James (00:01): If you’ve been paying attention at all to the world of longevity in the last few years, then you have certainly heard of a little molecule called NAD, a miracle molecule found in all living cells that has been found to be greatly correlated to all facets of healthy lifespan. Unfortunately, as we age, we begin to have less and less NAD available, which causes an assortment of age related diseases. There is an enormous amount of confusing information out there about NAD and in today’s interview, Joseph Bower, one of the world’s leading NAD researchers helps to clear up some of these age old questions. What’s better NMN versus NR. At what age should I begin taking an NAD precursor is injection more effective than oral supplementation. Joseph helps answer all these questions and a lot more. So if you’ve been extremely confused, just like I was NMN, NR and especially NAD, then this interview is for you.
James (01:17): The human experience is changing, and it’s going to happen a lot faster than you think the world is going to be a vastly different place in the next 10, 20 years because of what’s happening in the biotech industry right now. Welcome to the simple biotech podcast. My name is James rule, and I’m your host. The goal of the simple biotech podcast is to interview the researchers, founders, and investors that are working directly in the industry and to translate what they’re working on into simple and easy to understand language. If that sounds like something you’re interested in, let’s get started. Hi Joseph. Thanks for joining me.
Joseph (01:59): Hi, James. Happy to be here, Joseph, you have a very impressive resume when it comes to working in the world of anti-aging. What initially sparked your interest in this field and how did you get involved? Well, uh, James, I grew up in Halifax, Nova Scotia, and I was always interested in aging and physics. And when I moved to Dallas, Texas to pursue my PhD, I actually had my admissions essay read back to me at graduation, which included the future plans that I was going to become both an agent biologist and a physicist, but I would have to do the aging first because otherwise I might run out of time. That’s quite a plan, an aging biologist and a physicist. And how’s that physicist plan coming along. I’ve got to say that one, that one’s been on the back burner. We actually are getting into some areas of chemistry that have required some of the physics background that I used to have. And I’ve got to say it’s faded quite a bit. Well, yeah, so that’s great. So I mean, talking about the chemistry and let’s talk about some of the molecules that you’re working on in particular NAD, you are an expert to say a lot of the, that you’re working on
James (03:00): Is based around NAD, correct?
Joseph (03:02): Yeah. Yeah. A big part of my lab is now completely focused on Nat.
Seems like it’s going to be an extremely important molecule in the world of anti-aging in the tree of aging. It seems like it’s going to be a pretty big part of things, potentially even one of the most important molecules in the human body. Would you say that’s fair?
Yeah, absolutely. I mean, it’s, it’s certainly one of the molecules in your body that you just can’t live without. It’s required for many essential processes and there’s actually a disease called grab that is, turns out to be what happens when you just have a deficiency for Nat, but even the single cell in a dish can’t survive without it.
Right. And so let me try and give you my understanding of NAD, why it’s important and you can get back to me kind of fix maybe my, I guess layman’s understanding of it. So my understanding is essentially NAD for all those that are listening that may not particularly understand what it is. Maybe they heard Davidson Sinclair talk about it on Joe Rogan, but they don’t really know what it is or why it’s important. My understanding of NAD, it’s kind of the energy for the cell without NAD. The cell can’t do hundreds of thousands of millions of functions that it has to do when it comes to replicating when it comes to creating energy, all of these things they’re so important in the cell. It can’t do any of that without the NAD. NAD is kind of the energy behind all of those processes. Would that be a fair kind of simple
Way to explain things? Yeah, I think that that’s a pretty good explanation. I mean, I think when you, you need to speak to a general audience about metabolism, usually start with this idea that, you know, you have food coming in in the form of things like carbohydrates and fats, and that your body somehow was able to convert those into chemical energy in the form of ATP, which is the molecule that your cells are using when they require some energy to catalyst, some sort of process. And if it’s a general audience will usually say, you don’t want to get into the weeds of what’s happening in between to make that happen. But as you kind of alluded to NAD is very much the weeds and a D is the molecule that’s participating in each of these chemical transformations that it takes to get from the foods you eat to energy for the cells.
Right? And so without NAD, you’re going to have issues, DNA damage. I mean, de NAD has so much impact on things like DNA repair, all of these different areas, where without it, you can lead to things like cellular senescence, mitochondrial dysfunction, a whole mess of issues as you age. And those are all kind of, that’s kind of what happens, right? That’s part of the aging picture is a lot of the symptoms of lower NAD, correct?
Yeah, absolutely. That’s one of the reasons that model is so attractive. I mean, so the model has never been that if you have no NAD, is that causing aging, but that’s clearly fatal. The question is with the declinement of NAD that we do see during aging is that enough that some of the entity dependent processes aren’t working as well anymore. So we could just put it back to fix all those processes. If you just remove NAD, if you keep picking down the NAD levels, you’ll hit a point where it’s causing chaos and second lethal,
Do we know why the human body starts to slow down its generation of NAD as we age
We don’t. And you know, in fact we’re working on that right now, it’s of the research topics in my lab. And what we’re mostly finding is that the generation of NAD probably isn’t slowing down the data we have so far, at least as much more consistent with the idea that we are burning through some of the NAD faster as we age. So there are different classes of enzymes. We’ve sort of talked about the central function of NAD and metabolic reactions, and that doesn’t really destroy it. It gets converted back and forth between the high energy and the low energy form, but there are boxes of enzymes that also break down the backbone of NAD as part of their activity. And some of those enzymes may become more active with age. And so what’s actually happening is you’re potentially making the same amount of NTD, but consuming it faster. And that causes the overall concentration in your body to fall, which interferes with other NAD dependent processes.
Would it be fair to say that as you age you, your body consumes NAD less efficiently,
Let’s say your body potentially becomes less efficient at getting NAD to the places you would like it to be used. The model is probably that your body is consuming it, but it’s enzymes involved in things like inflammation and DNA damage responses that you don’t want chewing up all the NAD that are taking it instead of the other enzymes that are involved in this ATP generation that you really want to be getting access to. Right?
So as you age, basically, there’s all these other enzymes come into the picture and they start taking the NAD as well, leaving less NAD for all the more important things like DNA repair, all the really important stuff that the cell is going to need. In fact, cool. So this NAD really seems like kind of a miracle molecule. I read a study, I’ve read a lot of studies about it recently.
I think it was one that you wrote about targeting NAD metabolism to improve glucose homeostasis in obesity. And
So this is something that potentially has benefits outside of aging, maybe with obesity, I mean, athletic performance. Are there other types of benefits that come with taking an ID?
Yeah. With the caveat that most of the benefits demonstrated in rodent models. So for the most part, these are all theories about what we hope will also be true in humans, but in rodent models, we’re seeing definitely, as you alluded to some benefits in terms of diabetes and glucose homeostasis, there’s quite a bit of evidence now that you prevent heart failure in many different rodent models of that condition. There’s evidence for improved cognition in neurodegenerative disease models in the rodents. We’ve actually done a lot of work on liver regeneration just because it was known that that is a situation where NAD becomes deficient when you have a liver injury and it’s trying to regenerate. And so we tested and showed that indeed, it’s true. If you supplement NAD levels during regeneration deliverable regrow faster, we’ve taken advantage of that system actually to test some of the downstream mediators and things within a D precursors.
My question is, if you mentioned that most of these studies have been done in rodent models, there’s some of the precursors like NMN and are, as far as I know, I mean, they’re being sold on Amazon, so they must be pretty safe. Why have there not been
More human studies? Human studies are certainly ramping up now and there have been some, I mean, the problem is that they are expensive. I think there’s really the limiting factor at the end of the day. You know, there’s so many supplements out there where people want concrete, solid answers, thousands of people in randomized trials and just the financial support is not out there for things that aren’t really well protected by patents owned by big companies with deep pockets
Or new molecules being worked on right now, other than NMN I do want to get into NMN and NR because there’s a lot of debate over those two. I’m sure you’re more aware of that than most, but there are other molecules that potentially could be cheaper that are maybe coming out in the,
Yeah, I don’t know about cheaper exactly, but certainly, you know, anima and, and are, are pretty chemically similar in the first place. And there’s a lot of companies out there, you know, trying different derivatives and conjugating them to things, hoping to find something that’s a little bit more effective, either delivering to the right target tissue or getting NAD levels boosted faster,
Working on finding new molecules, or are you just doing the research with the current precursor?
So we are doing some work on NMN and NR, and also some of the other ones that are already known. And we do not sort of in the chemistry business as far as conjugating brand new things to them. But we collaborate a lot with a chemist named Marema goes to the University of South Alabama. She makes us a lot of a stable isotope-labeled version. So we can trace where they’re going in vivo and some interesting forms of these different molecules, including things like the nicotinic acid versions of molecules. So nicotinic acid drive aside instead of nicotinamide riboside NR. So we certainly are pursuing other molecules that are known to be in these pathways. But as I said, not really the exploratory chemistry, the way some other companies are
The money question, I guess, which of the two with all of the data that’s out there right now, which of the two and R versus NMN do you think, I guess, saturates the sell the most because I’ve read a lot of studies that they couldn’t really prove that the NR or NMA
Joseph (10:37): Was able to get past. I forgot what the exact verbiage was
James (10:42): And really get into the cell. Is that something that, am I saying that right?
Joseph (10:46): Not exactly. So this is, I mean, this is, I think this is our study you’re referring to where we use some of these tracers actually made by Marie and collaborated with a group at Princeton led by Josh Rabinowitz that does a lot of mass spectrometry. So we’re able to follow these labeled versions of the molecules around the body. And what we were able to show in that study was that when we give either NMN or orally, which is obviously the way humans are generally taking these things, it’s the intestines and it hits the liver. And then the molecules at that point, they get beyond the liver, into the circulation, seem to be broken down almost completely to nicotinamide, which is vitamin B three. This is the, the standard precursor for NAD in the body, as opposed to these novel precursors that they’re supposed to have advantages in terms of being energetically more favorable and potentially taking different pathways to get to NAD. So that was the really the controversial part is whether anything special about these molecules remains when you’re looking in tissues beyond the liver, because we really, we just saw that what was coming out was for the most part, the simpler, cheaper form, which is nicotine of mine
James (11:46): With those studies. Were you able to see any type of benefits? I guess you could say, were these rodents that you tested on or even humans, did they any type of, I guess, phenotypes
Big results in that particular study, it was really designed just to track where things were going. We were treating them long enough to see some of the other benefits people have looked for and weren’t really looking for them, but in other contexts, certainly my lab has seen benefits with both of those molecules. And I do want to emphasize that even knowing the way that we think the metabolism works, having the nicotine abide reached, the other tissues still can boost NAD levels. That’s not incompatible at all with the idea that both of these molecules will boost NAD levels throughout the body. It’s just a matter of challenging the novelty of, of using these particular molecules for some peripheral tissues. So for instance, for skeletal muscle minimize, what’s getting there, then it doesn’t really matter if you took nicotine or if you took nicotine. And my driver’s side at the beginning
Are the other methods of taking the NAD precursors. Like you’re wearing a patch or getting a direct injection, do those work better for lack of a better word?
So our studies suggest that it’s very different. If you deliver nicotine monitor nucleotide or riboside intravenously, that it gets to peripheral tissues like muscle much more effectively, as far as human studies is you start the safety questions all over again. And so in humans that, that hasn’t been tried yet. Although I think, I think it does have the potential to be much more effective what’s out there in terms of injection and patches that I know of at least is intact NAD rather than one of these precursors. And there I’ve never seen any scientific study done with the patches. Maybe you can correct me if you have seen something, but I’ve looked pretty hard and not seeing anything published on those, just a company sort of slogans and advertising. I mean, I think in theory that could work, but I just don’t have any evidence to judge it based on.
And as far as the intravenous intact NAD, there’s been clinics doing that for a while. I’ve been sort of dying to see, to trace that and see where it goes. And this has been a pet project of Murray’s in the background. It turns out to be really difficult to get enough labels in the positions. We need to be able to follow that intact NAD after intravenous injection. And we actually think we’re a couple of weeks out from having that molecule so we can do that experiment and see when you give intravenous NAD, does it really do anything different than if you just took a oral precursor,
That’d be a really exciting experiment to see. And how could I, how would one stay up to date on that when the results do come out on that
The meeting abstracts is usually the, the earliest place you’re going to see indications of results like that before they’re in print. Obviously we’re trying to get them published as quickly as possible as we, as we figure these things out.
Cool. Cool. Well, uh, for everyone listening, just pay attention, look for the abstracts. One question. I mean, the, the, the real, again, I wanted to kind of dive into NMN versus NR. And if you do have an opinion on that
And, or not even an opinion, I mean, what the research does say, because it’s really hard to decipher. I mean, there’s so many different articles, so many different videos saying which one’s better. This paper says this one’s better, or this paper says this one’s better. I’m curious as someone who’s really in the weeds, what your thoughts are on the two. Yeah. I mean, I get asked this a lot and I’ve got to say it’s really hard at this point to pick one over the other, the vast majority of studies that are out there have only one or the other, and not both side by side, a couple of papers ever that have really put them head to head, which just makes it really hard to judge. And a lot of the benefits are the same in terms of things like glucose homeostasis, there’s evidence for improvement in heart failure with both. And as I said, with our tracer studies, one thing we did see is with the intravenous delivery route, we saw that NR was better at getting into muscle than NMN, but if we delivered them orally, which again is the way people are pretty much talking about this for human studies, the tracing patterns look almost identical. So at this point, I just don’t know that I can honestly pick one. And I think we really do need a lot more of the studies to really put them head to head. So this becomes more clear.
Yeah, I agree with you on that. But generally I guess they both are probably fairly effective at doing what they’re supposed to do.
I mean, they both certainly boost NAD levels is at the end of the day, if that is the outcome that matters, they’re both achieving it. This is just for NIH, but this is, this is the reason why we need a lot of sort of impartially government funded research, where the players involved are not necessarily motivated to find one outcome of the other, because that is a big part of what’s driving. A lot of these studies to only include one molecule or the other is that they’re there they’re privately funded or somehow involved in the development of one molecule or the other aren’t interested in showing anything that contradicts their narrative. So I really think this field would be in a better place right now if more of the funding was coming directly from NIH.
I agree with you completely on that. It’s a bit sad that something so beneficial for humankind is so hard to do so hard to get that data.
Yeah, absolutely. The other thing that I really think as a field, we need to think harder about is collecting the data from people that are just taking these things voluntarily, you know, as you alluded to, there’s plenty of people taking both NMN and NR at this point, and it’s only really a tiny fraction of them are capturing in clinical trials where there might be, you know, an N of 10 versus 10 for a couple of months that gets studied carefully and reported, but 100,000 people taking it for years. And we just don’t really know what happened to those.
This will lead to my next question. I am one of those people who’s taken both of them, actually I’ve experimented with the extremely high dose that I think Davidson Claire recommended on Joe Rogan. When I first got into all of this longevity stuff and Mike, well, the thing is I’m 31 years old, my energy levels. I imagine haven’t dropped that far yet. Is there any benefit to it because I didn’t really feel much of a benefit from it. So is there any benefit for someone of my age to be taking this stuff
First with what we actually have data on, which is younger mice? Honestly, we don’t see that much in younger mice. We see that the data from my labs mostly consistent with when you’re in a situation that induces an NAD deficiency, then there’s a benefit to taking it. And, you know, aging may be one of those situations for the mice, certainly different disease models. There’s benefits. If we cut out the liver and that’s trying to regrow and under metabolic stress, there’s a big benefit. If we just load up really young, healthy mice, we don’t see much. We don’t see their glucose tolerance get better. That’s already pretty good. We don’t see their endurance get better. In fact, in study, it looked like it got a little bit worse and there’s one study at that reporting that trend and young rats too. I don’t have a scientific basis to say that there’s a benefit to, you know, if you’re already young and healthy and maybe have optimal levels. What it will say is anecdotally, if you read the comments on these supplements, if you talk to people, taking them improved athletic performance is one of the things that keeps coming up in that sort of anecdotal, not scientifically rigorous tested sense. So I’m certainly curious about it and that, that, I think that’s one of the studies that really needs to be done just to take a really young, healthy group of individuals and test them really rigorously for endurance and other aspects of athletic perform.
Yeah, well, from an outside perspective and again, from a very extremely shallow understanding of, of it, it would kind of make sense that NAD boosting your NAD levels would show some sort of athletic performance in even younger people, certainly in older people. Yeah.
Question again is just sort of whether how good your body is at adapting to that in the first place. Because one of the things that does happen when you exercise is you naturally get a boost in skeletal muscle NAD levels. So part of it may be that you just, the extra NAD that you’re adding may not be that significant compared to what your body is already deciding to do on its own when you’re young and healthy. Is that I’m very curious about that possibility. I would love to see a real study on that and I don’t think it’s been confirmed or denied very effectively in humans yet.
Yeah, well, let’s hope we can ramp up some more studies on this NMN and are all these precursors in the future, because again, it is a bit disappointing. There hasn’t been that those two studies comparing the two and there hasn’t been just more studies comparing it with younger people
Versus how it affects older people.
Well, my next question, what age should someone really start considering? I mean, at what age do we really start to lose NAD as we age I’ve heard around 35? Would that be about, about accurate? Yes.
The reasonable guesses, any, there’s just not enough evidence to really put a number on it like that. What husband’s seen, you know, there was one MRI study done in human brains and they really fit a pretty straight line to the decline in NAD with age. So, you know, it probably is ticking down incrementally, you know, from the time you are a very young adult, but as far as, you know, when it would cross the threshold where it would now be more beneficial to supplement, I just don’t think we can make that call based on what we know.
So to kind of go over everything we’ve learned this conversation, and man, it’s been super helpful to talk to you about all this stuff. Cause I’ve had so many questions when it comes to NAD and you really helped clear up a lot of it, but to kind of just go over, well, what I’ve learned NMN and NR, they both are going to likely increase NAD levels when it comes to which one does it better. There just hasn’t been enough studies comparing the two. We don’t know when someone should start supplementing NAD and yeah, NAD is basically the miracle molecule and it helps out with a ton of different stuff. It’s something that people should start paying attention to.
Is that again, it can come back to the rodent data. I mean, there’s really an overwhelming number of benefits in rodent models in different situations. And so I think it’s an exciting time to really take a good look at how much of this is going to apply to humans.
That’s great. And so I want to ask you a couple of fun questions. What, if any supplement or behavioral protocols, saunas, fasting, anything like that? Are you participating in right now?
I haven’t honestly settled into any consistent routine that I’ve sort of committed to. I do have bottles of a lot of familiarity in a NAD supplements around and I will take them. So they’ve been bursts for a week or two at a time. Just kind of like you alluded to earlier to really try to see if I feel any different or if I can convince myself to any of the anecdotal benefits I’m hearing from other people would apply to me too. As far as behavior, I do sort of a mild intermittent fasting, which wasn’t really intentional at first, I just found, I felt better not eating breakfast. So I tend to not consume any calories until around one or two in the afternoon, almost all the time. So it’s something like 12 to 14 hours off 10 hours on or so eating. But yeah, no, as far as the, as far as the supplements, I’ve just done things transiently and not made a commitment at this point, but I know some of the other people working in this field have a long list of precise doses at the same time every day. I haven’t reached that point yet.
Yeah. And generally the most people I’ve talked to and basically every podcast I asked this question, I don’t think anyone has really this episode six, I believe, I don’t think a single person I’ve interviewed so far has told me they actually are taking a supplement protocol or are working really on any behavioral protocol. They all just say, just wait 10 years. And that’s when all the good stuff’s gonna come.
Yeah, no, I mean, this is always that sort of underlying fear right? Of, you know, you could be, it’s much more believable that you could make a mistake and taking something chronically, then you could find the right one to actually extend your lifespan. So there certainly is that feeling that if we’re going to know so much more in five years, why don’t we pause sometimes? Yeah.
That’s a very logical way to look at things. And for my final question, uh, what other areas of biotech other than NAD that you are not directly involved in, are you particularly excited
In the short term and publicist analytics, this idea that you can remove senescent cells from the body potentially with a combination of drugs, just because that is something that, you know, that has a certain logic to it that I think again, in the rodent models seems to be pretty well supported at this point. And the really attractive thing about it, I guess, is that you could potentially remove the senescent cells once it stopped the treatment. Right. And they would still be gone. So this would just be a really intermittent type of therapy. So I think there’s a lot of potential in that idea and I’m really, really excited to see if any of those molecules work out. That’s kind of short term at this point. I think that’s becoming a reality sooner rather than later, I think in the longterm really excited about the potential of them oligonucleotide chemistry.
So this is sort of the idea that you could target specific DNA sequences by having the complimentary DNA or something similar chemically involved into your drug. That was an idea that sort of really came into fashion maybe 20 years ago. A lot of tried it, it didn’t really work out that well, most of the cases, the drugs aren’t getting where they wanted or they weren’t stable enough and the whole field kind of collapsed to some degree. But I really think that that was the chemical tools available at the time. And that, that there’s going to be a huge resurgence in the oligonucleotide chemistry thinking a little farther forward into the future and the potential, the original potential is still there as far as being able to dial into specific genes within specific cells, people have given up on that prematurely and then it will be back.
And so from an expanded, like I’m five perspective, what exactly would that mean? The, I can’t even say the word all again. Nucleotide chemistry
Is basically using DNA, right, as a double helix. So there’s two complimentary strands and it’s the idea of basically pulling those two strands apart and then using the secret specificity of one side to make a drug that will target the other side. So it allows you to, you know, say, choose a gene anywhere in your genome and make a short stretch of DNA that’s chorus. And like I said, something chemically similar, that’s involved a new drug that makes it perfectly targeted to hit that one gene. And you can do that. For instance, if you could successfully target these areas, the way people have envisioned you could take, say a cancer cell that has a mutation and target only those cells and kill them all. You can take a mitochondrial DNA mutations that when people have those mutations, they get a severe disease, but it’s, their cells have a mix of regular mitochondrial DNA and mutated mitochondrial DNA. And you could just eliminate all the mutated ones and turn them back to normal. So I think that potential to just be so specific about where you will have effects is just, you know,
Central of that. If I’m understanding correctly, it’s kind of silly. I mean, again, you know, I like to dumb things out as much as possible. It’s if there’s an issues with your cells, it’s basically selectively going through and, and switching out the bad DNA with the good DNA so that it fixes the cell, right.
And the targeting mechanism of using the DNA itself as the target is just generic, right. That doesn’t even determine what you have to do when you get there. Right. You could bring something along that would kill the cell. You could bring something along that way, try to fix that mutation. Or you could just try to clamp down on that DNA. So it doesn’t work very well in the case of something like mitochondria, where then it would give an advantage to the wild tech copies that aren’t used carrying. And they would just overgrow.
It’s super fascinating stuff. Joseph, thank you so much for joining me today. And I learned a ton. You really opened up my eyes to a lot of stuff I was very confused about. So really appreciate you taking the time and hopping on this call. Well, thank you.
If you got this far, I just want to say thank you so much for listening. If this was all interesting to you, I’d love to connect on Instagram and hear your feedback. I’ll also be posting clips from the latest episodes as well as anything else. I find it interesting about the biotech industry. You can find me on Instagram at simple biotech. And if you’re interested in the companies that I’m looking at and the companies that I’m excited about, connect with me on angel firstname.lastname@example.org slash James’ rule.