The Podcast After the Podcast: More on Age Reversal with Dr. Greg Fahy
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We’re doing a deep dive into NAD, a molecule that has received a lot of attention but still confuses many of us, clinicians included. My guest today is able to unpack the complexities of NAD in a way you’ll find extremely illuminating and useful. I’m excited to have Dr. Greg Kelly, Senior Director of Product Development at Qualia, back with us, explaining how NAD is foundational for energy, longevity, and overall cellular health. Dr. Kelly brings clarity on how NAD influences mitochondrial function, DNA repair, and pretty much all of the hallmarks of aging. Yet, problematically, it declines as we age. This episode will cover different NAD compounds, how deficiency might present clinically, and how to measure NAD reliably. Have a listen and get ready to expand your understanding around this essential compound. ~DrKF
How does boosting your NAD+ levels impact aging, energy, and cellular health? In this episode of New Frontiers, Dr. Greg Kelly, author, naturopathic physician, and Senior Director of Product Development at Qualia, returns to explore this crucial yet often overlooked molecule. NAD+ plays a key role in mitochondrial function, DNA repair, and cellular resilience. We’ll dive into the latest research behind Qualia’s NAD+ product and its precursors, revealing how they support longevity and overall vitality. With insights from Qualia’s clinical studies, you’ll discover how optimizing NAD+ could improve everything from energy levels to long-term health outcomes. If you’re looking to harness the power of NAD+ for better health and well-being, this conversation is a must-listen.
In this episode of New Frontiers, learn about:
- The Role of NAD in Aging: Discussion on how NAD impacts key hallmarks of aging, including mitochondrial dysfunction and DNA repair, and why it’s crucial for longevity.
- Cellular Stress and NAD: The impact of cellular stress on NAD levels, and how NAD+ depletion can lead to dysfunctional cells or premature senescence—affecting overall health and vitality.
- NAD and Mitochondria: The critical relationship between NAD and mitochondrial function—how sufficient NAD supports energy production, ATP synthesis, and even hormone synthesis (e.g., estrogens, testosterone, cortisol).
- Magnesium’s Role in ATP Production: The importance of magnesium as a co-factor in over 300 enzymatic reactions, stabilizing ATP production, and supporting NAD functions for optimal energy and cellular health.
- Gut Health and NAD Metabolism: The importance of the gut microbiome in metabolizing NAD precursors—how dysbiosis can affect NAD efficiency, influencing aging and metabolic health.
- NAD’s Impact on Mental Health: Potential benefits of NAD for mood regulation, brain fog, and cognitive clarity—why increasing NAD+ levels can improve mental resilience and emotional well-being.
- COVID, Long COVID, and NAD: The impact of COVID on NAD levels and cellular stress, and how NAD+ supplementation may support recovery and mitigate long-term effects like brain fog and fatigue.
- Pellagra and NAD Deficiency: Discussion on how a lack of NAD can present in clinical practice, including symptoms like fatigue, irritability, and gastrointestinal issues, and how supplementation can correct deficiencies.
- The Benefits of NAD+ Precursors in Clinical Practice: Feedback from clinical trials and patient reports showing improvements in energy, sleep, and mood with NAD+ supplementation—why it’s a reliable addition to treatment protocols.
- NAD and Inflammaging: The role of NAD in combating chronic low-grade inflammation associated with aging, and how NAD depletion can accelerate age-related diseases by fueling inflammatory processes.
- Timing and Dosing NAD: Recommendations on the best timing for NAD supplementation based on circadian rhythms—why taking it in the morning could optimize metabolic and mitochondrial function.
- Magnesium and NAD Synergy: The importance of magnesium in maintaining NAD function, ensuring efficient energy production and supporting cellular repair mechanisms that are critical for long-term health.
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Dr. Kara Fitzgerald: Hi everybody. Welcome to New Frontiers in Functional Medicine where we are interviewing the best minds in functional medicine. And of course, today is no exception. I am once again with Dr. Greg Kelly. Let me tell you his background and we’re going to jump into what will be a great and really first time conversation on all things NAD (nicotinamide adenine dinucleotide). And I will just add, Greg, in case I forget, there’s not a day that goes by that I don’t get at least one question on NAD. So this is an important and timely and really overdue topic on our podcast.
Dr. Kara Fitzgerald: Dr. Gregory Kelly is VP of Product Development at Qualia Life. He’s a naturopathic physician and author of the book Shape Shift. He was editor at the journal Alternative Medicine Review, where I first met him, and has been an instructor at University of Bridgeport in the College of Naturopathic Medicine. He taught advanced clinical nutrition, counseling skills, doctor-patient relationships, and he’s actually done a lot of stuff over there.
Dr. Kara Fitzgerald: He’s published hundreds of articles on natural medicine and nutrition. He contributed three chapters to the seminal Textbook of Natural Medicine. He’s got more than 30 articles indexed on PubMed. His areas of expertise include nootropics, anti-aging and regenerative medicine, weight management, sleep, and the chronobiology of performance and health. Greg, it’s really great to have you again on New Frontiers.
Dr. Greg Kelly: Thank you for having me. It’s always wonderful to get to talk with you.
Dr. Kara Fitzgerald: And today we’re going to talk about all things NAD. But I do actually, before we jump into this, want to let people know that there’s a discount. There’s actually a really, really great savings opportunity if you want to try the Qualia NAD. So just go to QualiaLife.com/DrKaraFitzgerald to try their NAD product. And we’re going to talk about how Greg and his team formulated it. You can get 50% off of it and then if you use the code DrKaraFitzgerald, on top of that, you’ll get an additional 15% off at checkout. It’s a great deal and a great way to get in to check it out and do your own experiment on NAD. So why don’t you just, first of all, introduce anybody who doesn’t know exactly what NAD is. And start by just defining the acronym.
Dr. Greg Kelly: Yeah, so NAD stands for nicotinamide adenine dinucleotide. When I would have taken biochemistry in 1993 or so, NAD would have been something I learned about. It’s always been known to be an instrumental part of physiology going back to the late ‘30s with the deficiency disease, pellagra. The original people sorted out that the end part of that nicotinic acid, or niacinamide, was the deficiency that led to that syndrome. And we’ll talk maybe a little bit about symptoms of that. But I think what really changed was somewhere in the late 1990s and early 2000s with the big names, people like (Leonard) Guarente and (David) Sinclair and (Charles) Brenner, that started to find that NAD had these other, what are often called “consumption roles” that were beyond redox reactions– And redox is NAD+ and NADH kind of flipping back and forth is what that means— And with these consumption roles, it was found that to activate enzymes called sirtuins or enzymes called PARPs– PARPS have to do with DNA repair— the NAD+ molecule was consumed and was a kind of fuel for these enzyme systems that tied into longevity. I think that’s really what led to the rebirth and interest in NAD.
Dr. Kara Fitzgerald: Well, let me just circle because I just want to tease something out. I’m a naturopathic physician and probably anybody who has training in any form of clinical medicine has encountered medical biochemistry and knows about the redox of NAD, and oxidative phosphorylation, I guess, perhaps one of the most famous roles for NAD. In that setting it’s recycled over and over again. A hydrogen is added and subtracted and so on, and in so doing, it’s fundamental to using oxygen to make ATP. Kind of incredible. But it’s recycled and you’re saying— I just want to make sure— In these other roles, in these anti-aging roles, in this area that we’re now really clearly seeing NAD declining with age, is it actually spent or is it recycled?
Dr. Greg Kelly: It would be recycled to some extent.
Dr. Kara Fitzgerald: Okay.
Dr. Greg Kelly: So what would happen– we’ll just take the sirtuin enzymes– they would consume the NAD molecule as part of that and it would then be broken apart into Niacinamide, NAM is the abbreviation for that, and then the NAM can be recycled or eliminated. The other big chunk of the molecule can also be recycled, but it’s consumed in the sense that it’s broken apart. Just to give a frame of reference, you mentioned the oxidative phosphorylation, making ATP a carrier for electrons, and riboflavin does that also with the FAD and FADH. The daily value for riboflavin is a little less than two milligrams and for B3, it’s way higher. It’s 16, and that’s probably because instead of just toggling back and forth in the oxidized and reduced state, the niacinamide NAD molecule is actually consumed and broken apart. And that salvage is less efficient than just flipping back and forth.
Dr. Kara Fitzgerald: You touched upon the scientists who sort of started to champion it and characterize its roles in the aging journey, the aging phenomena. And we think about aging sort of with the hallmarks of aging frame of reference, which we actually talked about on our last podcast, so we’ll make sure that’s linked in the show notes. So again, where’s NAD in the hallmarks?
Dr. Greg Kelly: Yeah. So stepping back, I think of NAD+ as having three main roles. We touched on two, the first being making ATP. The second, we touched on some of the consumption roles, the DNA repair. Sirtuins have a lot to do with metabolic stress response. And then NADP, NADPH, that’s about building molecules. So that would be involved, as an example, in glutathione synthesis. The third major role is about cellular resistance to oxidative damage and others. So I think of those as three main jobs, but then there are many, many minor jobs.
Dr. Kara Fitzgerald: Right.
Dr. Greg Kelly: And in terms of the hallmarks of aging, there’s some thought that NAD plays at least some indirect role in all twelve of them. But for sure, like direct roles, mitochondrial dysfunction. So with mitochondrial dysfunction, what you would classically see also is NAD+ levels inside mitochondria decreasing with age. DNA repair is another one. And so the PARPs, those enzymes that NAD+ provides the fuel for, are directly tied into that DNA repair thing.
Dr. Greg Kelly: Cellular senescence is interesting because one of the main things that Charles Brenner would say about NAD, if you pressed him about what does it really do? He’s said to me, it’s about metabolic stress. And when cells are stressed anyway, metabolically or otherwise, you kind of have a few different options. But one is that they get tougher, right? They build up their defenses. Two, is that they are damaged to some extent, right? DNA is damaged, proteins get misfolded, so autophagy, then, would be the repair mechanism. Or, there’s more damage and they become unrepairable, so a senescent cell. And I think within some of the research community now, it’s pretty widely established that NAD depletion would be the tipping point for cells to go through one of those two doorways.
Dr. Greg Kelly: So if they’re depleted in NAD, they’re much more likely to become senescent cells, as an example. And then senescent cells rely on NAD to fuel their SASP, right, the pro-inflammatory things they secrete, so they tend to be voracious consumers of NAD, and that’s the senescent cell connection.
Dr. Kara Fitzgerald: Oh, interesting. So the fate will be increased vulnerability to turning into a senescent cell, but once done, it’s going to steal all the NAD. So there’s like just two layers of good size problems.
Dr. Greg Kelly: Correct. Yeah, and part of the SASP is that it’s pro-inflammatory. It’s kind of that inflammaging piece and it’s why NAD is thought to, in part, plummet as we get older because that inflammation is just consuming more of its share with less leftover to drive DNA repair and the sirtuins, as an example. Dysbiosis is another interesting one because there’s now quite a bit– I said we get to the pellagra deficiency. So, the three D’s would have been what I learned about back in naturopathic school and biochemistry. And the three D’s stood for diarrhea, but with B3, diarrhea, constipation, indigestion, all kinds of things subclinically can be related to poor B3 status.
Dr. Greg Kelly: The second D was dermatitis, right? Like a really specific type of scaly rash. All the B3s are really important for skin health. And the third D, they would say dementia, but it was used in a different way than we use that term now. It had to do with mood, irritability, nervousness, but also loss of memory, confusion, brain foggy kinds of things were all bundled in that third D. And so, getting back to that dysbiosis with aging, the GI was one of the classic indicators of B3 issues. This has largely been preclinical, but there is a NR (nicotinamide riboside) twin study where they looked at the microbiome and each of the different forms–
Dr. Kara Fitzgerald: Nicotinamide riboside, yeah. Okay, go.
Dr. Greg Kelly: Correct. It seemed to have an impact on the gut microbiome.
NR in an animal model actually rejuvenated stem cells in the gut. So even before these forms of B3 or NAD+ precursors are absorbed, they potentially have a really big impact on our digestive system and the gut microbiome.
Dr. Kara Fitzgerald: And I just want to add the fourth D. Isn’t it? Death.
Dr. Greg Kelly: Death is the fourth, yeah, if you don’t correct it.
Dr. Kara Fitzgerald: Maybe you were going to add that in later.
Dr. Greg Kelly: Hopefully no one listening will get there or even close.
Dr. Kara Fitzgerald: Yeah, nobody’s going to get there from– But you know, it makes me think of– It’s a molecule that’s in incredibly high demand. I always think of gut issues, skin issues, in combination, because there’s massive cell turnover going on in both of those organ systems. And so they would show up first and prominently, and they’re just high-energy demanding tissues, and it stands to reason. And then I just remember from biochemistry as well, you know, tryptophan being involved in making NAD and maybe there’s a connection there to what’s happening in the central nervous system with regard to mental health.
Dr. Greg Kelly: Yeah, so this would be the general estimate. It would take about 60 grams of tryptophan to build the equivalent that one gram of, say, flushing niacin would build of NAD. So it’s like a 60:1 ratio, but that’s an average. I’ve seen some studies that women are a little less efficient at using tryptophan than men, but ballpark, it takes a lot of tryptophan to accommodate, but you could with enough, correct a B3 deficiency. At least in theory.
Dr. Kara Fitzgerald: Right, right. Well I guess I was more thinking about maybe the secondary role. I was just sort of waxing, incorrectly, on what the mechanism might be for driving the so-called dementia piece.
Dr. Greg Kelly: Yeah. And I’m sure it ties in because most tryptophan will be funneled into the serotonin pathway, relatively small amounts into what’s called the kynurenine pathway, which is what leads eventually to NAD+. Though I might actually have that flip flopped, but anyways, there’s two enzymes that would be the first step and either one can get the ball rolling. One of them is very, very much upregulated by acute inflammation. So when there’s any kind of trauma or inflammation, our cells try to make a lot more NAD+ starting from these precursors, whether it’s the NR that I mentioned or tryptophan as you mentioned.
Dr. Kara Fitzgerald: All right. We could keep going down this path because probably this is one of the ways that we’re just less efficient or we’re driving it towards some inflammatory response as we age. Maybe this is one of the buckets. But all right, so you left off with talking about the gut . Did you want to move through any of the other hallmarks to just link it to NAD?
Dr. Greg Kelly: Yeah. Another one is chronic inflammation. As I mentioned, that will deplete NAD for a variety of reasons. Then other ones, like telomere attrition, are more indirect, but there are others that have to do more with nutrient signaling and intracellular communication. Those are two other ones. Sirtuins and PARPs would be in that intracellular. Autophagy, again, would be a little bit more indirect than direct. The big ones for sure would be DNA, mitochondrial dysfunction, and intracellular signaling. These would be rock solid. All the other ones are a little bit more indirect. And then the other thing, and this has been observed in organisms all the way up to and including humans, is our NAD levels inside cells goes down progressively as we get older and that was one of the links, I guess, to building the case for why NAD becomes important.
Dr. Greg Kelly: I just saw, literally this morning, a link to a new study that was in a worm model, [note: the study was actually done in oocytes], right? A lot of the basic biochemistry of aging looks there. And what they found is that every way of building it— whether you started from nicotinamide, nicotinic acid, tryptophan– that all of those enzyme systems were less efficiently functioning as these organisms got older. And that maps to what I’ve seen in other organisms as well. We just become a little less efficient in the enzyme systems that make this really crucial molecule as we get older.
Dr. Kara Fitzgerald: I have two thoughts on what you’ve said. One is that we use it in– I was just doing a little review before you and I hopped on this podcast and it’s a player in over 500 reactions. We’re using it all over the place in incredibly important reactions, and so if we’re petering out on our ability to make it, it’s just going to be really profound– the potential influence of the deficit of this molecule.
Dr. Kara Fitzgerald: And the other thing that I was thinking of is this. You’ve brought up mitochondria a few times already, but again, in my little preview, just getting my brain in the space of thinking about NAD– It’s a player in not only the electron transport chain and cellular respiration, but it’s all right there in the Krebs cycle and elsewhere playing incredibly important roles in the mitochondria. I mean, if you wanted to the top 10 mitochondrial molecules , it’s got to be just right up there.
Dr. Greg Kelly: Yeah. I mean, ATP is probably number one, and I heard it estimated that we make our body weight in ATP every day because the turnover of that molecule is just so ridiculously fast. And I’ve seen estimates for NAD that we probably make and remake somewhere in the vicinity of 10 to 12 grams of the NAD molecule every day, which is a lot, right? When you think—
Dr. Kara Fitzgerald: Just cycling it.
Dr. Greg Kelly: Yeah, and it doesn’t spin quite as fast as the ATP molecule, but we are using, recycling, and remaking it quite a bit through the day just for ourselves to do all the jobs for mitochondria. And I’m sure I never learned this in biochemistry or naturopathic school, but mitochondria have a role in making steroid hormones, right? The estrogens and testosterones and cortisol. So, mitochondria do crazy important things beyond just ATP.
Dr. Kara Fitzgerald: What is its role in making steroid hormones? Is it actually providing precursor molecules or providing the energy? I mean, what is it?
Dr. Greg Kelly: That’s a great question. I would probably be hesitant to answer because I might misanswer, but I think it actually is foundational in making the molecule.
Dr. Kara Fitzgerald: That’s fascinating. Well, and all of those molecules require a bunch of energy. But that’s a lot, you know, 500 enzymatic reactions requiring some form of NAD. When does our ability to produce it start to slow down? And whatever this age is, in your opinion, when does the aging phenomenon begin and do you think there’s an association with this molecule?
Dr. Greg Kelly: Yeah. I think the person that’s done the most testing is the lab, Jinfiniti, because they’ve been doing their finger stick, which is just measuring whole blood. One thing that would be for sure true is that it would be a different rate of decline in different tissues.
Dr. Kara Fitzgerald: Okay.
Dr. Greg Kelly: I think would that would be fairly agreed upon. What he would see, at least in whole blood, is a decade by decade decline so that in the early 20s it would be at its peak for most people, and then each decade it would get lower, in a number of tests that he’s done. I saw something recently, again in an animal study, but a lot of the animal studies is where we build our knowledge, that NAD was tied to ovarian aging and keeping that higher allowed fertility to occur later in the animal’s chronological lifespan. So in that tissue, NAD is probably declining faster than in other tissues for women.
Dr. Greg Kelly: Using muscle tissue as an example, this was a human study [note: the study actually looked at RBC levels] and they measured younger people, older people, and then two different types of exercise: sprint-type exercise or more endurance. The older individuals that exercised maintained higher levels than the sedentary ones, with sprinting being better than the long distance running. And they still declined with age. They maintained more, but they were still ramping slowly downhill over time. I’ve done my own NAD blood test several times, and if I’m not doing something to intentionally give precursors to build NAD, my levels are just suboptimal based on how Jinfiniti would view it. They set their optimal, what the healthiest young 20, to say 25 year old adults would have, and no matter my exercise, sleep, all the things I would do to stay healthy, my levels would be below his optimal without paying attention to some way of supporting building it.
Dr. Kara Fitzgerald: That’s really fascinating. Jinfiniti is the lab that you’re using. I’m actually going to start measuring in practice. And you know what? You’re not in clinical practice right now, are you?
Dr. Greg Kelly: No
Dr. Kara Fitzgerald: I’m going to actually track it with hormones and some of the associated compounds we’re talking about and see what I notice and then when I supply precursor compounds– I mean, have you observed that in yourself? Have you observed a favorable change in other labs? And then we should talk about the clinical piece too.
Dr. Greg Kelly: When I’ve measured NAD+, my experiment has been, all right, let me go off anything that has a precursor– anything that has nicotinic acid or niacinamide or the NRs, NMNs, or a lot of tryptophan– for usually 30 days to see what kind of baseline I have. Then I’ll do an intentional stack of some sort. So Qualia NAD+ would have been what I did and I’ll do that for three to four weeks and then reassess. Compared to my baseline without supplementation, the last time I did it, my NAD+ levels went up 149%. So a big change. And at least in the Jinfiniti test, smack dab in the middle of what he would consider the optimal range.
Dr. Kara Fitzgerald: Wow. Okay. What did you take? What was your dosing structure?
Dr. Greg Kelly: Yeah. I just took two capsules of Qualia NAD+, and I was meticulous. I did that first thing in the morning, every day.
Dr. Kara Fitzgerald: Okay, two caps in the morning. You don’t have to divide it. Cool.
Dr. Greg Kelly: And, that was sufficient. And we can get a little bit into timing, but I do believe that the best time to take these NAD+ precursors is first thing in the morning or with breakfast, but sometime early in the day.
Dr. Kara Fitzgerald: Okay, all right. That’s great. We’re digressing a little bit and I know you’re doing clinical research and doing all sorts of really amazing stuff with humans. I’m going to stay in touch with you as I bring this. I have a micro clinical practice, but I’m just going to start looking at this, Greg, a lot more carefully than I have and I appreciate you just really bringing it top of mind. It’s just fascinating.
Dr. Greg Kelly: Yeah. And there’s more recently Chromadex launched a finger stick kit as well, which I think you can purchase through Fullscript, for listeners that have access to that.
Dr. Kara Fitzgerald: Cool, good. Okay, all right, fabulous, yay. This is changing my practice. If any of my patients are listening, get ready. All right, how does it show up? How might somebody suspect NAD could be— Well, actually, the thought that I wanted to share before you get into that is just thinking about declining VO2 max levels, this decade to decade drop. I mean, you can track a lot of the aging phenomena sort of in that decade by decade, but it makes me think of NAD. So with that in mind, how does it show clinically? Who’s going to be flagged?
Dr. Greg Kelly: I tend to go back to the three D’s and then think lesser of those issues. But the thing we see on a positive, and so far we’ve done a pilot study, a recently completed placebo controlled study, and the things that show up the most commonly is feeling like there’s more energy / less fatigue, and mood types of things. So, whether that’s apathy, nervousness, irritability, a lot of the things that become more extreme in that D (dementia) category of that. Energy would fit in there as well. One of the more consistent things is feeling like sleep was more rejuvenating. So not necessarily sleep showing up on your Oura or wearable as I had more deep sleep, but not feeling as much like you’re struggling to get through the day. Your sleep just did a better job at restoring you.
Dr. Greg Kelly: So it kind of gets into energy, but there’s a question that’s very related to feeling like your sleep was restorative that we use in our questionnaires and evaluation that always comes out strong in the people taking the Qualia NAD+. The other thing I would generally think of, and to me this goes back to Brenner, right? His story is like, this isn’t that you should feel it, though a lot of people seem to. It’s about our cells having more of this as a resource when they get stressed. The way I would frame it if I was working with someone is, if you feel anything from it, that’s the cherry on top.
Dr. Greg Kelly: The goal is the unfelt. That when our cells get stressed, they have this resource to draw on so that they can— and I think of it as door one through four, right? Door number one is what we want. They’re stressed, it’s a hormetic stress, or they’ve got enough resilience that they respond and adapt and they’re tougher for the experiment, right? Door number two is, stress was too much, they took on some damage, but it’s repairable. So that’s a better choice than door number three, which is becoming a zombie cell, right? Like now they’re unreparable or door number four, it’s so stressful they go right into apoptosis. So to me, the most fundamental reason that we would want to make sure that we have adequate NAD+ stores is that when cellular stress happens, which in our world it happens a lot and sometimes unpredictably, that they can march through door number one or two and not go through three or four.
Dr. Kara Fitzgerald: You know, I consistently used NAD as a part of my stack a few years back, ad then I kind of forgot. I guess I just tend to do less controlled N-of-1 experiments on myself. And yeah, it feels fundamental. I mean, would you say that it’s fundamental like we think about magnesium?
Dr. Greg Kelly: Yeah, and magnesium is super interesting. One of the studies– If it’s okay, I’m going to go off on a magnesium tangent.
Dr. Kara Fitzgerald: Go, go.
Dr. Greg Kelly: One of those studies was James Clement, who’s a really famous name in the researching longevity space and was the lead author on a study called The Plasma NAD+ Metabolome Is Dysregulated in “Normal” Aging. Plasma is outside of blood cells, you know, whole blood is inside, and there’s a distinction there that is a little bit important. The bottom line is no surprise in that study, compared to younger people, they evaluated the older people and they had less NAD+ in the plasma. But some other molecules in that metabolome— and for listeners, the metabolome just means all of the different molecules with an N in it. So NR, NMN (nicotinamide mononucleotide), nicotinic acid, the NADH, the NADP that we talked about. The whole collection of molecules.
Dr. Greg Kelly: As an example, NMN was actually normal levels in the older group in plasma compared to the younger group, but NAD+ was decreased, which then you’d think enzymes are the issue. At the time I remember looking and thinking that this makes no sense. Why are some of the molecules what would be theoretically normal and other ones are decreased? And one of the things that led me to was looking at just a biochemistry drawing and then a couple of different drawings and eventually finding two drawings that had ATP drawn in the biochemical pathways and they didn’t agree. They each had ATP in some of the same spots but not in some of the others.
Dr. Greg Kelly: Eventually I looked up all of those enzymes and it turns out that literally every single enzyme in the metabolome pretty much requires ATP. The interesting thing about ATP is that NAD is required to make ATP, but you cannot make NAD and you can’t get good flux through the entire metabolome without ATP. And we know because of mitochondrial dysfunction, ATP goes down with age, right? So I think that ATP piece of playing a role in keeping the flux through this complicated network of molecules is just underappreciated. So that brings us to magnesium.
Dr. Kara Fitzgerald: Yes, say it! I know this.
Dr. Greg Kelly: Because whenever you see ATP in any drawing, it’s usually left off, but in cells, it’s always an ATP magnesium complex.
Dr. Kara Fitzgerald: I know this because I was the lead author on the elements chapter in the Laboratory Evaluations For Integrative And Functional Medicine textbook, and we included a figure of what ATP is doing. It’s actually hanging onto the phosphates to keep them intact. And then as you bust them off, magnesium takes off and it recycles, and just like NAD, you recycle a massive amount of it in that journey to make ATP. But that’s what magnesium is doing. It’s right in there kind of hunkering down those wildly energetic phosphate groups as they get clumped up for energy, which I think is so cool. So yeah, you link them both intimately together. Right? You just need them. Good.
Dr. Greg Kelly: Yeah, and I guess getting to your question, is this as foundational as magnesium? And it’s like, yes. With magnesium, this is one of the reasons that it’s also foundational and, you know, hundreds of other reasons that magnesium is, but a lot of those are because of pathways where it’s interacting with the ATP molecule to facilitate it.
Dr. Kara Fitzgerald: Yeah, that’s nice. It almost causes a pause. It’s just like, let’s take in how important these compounds are and the fact that we’re just not making them as well. You know, as you were dialoguing around how that deficiency will present on the aging journey, it just made me wonder about COVID, you know, and COVID survival and maybe even long COVID and how these molecules are essential to have on board for our ability to respond.
Dr. Greg Kelly: Yeah. Viral stress is just a different type of stress for cells, right? The same principles are going to apply. When a cell is stressed, if it has more resources, it’s going to typically do a better job at being resilient to that stress and if it doesn’t, then it isn’t. I do know there’s been both preclinical and a little bit of human studies that have looked at COVID and I think NR is what’s been looked at more specifically. But yeah, it’s critical. I’ve seen a few animal models of things that would be more like traumatic brain injury, right? Something where inflammation goes up and if there’s enough, even of niacinamide, available locally in the pool, then that region of the brain will perform better. It’ll adjust to that stress quicker and bounce back better.
Dr. Greg Kelly: So that’s why I go back to it’s about being prepared for stress. The subjective benefits we get, those are the icing on the cake, cherry on top type of thing for me. I want to make sure that my cells are going to be as resilient as possible and having adequate resources is a big part of that resilience game.
Dr. Kara Fitzgerald: Right. What form is in the Qualia NAD+ product?
Dr. Greg Kelly: We do a blend of nicotinamide riboside, nicotinic acid and the nicotinamide, also known as niacinamide. And partly we do that because there’s a couple of different ways to make the NAD+ molecule. We’ve mentioned the tryptophan and that’s a long process. I think there’s 11 or 12 enzyme steps to go through and it’s inefficient. But nicotinic acid, the flushing niacin goes through NAD+ in something called the Preiss-Handler pathway, so it has a unique entryway into that. It is something that for sure builds the NAD+ molecule. And then NMN, nicotinamide riboside (NR) or niacinamide are all part of what’s called the salvage pathway. All of those at some point go through the same NMN to NAD+ enzyme, so it’s just where in that group of molecules they plug in.
Dr. Greg Kelly: But NR and NMN are pretty big molecules, meaning that in our diet, as an example, most animal products will have some of many molecules from the metabolome, right? They’ll have NAD+ they’ll have the NADH, they’ll have the NADP, et cetera. And it’s been pretty known for decades and decades that enzymes in our digestive tract largely then break down the bigger molecules step by step to smaller molecules like niacinamide. What’s interesting is with NR and NMN, I’ll sometimes see the different camps argue about which is better.
Dr. Kara Fitzgerald: Yeah.
Dr. Greg Kelly: One of the arguments invariably comes to, well, NMN is too big to get into cells. And that would be true in a passive sense, but if there’s a receptor for it, it can take it in. Outside of our digestive tract, neither of those orally get to remote tissues in one place. Those studies have been done many times. But they’re all efficient at building the NAD+ molecule in remote tissues. One of the things I think that’s crazy underappreciated is the gut microbiome. The different forms (of NAD) probably slightly feed different organisms because they’re going to break apart the molecule and feed on it.
Dr. Kara Fitzgerald: Sure.
Dr. Greg Kelly: One of the interesting things, super premature to say how it would translate to humans, but I think there’s been two rat studies so far that if the gut microbiome doesn’t break NR down into the N and the R and then convert the N part from niacinamide into nicotinic acid, liver NAD+ levels don’t go up. My suspicion is there’s a gut microbiome important piece to how efficient any of these different molecules are at building NAD+ an individual. It’s rare in the human studies I’ve seen on NR and NMN, but when they’ve given each individual’s data, it’s really variable. Say on average, NR at 300 milligrams increases NAD 50%, there’s going to be people way less than that and people way more. Some people like me with the Qualia NAD+ that had close to 150% increase and others much less. My guess is that some degree of that is microbiome driven.
Dr. Kara Fitzgerald: Yeah, hence your multiple forms. That’s super smart.
Dr. Greg Kelly: Yep. Yeah. Because what would also have been done a while back is that certain tissues, some would prefer nicotinic acid to make NAD+. Some might prefer niacinamide. So, one of my, I guess, principles I approach, is let’s not try to block and tackle and think that we’re smarter than cells. Let’s give them more options to do what they want to do. I tend to believe systems with more options available end up making better decisions and better outcomes over time. Rather than just say, this one form is the best and that’s all we need, let’s give options for making it and let different tissues sort out their preferences.
Dr. Kara Fitzgerald: Make the decision? Well, and to your point around the microbiome, it may act on the different structures, depending on the microbiome that you carry, it’s going to have a different effect, likely, on the different structures. It makes sense to me that you could get a very different bang for your buck given microbiome and perhaps cellular demand, out of individuals. I mean, there were similar data looking at the absorption of omega-3s. It’s wildly variable. I mean, really, the only way you’re going to know if you’re getting people to a reasonable level is to test.
Dr. Greg Kelly: Mm-hmm.
Dr. Kara Fitzgerald: You guys do not have NMN in your product?
Dr. Greg Kelly: Yeah. As we were making Qualia NAD+, the FDA decided that NMN was no longer a dietary supplement.
Dr. Kara Fitzgerald: Oh right. Okay. Yeah.
Dr. Greg Kelly: And so because of that, we decided to not include it. But NMN, like any of these things, will absolutely increase NAD+ levels in many, many people. It’s a good molecule. I think sometimes, like I said, there’s a tendency to get into debates about which is better. Well, they’re all good. I think what makes the Qualia NAD+ somewhat distinctive, in addition to us studying it and knowing that it works…
Dr. Kara Fitzgerald: Yeah, and doing clinical research on it.
Dr. Greg Kelly: Is that there is magnesium and there’s low amounts of the other B complex vitamins because directly or indirectly they’re all involved in making ATP. As I mentioned, ATP is just so fundamental to making the NAD+ molecules that I think it’s smart to support that as well.
Dr. Kara Fitzgerald: And you’ve got an NR, so you’ve got the ribose molecule that will also support ATP. I just wanted to go back to the study that you referenced, and we’ll link it in our show notes everybody, around the NAD metabolome and how older adults had plenty of NMN. What does that mean? It makes me think that perhaps having a selection of other molecules makes sense in that regard as well. Am I thinking correctly or what do you think?
Dr. Greg Kelly: Well, partly they measured plasma and loosely, just think of there being intracellular and extracellular NAD metabolomes.
Dr. Kara Fitzgerald: Okay, sure.
Dr. Greg Kelly: The enzymes inside cells aren’t all replicated outside cells, so that study may not exactly map to what would happen intracellularly. But in that particular study, yeah, like NAD+ levels were lower in plasma in the older group, but certain other things weren’t. They were more consistent with what the younger group had, NMN being one. So right away then I think, is that enzyme that can turn NMN into NAD+ extracellular? And the answer is yes and that enzyme is activated by ATP, which there’s much less ATP outside of cells. Virtually none, right? Unless the cell is damaged, in pain, or something where it’s like, effusing ATP out, right? The main reason I brought that up is it was what led me to this underappreciated role of ATP. But inside cells, ATP would be expressed, and so my guess would be the metabolome, if it was measured inside red blood cells or muscle cells, would look different with aging than in plasma.
Dr. Kara Fitzgerald: Interesting. Sure. Okay, all right. Let’s see what else I want to ask you about. I guess I have two questions. One, any other pearls to share from your clinical experience, your own experience? And then let’s talk about dosing and timing. So you’ve worked on some research, you do your own N-of-1 research, and you’re pretty much always in a research study. And then I want to make sure we circle back to dosing and timing.
Dr. Greg Kelly: I think the one thing I periodically will hear someone say, you know, is that you have to be careful of not making too much NAD +. I literally have not seen that to be an issue in any of the NAD testing we’ve done. Jinfiniti, the same. I asked him at one point. So I think there’s always too many checks and balances in physiology for that. Another thing I see misrepresented, a fair amount is that niacinamide will inhibit sirtuin s and so that’s a bad form of things. The reason I think that’s disingenuous is several fold. One, you would know end product inhibition, right? Any product of an enzyme, if it builds up, will shut down that enzyme, right? That’s just kind of basic biochemistry. And in vitro, in a cell culture, you can do things that would cause niacinamide to build up enough. But in cells, it either gets salvaged, and then the pathway goes niacinamide to NMN, NMN to NAD, or it gets methylated and eliminated. So methylation is a big way that we remove excess vitamin B3. So in a living system, that becomes a moot point, right? Niacinamide, if it builds up, then one of those two things happens.
Dr. Greg Kelly: And the other thing is that no matter how we build NAD+ the first time, when it gets consumed, the leftover is always niacinamide. So if we built it from NR as an example, and measured niacinamide in the blood, we would see it go up, even though we gave NR. If we gave NMN, we would still see niacinamide go up. If we gave flushing nicotinic acid, which is different than niacinamide, we would still see niacinamide go up because no matter how you make NAD+,
Dr. Kara Fitzgerald: All points lead…
Dr. Greg Kelly: …all points eventually lead in the consumption role to niacinamide going up. It always saddens me when I see smart people say things like that, often with an agenda right, because they’re promoting their NMN or NR or something as better. That said, the NRs and NMNs in my testing, work better than just niacinamide for more reliably promoting at least red blood cell increases in it.
Dr. Kara Fitzgerald: Okay, okay, cool. All right, and using Jinfiniti. Okay, so any feedback from your clinical trials or your own N-of-1?
Dr. Greg Kelly: Yeah. So, my own N-of-1, when I did it, I wouldn’t say that I noticed– My sleep’s good, anyway. For listeners, I’m 62 and I have no issues sleeping. It takes me three or four minutes to fall asleep and I usually sleep through the night. So I didn’t notice sleep, which is a big thing anecdotally that shows up, as I mentioned. My energy is fine, so I honestly didn’t notice anything different in my N-of-1 subjectively, but in our studies, typically we’ve used the SF-36 by Rand (36-Item Short Form Survey) a lot in that. That’s a general health questionnaire that has eight different buckets, one’s energy and fatigue. We’ve consistently seen that improve and we would think of that as a secondary endpoint. So we haven’t always been powered to see a statistical significance, but we always see a better increase in that subscale than we do in the placebo group.
Dr. Greg Kelly: Emotional well-being or mental well-being is another subscale that’s the same. We consistently see a much better improvement in the questions related to that. There’s another one that has more to do with how emotional issues impact your ability to work and get through your day. We also see a consistent, much better increase in that one as well. The pain, physical- those are usually better than placebo, but not quite as dramatic. So energy /fatigue and emotional, by far, are where I’ve consistently seen it show up subjectively. And then as I mentioned sleep, but more sleep in the context of feeling like you’re more rested as you get through your day. And then a piece I’ve heard but we’ve not tried to study, is recovery from exercise quicker. There’s a lot of anecdotal reports of people just feeling like they bounce back quicker, especially as they’re getting older from exercise if they’re doing things to boost NAD+.
Dr. Kara Fitzgerald: Cool. Alright, so with the molecule you’re really not supposed to feel anything with it. You guys, people are consistently feeling pretty great in some key areas. I mean, I think 70% of patients seeking out medical care, the complaint is fatigue. It’s like a top complaint. It’s probably greater than that. And how long was your study out of curiosity? When did the people notice these?
Dr. Greg Kelly: Our studies have been 28 days.
Dr. Kara Fitzgerald: Short.
Dr. Greg Kelly: Yeah, so usually by about 14 days is when the subjective symptoms are separating noticeably from the placebo group. And then in addition to the SF-36, we’ve used what’s called the Aging Males’ Symptom scale. Think of it as a low T-ish type of scale. And then we created our own female version of that shares many of the questions and then makes a few that are specific, just to have a similar thing for women. In the latest placebo study we did on that, there’s three subscales of that, a sexual one, a somatic and a psychological. The psychological, again, it’s irritability, nervousness, and mild mood issues. The somatic has to do with with fatigue and bodily sensations.
Dr. Greg Kelly: What was interesting is that actually was statistically significant in women in the somatic and the psychological scales, again, over 28 days. In men, we didn’t see a statistically significant change. But again, it groups into those same things we talked about, right? A lot of things that go to the brain and energy.
Dr. Kara Fitzgerald: Yeah. Well, and hormones, potentially. I’m really curious about that. Wow, all right, what else do we need to talk about? Timing. You were going to circle back and talk about timing and dosing.
Dr. Greg Kelly: Yeah. So, chronobiology, the when of things, has been an interest of mine since, you know, around 2000. I think one of my two-part articles on AltMed Review was about the variability of body temperature paying attention to circadian rhythms. But the default in studies is often, well, let’s just give something twice a day and call it good. Many of the NR or NMN studies are like that, you know, just take them at breakfast and dinner.
Dr. Kara Fitzgerald: Just because? What’s the rationale for that? Just because?
Dr. Greg Kelly: It’s just because, right? It’s just the default, right? It’s like the timing does not get factored in often. Again, this is an animal study, so take this with a grain of salt. But in an animal study, they infused NAD, so intraperitoneal, at either the beginning of their active cycle or the beginning of their rest cycle, so the time of day would flip-flop, because they’re nocturnal and we’re not. But when they gave NAD+ at the beginning of the day, things related to metabolic health improved that they measured, right? Your insulins, your glucose, your liver enzymes, things like that. When they gave the NAD+ infusion at the beginning of their rest period, so the equivalent of our night, it actually worsened all of those same things.
Dr. Kara Fitzgerald: Interesting.
Dr. Greg Kelly: And so then in that study, they decided to follow that up and give niacinamide, that form of B3, also timed, and it was the same. Niacinamide bolused all at the beginning of their day equivalent made a positive impact and at the end of the day, not so great. So there’s that piece of evidence. There are several different studies in humans that in small numbers of people have tried to look at NAD+ levels in the blood in a circadian sense and it seems like for most people it peaks somewhere early to mid afternoon. If we were to take, say niacinamide or NR orally, it takes a bit to get through digestion, make it into the liver, get released into circulation and then peak in the blood. So to get that peak at say two in the afternoon, we would have needed to consume the NAD booster with breakfast, as an example.
Dr. Greg Kelly: I think when you start to stack the different evidence, the experiment I’m most comfortable running is just take all of it first thing in the morning. Maybe things don’t play out exactly the same way in us as they did in that animal study, but when it comes to circadian functions, often if something has a circadian rhythm in one organism, it will have it in all of us.
Dr. Kara Fitzgerald: You’ll see it elsewhere. And it just makes life easier for everyone. You can just bang it out in the morning. Well, this was great. You know, it’s funny. Our producer is listening in and I know his wheels are turning. He wants to start taking it. It just makes a lot of sense and I’m going to really focus on it in my practice with some intentionality and actually run the Jinfiniti test. And then you said Chromadex. If it’s okay, we’ll throw some of those links on the page, if people want to actually start measuring. And you’re bringing it into clinical practice, so we’ll sort of throw some of those links on the show notes page.
Dr. Kara Fitzgerald: I also want to remind people that if you go to Qualialife.com/DrFitzgerald you’ll get a really nice discount, like a heavy discount. There’s already a discount built in and then you can layer an additional. So you could get like up to 50-65% off to start it. So that’s awesome. All right, with that, just tell me anything you want to talk to me about with regard to what’s coming for you guys over there at Qualia/Neurohacker?
Dr. Greg Kelly: Yeah, sometime at the end of Q1 2025, we’ll be launching, I think, what’s going to be called Qualia Joint Health. We did a pilot study of that so think of it as something for healthy joints and targeting that chronic inflammaging type of hallmark. So that’s exciting. We have a bunch of other things kind of somewhere early in the development pipeline. So that would be the next thing, but I’ve been working a lot in the longevity researching ingredient space. You and I talked offline not too long ago and I’d say over the last four months our emphasis has just been to get smarter on all these different compounds and figure out which ones look the most interesting.
Dr. Greg Kelly: Many of them, the research is still premature, but polyphenols come up a lot as super cool. I think glycine is really interesting. So we’ll continue to do more in, for lack of a better way to describe it, in the longevity category. And then we’re somewhere in the midst of doing a hydrogen tablet that has a Qualia proprietary blend that will be built in. That’s probably a Q2 next year. Recently we launched the Qualia Magnesium+. For listeners, when I think of what really works, magnesium is one of those things and many people actually do notice an impact. That’s something if people want to check out. There are always cool things and one of the things I really like about the Qualia brand and working for them is that before launching any product, I’m allowed to put prototypes together and actually do a human study to make sure that they do what they’re supposed to do.
Dr. Greg Kelly: So I guess the final thing with Qualia NAD+ is we’ve done two of those compared to placebo. The first study, was an average 74% increase in NAD and the second study was an average of 67%. There are other NAD boosting things out there, but the one thing I can say is I know with confidence ours works because we’ve studied it now twice.
Dr. Kara Fitzgerald: You’ve tested it. Yeah, yeah. That’s exciting. It’s really exciting. Well, geez, I hope that you can circle back and share with us some of the other launches you guys have coming, and especially just the research. And then it’s always fun to talk to you about the mechanisms and what’s going on intracellularly and just a sweep of the research more broadly. So as always, Greg, thanks. It was awesome to have you here. It was really good to connect.
Dr. Greg Kelly: Thanks for having me today, Kara.
Dr. Greg Kelly is Senior Director of Product Development at Neurohacker Collective, naturopathic physician (N.D.), and author of the book Shape Shift. He was the editor of the journal Alternative Medicine Review and has been an instructor at the University of Bridgeport in the College of Naturopathic Medicine, where he taught classes in Advanced Clinical Nutrition, Counseling Skills, and Doctor-Patient Relationships. Dr. Kelly has published hundreds of articles on natural medicine and nutrition, contributed three chapters to the Textbook of Natural Medicine, and has more than 30 journal articles indexed on Pubmed. His areas of expertise include nootropics, anti-aging and regenerative medicine, weight management, sleep and the chronobiology of performance and health.
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