DO NOT USE The Role of NAD+ in Aging, Chronic Disease, and Epigenetics with Dr. Nichola Conlon

hi everybody this is Kara Fitzgerald New Frontiers in functional medicine is here every month bringing you the best Minds in functional medicine and we would not be able to do this over the years without the generous contributions from our sponsors biotics research for four over 40 years the foundations of biotics research has been Innovation and quality their goals remain unchanged innovative ideas carefully research Concepts and product development with Advanced Analytical and Manufacturing techniques biotics nutritional products are of superior quality and Effectiveness and available exclusively to Health Care Professionals visit them at bioticsresearch.com integrative Therapeutics is focused on inspiring a better lifestyle through Better Health by providing meticulously formulated nutritional supplements and valuable resources integrative Therapeutics promises to enrich your patients and embolden your practice welcome to your integrative Therapeutics find them at integrativepro.com I also want to give a shout out to our friends over at Rupa Health they make lab testing easy fabulous doable for both you the clinician and you the person being prescribed the lab the patient considered using Rupa as just a super super smart solution to all your functional laboratory needs thanks again to my wonderful Platinum sponsors hi everybody Welcome to a New Frontiers in functional medicine where we are interviewing the best Minds in clinical medicine and 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 and um today I'm going to be chatting with Dr Nicola conlon and Nicola is a molecular bio biologist by training she's specializing in the study of Aging as a biologically complex disorder uh after years focused on the early stage drug Discovery with a leading biotech firm Dr Nicola founded nuchito 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 Nicola Dr Nicole is on a mission to democratize science and has a skill for translating and presenting Advanced scientific 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 science scientists at Cheeto Dr Nicola 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 lucido time plus Dr Nicola welcome to New Frontiers hello thank you so much for having me Cara I'm really excited to have a chat with you today so I'm excited because you're bringing really a great scientific background to longevity science um to the natural products industry to uh you know continuing researching natural products and and looking at things that are really important to us here in sort of functional Longevity if you will but um you're you're you are are uh bringing together many many different areas that I'm particularly enthusiastic about and and you've launched this extraordinary um NAD booster product that we're going to speak about today in careful detail so I you know you're just perfect for me to join me on my podcast and um I just I want to get into understanding you your background your company you know kind of you know maybe a little more detail a little more blowout of of what brought you here so let's start with like a big overview picture and then we'll move into the nitty-gritty yeah of course so so I'm I'm not a a medic I am a Scientist um and my sort of area of specialty is the science behind why we age but at a cellular level so obviously everything that we're experiencing in terms of Aging is really starting deep with inside ourselves in ourselves and all the pathways and different compartments within there although we tend to recognize agent on the outside so my sort of background is to be really understanding what is going wrong at the cellular level to cause what we recognize as aging and I've been really fortunate to have a quite an interest in um background in that I actually um 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 age and they're like what you know that's crazy you can't do that um but you know it's a huge area now and within drug development because as you and I both know age is your biggest risk factor for all of the major diseases that drugs companies are trying to treat and you know cancer heart disease Alzheimer's everything your biggest risk factor is your age so the idea of it is is there a way that we can slow aging and the cellular level and if we can will that have an impact on actually reducing our risk of chronic disease age-related chronic disease and the idea is that we would be looking to extend our period of healthy lifespan so extend our health span so that we're not getting chronic age-related diseases as we get older so I was fortunate enough to sort of enter that world as it was just beginning and within the world of farmer and so this was back in around 2013 2014 and 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 age and in the longevity community and and then the ultimate goal is you know how can we take all this knowledge and look at Targets within ourselves but you know there was two main things that really bothered me um in in the world of farmer or drug development the first was how long it takes so you know 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 at least 10 years more like 50. right so that was just oh you know 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 um was part of my job we would send a load of molecules for screening in the labs we then get the data back and we'd literally you know have a list of uh these molecules work exceptionally well to at the bottom of the list these just don't work at all and everything in between and part of my role was I had to look at which molecules were patentable so which molecules could the drug company own and therefore they would be the ones that they would take forward into development and 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 there were things that were approved as supplements they were they were not what a company could patent and take forward so these things would just sort of get pushed to one side and then the things that would go into development were you know half as good and it was like wow they're actually going to put all this money in the develop and something that just works half as well so I get it commercially but ethically I was like this is crazy because I just saw that time and time again so 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 you know were there any drugs in the pipeline that we might we might have heard about uh but I think you've answered that I'm sure that anything that you guys have discovered so far are still sort of hanging around in the lab going through many many many many many many hoops and not even close to being ready for prime time is that is that true exactly that so 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 I already known to be safe and well tolerated and have you know 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 so I decided that I was going to leave that world so I left in 2017 and I decided I found nichido Laboratories and my whole mission was how do we do something with those molecules how do we get them their research and you know all of the evidence base and the testing that they actually deserve um but I'm sure you can imagine what people said you know they thought I was crazy when I was leaving my really credible job in drug development to start a supplement company yeah oh my God that must that had to be pretty hard yeah it was it I you had some good support behind you I hope but yeah that's I I can only imagine the kind of yeah because obviously you know supplements have a bad name and you know a lot there's a lot of things out there that don't work as advertised and don't have much science behind them but you know 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 and actually you know our bodies have no idea what a 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 and that's the nutrient so it can't possibly do anything and you know our bodies have no idea they all have and equally you know strong physiological effect it's just that I wanted to bring the more credible side of testing and you know the scientific credibility out of the drugs world but bring it into the supplements world very interesting you know we saw this a lot in or the the cover the fervent covered research happening where um there was a lot of exploration in molecules that might be effective before we had any grip on how to address this this virus um and and as often as not we were all coming out in pre-print at the time but as often as not it was a natural product that appeared to be as potent or more so uh you know than some of the uh you know some of the drug molecules that they were exploring for for efficacy with cobit so very very interesting my kiddo was here Isabelle yeah you want to say a quick hello no okay go go go we'll edit this out you guys she just wants to talk about in love with this dog up the street um make sure yeah I can't I can't be interrupted no Tango um oh uh no uh uh see no this is yeah gracias okay all right we'll edit that out I think it was a good point anyway it was easy to pick up good um any just okay so very very cool what so you you took this huge risk in leaving a credible probably you know an interesting career I think you've explained it well and it'll be interesting to a lot of our listeners you know that you were seeing all these molecules that were fabulous it's kind of cool to get a behind the scenes look from um from a scientist who's there you know that and these are natural molecules so let's just sweep them off to the side and I could see that that would be an ethical tug for for a lot of us listening um so you decided to make this leap and you know what molecules grabbed you and you know let's kind of move over to to talking about about that stage in your career and and you know what what you've decided to focus on yeah I mean I think um one thing I did learn uh from drug development and was that again I was I was fortunate to work for a very forward-thinking company that was investigating new drug development techniques um and you know they specialize in something called systems pharmacology so conventional drug development um basically we'll go okay we have a disease we have a gene or a protein or an enzyme or something that goes wrong and we'll just get a drug and we'll stick it to that particular pathway or protein or whatever and that'll fix it and as we know nine times out of ten it doesn't because biology is incredibly complex and often there's not just one thing that's going on and also molecules and drugs don't stick to just one thing in the body they have Footprints and they affect many different things so I specialized in something called systems pharmacology which actually was a more advanced um Discovery technique that took into account all of this so it was 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 um at the same time and and there you would get a much bigger effect and the hit rate using that approach was way higher so you know not only did I want to look at how can we bring some of these you know more natural molecules out of that world and and test them but actually is the way that you could be put in combinations of different molecules together so they actually work in a slightly different way or they're synergistic um and have a more powerful effect and so so a huge part of of what we focused on at nachita laboratories was um you know 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 you know use that system's approach to identify potent combinations and molecules that will then be regulated and approved as a supplement so we can get it out to people very quickly and rather than waiting 10 to 15 years and one of the first things that I really wanted to look at was NAD because this had you know back in in 2017 had become a lot more popular where it was there was a lot more people talking about NAD within the age in space and you know for me looking at all the research behind it there was good promise and you know we had it we now had a good idea of what was the underlying physiology surrounding it and so I really wanted to look at developing our first product as an NAD booster but that worked better than the ones that were already out there awesome so and and you had some did you have some kind of a notion um on the on the natural products we were going to you know really hone in on I mean you must have at the time no it was actually the cop the targets so we knew what targets that we were going to be looking at based on you know the latest science around NAD um I mean would it be helpful to do a bit of a nad101 I mean I'm sure everyone's familiar with it but you know so we we know the reason um you know nad's it's just an incredibly important molecule in the body and anyone that's done any sort of um biology or medical training will have heard of it um because it's important for over 300 different reactions in the body as a coenzyme substrate I just want to underscore that we're using NAD in different structures like all of the time you know I think in literally every every cell if I'm not mistaken it's just it's every cell and I 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 and it's most famous for its role in energy production so 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 their functions and so incredibly important for that the other thing that it's been more becoming more famous for now is its role in cellular maintenance and repair so Nadine is now known to basically act as a bit of a signal in molecule in the cell and where it tells the cell to switch on and off maintenance and repair Pathways such as DNA repair enzymes and the the things that are going to make sure our cells stay in good health so 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 and if you have low NAD energy goes down maintenance and repair goes down so the one 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 situins and some people might have heard them referred to as longevity proteins and this is because these These sirtuins are known to actually switch on a whole host of Downstream Pathways and processes that are beneficial for cellular health so that's switched on recycling switch on repair switch on DNA repair and the search ruins basically switch all of these things on and the link with NAD is that they are absolutely critically dependent on NAD so NAD basically acts as a fuel to power the circulines so without NAD they don't work what's interesting about that just to kind of link it back to aging is I mean 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 in my um group the most recent Hallmarks of Aging paper so this is this is teasing out all the mechanisms that really seem to drive aging and uh NAD seems to have a finger in in a lot of them so they've expanded to 12 Hallmarks I think that originally there were nine and this group is just recently expanded them but NAD is right is right in the middle yeah it is it's and that is one of the reasons why I i cho you know 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. and you know we have done a lot of research in areas like senescence but for me NAD it was something that just seemed everything seemed to come back to NAD you know 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 Agents so it's it's very intertwined and I guess it's not surprising because it's in every cell it performs so many different functions that you know it's it's unsurprising that it's it's going to impact multiple Hallmarks but yeah the reason that NAD is linked to aging is because it's been found to decline exponentially in ourselves as we get older why why why does it drop like a tank yeah so well it's estimated actually to drop by about 50 every 20 years um and that's from birth in the tissues that have been studied that's actually from birth so you know you can see that even by the time you're 20 you it's halved then that half's again then that half again so by the time we're in more advanced ages you know there's there's really um not very much NAD left in ourselves 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 and and 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 and but it is now become well established what is causing this but I think first of all a key thing to point out is that our cells are actually really good at making their own NAD so when we're young all of our NAD is actually just produced used internally so I think a lot of people think it comes from a diet or it comes from you know some external Source but it doesn't um in in young youthful cells we actually have um a pathway called the Salvage pathway and what this does is it basically recycles NAD continuously so when NAD is used by cellular processes such as the DNA repair enzymes or the situins they actually split it apart back down into some of its building blocks and one of these building blocks is nicotinamide um you know vitamin B3 and this nicotinamide is then actually recycled back into fresh NAD again and and that makes sense because NAD is so critically important that our cells almost have to have this Fail-Safe way and to to have a continuous Supply we wouldn't really want to rely on it coming from our diet for example so that's how it's produced in young cells but we now know that the main reason why it's decline in is actually this process becomes dysfunctional as we get older so we start to see sorry I'm gonna just I want to ask I don't want to ask you a question about that process but I just want to say we had an interruption from my my five-year-old my newly minted five-year-old who just turned five and she's an insane bundle of energy right like kids and you can see them you can see NAD just busting out of the seems like it's it's interesting to think about it and the time the more exhausted she gets the more energy she gets which is such a paradox but it's funny that likely an idea is playing a big role in that and by the time she's 20. it's you know it's gonna she's gonna have a very different and she's still going to have a lot of energy but it'll be different so it's fascinating for me to think about that Pearl that you just gave about NAD being so high at Birth and then having and laughing and having over time why is the Salvage pathway breaking down so yeah so what we see is that there's a there's a key enzyme within the Salvage pathway it's it's called it's got a very long name but we abbreviate it to nampt so this nampt enzyme is what we would describe as a rate limit in enzyme so out of the whole pathway it's the really really critical one which its levels of activity are directly correlated to the amount of NAD that will be produced and what we see in older cells is that nampt starts to get turned down so this means that the key enzyme that's power in this recycling pathway just starts to get go down with age so it means our cells just simply can't make and recycle as much NAD as they did when they were young so that's one key reason but what we also now know is that the demand for NAD in older cells actually goes up as well so right at a time when um your cells actually need more NAD you actually see a reduction in the the ability of the cell to make it and 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 uh 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 like uses so much of it and when it uses NAD it gets broken down and this is broken down in a 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 and then the cells like oh my goodness like we need to maintain homeostasis we don't like it when things build up how do we get rid of it and what it does is it increases expression of another enzyme called nnmt which is a key methylation enzyme and this enzyme sticks a methyl group on nicotinamide to Signal its excretion from the cell and 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 and then you don't have the methyl groups to be involved in other critical processes like epigenetics so you can quickly see in older cells how you have in all of you know you've got lack of recycling you've got increased demand for NAD you've got inflammatory processes using up NAD suddenly this is everything's going out of whack and you know one negative thing leads to another and then it's you know it's like the perfect storm for major NAD depletion so 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 the decline all right and and I know we're gonna this is gonna a lot of people are going to immediately be thinking about then you know maybe B3 actually becomes sort of toxic like like to take and I and and you I think you're going to address that in a little while but you know we we prescribe nicotinamide in in practice we describe you know we prescribed niacin it didn't 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 I my area of research has been in in DNA methylation and so we're always thinking about uh ways that we can preserve it but and I and 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 of a wild card question but it it's I I'm curious if you have anything to say about uh we when we see this you know the breakdown of the Salvage pathway the demand for for it the increased speed as we age so we need more NAD as we age but we can't recycle it it ends up accumulating it's getting sucked up by cd30a and um it's almost like aging looks almost like this program phenomena sometimes like on purpose we're just breaking we're just putting the body into Dire Straits so that it's vulnerable to as you pointed out earlier all the chronic diseases associated with like all the big diseases are all associated with aging it's it's it it seems it seems like there's some sort of a program phenomena that's potentially occurring and do you have any thoughts on that or do you want to just kick that down yeah well it's a hugely controversial area in the world of longevity is aging programs or not I think my take on it is is that aging only ever makes sense when you think of it in terms of evolution so you know we've evolved to live to a particular age um you know we we have evolved to live not long past childbearing age so every process that we have in our cell is is basically trying to protect us until we get to that point and we've almost fulfilled our purpose and then off we go and so you know why why would Evolution ever you know give us cellular abilities to live beyond that to reach an age that we were never likely to naturally live and this is why you have processes like senescence which are highly beneficial When We're Young because they forget the prevent us from getting cancer but then as we get older they become hugely problematic but in the reality when Evolution designed that process we were never supposed to live until our 80s and these cells weren't supposed to accumulate so with agent I always you know say if you're trying to explain anything in Asian just think of it from evolutions kind of point of view um but you know everything is so complex when you look at the Hallmarks of Aging they're all highly interconnected you know you can never look at anything in isolation and this is the beauty of systems pharmacology it really acknowledges that and and doesn't ignore it which unfortunately you know 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 and fail to see the bigger picture of how their particular interesting area may be impacting something that they've never thought about before um so yeah it's great it's just really cool that you're that that you have studied and work in that systems model it's it's just really refreshing and and indeed I've interviewed um people who are focused on single molecule activity and controlled activity and yeah it just misses so so so so much um all right and so that was that was a fun little tour through the importance of NAD and what happens as we age um anything you want to add there or do you want to Circle back in and start talking about you know is there an issue with taking prescribing you know nicotinamide or some of the you know the precursors like nicotine might riboside or or um I think a lot of people well I think first of all you know going back through the sort of Science of Nadine has seen this molecule it's incredibly important um it's it declines with age so 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 and would we improve health span like how how would it improve you know or all the things that are associated with NAD Decline and so science has begun to do things in cells and animals than humans that would boost in NAD um and lo and behold found that if you maintained NAD or topped it back up and that you had a whole host of benefits um you know obviously everything from increased mitochondrial function energy production physical energy cognitive energy reduction in new regenerative diseases um muscle everything it was like NAD seemed it'd just be you know this magic molecule that was that was addressing a lot of different issues when it came to aging and again it's like it almost sounds too good to be true but when you think about it it's in every cell it declines it it has all of these beneficial processes that if they're getting Switched Off is not good for cellular health so you know it's no surprise that the benefits were so vast hey there listeners it's your host Dr Kara Fitzgerald I have a question for you I'm do you spend ordering functional lab tests for your patients I bet it's a lot ordering from multiple lab companies for hundreds of patients can quickly turn into hours of admin time but there's a new way to order lab tests I'm excited to share with you Rupa health is a tool that lets you order from over 30 specialty labs in a single portal you can order all the tests you normally do from companies like Dutch vibrant Genova and Great Plains and so many more imagine you're ordering a hormone panel for a patient that includes tests from three different Labs you have to log onto three different websites Place separate orders come back weeks later to check on tracking numbers download results etc etc Rupa eliminates all of that by having all ordering tracking results in a single place and they also handle invoicing tracking shipments automated follow-ups personalized instructions for completing tests and much more the best part about Rupa is that it is free for you go to rupahealth.com that's r u p a health.com and join a live demo or sign up to see how it works now let's get back to Today's Show and so mostly in animals though right an animal forms you know mice and mice and worms I think but yeah yeah so the the you know the early early studies would have been your classic um model organisms like yeah C elegans worms you just software Etc then it was it was the the mammals and then more recently it's been the human studies um but there was a lot of you know how can we boost NAD um and it's known that nad's quite a large and stable molecule so the idea of just taking NAD as an oral pill was immediately you know wiped wiped off the table it's it's not possible and so the next sort of best idea was well what why don't we use precursors to NAD so like the raw material the building blocks that that our body uses to make NAD why don't we take that can you ecologists speak to why energy was wiped off the table just just say that again I didn't quite grab it and I'm guessing some other people like why why was it kicked out yeah so so NAD by its very nature is an unstable molecule okay so 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 and that basically means that it's it's just very very unstable and so if you try and put it in a pill or put it through your digestive system it just gets degraded the other thing is let's say hypothetically um it it did get intact into your body um actually it's a big molecule and it's too big and um charged to actually fit through our cell membranes and so there are not many cells in our body that have a transport protein that will actively intake it into the cells and so yes you know you could take NAD but most of it would have to be broken down and then transported through as the precursors anyway and so they're the main reasons why NAD and appeal you know an oral pill was was just not a practical solution so the next um best thing was let's use um the precursors the raw materials so these are what nads naturally made up of anyway and these are things like um yeah niacin your nicotinamide your nicotinamide riboside or NR it's commonly known as annual nicotinamide mononucleotide or nmn and the most popular ones seem to be NR and nmn and again these are just precursors to NAD they're the building blocks that our bodies use to make NAD so the idea was if we give the body and the cells more of the raw material hopefully the body will convert it into NAD and at the time it was so brilliant you know you can see it it boosts energy and and it's doing the job but then this was in cells in model organisms then you know when it started moving through into humans in the human clinical trials there wasn't that amazing results with the likes of NR um and it was a bit puzzling it's like why have we had all this you know extending the lifespan of cells and health span and everything and we're not really getting the effects translated into humans so I think since those you know those the idea of using precursors came out the science has obviously moved and we Now understand why NAD declines um as I've just explained the reasons so 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 limit and enzyme so 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 is being used at once via the search ruins or the DNA repair or cd38 or whatever it is it's broken down and nicotinamide and 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 so essentially yes you're getting NAD it's getting used once but then you're getting a buildup of nicotinamide and then you've got the problem of oh my goodness we've got to get rid of this nicotinamide so the methyl donors start coming out tagging tagging the um nicotinamide and excrete in it and this is why you'll see um a lot of people talking about the fact that you should be taking methyl donors like um you know trimethylglycine um choline Etc and when you are taking NR nmn because you can suffer from methyl donor depletion let me ask you a question too also so you've got this accumulation this intracellular accumulation of nicotinamide does that have any feedback inhibition on the Salvage pathway so this so This Salvage pathway that's already limping along as we age is it further inhibited inhibited or I mean there's there's always a worry that nicotinamide can inhibit key things like the certuins so you know some something that I always get asked is only you know would you why would you take nicotinamide because it inhibits the situents however if you look at the date air actually in cells at ridiculously high concentrations that physiologically would never be possible yes it inhibits certuins but in a physiological system it it doesn't inhibit certains it actually activates them via its role with NAD and so that's a bit of a myth that everybody seems to get a bit lost in that it's it's an inhibitor um and 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 so that's when you start seeing a regulation of nmt to get rid of it and so in some of the studies that have been the human studies that have been done with NR and 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 you know 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 so again you're not addressing the root causes of the NAD Decline and by not doing that you're actually causing another problem another thing to kind of think about and acknowledge which is now people are now thinking about more is is that NAD that you're topping up actually going to the right place where you want it to be going because we want it to be activating the search ruins 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 search ruins or the DNA repair enzymes so 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 so again you could be thinking that by taking nmn or NR you know you're actually boosting NAD and it's good because it's going to activate the situents and repair but actually all at NAD you're putting in is actually driving in inflammation and if you don't look at addressing that other root cause of NAD decline that's really interesting where are where what cell type seems to house cd38 I mean a lot of the immune cells um but you know it's it's one of those that seems to have a bit more of a ubiquitous expression um but for us you know this is a this is this is why you know we talk about maybe second generation NAD boost in back then we didn't understand all that it was thought that you know using NR or nmn 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 um so 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 so that's how we designed our formulation and our product to actually fix those issues so let's talk about it I don't know what you figured out and how you put together this system's approach to dealing with that and what you've found in your research let's let's yeah let's get into it yeah well you know obviously from what we've discussed one of our main targets that we want it to affect was the Salvage pathway we know it's a leading cause of NAD decline we know it's that key enzyme and ampt that declines so we wanted to boost levels of it so for that we basically use two different ingredients to do it that act on slightly different Pathways so um routine um it's it's derived from something called the forage of Hanukkah and it has a high amount of natural conception in it we know that that is an nampt activator so that is a direct activator the other ingredient is alpha lipoic acids and this activates an ampt but via a slightly different pathway so what alpha lipoic acid does is it actually activates an energy sensor in the cell called ampk and what ampk does is it signals if the cells in a bit of energy stress and if it is an energy stress what it does is it goes oh we need to switch on NAD production so it sets off a series of reactions that basically lead to increased levels of namp to increase NAD in the cell and amp and alpha lipoic acid actually activates ampk and the really interesting thing about that is it's that 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 um and it's known that a lot of the beneficial effects of these things are by increased NAD production because again if you think about it the reason uh our bodies are increasing NAD is that they've sensed this energy stress from the X size of the fasting our body's setting up 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 and so yeah that's that's a natural way of boosting levels of that enzyme but obviously we're using a molecule to actually do that and very interesting yeah keep going ala is a really interesting one so you know it's something that you do come across frequently in the in the longevity space um as a you know an antioxidant as well um and you've got to be really careful with ala because um in terms of what what form that you use so there's two different isomers you've got an r and an S version um and quite often if you look in products they'll have the S which is like the synthetic and when you look at all the data that does absolutely nothing in the body it doesn't work at all um at best you'll get a 50 50 mix of RNs forms and so again you're kind of paying for half of it that doesn't do anything so I was really Keen with our product that we only use our ala so it's only the form that we know actually works um and ala is you know it's one of these molecules that acts on many different Pathways in the body and another way that we know that it increases NAD is it actually activates a pathway or an enzyme called nq01 um an mq01 and what that does is it converts nadh to NAD plus so remember earlier I said NAD is a Redux molecule um well nadh um and NAD plus are the reduced in the oxidized forms and it flips between those constantly but what you tend to find is that in older cells it favors more towards nadh and that's not good if you want it more towards NAD plus so what this enzyme does is it basically flips nadh to NAD plus so you rebalance um the more favorable ratio of NAD plus to nadh so ala acts as kind of a dual purpose the other thing again that we wanted to fix was um you know if we've switched back on this nampt enzyme so 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 sure that we know in older cells they've started to express more of this enzyme and and empty that methylates so we use a green tea leaf extract which has a high concentration of a molecule which I'm sure you'll know egcg and and that is known to inhibit that enzyme so what we want to do there is push the nicotinamide towards recycling rather than excretion and the other interesting molecule that we use is parsley which again everyone's like parsley like why and but 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 epigenin um and um people in the longevity world will probably know Abby jennin is a cenolytic molecule um but for us um 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 so again all things that are just trying to restore the balance of the cell back to like a youthful profile like what it was doing when it was younger because 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 a bit out of whack so um so yeah so that's we also have nicotinamide in there as a precursor um alongside these ingredients and lots of people say well why would you not use NR or nmn and the reason is because NR and nmn cannot freely diffuse through cell membranes so again they rely on transport proteins to actively take them into the cells so they will only go in cells that have those transporter proteins whereas nicotinamide is uh you know it's uncharged it freely diffuses through all cell membranes and also we know because of the Salvage pathway that it's the body's preferred precursor for NAD synthesis but you're giving it in combination with all of these nutrients to help stimulate you know the various Pathways so it's not just hanging around accumulating exactly so we would always say we would never give a precursor alone especially in an older cell like you know when you're trying to Boost energy you really need to be given a precursor in combination with the other things to make sure that the precursors are pulling the way you want it to go and the nads being used in that way so yeah that so you know back when I started the company this is all the research we did and then we were like right well we've got to test it um because you know I was like no this this 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 and the benefit of using molecules that are known and tolerated in Grass are recognized is that you can put them into humans and you know you don't have to go through the really long drug development routes so we initially did a pilot study and 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 and we confirmed this so that was back in 2019 and and then I was like okay so we know we have a formulation that works and it's stable let's do a bigger clinical trial so we started a double-blinded placebo-controlled crossover study um which in you know the world of Trials is a gold standard trial in terms of design and we have 20 28 people enrolled and the the the people that we were enrolled were between age 20 to 80 and there were also male and female and which is really unusual because obviously a lot of clinical trials you have to only use a very specific age group and usually men and just to try and eliminate any other factors but for me I was like I want this child to be as representative as the real world because this supplement is going to go into the real world so we need to know it works in a normal population of people and so we basically um started that trial then obviously covert hit um so we had to stop it and we started so we were we wanted the the data out for this you know years ago um but we've we've actually now just finished and it's unblinded um and what we measured in this study was first of all we again we wanted to see what's it doing NAD and so we found it did significantly increase NAD thank goodness yeah right yeah we then looked at nampt and again in all of these volunteers we saw that nampt um protein was up regulated you know it went from barely detectable to actually being detectable in the cells of these people and we looked at the search ruins and saw that again the one and the most probably the most famous search you're in when it comes to longevity was um it had significantly increased expression as well we then wanted to look at okay so we know the nad's gone up we know the mechanism of action like what are some biomarkers of Aging that should be changing so one of them that we looked at was levels of inflammation um because you know we know that chronic low-grade inflammation is is associated with aging we know that if we're inhibiting cd38 we should be reducing inflammatory factors and let's see what happens so we found a significant reduction in in four different inflammatory cytokines um and then um obviously that you know is a is a is one inflammation chronic inflammation is one of the new Hallmarks of aging and so for us that was exciting and you know inflammation is also something that can be measured in a clinic and like situents or nampt and which I think is important and we also looked at levels of glycation and so glycation is you know when sugar molecules start to become stuck to proteins in the cells irreversibly and it leads to a lot of problems like stiffening of the arteries the skin and and you know it's a good biomarker of agent as well well and again we saw a significant reduction in glycation um what else to measure oh yeah it's a minor detail yeah how did you look at biologically so biological age was something we put in there because again this is a consumer product this is you know something that we want people to be able to understand and we think looking at biological age is a really easy way of understanding some and scientific it's a number you want it to go backwards you don't want it to be higher than you know your chronological age and that's kind of all you need to know so we actually looked at glycan age so we didn't do that because we looked at glycan age and so everybody that was at a trial and did the glycon age test and before and after each arm of the the study and again we found a significant Trend towards um a reduction in biological age after only a month of taking the study it was about 1.26 years decrease um so I think we want to look at that in larger populations of people and now but you know for us it's it's a good start it's a lot more um you know we want to do a longer study that's you know more than a month and but to see all of those parameters changing um you know in just 28 days for us we were you know really pleased that it's something you know it's something that is available it's not a drug um um but it actually could have some significant benefit um and it's got data to support it and I know this is finished the peer review process and it's heading towards publication shortly um we'll we will uh we're gonna link to all your papers and any sort of primers that you want the audience to have access to we'll put them in our show notes um this is going to be a great paper to check out I can't wait congratulations yeah really congratulations on all that you you know you put together something that's that's moving the needle thank you no it's been a it's been an interesting Journey um you know naively when you start you think oh how hard can it be you know it's not a drug it can't be any worse than a drug but all the things you have to jump through and then yeah um but you know I'm really proud of the team and what we've achieved and you know managed to fulfill our mission of taking something from a lab and getting it into the hands of an everyday person uh you know and being accessible um and you know being able to benefit people I would love to look at how this influences DNA methylation and you know gene expression through an epigenetic um lens because you know it's your your product is packed with with what we call every nutrients you know that have evidence in the literature for influencing specifically DNA methylation not just that you know the enzyme as you mentioned earlier but uh you know and I've really come to appreciate the combination of nutrients like you would get in food you know it's that combination of information being given at a single time that really seems to direct the Symphony of information if you will to optimize cellular function so I I appreciate your product design quite a bit yeah and I think as well you know some of the the forms that we put the ingredients in so like using Rootin rather than placating and parsley for the epigenous um you know that in those forms that you can have like the glycosides and the protected slightly going through the gut and you know they get cleaned and um so so my PhD was actually all in bioavailability and so it's always incredibly passionate about putting things in in the form that they're most likely to get absorbed and in the amounts that you need to get the oral bioavailability and so yeah sometimes people say well you know why wouldn't you just use epigenin or just use corset and why is it in different forms but you know again there's there's a well thought out reason for that as well another Pearl I'm glad that you wrote that in you know yeah yeah it it caught me earlier when you had mentioned that the the Rootin you know for quercetin but yeah thanks for thanks for clashing that out that's really fascinating what about like you know you had NAD I know actually a lot of my colleagues are offering Nat IB infusions in practice or they're getting them themselves I mean it's just another um huge route of delivery and any thoughts on that yeah so I think I really wish there were more studies on any divs to you know clinically show what's happening when people are having them I think there's a real lack of data and studies out there but we know mostly anecdotally that people do report a big benefit from them especially in areas of like um cognitive decline and um addiction and things like that so I think 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 it can be actively transported into like neurons heart cells and so I think in those cells when NAD does go into them you've kind of got a 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're delivering like a huge hit of NAD and that NAD is going to get like 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 the nicotinamide that the body suddenly has to deal with so again um you know some people report when they're having these IVs that they feel a bit sick and they have palpitations and I think a lot of that probably is this big influx of nicotinamide that the body's suddenly trying to methylate and it regulate and excrete and deal with it and so actually what we've started working with it with a couple of our practitioners that we work with who do IVs are saying you know what theoretically if you combine our product with an IV and you know give the product for a month before you give the IV and it's almost Prime in 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 and you know because if you think about it if you're up regulating your Salvage pathway and it means that when you are 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 kind of had a had a one hit and then it's gone and so you know we want 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 and again theoretically it all makes sense we want to test it but um anything you can do to make sure your cells are optimally ways to deal with the large dose of NAD is always a good thing so again you don't want to be put in a huge nadiv infusion into massively inflamed cells with cd38 that are just going to take all of the NAD into the wrong processes you know and not the beneficial ones and so that's something we're looking at testing a bit more but certainly um you know anecdotally we've had some good feedback from that awesome yeah it makes sense mechanistically and it'll be interesting to see what you find since um you know since you're looking at it you had said before and I just want to kind of underscore it again that the using your products can it's almost about it could be a fast like a fasting mimetic it's actually up regulating some of some of the pathways that uh that fasting does and exercise does as you mentioned earlier um but you might use it concurrently if you're doing it fast or if you're in a Time restricted eating structure yeah so what so you know a lot of our customers say you know I practice fasting or time restricted eating and like when should I be taking this so we what we say is take it with your first your first meal because we know that fasten um is obviously increasing your NAD levels because it's activating ampk then usually when you eat in your first meal you know that NAD then drops again because that energy stress is being relieved so by taking the taking like a supplement with those mimetics in that are actually still triggering ampk you're actually prolonging the activation of those Pathways even though you've began to eat and so in that way effectively your prolonging and you know the activation of the pathways that you've been activating for the last 16 hours fasting and even when you you start to start to re-feed and certainly there's plenty of people who don't have an appetite no pun intended for doing any kind of structured food restriction you know it can be it can be really triggering um we see it in our our clinical practice actually with some frequency so this might be an alternative to getting some of those benefits yeah absolutely absolutely you know that's not for everyone and but we know that you know lifestyle ways to boost NAD it's exercise it's you know it's clinically proven in clinical trials that you know weights lifting weights and doing um high intensity infill training will boost NAD and calorie restriction intermittent fasting but again not everyone is able to do that or not everyone wants to do that so um yeah this is another way of actually activating those pathways so just in our final I have one more one more question for you and then we'll kind of wrap up here um we're wanting to test NAD levels in clinical practice um there's I think there's kits offered to Consumers these days uh how are you know are these Labs ready for prime time so 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 and the reason is is you know we'd love to be able to offer NAD tests and kits to our customers because we know it works and you know 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 so obviously if you wanted to just do a blood prick 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 and you know when we um we're doing our testing in a trials Etc and we actually did an experiment to look at stability of NAD in blood just you know at room temperature then on ice and things like that and you know if you just left it on the bench it pretty much gone in 20 minutes so when analyzing it in in the labs you know it would be intravenous blood sure it would be straight on ice and then it would be straight to be prepped like immediately to extract the cells and choir preserve so you were preserving um any of that NAD that that that was there and so I haven't come across a company 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 um and this is why we went with you know for a consumer kit a biological age kit because you know there's good data on that it could be a fingerprint blood test it's you know it's stable it can be sent away and it's things that customers and practitioners can actually do themselves for for themselves other patients right right and also you mentioned you know inflammation we can easily measure yeah and information practice yeah for sure well um Dr Nicole is 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 the the money that you're investing into kind of teasing out what it's doing in humans um again everybody will link to the show notes all the papers uh that we covered today so you have access and as soon as the human study is out the most recent one that that will be coming out shortly we'll we'll get that up on the show notes um thank you so much for coming and I look forward to continuing the conversation with you yeah no amazing I've really enjoyed that chat so thanks very much for having me as always thank you for listening to New Frontiers and functional medicine 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Channel: Dr. Kara Fitzgerald FxMed, Longevity & Epigenetics

Views: 29

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Id: 1V7g97NQ2BU

Length: 68min 52sec (4132 seconds)

Published: Tue Apr 11 2023