’s all being used up trying to get rid of this nicotinamide. Then you don’t have the methyl groups to be involved in other critical processes like epigenetics.
You can quickly see in older cells how you’ve got lack of recycling, you’ve got increased demand for NAD+, you’ve got inflammatory processes using the NAD+. Suddenly, everything’s going out of whack and one negative thing leads to another. Then it’s like the perfect storm for major NAD+ depletion. I think the key takeaway is it’s complicated. It as with anything in biology, NAD+ biology is complex and the reason it declines is complex. There’s not just one thing causing it. There’s multiple different things going on that cause a decline.
Dr. Kara Fitzgerald: All right. I know a lot of people are going to immediately be thinking about then maybe B3 actually becomes toxic to take. I think you’re going to address that in a little while. We prescribe nicotinamide in practice. We prescribe niacin. You can really get a whole variety of those things and if it can’t be activated, then that may be a contraindication for use. And if it’s not only not activated, but then it’s methylated so that it can be eliminated, that could be another contraindication. My area of research has been in DNA methylation, and so we’re always thinking about ways that we can preserve it. You’re going to talk about that, but before you jump into that, I just wanted to ask you, this is a little bit of a wild-card question. I’m curious if you have anything to say about… When we see this, the breakdown of the salvage pathway, the increased need as we age.
We need more NAD+ as we age, but we can’t recycle it. It ends up accumulating. It’s getting sucked up by CD38. Aging looks almost like this program phenomena sometimes. On purpose, we’re just putting the body into dire straits so that it’s vulnerable to, as you pointed out earlier, all the big diseases are all associated with aging. It seems like there’s some program phenomena that’s potentially occurring. Do you have any thoughts on that or do you want to just kick that down?
Dr. Nichola Conlon: Yeah. Well, it’s a hugely controversial area in the world of longevity, is aging programmed or not? I think my take on it is that aging only ever makes sense when you think of it in terms of evolution. We’ve evolved to live to a particular age. We have evolved to live not long past childbearing age. Every process that we have in our cell is basically trying to protect us until we get to that point and we’ve almost fulfilled our purpose and then off we go. Why would evolution ever give us cellular abilities to live beyond that, to reach an age that we’re never likely to naturally live? This is why you have processes like senescence, which are highly beneficial when we’re young because they prevent us from getting cancer. But then as we get older, they become hugely problematic.
In reality, when evolution designed that process, we were never supposed to live until our ’80s and these cells weren’t supposed to accumulate. With aging, I always say, “If you’re trying to explain anything in aging, just think of it from evolutions point of view.” Everything is so complex when you look at the hallmarks of aging. They’re all highly interconnected. You can never look at anything in isolation. This is the beauty of systems pharmacology. It really acknowledges that and doesn’t ignore it, which unfortunately a lot of scientists tend to have a bit of a reductionist approach where they’re very focused on very particular areas of biology and fail to see the bigger picture of how their particular interesting area may be impacting something that they’ve never thought about before, yeah.
Dr. Kara Fitzgerald: It’s great. It’s just really cool that you have studied and work in that systems model. It’s just really refreshing. Indeed, I’ve interviewed people who are focused on single molecule activity and controlled activity. Yeah, it just misses so much. All right. That was a fun little tour through the importance of NAD+ and what happens as we age. Anything you want to add there, or do you want to circle back in and start talking about is there an issue with prescribing nicotinamide or some of the precursors like nicotinamide riboside or NMN?
Dr. Nichola Conlon: I think a lot of people… Well, I think first of all, going back through the science of NAD+. Scientists seeing this molecule, it’s incredibly important. It declines with age. Why don’t we just stop it declining with age, and if we did stop it declining with age, then would all of these important cellular processes remain switched on? Would we improve health span? How would it improve all the things that are associated with NAD+ decline? Scientists began to do things in cells and animals than humans that would boost NAD+, and lo and behold found that if you maintained NAD+ or topped it back up, that you had a whole host of benefits. Obviously, everything from increased mitochondrial function, energy production, physical energy, cognitive energy, reduction in neurodegenerative diseases, muscle, everything. NAD+ seemed to just be this magic molecule that was addressing a lot of different issues when it came to aging. Again, it almost sounds too good to be true, but when you think about – it’s in every cell, it declines. It has all of these beneficial processes that if they’re getting switched off, is not good for cellular health. It’s no surprise that the benefits are so vast.
Dr. Kara Fitzgerald: But mostly in animals though, right? In animals, worms, mice and worms, I think.
Dr. Nichola Conlon: Yeah. The early studies would’ve been your classic model organisms like C. elegans worms, drosophila, et cetera. Then it was the mammals. Then, more recently it’s been the human studies. There was a lot of, “How can we boost NAD+?” It’s known that NAD+’s quite a large and stable molecule. The idea of just taking NAD+ as an oral pill was immediately wiped off the table. It’s not possible. The next best idea was, “Well, why don’t we use precursors to NAD+?” Like the raw material, the building blocks that our body uses to make NAD+, why don’t we take that?
Dr. Kara Fitzgerald:
Can you Nichola just speak to why NAD+ was wiped off the table? Just say that again. I didn’t quite grab it and I’m guessing some other people like, “Why was it kicked out?”
Dr. Nichola Conlon: Yeah, NAD+ by its very nature is an unstable molecule.
Dr. Kara Fitzgerald: Okay.
Dr. Nichola Conlon: It’s what we call a redox molecule, which means it flips between different states, so it loses and gains electrons and hydrogen all the time, and it flips really easily between these states. That basically means that it’s just very, very unstable. If you try and put it in a pill or put it through your digestive system, it just gets degraded.
Dr. Kara Fitzgerald: Okay.
Dr. Nichola Conlon: The other thing is, let’s say hypothetically, it did get intact into your body. Actually, it’s a big molecule and it’s too big and charge to actually fit through our cell membranes. There are not many cells in our body that have a transport protein that will actively intake it into the cells. Yes, you could take NAD+, but most of it would have to be broken down and then transported through as the precursors anyway. They’re the main reasons why NAD+ in a pill, an oral pill, was just not a practical solution. The next best thing was, “Let’s use the precursors, the raw materials.” These are what NAD+s naturally made up of anyway. These are things like your niacin, your nicotinamide, your nicotinamide riboside or NR. It’s commonly known as nicotinamide mononucleotide or NMN. The most popular ones seem to be NR and NMN. Again, these are just precursors to NAD+. They’re the building blocks that our bodies use to make NAD+. The idea was if we give the body and the cells more of the raw material, hopefully the body will convert it into NAD+. At the time it was so brilliant. You can see it boosts NAD+ and it’s doing the job. This was in cells and model organisms.
Then when it started moving in the human clinical trials. There wasn’t that amazing result with the likes of NR, and it was a bit puzzling. It’s like, “Why all this extending lifespan of cells and health span and everything and we’re not really getting the effects translated into humans.” I think since the idea of using precursors came out, the science has obviously moved and we now understand why NAD+ declines, as I’ve just explained the reasons. In light of all of that, if you think now about what happens when you take a precursor such as NR or NMN, what we know is that it enters the salvage pathway. It actually enters lower than the rate-limiting enzyme. It does actually get converted into NAD+, which is why in the studies you do see an NAD+ boost, but as soon as that NAD+s been used at once via sirtuins or the DNA repair or CD38 or whatever it is, it’s broken down in nicotinamide.
Then you’ve got the roadblock, because if they’re older cells, then that nicotinamide and that pathway that’s recycling it is not as functional as it should be. Essentially, yes, you’re getting NAD+. It’s getting used once, but then you get in a buildup of nicotinamide, and then you’ve got the problem of, “Oh my goodness, we’ve got to get rid of this nicotinamide.” The methyl donors start coming out, tagging the nicotinamide and excreting it. This is why you’ll see a lot of people talking about the fact that you should be taking methyl donors like trimethylglycine, choline, et cetera, when you are taking NR or NMN, because you can suffer from methyl donor depletion.
Dr. Kara Fitzgerald: Let me ask you a question, also. You’ve got this accumulation, this intracellular accumulation of nicotinamide. Does that have any feedback inhibition on the salvage pathway? This salvage pathway that’s already limping along as we age, is it further inhibited? Is there-
Dr. Nichola Conlon: There’s always a worry that nicotinamide can inhibit key things like the sirtuins. Something that I always get asked is, “Why would you take nicotinamide?” Because it inhibits the sirtuins. However, if you look at the data, actually in cells at ridiculously high concentrations, that physiologically would never be possible. Yes, it inhibits sirtuins, but in a physiological system, it doesn’t inhibit sirtuins, it actually activates them via its role with NAD+. That’s a bit of a myth that everybody seems to get a bit lost in that it’s an inhibitor. Again, this is because our bodies will do everything that they can to not let it get up to the concentrations where it becomes an inhibitor. That’s when you start seeing upregulation of NNMT to get rid of it. In some of the studies that have been the human studies that have been done with NR, if you look at the data, what you will see is that as they increase the concentration of NR that they’re given to the subjects, you can see a huge increase in the levels of methyl nicotinamide that are excreted in the urine, because again, that is not getting converted into NAD+, it’s not getting going around the salvage pathway.
The body’s suddenly having to upregulate a process of excretion because it simply can’t deal with the amount that’s coming in. Again, you are not addressing the root causes of the NAD+ decline, and by not doing that, you’re actually causing another problem. Another thing to think about and acknowledge, which is people are now thinking about more is, “Is that NAD+ that you are topping up actually going to the right place where you want it to be going?” Because we want it to be activating the sirtuins. We want it to be activating the DNA repair enzymes.
However, we know in older cells they have increased expression of CD38 and CD38 has a much higher affinity for NAD+ than either the sirtuins or the DNA repair enzymes. In a cell, what that means is that if CD38 is there enough, it’s going to grab all of the NAD+ before any of the beneficial pathways actually have a chance to use it. Again, you could be thinking that by taking NMN or NR, you’re actually boosting NAD+ and it’s good because it’s going to activate the sirtuins and repair, but actually all that NAD+ you’re putting in is actually driving inflammation. If you don’t look at addressing that other root cause of NAD+ decline.
Dr. Kara Fitzgerald: That’s really interesting. What cell type seems to house CD38?
Dr. Nichola Conlon: A lot of the immune cells. It’s one of those that seems to have a bit more of a ubiquitous expression. For us, this is why we talk about, maybe, second-generation NAD+ boosting. Back then, we didn’t understand all that. It was thought that using NR or NMM was the best way to approach the problem. We now know that actually it doesn’t address the root causes and it’s potentially making some of the issues worse. What we wanted to do was go, “Okay, we now know we’ve got an issue with NAMPT in the salvage pathway. We know that we have an issue with CD38. We know that we have an issue with methylation. What can we design in targets with system pharmacology that’s going to target all of those different things and actually address the root causes of the decline rather than ignoring them and address the complexities? That’s how we designed our formulation in our product to actually fix those issues.
Dr. Kara Fitzgerald: Let’s talk about it. Let’s talk about what you figured out and how you put together this systems approach to dealing with it and what you’ve found in your research. Yeah, let’s get into it.
Dr. Nichola Conlon: Yeah. Well, obviously from what we’ve discussed, one of our main targets that we wanted to affect was the salvage pathway. We know it’s a leading cause of NAD+ decline. We know it’s that key enzyme NAMPT that declines. We wanted to boost levels of it. For that, we basically used two different ingredients to do it, that act on slightly different pathways. Rutin, it’s derived from something called sophora japonica. It has a high amount of natural quercetin in it. We know that is an NAMPT activator. That is a direct activator. The other ingredient is alpha-lipoic acid, and this activates NAMPT, but via a slightly different pathway. What alpha-lipoic acid does is it actually activates an energy sensor in the cell called AMPK.
What AMPK does is it signals if the cell’s in a bit of energy stress, and if it is in energy stress, what it does is it goes, “Oh, we need to switch on NAD+ production.” It sets up a series of reactions that basically lead to increased levels of NAMPT to increase NAD+ in the cell. Alpha-lipoic acid actually activates AMPK. The really interesting thing about that is it’s this exact pathway is activated by both exercise, calorie restriction, fasting, all things that are shown to promote cellular health and health span and lifespan in some cases. It’s known that a lot of the beneficial effects of these things are by increased NAD+ production. Again, if you think about it, the reason our bodies are increasing NAD+ is that they’ve sensed this energy stress from the exercise or the fasting. Our bodies setting off a reaction saying, “We need to survive this stress. How do we do it?” We increase NAD+. We tell us, give the mitochondria more NAD+ to keep producing its own energy. We have NAD+ as a signal molecule to increase maintenance and repair and recycling so that we can get the cells through this period of no nutrients and energy stress.
Yeah, that’s a natural way of boosting levels of that enzyme, but obviously we are using a molecule to actually do that.
Dr. Kara Fitzgerald: Very interesting. Yeah, keep going.
Dr. Nichola Conlon: ALA is a really interesting one. It’s something that you do come across frequently in the longevity space as an antioxidant as well. You’ve got to be really careful with ALA because in terms of what form that you use. There’s two different isomers. You’ve got an R and an S version, and quite often if you look in products, they’ll have the S, which is like the synthetic. When you look at all the data, that does absolutely nothing in the body. It doesn’t work at all. At best, you’ll get a 50-50 mix of R and S forms. Again, you’re paying for half of it. That doesn’t do anything. I was really keen with our product that we only use our ALA. It’s only the form that we know actually works. ALA, it’s one of these molecules that acts on many different pathways in the body. Another way that we know that it increases NAD+ is it actually activates a pathway or an enzyme called NQO1. NQO1, what that does is it converts NAD+H to NAD++. Remember earlier I said NAD+ is a redox molecule? Well, NAD+H and NAD++ are the reduced in the oxidized forms, and it flips between those constantly.
What you tend to find is that in older cells, it favors more towards NAD+H, and that’s not good. You want it more towards NAD++. What this enzyme does is it basically flips NAD+H to NAD++. You rebalance the more favorable ratio of NAD++ to NAD+H. ALA acts as a dual purpose. The other thing, again, that we wanted to fix was… If we’ve switched back on this NAMPT enzyme, we know that the recycling pathway should be fully functional like a young cell, then what we want to do is prevent that methylation because we want any nicotinamide to be getting promoted towards the recycling pathway rather than methylation and excretion. We know in older cells they’ve started to express more of this enzyme NNMT, that methylates.
We use green tea-leaf extract, which has a high concentration of a molecule, which I’m sure you’ll know EGCG, and that is known to inhibit that enzyme. What we want to do there is push the nicotinamide towards recycling rather than excretion. The other interesting molecule that we use is parsley, which again, everyone’s like, “Parsley? Why?” The reason we use parsley is because it’s got a very high concentration of an active molecule that continuously came up in drug development called apigenin. People in the longevity world will probably know apigenin as a senolytic molecule. For us, what we’re using it as is to inhibit CD38 because it’s been shown that even just inhibiting CD38 a tiny bit, you can have a huge impact on cellular NAD+ levels because it wastes so much NAD+.
Again, all things that are just trying to restore the balance of the cell back to a youthful profile like, “What it was doing when it was younger?” At the end of the day, our cells are very good at making and recycling NAD+ when they’re younger, it just all goes a bit out of whack. We also have nicotinamide in there as a precursor alongside these ingredients. Lots of people say, “Well, why would you not use NR or NMN?” The reason is because NR and NMN cannot freely diffuse through cell membranes. Again, they rely on transport proteins to actively take them into the cells. They will only go in cells that have those transporter proteins. Whereas nicotinamide, it’s uncharged, it freely diffuses through all cell membranes. Also, we know because of the salvage pathway that it’s the body’s preferred precursor for NAD+ synthesis.
Dr. Kara Fitzgerald: Fascinating. You’re giving it in combination with all of these nutrients to help stimulate the various pathways, so it’s not just hanging around accumulating.
Dr. Nichola Conlon: Exactly. We would always say we would never give a precursor alone, especially in an older cell. When you’re trying to boost NAD+, you really need to be given a precursor in combination with the other things to make sure that the precursors pulling ] the way you want it to go and the NAD+s being used in that way. Yeah, back when I started the company, this is all the research we did. Then we were like, “Right, well, we got to test it.” I was like, “No, whatever we do, it has to be very well scientifically thought out, but also proven and tested.” Which is the key part that’s missing with a lot of supplements. A lot of supplements make a lot of claims, but don’t have any evidence in humans to back it up. The benefit of using molecules that are known and tolerated and GRAS recognized is that you can put them in humans. You don’t have to go through the really long drug development route.
We initially did a pilot study. It was just with two human volunteers, but we wanted to check, is it increasing NAD+? Is it acting on the pathways that we wanted it to activate? And we confirmed this. That was back in 2019. Then it was like, “Okay, so we know we have a formulation that works. It’s stable. Let’s do a bigger clinical trial.” We started a double-blinded placebo-controlled crossover study, which in the world of trials is a gold standard trial in terms of design. We have 28 people enrolled. The people that we enrolled were between age 20 to 80, and there were also male and female, which is really unusual. Obviously, a lot of clinical trials you have to only use a very specific age group and usually men just to try and eliminate any other factors.
But for me, I was like, “I want this trial to be as representative as the real world because this supplement is going to go into the real world. We need to know it works in a normal population of people.” We basically started that trial. Then obviously COVID hit, and we had to stop it. We started, we wanted the data out for this years ago. We’ve actually now just finished and it’s unblinded. What we measured in this study was, first of all, again, we wanted to see what’s it doing in NAD+. We found it did significantly increase NAD+, thank goodness.
Dr. Kara Fitzgerald: Yeah, right.
Dr. Nichola Conlon: Yeah. We then looked at NAMPT, and again, in all of these volunteers, we saw that NAMPT protein was upregulated. It went from barely detectable to actually being detectable in the cells of these people. We looked at the sirtuins and saw, again, one, probably the most famous sirtuins when it comes to longevity was it had significantly increased expression as well. We then wanted to look at, “Okay, so we know the NAD+ has gone up. We know the mechanism of action. Like, “What are some biomarkers of aging that should be changing?” One of them that we looked at was levels of inflammation, because we know that chronic low-grade inflammation is associated with aging. We know that if we’re inhibiting CD38, we should be reducing inflammatory factors. Let’s see what happens. We found a significant reduction in four different inflammatory cytokines, and then obviously that chronic inflammation is one of the new hallmarks of aging.
For us, that was exciting. Inflammation is also something that can be measured in a clinic, unlike sirtuins or an AMPT, which I think is important. We also looked at levels of glycation. Glycation is when sugar molecules start to become stuck to proteins in the cells irreversibly. It leads to a lot of problems like stiffening of the arteries, the skin, and it’s a good biomarker of aging as well. Again, we saw a significant reduction in glycation. What else did we measure?
Dr. Kara Fitzgerald: You looked at biological age is something we talk about a lot in some minor detail. Yeah.
Dr. Nichola Conlon: How can I forget that.
Dr. Kara Fitzgerald: How did you look at biological age?
Dr. Nichola Conlon: Biological age was something we put in there, again, this is a consumer product. This is something that we want people to be able to understand. We think looking at biological age is a really easy way of understanding something scientific. It’s a number. You want it to go backwards. You don’t want it to be higher than your chronological age, and that’s all you need to know. We actually looked at glycan age. We didn’t do epigenetic markers we looked at glycan age. Everybody that was at a trial did the glycan age test before and after each arm of the study. Again, we found a significant trend towards a reduction in biological age, after only a month of taking the study, it was about 1.26 years decrease.
I think we want to look at that in larger populations of people now. For us, it’s a good start. We want to do a longer study more than a month. But to see all of those parameters changing in just 28 days, for us, we were really pleased that it’s something that is available. It’s not a drug, but it actually could have some significant benefit, and it’s got data to support it.
Dr. Kara Fitzgerald: I know this is… finish the peer review process, and it’s heading towards publication shortly.
Dr. Nichola Conlon: Yes.
Dr. Kara Fitzgerald: We’re going to link to all your papers and any primers that you want the audience to have access to. We’ll put them in our show notes. This is going to be a great paper to check out. I can’t wait. Congratulations. Yeah, really congratulations on all that. You put together something that’s moving the needle.
Dr. Nichola Conlon: Thank you. No, it’s been an interesting journey, naively, when you start, you think, “Oh, how hard can it be? It’s not a drug. It can’t be any worse than a drug.” All the things you have to jump to and then… Yeah. I’m really proud of the team and what we’ve achieved and managed to fulfill our mission of taking something from a lab and getting it into the hands of an everyday person and being accessible and being able to benefit people.
Dr. Kara Fitzgerald: I would love to look at how this influences DNA methylation and gene expression through an epigenetic lens. Your product is packed with what we call epinutrients that have evidence in the literature for influencing specifically DNA methylation. Not just the enzyme, as you mentioned earlier. I’ve really come to appreciate the combination of nutrients like you would get in food. It’s that combination of information given at a single time that really seems to direct the symphony of information, if you will, to optimize cellular function. I appreciate your product design quite a bit.
Dr. Nichola Conlon: Yeah, I think as well, some of the forms that we put the ingredients in, like using rutin rather than quercetin and parsley for the apigenin. In those forms, you can have the glycosides and they’re protected slightly going into the gut, and they get cleaned.
Dr. Kara Fitzgerald: Fascinating.
Dr. Nichola Conlon: My PhD was actually all in bioavailability. I was always incredibly passionate about putting things in the form that they’re most likely to get absorbed and in the amounts that you need to get the oral bioavailability. Yeah, sometimes people will say, “Why wouldn’t you just use apigenin or just use quercetin and why is it in different forms?” Again, there’s a well-thought-out reason for that as well.
Dr. Kara Fitzgerald: Another pearl. I’m glad that you got that in. Yeah, it caught me earlier when you had mentioned it, the rutin for quercetin. Yeah, thanks for flushing that out. That’s really fascinating. NAD+, actually a lot of my colleagues are offering NAD+ IV infusions in practice, or they’re getting them themselves. It’s just another huge route of delivery. Any thoughts on that?
Dr. Nichola Conlon: Yeah, I really wish there were more studies on NAD+ IVs to clinically show what’s happening when people are having them. I think there’s a real lack of studies out there, but we know mostly anecdotally that people do report a big benefit from them, especially in areas of cognitive decline and addiction and things like that. As I mentioned earlier, NAD+ is a big molecule. We know that it doesn’t get into every cell. We know there are certain cells that can be actively transported into, like neurons, heart cells. I think in those cells when NAD+ does go into them, you’ve got a little bit of a similar problem as what you have with the precursors, because in older cells or cells that have some sort of dysfunction, that means that their salvage pathway is not working properly or they’ve got more inflammation or things like that.
Again, you are delivering a huge hit of NAD+ and that NAD+’s going to get a first pass, if you want to call it that. It’s going to get broken down and used, and then you’ve got this massive influx of nicotinamide that the body suddenly has to deal with. Again, some people report when they’re having these IVs, they feel a bit sick and they have palpitations. I think a lot of that probably is this big influx of nicotinamide that the body’s suddenly trying to methylate and upregulate and excrete and deal with it. Actually what we’ve started with a couple of our practitioners that we work with who do IVs is saying, “You know what? Theoretically, if you combine our product with an IV and give the product for a month before you give the IV, it’s almost priming the cells, ready to be in a better situation to be able to deal with that sudden large hit of NAD+ that it’s going to get.
If you think about it, if you are upregulating your salvage pathway, it means that when you’re getting that huge dose of NAD+, it gets used, it gets broken down, but again, gets recycled and it can be used again and broken down and recycled, as opposed to you have it once and then the cell can’t do anything with it and it just gets rid of it and you’ve just had a very expensive IV and it’s had a one hit and then it’s gone. We want to do a trial on this, but anecdotal evidence shows that people seem to have a more prolonged benefit when they’ve almost primed their cells beforehand.
Again, theoretically it all makes sense. We want to test it, but anything you can do to make sure your cells are optimally placed to deal with the large dose of NAD+ is always a good thing. Again, you don’t want to be putting a huge NAD+ IV infusion into massively inflamed cells with CD38 that are just going to take all of the NAD+ to the wrong processes and not the beneficial ones. That’s something we’re looking at testing a bit more, but certainly, anecdotally, we’ve had some good feedback from that.
Dr. Kara Fitzgerald: Awesome. Yeah, it makes sense anecdotally, and it’ll be interesting to see what you find since you’re looking at it. You had said before, and I just want to underscore it again, that using your product, it could be like a fasting mimetic. It’s actually upregulating some of the pathways that fasting does and exercise does, as you mentioned earlier. You might use it concurrently if you’re doing a fast or if you’re in a time-restricted eating structure.
Dr. Nichola Conlon: Yeah. A lot of our customers say, “I practice fasting or time-restricted eating. When should I be taking this?” What we say is take it with your first meal, because we know that fasting is obviously increasing your NAD+ levels because it’s activating AMPK. Then usually when you’re eating your first meal, you know that NAD+ then drops again because that energy stress has been relieved. By taking a supplement with those mimetics that are actually still triggering AMPK, you are actually prolonging the activation of those pathways, even though you’ve began to eat. In that way, effectively you’re prolonging the activation of the pathways that you’ve been activating for the last 16 hours fasting, even when you start to start refeed.
Dr. Kara Fitzgerald: Certainly there’s plenty of people who don’t have an appetite, no pun intended for doing any kind of structured food restriction. It can be really triggering. We see it in our clinical practice actually with some frequency. This might be an alternative to getting some of those benefits.
Dr. Nichola Conlon: Yeah, absolutely. That’s not for everyone, but we know that lifestyle ways to boost NAD+, it’s exercise. It’s clinically proven in clinical trials that lifting weights and doing high intensity interval training will boost NAD+, calorie restriction, intermittent fasting. Again, not everyone is able to do that, or not everyone wants to do that. Yeah, this is another way of actually activating those pathways.
Dr. Kara Fitzgerald: Just in our final, I have one more question for you and then we’ll wrap up here. We’re wanting to test NAD+ levels in clinical practice. I think there’s kits offered to consumers these days. How are these labs ready for primetime?
Dr. Nichola Conlon: As of yet, I haven’t come across any lab that’s been able to offer a test that I would say is robust enough. The reason is we’d love to be able to offer NAD+ tests and kits to our customers because we know it works. Being able to measure it yourself just seals the deal. However, NAD+, as I mentioned, is incredibly unstable and that means that it breaks down really quick. Obviously, if you wanted to just do a finger prick test and send it off in the post. By the time it gets to the lab, I can guarantee there will be no NAD+ left in there. When we would do a testing in a trials, et cetera, we actually did an experiment to look at stability of NAD+ in blood just at room temperature, then on ice and things like that.
If you just left it on the bench, it’d pretty much gone in 20 minutes. When analyzing it in the labs, it would be intravenous blood draw, it would be straight on ice and then it would be straight be prepped immediately to extract the cells and try to preserve. You were preserving any of that NAD+ that was there. Although there are companies offering NAD+ testing, I haven’t come across anyone that’s convinced me that they’ve found a way to preserve it. This is why we went for a consumer kit, a biological age kit because it’s got data on that. It could be a finger prick blood test, it’s stable. It can be sent away and it’s things that customers and practitioners can actually do themselves for themselves or the patients.
Dr. Kara Fitzgerald: Right. Also, you mentioned inflammation. We can easily measure it.
Dr. Nichola Conlon: Yeah, and inflammation.
Dr. Kara Fitzgerald: in our practice. Yeah, for sure. Well, Dr. Nichola, it’s just fabulous to get to talk to you. Really interesting conversation. I’m excited about your new product. I’m excited about the research, the effort, the time, the energy, the money that you’re investing into teasing out what it’s doing in humans. Again, everybody will link to the show notes, all the papers that we covered today so you have access. And as soon as the human study is out, the most recent one that will be coming out shortly, we’ll get that up on the show notes. Thank you so much for coming and I look forward to continuing the conversation with you.
Dr. Nichola Conlon: Yeah no, amazing. I’ve really enjoyed that chat. Thanks very much for having me.
Dr. Kara Fitzgerald: My pleasure.
Dr. Nichola Conlon is a molecular biologist specializing in the study of aging as a biologically complex disorder. After years focused on early-stage drug discovery with a leading biotech firm, Dr. Nichola founded Nuchido Laboratories to deliver disruptive innovation in the field of anti-aging, rejuvenation and healthspan, driven by her belief that cutting-edge science should not lie hidden.
Dr. Nichola is on a mission to democratize science and has a skill for translating and presenting advanced science in a way that helps to educate and support people to take control of their health. Along with leading scientists at Nuchido, Dr. Nichola has identified the right combination of targets to restore cellular NAD+ production back to youthful levels, leading to the development of a second-generation NAD+ booster called Nuchido TIME+.
International Conference Undoing Ageing in Berlin (full study presentation)
Preclinical and clinical evidence of NAD+ precursors in health, disease, and ageing. Mechanisms of Ageing and Development, Reiten, O. K., Wilvang, M. A., Mitchell, S. J., Hu, Z., & Fang, E. F. (2021). 111567.