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Is Your NAD+ Supplement Actually Working Against You?

Pushing The Limits — Transcript

You know, I just had my NMN and my drink on the way to work and now I've got energy. It doesn't work like that. Like that's just complete and utter rubbish. And there's a lot more to the story.

Well, hi everybody. Lisa Tamati here. Welcome to my channel. Today I'm going to be talking about the NAD pathway. Now this is something that's been popularised — taking NAD precursors like NMN and NR — and of course Dr. David Sinclair's work in this area and the book Lifespan, which I devoured. I've been a huge fan of NMN over the past few years.

However, the science has sort of moved on from when he wrote that book, and there are a few things that actually concern me — things that I've been studying for quite a long time — about why NMN and NR, nicotinamide riboside, alone could actually be hurting you. It's not catastrophic or anything like that, but there are some studies that have come out in this whole area. And I've had the privilege of interviewing luminaries in this space like Professor Joseph Baur, Courtney Vanosom, and Dr. Elizabeth Yurth about these sorts of things.

I've also been designing my own NAD+ Next Generation supplement. The reason I wanted to do that was that I've been selling NMN for a number of years and it's been very popular. Millions of people around the world take it. And there are just some things I want you to know about it. It's not to demonise it or anything — quite the contrary — but it is to know some of the risk factors with it, and what happens when you go too high with your dosing.

So let's have a look at the full NAD story that nobody's really talking about. Well, not enough people are talking about.

The Problem With How Most People Supplement NAD+

Right now there are millions of people taking NMN and NR — nicotinamide mononucleotide or nicotinamide riboside — thinking that they're doing one of the smartest things they can do for longevity. And I genuinely get it. It's not something I've been against.

The science behind NAD+ is extraordinary and it's quite complex. David Sinclair's work, the Harvard studies, the animal data — it's all very compelling. And NAD+ really is central to how we age. That's completely correct.

But here's the problem. Most people are supplementing NAD+ by just taking NMN or NR in isolation. It's incomplete when we do it that way. And there's a growing body of evidence suggesting it could actually be doing some harm. Not in a scary, catastrophic way, but in a quiet, downstream way that most people never connect back to their supplement.

So it's not about scaring you off NAD supplementation. It's about NAD+ optimisation. It's one of the most important tools we have in longevity medicine, but I want you to do it intelligently. And today I'm going to show you exactly what that means and why it matters.

A Bit of Context on Why I Care About This

If you know my story on this channel, you'll know that I've been an ultra-endurance athlete. I spent 25 years racing the world's hardest ultramarathons — from the Sahara to the Himalayas, to Death Valley, the Gobi Desert, and all around the place. I ran right through New Zealand, 2,250 km. My body knows what it's like to push the limits, to go to places that most people can't imagine from an endurance perspective.

But what really changed my whole approach was my mum's story. About ten years ago now, she had a massive brain aneurysm. That threw me into the world of rehabilitation, longevity, and anti-ageing in a desperate attempt to save her life and get her back. We were told she would never have any quality of life again — that she was lucky to be alive and would never know who she was or do anything meaningful again.

I've written a book about this. Well, ten years later, I got her back to full capacity after two and a half years. Full driver's licence, full power of attorney — everything. That was really an opening door for me to understand that this body can repair, our brains can repair, and we can do a lot more than we think we can to control the ageing process. And today my mum's still going. She's 84. She's been through terminal cancer — which turned out not to be terminal — hip fractures, sepsis, gastrointestinal bleeds. Every time I've been told she's dying and that there's nothing we can do, they've been wrong.

So I'm very much about: what can we do? And it took me deep into the science of cellular repair, neuroplasticity, mitochondrial function, and yes, NAD metabolism.

I didn't just read the headlines though. I read the studies. I talked to the researchers. I've also co-developed our Aevum Labs formula, Rejuvenate Pro, with Dr. Elizabeth Yurth from the Boulder Longevity Institute, as well as Peter Lei, a biochemist. Dr. Yurth is one of the leading longevity clinicians in the world and really knows her stuff. And what I found changed how I think about NAD+ supplementation entirely.

The story being sold to you — take NMN or NR, raise your NAD, live longer — is missing about 80% of the actual biology. And some of what's being left out matters enormously.

The 2023 Study Most Supplement Companies Don't Want You to Know About

Let's go through it. I'll keep the science accessible but I won't dumb it down, because you're smart enough to handle the real version. And I hate seeing influencers going: "I just had my NMN drink on the way to work and now I've got energy." It doesn't work like that. It's complete and utter rubbish.

So let's start with the data that most NAD supplement companies would rather you didn't know about.

In 2023, a study published in Nature Cardiovascular Research — which got a lot of attention in the research community, though not so much in the wellness media — found that a metabolite of NMN called ADMA, or asymmetric dimethylarginine, was elevated in people taking high-dose NMN supplementation.

Now ADMA is a well-established cardiovascular risk marker. It inhibits nitric oxide synthase — I've interviewed Dr. Nathan Bryan all about nitric oxide and how important it is — and this is the enzyme that produces the nitric oxide that keeps your blood vessels relaxed, flexible, and healthy. When ADMA goes up, nitric oxide goes down. And when nitric oxide goes down, you get endothelial dysfunction — dysfunction of the lining of your blood vessels — which is a key precursor to atherosclerosis, hypertension, and even strokes.

Let me be clear about what this does and doesn't mean. This is not a study showing that NMN causes strokes. It's not that clean. The picture is more nuanced. But it's a mechanistic signal — a biochemical flag that says: at high doses, in certain people, isolated NMN supplementation could be pushing your cardiovascular risk in the wrong direction.

And there's more. The same research ecosystem, looking at the NNMT pathway — which I'll explain in a minute — has flagged that NMN and NR metabolism produce compounds that, in the absence of proper methylation support, can accumulate and drive inflammatory and vascular pathways you really don't want activated.

There is also work from 2023 in mouse models — I know, only mice, not humans — but showing that at supraphysiological doses, well above what you'd get from food, NMN supplementation accelerated tumour growth in mice that already had cancer. I want to be really careful here. Mice are not humans. This was in mice with existing cancer. And a lot of positive things you take in the supplement or food world could promote cancer if you already have it. But it does raise flags and it's worth paying attention to.

Here's my take on all of this. The companies selling you 1,000 mg or 1,500 mg of NMN per day are working on the assumption that more is better. But biology almost never works that way. Biology works on thresholds, feedback loops, and balance. If you flood any single pathway, you create imbalances elsewhere. It tips the seesaw out of balance.

The question isn't whether NAD+ matters — it absolutely does. The question is: how do you raise it intelligently without creating collateral damage in other systems?

And there's also a 2024 meta-analysis looking at NAD+ precursor safety across human trials. The conclusion was nuanced: short-term, moderate doses appear generally safe, which is great. But longer-term cardiovascular signals, particularly around ADMA and homocysteine elevation, warranted more investigation.

Homocysteine, by the way, is another cardiovascular risk marker — and it's directly connected to the methylation story I'm about to tell you. I'm a huge fan of people getting their homocysteine measured when they go for a blood test. It's not part of the standard workup, unfortunately, and you may have to pay privately for it. But it's well worth doing, especially if you have methylation defects in your genetics or you're taking NMN. You might want to have a look at what your homocysteine level is doing.

The Methylation Trap

Now I want to teach you something that most doctors don't know, let alone the wellness influencers. This is genuine biochemistry. Once you understand it, you'll never look at NMN supplementation quite the same way again.

When you take NMN or NR, your body converts it to NAD+. That's the goal. But NAD+ doesn't just sit there — it gets used. And the primary way your body disposes of NAD+ is through an enzyme called NNMT — nicotinamide N-methyltransferase. NNMT methylates nicotinamide, the waste product from NAD+ usage, to get rid of it. And to do that methylation, it needs a methyl group.

Where does it get that methyl group? From something called SAM — S-adenosylmethionine. All these big words.

Now, SAM is one of the most important molecules in your entire body. It's called the universal methyl donor for good reason. It donates methyl groups — tiny carbon-hydrogen clusters — to dozens of critical biological processes. We're talking about:

• DNA methylation — how your genes are switched on or off, your epigenetic regulation

• Neurotransmitter synthesis — making dopamine, serotonin, adrenaline

• Myelin synthesis — the insulation around your nerve fibres (think of people with multiple sclerosis having issues with this)

• Detoxification pathways in the liver

• Phospholipid synthesis — building healthy cell membranes

• Histamine breakdown

• Creatine synthesis

This is not a peripheral pathway. SAM methylation is absolutely central to how your brain works, how your genes express, how your liver functions, and how your mood is regulated.

Here's the problem. When you flood your system with high-dose NMN or NR, you're generating a massive amount of NAD+ — which is the goal, right? But consequently, a massive amount of nicotinamide as a byproduct. Your body has to clear that, and NNMT gets called into overdrive to methylate it, which burns through your SAM at an accelerated rate. This is what I call the methylation trap.

So you're taking NMN thinking you're optimising your health, but you're quietly draining one of the most critical co-factors in your body. And because the downstream effects of SAM depletion — things like mood changes, cognitive fog, changes in gene expression, methylation of homocysteine — don't obviously look like "my NAD supplement is causing this," most people never make that connection.

Let me make this concrete. You have an enzyme called COMT — catechol-O-methyltransferase — and it needs SAM to break down dopamine and oestrogen. If your SAM is depleted, COMT can't work properly. You might see oestrogen dominance. You might see dopamine dysregulation, anxiety, mood swings, difficulty with focus.

Your DNMT enzymes — your DNA methyltransferases — need SAM to maintain proper methylation patterns across your genome. Disrupted DNA methylation is one of the hallmarks of ageing. It drives cancer risk, immune dysfunction, and epigenetic ageing.

And here's the homocysteine connection. When SAM donates its methyl group, it becomes SAH — S-adenosylhomocysteine — which then converts to homocysteine. Normally, homocysteine gets recycled back to methionine and then SAM in a cycle that requires folate and B12. But if you're draining the system faster than it can recycle, homocysteine accumulates. And elevated homocysteine is a well-established, independent risk factor for cardiovascular disease, stroke, cognitive decline, and all-cause mortality.

So now you're starting to see why the picture is more complicated than "take NMN, feel great."

For some people — particularly those with MTHFR gene variants, which affect folate metabolism, or those with already compromised methylation — high-dose NMN or NR could be actively worsening cardiovascular and cognitive risk markers.

I want to be fair. That doesn't mean everyone taking NMN is going to have a stroke. That is not what the data is saying and I won't overstate it. Many people taking NMN will have no obvious ill effects. But no obvious ill effects is not the same as optimal. And for people with certain genetic backgrounds, who are already under stress, or who have compromised detox pathways, the methylation drain could be really clinically meaningful.

The solution is not to panic and throw out your NMN. It's still a very good thing. The solution is to understand the full pathway and supplement intelligently — to think about what you put around it that can help it, what combination would actually support that NAD system. And that means we need to understand the whole NAD system, not just one end of it.

The Full NAD Pathway: The Bathtub Model

This is where it gets into the real biology. I'm going to give you a systems view of NAD+ metabolism because if you understand this, you'll immediately see why single-ingredient approaches are missing the point.

Think of the NAD system as a bathtub. Your goal is to keep the water level high — that's your NAD+. To do that, you have two options: you can turn on the tap, or you can fix the leaks. Most supplements only focus on the tap — putting more in. But there are multiple massive drains in this bathtub. And if you don't address them, you're filling it with the garden hose while the plug's been pulled.

The Precursors — Turning On the Tap

There are several NAD precursors — different starting materials your body can use to make NAD+.

NMN is the one Dr. David Sinclair famously takes. It's expensive, well-researched in animal models, and human data is growing. It enters the salvage pathway and can effectively raise NAD levels. But as we've discussed, high doses drive significant nicotinamide clearance through NNMT, with the methylation consequences I've described.

NR — nicotinamide riboside — similar story. Gets converted to NMN and then NAD+ in the cells, though that's also quite complex. It also raises NAD+ effectively and has a longer track record in human trials than NMN. But the same methylation concerns apply because it ultimately goes through the same degradation pathway.

Niacinamide — also called nicotinamide, just to confuse matters — this is one that doesn't get talked about enough. And honestly, I think it's the most intelligent precursor choice when you understand the full picture. It's also considerably cheaper. It's the direct form that enters the salvage pathway. It raises NAD levels effectively — there's solid data on that — and critically, at moderate doses, it does so without generating the same NNMT-driven methylation drain as high-dose NMN or NR.

Why? Because niacinamide is the nicotinamide that NMN and NR ultimately convert to anyway. But you're delivering it in a more direct, controlled dose without the conversion bottlenecks or the excess that needs to be rapidly cleared. There's a sweet spot where you get meaningful NAD+ support without overwhelming the clearance pathway.

The Leaks — Where the Game Is Actually Played

Drain number one: CD38.

CD38 is an enzyme — an NADase, meaning it breaks down NAD+. And it is, by a significant margin, the biggest drain on your NAD levels in ageing. I'll say that again: it is the most significant drain on your NAD levels in ageing.

Here's the critical thing. CD38 expression goes up dramatically as you age — the same time you're starting to take these supplements, and the same time NAD levels are falling. Researchers including Johan Auwerx at EPFL have done work showing that CD38 alone can account for the majority of the age-related decline in tissue NAD+ levels.

And CD38 is activated by inflammation — particularly by NF-κB signalling, which is a key inflammatory pathway. So chronic low-grade inflammation, which most people over 40 are quietly running, directly cranks up CD38, which directly depletes your NAD. This means if you're supplementing with NMN or NR but not addressing CD38, you're filling the bathtub with the plug pulled out. You're fighting against the biochemical tide.

Blocking — or at least inhibiting — CD38 may be more important than adding more precursor.

Drain number two: the PARP enzymes.

PARP stands for poly-ADP-ribose polymerase. These are your DNA repair enzymes. They swing into action whenever your DNA is damaged, which happens constantly — radiation, oxidative stress, replication errors. DNA damage is a daily occurrence. When PARPs do their repair work, they consume NAD+ as a substrate. DNA repair is essential, but the more DNA damage you have, the more PARPs are running, the more NAD gets consumed.

The answer here isn't to block PARP — we need it for DNA repair. The answer is to reduce DNA damage through lifestyle, and to ensure your NAD+ levels are robust enough to supply the PARPs and everything else.

The Target: Sirtuins.

Now let's talk about why you're raising NAD+ in the first place. The primary effectors — the molecules that NAD+ feeds — are the things called sirtuins. There are seven human sirtuins, SIRT1 through SIRT7, and they are deacetylases. They remove acetyl groups from proteins and histones, regulating gene expression, metabolic function, stress responses, mitochondrial biogenesis, and DNA repair.

SIRT1 is probably the most famous — a key regulator of metabolism and the target of much longevity research. SIRT3 is critical for mitochondrial function. SIRT6 is involved in genomic stability.

Here's the key point: sirtuins require NAD+ to function. No NAD, no sirtuin activity. This is why NAD+ levels matter so much for ageing. As NAD+ falls, sirtuins go quiet, and the downstream effects are profound.

But — and this is important — you can also activate sirtuins more efficiently. Meaning you can get more sirtuin activity from the same NAD level if you give the sirtuins the right activators. So raising NAD+ and activating sirtuins simultaneously is a more powerful strategy than just raising NAD+ alone.

So look at what we've got. We have precursors to raise NAD. We have CD38 inhibition to stop NAD+ being destroyed. We have PARP management through DNA protection. And we have sirtuin activation to make the NAD+ work harder. A genuinely intelligent NAD+ strategy addresses all of these — not just one.

The Formula: Why Every Ingredient Is There

This is exactly the framework we used to develop our NAD+ Next Gen supplement at Aevum Labs. When I sat down to learn about the NAD system and how it works with Dr. Elizabeth Yurth, we started with a simple question: if you're going to build the most intelligent, systems-level NAD+ intervention possible — one that addresses the full pathway without creating collateral damage — what would it contain?

We worked through the biology systematically. Every ingredient in this formula is there for a specific mechanistic reason.

Niacinamide

We start with niacinamide as our precursor — not NMN or NR, for the reasons I explained earlier. It's a meaningful dose that will raise your NAD+ levels, but through a more direct pathway without generating the excessive nicotinamide load that overwhelms the NNMT pathway and drains your SAM, your methylation donors. This is the tap in our analogy. But we're not stopping there, because the tap alone isn't enough.

EGCG

EGCG — epigallocatechin gallate — is the primary active compound in green tea extract. It's one of the most potent natural CD38 inhibitors we have. Remember, CD38 is the biggest drain on your NAD+ as you age. EGCG hits it directly. Research by Eduardo Chini and colleagues has demonstrated that natural polyphenols including EGCG can meaningfully inhibit CD38 activity — meaning less of your NAD+ gets destroyed.

But EGCG does more than just block CD38. It's also a potent antioxidant, has anti-inflammatory properties, supports mitochondrial function independently, and there's compelling data around its effects on metabolic health and certain cancer pathways. It's a genuine Swiss Army knife — genuinely multifunctional.

Trans-resveratrol

Resveratrol you've probably heard of. It's the compound associated with the health benefits of red wine — though in red wine it's present in amounts too small to really matter. But as a supplement at meaningful doses, the story is very interesting.

Trans-resveratrol is a direct SIRT1 activator. Remember the sirtuins — the longevity enzymes that NAD+ feeds. Resveratrol switches SIRT1 on more efficiently. It's like pressing the accelerator on the very pathway NAD+ is supposed to support.

The research on resveratrol has had a complicated history — some studies show strong effects, others were more equivocal. But the key insight from more recent work is that resveratrol works synergistically with NAD+. When NAD+ and resveratrol are present together, sirtuin activation is substantially greater than either one alone. They potentiate each other. That's why combining them in a single formula makes mechanistic sense.

Apigenin

Apigenin is a flavonoid found in chamomile, parsley, and celery. It's another CD38 inhibitor, working in concert with EGCG to put the brakes on your biggest NAD+ drain. But apigenin has a particularly interesting additional property — it's neuroprotective. Research shows it supports BDNF, brain-derived neurotrophic factor, which is essentially fertiliser for your brain. It promotes neuronal differentiation and has been studied in the context of anxiety, cognitive function, and neurodegenerative disease risk.

So we're doubling down on CD38 inhibition — two compounds hitting that drain from slightly different angles — and getting brain support as a bonus. That's intelligent formulation. That's not just picking a buzzword compound.

Quercetin

Quercetin is doing several jobs simultaneously.

First, it's anti-inflammatory — and inflammation, as I mentioned, directly activates CD38. So quercetin helps address one of the root causes of NAD+ drain, not just the enzyme itself.

Second, quercetin has senolytic properties, meaning it helps clear out senescent cells — what we call zombie cells. They've stopped dividing but they won't die, and they pump out inflammatory signals that damage surrounding tissue. Senolytics are increasingly recognised as one of the most important interventions in longevity medicine, and quercetin — particularly in combination with compounds like fisetin — is one of the better-researched natural senolytics we have.

Third, quercetin supports mitochondrial function, enhances mitochondrial biogenesis — the birth of new mitochondria — and protects against mitochondrial oxidative stress. Given that mitochondrial dysfunction is central to the ageing process and to everything we're trying to address here, that's really meaningful.

Quercetin is generally one of those compounds where the more you look at the research, the more you find it's doing. We included it because it addresses multiple convergent pathways — inflammation, senescence, mitochondrial health — all of which intersect with NAD+ metabolism.

Rutin

Rutin is less famous than resveratrol or quercetin, but it's doing important work. It's a bioflavonoid — a glycoside of quercetin — and its primary role in this formula is twofold.

First, it supports the bioavailability of the other polyphenols. Polyphenol absorption can be notoriously variable and poor, and rutin helps improve the effective absorption of the other compounds in the formula.

Second, rutin has specific vascular protective properties. It strengthens capillary walls, reduces capillary fragility, and has anti-thrombotic effects — it reduces inappropriate tendency to blood clotting. Given the cardiovascular signals discussed in the context of high-dose NMN supplementation, having a compound specifically supporting vascular health in the formula isn't incidental. It's very much intentional.

What This Formula Is Actually Doing

Look at what we have here:

• A precursor that raises NAD+ without hammering methylation

• Two CD38 inhibitors stopping the biggest drain

• A direct sirtuin activator making the NAD+ work harder

• Anti-inflammatory, senolytic, and mitochondrial support

• Vascular protection built in

• Bioavailability enhancement

This is not a one-trick pony supplement. This is a systems intervention. Every ingredient is talking to a different part of the same pathway.

This isn't the cheapest way to supplement NAD+. You can buy a 500 mg NMN capsule that'll be a little cheaper. But if you understand the biology now, you'll understand why cheap and simple may not be serving you — and why the single-ingredient approach is leaving so much on the table, and may even be increasing risk for certain people.

Practical Takeaways

There was a lot of science here. Here's what I want you to walk away with.

1. Question any NAD supplement that's only one ingredient. I've sold them in the past — I'm not saying they're bad. But they're not looking at the whole picture. If your product is just NMN or just NR, ask yourself: where is the CD38 inhibition coming from? Where's the sirtuin activation coming from? Where's the methylation protection? If those questions don't get answered, you're only getting a fraction of the story.

2. High dose isn't automatically better — it might actually be worse. The trend in NMN supplementation has been toward higher and higher doses: 500, 1,000, 1,500 mg. But the methylation drain I described scales with the dose. The NNMT-driven SAM depletion gets worse as you go higher. Lower doses with a more comprehensive formula may serve you better than high doses in isolation.

3. Get your homocysteine checked. I want everyone to do this if at all possible. Unfortunately you usually have to pay for it — it's not that expensive, but it's not standard. It gives us so much information and I don't know why it's not part of a standard blood panel. If you're taking NMN or NR and you haven't checked your homocysteine levels, do it. If your homocysteine is elevated above about 10 µmol/L, that's a sign your methylation cycle is under stress and you need to address it. This might mean adding methylated B vitamins — methylfolate, methylcobalamin — reducing your NMN or NR dose, or switching to a more balanced formula. Optimal is somewhere between 7 to 8, maybe up to 9. Above 10 is a real concern.

4. Address the root causes of NAD decline. Supplements work best on a foundation of healthy habits. The things that most aggressively drain your NAD+ and activate CD38 are chronic inflammation, poor sleep, excess alcohol, UV damage, and sedentary behaviour. Exercise — particularly high-intensity interval training — is one of the most powerful natural NAD boosters we know of, working through AMPK and PGC-1α activation. Not everyone can do that, of course — if you're older, impaired, or have disabilities, do what you can. Sleep is when your body does most of its NAD-dependent repair. Exercise and sleep are free NAD boosters. Use them.

5. If you have a methylation issue, be especially cautious. If you've done your genetics and you know you have MTHFR variants, if you have high homocysteine, a history of depression or anxiety, or any known issues with folate metabolism — these are all signals that your methylation cycle may be under pressure. In those cases, high-dose NMN or NR could be making things worse. Get tested, know your baseline, and work with a practitioner who understands this.

6. Look for formulas that address CD38. This is probably the single biggest thing missing from most NAD supplements. If a formula doesn't have CD38 inhibitors — EGCG, apigenin, luteolin are the main natural options — it's not addressing the primary drain. And in ageing, that drain is enormous.

I know this was a lot. And I know the supplement world can feel overwhelming. Everyone's claiming their product is the best and it gets exhausting. But the decisions you make about your supplementation are the decisions you make about your healthspan, your cognitive function, your quality of life. And that's what I'm passionate about.

NAD+ is like a bathtub. You need to turn on the tap, but you also need to fix the leaks, and you need to make sure the bathtub is being used efficiently. Any product addressing only one of those things is leaving a lot on the table.

Our NAD+ Next Gen formula is coming soon. In the meantime, Rejuvenate Pro is available at aevumlabs.co.nz. I've linked everything in the description below, including some of the studies and my interview with Professor Joseph Baur. If you want to go deeper, reach out to me or my team.

Please share this video. The reason I make this content is that I genuinely think most people are getting an incomplete picture, and everything gets dumbed down and simplified. I hate that. I want people to understand the science behind what they're taking.

Hit subscribe if you haven't already. I also have a podcast, Pushing The Limits — top 2% of podcasts worldwide, one of the longest-running in the longevity and biohacking space, going for over 11 years now. I'll see you on the next one.