How to slow down your aging with Dr. Nichola Conlon

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You're listening to Bulletproof Radio with Dave Asprey. Today is an interview I'm really looking forward to because we're going to go into some molecular biology, NAD pathways, anti aging, and some things that are pretty interesting around how we can have this precious molecule in the body. And it's not probably what you think it is. Our guest is Dr. Nicola Conlon, who's a scientist who got really frustrated between the lag time between discovering something and then getting new supplements or drugs out to consumers. It takes about 15 years. When scientists go, oh, we know this works. And the really adventurous ones are like, using it on themselves. And then you and me, we get access to it after we've wasted 15 years of lower performance and not feeling as good. It's something that really, really, really pisses me off, to be honest. I, I think we have a fundamental right to buy whatever molecules we want, whether or not we have a permission slip from a government. And this is why you can buy almost whatever you want. You just have to buy it from another country. And it's ridiculous. So what Nicola did, she took her molecular biology background and early stage drug discovery work that she'd done, and she founded a company called Nucito and she's the CEO of it. So she brought in a team of scientists and they said, all right, how do we do multivariate analysis to figure out? Because maybe it's more than one thing that's going to give you the results you want, which is also something that makes me happy. There is no reason, no reason whatsoever to believe one thing is going to fix you or one thing is going to be what it is going to be. The magic bullet. But that's what all drug discovery is about. The one compound. But you might need 10 compounds to get the results you want. And that's what anti aging and functional medicine is about. So we got someone who came from the dark side who is now saying, all right, how do I just make stuff that works? Whatever has to be in there and get it out there. So that's what we're going to talk about today. Welcome to the show, Nicola.

Hi, Dave. It's really great to be here and thanks for the lovely introduction.

You are welcome. What did I get wrong in that introduction? I mean, you've done a lot of.

Interesting stuff, but not much. Actually, I think that was a pretty good summary of where I've come from. I mean, my background is, is a very academic route, so very traditional. I mean, I've always been just fascinated by the body, how it works, just everything just that makes us tick. It's just so fascinating. And that led me down this academic route of trying to learn more and more about it. I did, my background was in molecular biology. I did a degree, a master's. I went on and did a PhD where I specialized in bioavailability. So how, when you take a drug or a supplement or a nutrient or anything like that, how does it get into the cells and actually perform its function? But the issue for me really was in academia, just as you hit the nail on the head before in science, it's like all of science is encapsulated in this bubble where it never actually gets out to real people in the outside world. And for me that was really frustrating because I just wanted to talk about it and nobody knew what I was talking about half the time because it was just not available knowledge. And the other thing that was really frustrating was that in academia you tend to focus on like this tiny little bit of science. So you, you spend your life working on a gene or a protein or a pathway at the most, and you just block out the rest of biology, which is this huge thing, which is phenomenal. Me was crazy. It's like that is a crazy idea to just ignore everything else and focus on one tiny little piece. So that really didn't sit right with me.

What are some of the drugs that you worked on?

So when I was working on PhD and things like that, we were looking more about the bioavailability, so looking at joining things like peptides to drugs to help with their absorption. So trick the gut into absorbing them and then releasing the peptide and then actually releasing the active molecule. When I actually then moved into drug development, was working on immunotherapies, so the more cutting edge cancer treatments and also things to do with, with neurodegeneration. But naively, when I went into drug development, I thought that was my opportunity to, you know, not just focus on one thing and focus on multiple diseases and multiple pathways. But how wrong I was. Actually.

The, the deeper I dig, the more I understand that that much of the thinking that we've had in the last hundred years is very high level. And if you get down further and further and further, like there are systems in here that affect everything and you can affect those systems. And of course Alzheimer's and Parkinson's risk is going to go down, but if all you care about is Alzheimer's, you just would never even notice. And of course, if you fix diabetes, your Risk of cancer and heart dis goes down. But if you're doing heart disease, you're not going to look at diabetes. And it's always confounded me, but as I unpacked my own biology, I just keep going lower and lower into these really basic mechanisms of life. And you're like, make those better and everything else just fixes itself. Is that a good way of thinking about it?

Yeah, I mean, you know, you can understand why signers do pick apart tiny little bits, because if you really want to understand something, you have to do that. But, but I think the bit that generally that we're really bad at is actually piecing it all together and looking at the wider picture and actually what, what is going on at a, at a higher level, like you say, I think that is something that is, is almost has a blind eye turn to it. And that's a key example in drug development. So that still to this day, they're just absolutely, you know, set on just having this magic bullet approach of, oh, there's a gene or a protein that's involved in a disease, so let's get a drug and stick to it and we'll knock it out and we'll cure the disease. And that never happens because biology is so complex. And also drugs don't stick to one thing. The promiscuous molecules, they have a huge footprint, so you get off target effects. And also generally you just have a really, really poor hit rate when you're trying to develop any new molecules.

Why is drug development so slow? Or frankly new supplement development? But let's talk about drugs first, because that's where you came from before. You're like, I could do supplements. What's taking us 10 or 15 years?

Well, exactly that approach, because I would refer to it as like a reductionist approach. It's again, it's just looking at these tiny little parts of biology which is incredibly complex and you can't look at tiny little parts and because they're still really focused and ignore the fact that there's this complex biology going on and ignore the fact that drugs stick to multiple things. You get a lot of things that simply don't do what you expect them to do when they go in the body, because the body's highly redundant, it has lots of other different pathways and processes that'll upregulate when you try and knock one thing out. And then also the drugs are sticking to things and having all these side effects. So the hit rate of actually looking and finding new molecules that actually work is like Way less than a percent. So that, you know, like one in every 10,000.

So it's just finding, so it's the screening time. But once you identify one, it still takes 10 years to get it to market, if you're lucky. Right. Why does it take so long after, oh, look, I found something that works. Why do we take 10 years?

And that's where the complexity and all the red tape comes in. You know, it's all of the phases that everything has to go through in a very specific order. You know, a phase one, a phase two, then a phase three. And they were all done like one after the other. But I think, you know, actually what if there's one good thing that's come out of COVID that is demonstrated is how quickly that you can actually get a drug or a vaccine or something to market if you have to, by running phases in parallel, by actually not just focusing on single molecules and having multiple eggs in your basket at the same time and, you know, working on them in parallel. So I think that's one good thing to be learned.

Well, I am terribly offended that we just spent all that money and time fast tracking the vaccine for Covid. But we haven't fast tracked any of the 15 anti aging drug candidates because I hate to tell you, old age has killed at least half the people who died from COVID because they were already on death's door. And it kills way more people than Covid every single year because people die. And usually it's the chronic diseases of aging. So we can't fast track those, but we can fast track this. Maybe we could just fast track all drugs or better yet, just say, here's all the studies. You want to buy this new research compound, you can buy it, by the way. That's what I do. I do buy research compounds. But it's a ridiculous, ridiculous thing. If you're dying of a disease or you have really severe diabetes and you want to try something new, it is your God given right. And when any government on the planet says, oh, we're not going to let you do it because it might not be safe, it's like, who do you think you are? I don't know. Am I too radical?

Well, you know, not, not at all. I completely agree. And this, this is exactly what I was so frustrated by. I was so frustrated. So, for example, part of my job working in a drugs company was we would test a list of molecules in the lab, you know, maybe a thousand compounds. I'd get a list back that said in order of best to worst which ones worked, which ones didn't. And then what I would have to do is look at which ones you could punt. So which ones had freedom to operate around them. And Drake's companies do this because they will not take forward the development of a drug that is going to cost, you know, hundreds of millions and 10 to 15 years if they cannot absolutely own it outright and have exclusivity to it. So commercially I get why they do it, but ethically I would be sitting there looking at compounds that worked really, really well but were actually, you know, weren't considered patentable because they were natural molecules. They were things that were really common already, things that were safe for supplements, things that had GRAZ approval and they were just getting put in the bin along with this amazing data that showed actually this, those things work better than the drugs that they're going to spend hundreds of millions on. So for me that was a big eye opener.

I get it. And as a person with the Wharton mba, if you can own it, you do make a lot more money. There's a reason that pharmaceutical companies own a lot of the governments out there, not the other way around. And you look at supplements, well, let's see, I'm the guy who made collagen a big thing. You can't own collagen. Right. I know how to make it in a certain way so it doesn't taste like socks, but there's lots of knockoffs, you know, of all sorts of different grades. And the deal is it works. And every supplement company out there has dealt with this. You can get some patents and I've got patents on some of the things I've formulated, but it means you can't copy the same thing. So what people do is, oh, I'll just make the same thing and add vitamin C there. Now it's different. And so in the supplement business it's simply less profitable than pharmaceuticals. But I think it helps a lot more people. And that's why pharmaceutical industry keeps trying to shut down supplement companies because compete with pharmaceutical companies. And of course pharmaceutical companies, they like nothing better than a monopoly. I don't know why.

Yeah, and that is exactly why I found in a Cheeto. That is our mission. It is to take the cutting edge science and also our expertise in how you find molecules or combinations of molecules that actually work in the body and then actually sort of cut out all that complex stage and get them as over the counter products where people can benefit from them now, but they actually have scientific credibility behind them. Good scientific thoughts, some testing so it was really to try and bring that into the world, which I know you're obviously really passionate about as well.

Now you're using an approach called systems pharmacology, which came out of Big Pharma, but you're using it for natural compounds. Explain what that is.

Yeah, so systems pharmacology was something I was really lucky to learn about. Well, probably back in about 2015 when I'd realized that Big Pharma still has this approach of the magic bullet. And I was looking like, seriously, does anyone have a better way to do this? And I came across a company which specializes in systems pharmacology. And basically what systems pharmacology is, it's like three main principles which make it different to conventional pharmaceutical discovery. And the three main things are, is that it respects the fact that actually biology is really, really complex and there is a lot going on and it is very robust, it's built to withstand impact generally. And it doesn't ignore that. It actually respects the fact that there's this complexity. And when looking at diseases or conditions or whatever it is that you want to treat, it actually looks at the whole picture and not just a single protein or a single gene. It actually looks at every single gene, every single pathway, every single protein, every single feedback, feed forward, you know, inhibition, everything that is going on. And almost looks at it as a big network. That's what we call it as. And then the second principle is just bearing in mind this complexity is that it is never ever scientifically plausible to take a single target approach because it's just a stupid idea, as you said earlier, like trying to like put your finger on one tiny little piece of that massive complex puzzle is just never going to work. Which leads to the third thing, which is that if you want to have any impact on biology, you've got to take a multi targeted approach. So you've got to look what the best combinations of targets are within all of that complexity and understand how you can target them. And also what molecules actually already have that footprint to stick to that sort of combination of targets, or alternatively use a combination of different molecules that are going to have the action that you want in the body. And with this approach, it improves the efficacy of drug development massively. Like the hit rate hugely improves. Because instead of ignoring the complexity and ignoring the fact that drugs stick to multiple things, you actually use it to your advantage. And it's just a much more sophisticated way of molecular discovery.

If I had known what, you know, 20 years ago when I first started working on using supplements to fix the 300 pound problem that I had and all the other mitochondrial issues and autoimmune and whatever. The first two, three years, I would say I'm going to test this one vitamin. I'll test it for a month. Well, it didn't get a result. Then I'll test another vitamin for a month. And I just sat down one day and I said, you know, there's more vitamins than I have months left in my life. And then I was like, well, wait, why do I believe that only one is going to work? It doesn't even make sense on its face. So maybe I'll do everything that might work all at the same time. As long as there's no evidence it's going to fight with itself. And if I get the result I wanted, hooray. And then I can start taking them out at least. But that algorithm for biohacking has served me really well. And it seems like sort of the homebrew version of systems pharmacology. So like, let's hit all the pathways. At least it's results driven. Okay, so you decided to apply systems pharmacology from Big Pharma at Nuchito, but you could have gone after a bunch of stuff. And you partnered with some really well known guys. A biogerontologist named Tom Kirkwood and Thomas von Zlinki. I can never say his name right, but this is a molecular biologist who was the first to discover oxidative stress and DNA damage. Kind of, you know, very big names in biogerontology, which is a small field, but still, why did you go after aging? You could have gone after many other medical things.

Well, actually we were approached by. By quite a prominent figure in the world of aging research. And who says so? Aubrey de Gray.

He's a friend I love. Aubrey's been on the show a couple of times. He has the best beard ever, right?

He certainly does. Yeah. So. So Aubry actually approached us and said, you know what? The way that you do drug discovery is really forward thinking and I really agree with the way you do in it. And have you ever thought of looking at aging? Because aging is perhaps one of the most biologically complex things we know, and we know for a fact there is no way conventional discovery is going to come anywhere near to finding anything with the way they do it. So how about using the systems pharmacology approach to look at, you know, aging as a whole? Because aging is just a huge mashup of all sorts of different things that.

Are going on Are you gonna cut your head off and freeze it like Aubry?

I don't know. Actually, I've had some very interesting conversations with people about cutting their heads off and transporting it to Russia and things like that.

But I have two. I'm not signed up for it. In fact, Aubrey and I had a really passionate discussion in the back of a car one time about that. He's like, but you have to. It's a backup plan. And I'm like, yeah, but I don't know. So I'll have to do an episode on that again. Maybe I'll get Max Marmor on here or something. But I always ask figures in anti aging. Okay, do you have a backup plan? And since I don't have a backup plan other than maybe, probably reincarnation. So there you go. There's a backup plan that's less work if it's real. But of all the things you could have done. So Aubrey influenced you, as he's influenced a lot of people, including me. And. But you look at aging, I mean, there's hormones, there's all kinds of pathways, and you ended up on nad, but with a different perspective than a lot of people. And for new listeners. NAD is a compound I've written about extensively in my anti aging book called Superhuman, something I've done intravenously. I take all sorts of precursors. I do all kinds of stuff, and I learned some really neat stuff. The first time that Nicola and I sat down, she walked me through some cool pathways that she's going to share with you guys today. But I think it's a fundamental molecule. But I want to know, how did you get to that one when you could have done like, you know, 50,000 different other molecules?

Yeah. So we literally had probably 50,000 different ideas on the list of things that we could be doing. But in all honesty, there was two reasons. The first was that, you know, our idea was we wanted to get some cutting edge science out to people really quickly so they could benefit from it. NAD had the benefit where people had already started to hear, hearing about it and accepting that it was a, you know, an important thing, as opposed to some of the other things that we were working on, like epigenetic reprogramming. That was a bit too far out there for the general public at the time. However, nad, we felt, was just on the edge of people starting to understand maybe that what it was and that it was something beneficial to do with aging. So that's why we started looking at that initially and also because NAD is actually A really, really good example of something that is biologically very complex and something that is actually well suited to a systems pharmacology approach rather than a single target approach.

I just put a question through to the Upgrade Collective. Who's our live audience today asking how many of them are taking NAD or precursors? So I'll probably get a few answers in a minute here. Can you talk about what NAD does in the body? Because I think a lot of listeners probably didn't catch one of my earlier episodes about that. So walk me through why it's a fundamental aging molecule.

Yeah. So nad, it's a natural molecule, first of all. It's found in everywhere in your body, every single cell. And it is so important that if you didn't have it in your cells, you would literally die in 30. And one of the main reasons is that it's involved in your energy production. So it literally helps convert the food that you eat into the energy that your cells need stay alive. So into ATP, the sort of cellular energy currency. And the way it does this is it acts as an electron carrier. So some people are familiar with nad, might sometimes see it called NAD with little plus next to it, or they might see it called nadh. And what this means is that NAD can flip between two states. NAD is its oxidized form, and that's when it is ready to accept electrons. So it's a bit like an empty bus picking up passengers. The other side, nadh, that's its reduced form, and that's when it's already full of electrons and it's ready to drop them off at another molecule. It's this movement of electrons back and forwards that allows energy to be generated in the mitochondria. So NAD is absolutely fundamental to energy production in the mitochondria by all the pathways that produce energy. So that is why you would be dead in 30 seconds if you didn't have NAD in your body.

It'd be like having a house without wiring to carry the electricity around. Nothing would work, right?

Yeah, absolutely. It is absolutely critical, and that's the most well known function of nad. However, it's become a lot more apparent recently that it's not just energy production that NAD is involved with. It's actually involved also in cellular maintenance and repair. So NAD almost acts like a. Well, it acts as a substrate for a lot of different repair pathways. So when I say a substrate, it's almost like the fuel which switches on different enzymes and different processes. And a key example is DNA repair. So DNA damage is. Is Is, you know, one of the major causes of aging. And every day, the UV lights, damage in our DNA, we've got our own oxidative stress from our metabolism, damage in our DNA, all sorts. And our body has to continually repair it. And it has DNA repair enzymes that do this. And NAD is critical in actually driving this DNA repair and making sure the DNA repair enzymes get to the damage site and actually do the job that is required. So that's an example of it being used as a substrate.

That makes sense. And I've seen studies, in fact I reference them in my book. Between age 0 and age 90, there's a 90% decline in NAD levels. So when I'm looking at biohacking and living to at least 180, like I'm pretty sure I want the levels of compounds that are found in a 25 or 30 year old to be in my body when I'm 125. Generally a good way of looking at aging.

Yeah, it's actually quite scary, you know, how much NAD declines. In all of the studies that they've shown in brain and skin and different tissues. The decline is really exponential. And that's not good when you know the important things that it does and especially when it comes to aging. So one of the key things that NAD is known as is, is an activator of something called the sirtuins. And the sirtuins are also known as the longevity proteins. And what they do is they switch on and off lots of different genes and pathways that are associated with cellular health and, and, and basically good agent. And NAD is critical for those searching proteins to work. So again, your NAD's dropping, your energy is mis, malfunctioning, you're getting mitochondrial dysfunction, which means that you don't physically have as much energy. But that mitochondrial dysfunction also gives off oxidative stress, which then goes around the rest of the cell and starts damaging all sorts of things there. And then what you'd really want is your DNA repair and your search you and step up and start repairing all the damage. But they can't because they need NAD as well. So it's so critical to cellular function.

So you decided to go after that. And David Sinclair is a friend who's been on the show a couple times talking about some of the precursors. I take pretty much all the precursors. I've done a couple different episodes about them. And at upgrade labs I've had at least 10 IV infusions of it. Actually, I've probably had closer to 30 over my life. And an IV infusion of NAD is expensive. It's actually used for drug and alcohol recovery. People do about 10 of those infusions, and they just don't want alcohol anymore because they feel better, which is pretty strange. But from an aging perspective, man, my sleep improved so dramatically when I did it. So getting those levels back up to youthful has been a really big deal for me. But most people are not going to sit through 20 hours of feeling like there's something sitting on your chest and with a needle in your arm, unless you're a pretty dedicated biohacker. What did you figure out when you looked at systems pharmacology and nad? I know because we got to talk about it in person last time I was in London, before all this pandemic stuff. But what did you figure out about it?

So I think a key thing for people to understand is to go back to why NAD actually declines. And to understand that, you really need to understand actually why, like how NAD is produced by the cells when they're young. And because NAD is so critical, the cells are actually really good at making nad. So your body's really good at producing it. And the way it does this is it takes precursors, which you've mentioned, which are usually vitamin B3 derivatives. And these are like the raw materials that the cell needs to make nad. And it ships them into the cell. And once they're in the cell, there's multiple different pathways and multiple different enzymes that actually convert this precursor, raw materials into nad. So then you've got this lovely NAD in the cell, and then the NAD is actually used up. So the search you ends are using it up. The DNA repair enzymes are using it up. And when they use nad, they actually break it back down into a precursor. And the precursor that they break it back down into is nicotinamides. And then this is where it gets really interesting. And this is what most people don't actually realize is that the cell actually has a really good ability to recycle that precursor straight back into useful NAD again. And this pathway is called the salvage pathway.

So we use nad, it becomes nicotinamide, and then we recycle it back into nad.

Exactly that, yeah. And in youth, that is the main way that our cells make nad. They're continually recycling it.

It's pretty cool. Our bodies are so lazy. Anything that's hard to make, we recycle. It's like the ultimate efficiency machine. Same thing with ATP that a lot of people have heard of in the mitochondria, right? We take ATP and It goes to adp, which it goes from tri to die. And they're like, oh, let's just put another phosphorus on there. Let's just reuse that molecule forever. And if you're good at that, magically you make more electrons. But then if you don't have nad, even if you make electrons, you can't move them around. So you have to have both of those things at high levels and both of them salvaging themselves or recycling themselves efficiently. And those are hallmarks of youth.

Yeah, okay, exactly. So that is the major way that our cells provide themselves with nad. And I guess the recycling thing makes sense because it is so important that the body wants to have this kind of, well, fail safe. Can't really say that, but way of actually making sure that it's continuously got this NAD available to do all of this repair and all of this energy metabolism and things that it's actually needed for. But the problem is, is that as we get older, there is a fundamental failing in that system. And that it's now known that the main rate limit and enzymes like the pinch point in the salvage pathway, this enzyme called nampt, actually declines as you get older. And what this means is that as your body's using up NAD and breaking it back down into the precursor, this precursor then can't actually be recycled back in NAD again. So what happens is it starts to pile up in the cell, and cells generally don't like anything building up. So then the cell has to find a way to get rid of it. So what it does is it starts up regulating other pathways, namely a methylation pathway. And this upregulates an enzyme called nnmt. And that enzyme actually starts trying to methylate nicotinamide and excrete it out the cell to get rid of it because it's not getting recycled.

So your recycling doesn't work. So your pile of aluminum cans builds up your recycling pile inside a cell, which is nicotinamide. Right. And the body can't get rid of that via normal things. So it says, all right, we've got to start getting rid of it via say the normal tr. Right. So it's trying to pull stuff off that pile because it can't melt it down into new aluminum. If I'm making a kind of a.

Rough analogy there, exactly that. And that's problematic because you can see straight away how this whole systems approach comes into play because one thing stopped working that's had an impact on the nicotinamide building up or the cans. And then the cell has to get rid of it. And then that's meant another enzymatic pathway has been thrown out of its usual, you know, balance. And then you start methylating this nicotinamide to get rid of it. And what this means is that you're actually using methyl groups that are used for other things in the body, like epigenetics and things like that, and then they're not available for that job. So you can soon see how it all starts escalating.

It's funny, when you're getting an IV NAD infusion, which I'm still a huge fan of, you get really flushed and red and sometimes you get some nausea, kind of like a niacin flush. But if you take a methyl donor before you do it, then magically you have almost none of those side effects, which is, which is a really neat thing. So a lot of the more advanced practitioners, and that's the sort of stuff that we would do at upgrade labs as well, you can take some betaine ahead of time and then magically it's a methyl donor. And then. And that's probably why, right, because you're have, you have enough methyl groups to handle any excess nicotinamide. Is that a likely explanation?

That is exactly it. But what it also shows is, it also shows that probably your salvage pathway isn't functioning efficiently. Because if so, classic case with IVs, put the NAD into the cell. If you actually had a really well functioning salvage pathway, then rather than that NAD getting used once and then getting chucked straight back out, that expensive nad, it could actually get recycled round and round. So actually improving that would be good.

So what you're doing with neutral, basically is you're saying, why don't we fix the recycling pathway so that you can use it? And with an NAD infusion, like, hey, why don't we just give you a lot more new aluminum cans? But you're going to get a bigger pile in the cells and you're going to have to clear that out. So one of the ways around that is, okay, take more methyl donors so that you can at least clear out the extra nicotinamide. Okay, is that the. But the bad recycling pathway is one of the ways we lose nad, but there's another major way we lose nad. And then I want to talk about how to fix the recycling pathway. So we've got some inflammation that sucks NAD out. Walk me through that.

Yeah. So as well as being not as good at recycling nad, there's also things that are wasting NAD in the cell. And this is hugely linked to inflammation so it's been found that one of the major causes of NAD loss in the cell via a protein called CD38 and what CD38 does is it's basically involved in immune activation. And in order for it to activate immune cells it has to use a huge amount of NAD as its substrate to make the enzyme go basically. So for every one molecule of its downstream substrate that it makes, it requires 100 molecules of NAD. So you can see that if you get upregulation of CD38 and you get 100 molecules every time with each molecule of CD38 being used, this is going to put a massive dent in your NAD levels. And for a while it wasn't really understood like why, why is this affecting NAD and why is it up regulated. But recently it's been found that the reason that CD38 is increasing is actually linked to another area or another hallmark of aging, which is cellular senescence. So senescent cells, they secrete a lot of inflammatory factors and these inflammatory Factors increase your CD 38 expression and then your CD.