Science of NAD
How are your NAD levels today?
What Is NAD?
And Why Should You Care?
I recommend to friends of all ages that they care about their NAD levels. I think you should, too. Even though NAD boosters like Nicotinamide Riboside (NR) and Nicotinamide Mononucleotide (NMN) cannot cure, treat, or prevent any disease or medical condition, they can still help you immeasurably, in some ways that you can feel, and some that you cannot.
In fact the mouse studies are amazing. Any mouse not taking an NR supplement is crazy. But NAD boosters can help humans, too.
There must be a thousand articles and podcasts about NAD that are confusing, incomplete, or just plain wrong. What follows is a clear, plain-language explanation that will help you decide whether an NAD precursor is right for you.
Before we’re done, we’ll get pretty deep into the science of metabolism and the different metabolic pathways that cells use to get the energy they need, and even the reason why there are so few really good articles on this topic.
But you don’t have to read all the sub-articles if you aren’t interested in the underlying science. We’ll start with a simple Overview, and then keep adding more science in subsequent sections.
NAD (Nicotinamide Adenine Dinucleotide) is the fuel that powers every cell in your body. Your cells use that energy not only to go about their daily business, but also to defend themselves and repair themselves. If your cells run low on energy they’ll have difficulty doing their jobs, or even maintaining themselves. The cells could malfunction or die. And if those malfunctioning cells are neurons in your brain, that could be scary. But even if it’s just the cells in our skin, we don’t want malfunctioning cells.
Most conditions we associate with aging are also associated with reduced NAD levels. That’s one reason why anti-aging enthusiasts are so excited about NAD. Another reason is because NAD levels drop as you get older – not only in humans, but in all animals, from yeast to fish to mice to humans. So it’s not a stretch to imagine that many or most conditions we associate with aging – like weakening eyesight, wrinkling skin, diminished hearing, and stiffening arteries – are all local manifestations of the global decline in NAD.
For most of the 20th century, [15mg of niacin] was considered optimal [to sustain NAD levels]. It is now known that NAD+ levels decline with age and that raising levels back up to or even above baseline provides a surprising number of health benefits in a wide range of organisms, from yeast to rodents.
-- Cell Metabolism, March 6, 2018
You’re right to wonder whether preventing the decline of NAD levels could keep your body young. But NAD isn’t about preventing aging or aging backwards. It’s just about making sure your cells have enough NAD to function well. And that’s about keeping you healthy, no matter your age.
So that’s why I tell all my middle-aged and older friends that they should be boosting their NAD levels.
Read More: Can NAD Boosters Help Me Live Longer?
Boosting NAD in Young People
But that’s not the end of the story, because chronic age-related NAD declines are not the only things that lower your NAD levels, and it doesn’t only happen to old people.
It turns out that any kind of metabolic disruption can reduce NAD levels, including normal activities that young people engage in all the time, like alcohol consumption, sun exposure, overeating, sleep disruption, vigorous exercise, post-partum, and even just getting sick with a virus. Those temporary NAD reductions might, in young people, eventually right themselves. But until they do, your cells could be at risk and your performance could be impaired.
That’s why I tell my friends of all ages that they should seriously consider an NAD booster, especially after a rough day.
How to Raise NAD Levels
You might be excited now about the potential for fighting the symptoms of aging by replenishing NAD levels that are chronically reduced by age, or episodically reduced by metabolic stress. I certainly was when I learned the above.
But there are lots of different ways to boost NAD. They don’t work the same, and each one has a mini-industry of marketers pitching it.
And most important, not every approach to replenishing NAD is going to work. For example, your hair is made of protein, and beans are high in protein, but you can’t grow more hair by rubbing beans on your head. Similarly, your body already has a complex system for creating and replenishing NAD levels. The trick is to support that system, not to just rub NAD on your cells and hope that somehow the magic happens.
But that is what lots of people try first: They try eating NAD, usually in the form of a pill sold as a health supplement, or they inject it into their veins as IV NAD therapy, or even snort it up their nose.
That's not the smartest thing to do. NAD isn’t a rare molecule -- it’s in every single cell of every living thing. So if you guess that your steak and salad must be good sources of NAD, you are right. That’s the first reason why NAD supplements don’t work well. You’re already eating lots of NAD in whatever you bought at the supermarket, and yet your NAD levels may still be depressed. Why is that?
The problem isn't getting NAD into your
body; it's getting NAD into your cells.
The problem isn't getting NAD into your body; it's getting NAD into your cells. You need the NAD inside your cells, not outside your cells. And to get inside each of trillions of tiny cells, the NAD has to get through the cell walls. So how does extra-cellular NAD ever replenish intra-cellular NAD?
NAD is a big molecule. It won't go through. So eating NAD or taking an NAD supplement does not directly increase intra-cellular NAD levels. For NAD levels inside the cell to go up, the NAD you eat has to break down into smaller units ⎼ called NAD precursors ⎼ that CAN get through the cell wall -- then get built back up into NAD once inside.
So when you take NAD, that’s not going to do anything good unless it somehow breaks down into the right NAD precursors. Might it do so on its own? It might. The problem is that you can’t control how the NAD breaks down, so this isn’t an efficient or controlled way of replenishing NAD.
Not only is eating NAD not efficient, but it is also not effective. You’re already probably eating a lot of NAD, and so if your NAD levels are reduced anyway, that’s a good sign that the NAD you are already eating isn’t breaking down into the NAD precursors you need. There’s no good reason to think that eating more NAD or taking an NAD supplement will do you any better. Later we’ll see why this probably is – it has to do with different metabolic pathways that can be blocked or down-regulated by rate-limiting reactions. That means that not all NAD precursors are equal.
And the problem is the same whether you eat NAD, inject it into your veins, spray it up your nose, or dissolve it under your tongue (all of which are common practices). Some of that NAD will be excreted since it cannot be absorbed, and some of it may happen to break down into useful subcomponents and be absorbed, which is one reason why people who eat or inject NAD often report positive results (another reason is the placebo effect). But if ingesting NAD isn’t working, that’s probably because it is mostly being excreted before it breaks down, or it is not breaking down into the right NAD precursors.
Moral of the Story: You don't want NAD, you want an NAD Precursor.
Read More: So Then Why Are People Using NAD IVs?
Instead of ingesting NAD itself, there are smaller molecules that your body can use to build NAD. The smaller molecules are called a “NAD precursors.” They are natural and safe. In fact, most of them are forms of vitamin B3. You can buy them online without a prescription. You can either swallow them as pills, stir them into your drink, or skip the GI tract by injecting it, snorting it, or dissolving it under your tongue. We’ll look at all the options. (Spoiler: It's okay to just swallow a pill or mix it into a drink; the other techniques are unnecessary, and possibly counterproductive.)
The reason there are several different NAD precursors is because your cells know several ways to manufacture NAD ⎼ they just need the building blocks to do it. Those building blocks are pieces of NAD that are (1) small enough to enter the cell, and (2) can be used by your cells to build NAD inside the cell.
The NAD precursors are Tryptophan, Niacin, Niacinamide, Nicotinamide Riboside, and Nicotinamide Mononucleotide. But we'll call them by their scientific nicknames: Tryp, NA, NAM, NR, and NMN.
Actually, let's simplify things by getting rid of two of the precursors right away: Tryp and NMN.
Tryptophan is a protein that you might associate with turkey or milk. Your body CAN make NAD out of Tryptophan, but it tends not to, because Tryptophan is good for all kinds of things. So consuming Tryptophan does not typically result in NAD replenishment.
NMN we'll get rid of for a separate reason discussed at length here. Suffice it to say that NMN, like NAD itself, cannot directly enter most or all cells and must be broken down into precursors. So once again, it is better to just take the precursors.
That leaves NA, NAM, and NR. If you see the diagram and have sharp eyes, you can see that NA, which stands for "Nicotinic Acid," but which we know as "Niacin," is extremely similar to "NAM," which stands for "Niacinamide" or "Nicotinamide." Indeed, NAM is actually a piece of the NR molecule.
So they are very similar. They are all forms of Vitamin B3, but they are slightly different, so they act slightly differently.
Read More: Is NMN going to be illegal in the US?
Metabolic Pathways for NAD Biosynthesis
In order to understand those differences, and why they matter, it will be helpful to understand the different metabolic pathways that each one uses -- the steps it takes -- for each one to get turned into an NAD molecule. For anyone who wants to dive into it, the details are available here:
More Detail: What Are the Metabolic Pathways for NAD Biosynthesis?
For everyone else, here is the TL;DR version:
Once an NAD precursor enters a cell, it goes through a series of steps that eventually build up to an NAD molecule. Each of those steps requires the presence of a particular enzyme that does the building. Different metabolic pathways require different enzymes. If the enzyme needed to take the next step is not present, then that pathway is blocked and NAD cannot be made. If the enzyme is present but in too-small quantities, then the pathway is not completely blocked, but slowed down, and maybe not enough NAD can be made.
Because different enzymes are present in different tissue types at different times, some metabolic pathways are unavailable in different places and different times. For example, the NA pathway is not active in neurons, and is slowed during viral infection. The NAM pathway slows down with age and in times of metabolic stress. The NR pathway bypasses steps that can block the NAM pathway.
That's why the different forms of Vitamin B3 perform differently in different tissues in different people at different times.
NAD Precursors In Action
That different precursors work differently in different tissues in different people under different circumstances is no small thing. It is very difficult to make sense of anecdotal reports when one person is worried about their neurons, and they take niacin, but the metabolic pathway to synthesize NAD from NA is inactive in neurons. Somebody else takes nicotinamide, but they are older and/or suffering from a chronic metabolic stress (like inflammation or obesity), and the NAM pathway is downregulated for them. They report no effect. Somebody else has NAD levels that are not depressed at all. They take an NAD precursor and also report no effect, which they should, because extra NAD isn't likely to do you much good. Putting 20 gallons of gasoline in a 15 gallon tank doesn't do anything good.
On the other hand, some people experience significant improvements as a result of boosting their NAD. Their hair and nails grow faster. They feel more energy.
The energy part is real. Caffeine makes people feel like they have more energy, but really it is just a stimulant, and once it wears off, the feeling crashes, and, indeed, can become addictive. Sugar gives you real energy, but in the worst way, potentially leading to obesity or metabolic disorders.
NAD boosters provide real energy, and they deliver it directly to where it can be used at the cellular level.
The reason I recommend nicotinamide riboside is because (1) NR is available to every type of cell, (2) cells are specifically looking for NR when they get stressed (the NR pathway is upregulated with stress, the opposite of the NAM pathway), (3) NR is not subject to the rate-limiting steps that can reduce the effectiveness of NA or NAM, (4) NR has the strongest safety dossier by far.
Here is how the scientists say point three above:
The first reaction catalyzed by NAMPT in the NAD+ salvage pathway is rate-limiting, energetically expensive, and exposed to feedback inhibition by NAD+. Thus, NR is an interesting player which could be able to boost NAD+ levels beyond what is attainable via the conventional B vitamin metabolism. (emphasis added)
-- Antioxidants, February 4, 2023
Nicotinamide Riboside seems to be a better precursor because it is less likely to be blocked, and thus more likely to be effective. Also, the other precursors have known bad side effects at higher doses that are not present with NR.
Read More: Should I just use Niacin?
Read More: Is NAM the best NAD precursor?
Read More: FAQs on NAD
So Why Do People Talk About NMN?
Nicotinamide Mononucleotide, or NMN, has been made famous by the work of David Sinclair, who wrote a book about longevity, and who co-founded a pharmaceutical company (MetroBiotech) that is hoping to develop NMN-based medicines. Dr. Sinclair has a large following, and his book has a great reach, so a lot of people know about NMN.
NMN is simply an NR molecule with a phosphate attached. That phosphate is just a small collection of atoms, but it makes a world of difference, because it prevents the NMN from entering the cell.
That doesn't mean NMN doesn't work. In fact, there are circulating enzymes that degrade NMN to NR and NAM. So the way NMN works is as a way of delivering NR and NAM to your cells. It's not a bad thing to do, but it's inefficient, and potentially more expensive.
Some say that there is an "NMN transporter" that allows NMN to enter cells directly. Whether it exists is controversial, but what is not controversial is that the alleged transporter is not present in all cells, or even most cells. So even if the transporter exists, it would likely not be important. Therefore, NR is the better choice to replenish intracellular NAD.
Read More: NR versus NMN?
Is NMN Legal to Sell in the US?
The FDA says no, and they may have the final say. This isn't about the safety of NMN. There is a technical requirement that health supplement sellers must comply with if they wish to sell a new ingredient in the US. Specifically, they have to get approval before any pharmaceutical company starts clinical trials on the new ingredient as a pharmaceutical. This the NMN sellers did not do, according to the FDA, so they missed out. You'd probably rather be using NR anyway.
READ MORE: Will NMN Be Prohibited in the US?
Is NR That Much Better Than the Others?
Because Niacin and Nicotinamide are both less expensive than NR, it's reasonable to ask whether NR, even if better, is worth the difference?
With Niacin, it's difficult to take a high dose, because NA causes flushing, which is harmless but annoying. If the dose gets very high, there can be negative side effects, including liver and kidney damage. You wouldn't likely see any harm at a dose of 300mg or 500mg, but you also would see less benefit than a higher dose, and certainly in the tissues where the NA pathway is not active, like nerves and muscle, or if the NA pathway is down-regulated episodically, as with COVID infection.
READ MORE: Should I Just Take Niacin?
Nicotinamide is a closer call, because it's available in every cell, and there are lots of studies showing the NAM successfully replenishes NAD and helps in a variety of circumstances. However, because the NAM pathway is downregulated with age and metabolic stress, NAM might be less effective right when you need it most. It is a fair guess that if NAD levels are low even though you are getting a reasonable amount of B3 in your diet anyway, then the metabolic pathways you are relying on may be down-regulated, which would be reason enough to favor a precursor that is not subject to the rate-limiting steps in the NA and NAM pathways. Also, NAM has shown to have a number of negative side effects at higher doses, including suppressing sirtuins and PARPs that are protecting your cells. That makes high dose NAM a self-defeating proposition.
READ MORE: Is Nicotinamide Good Enough?
Can NR Help Me Live Longer?
We don't know. The difference between lifespan (more years) and healthspan (healthier years, or staving off decline) is really important.
There are some studies that show NAD boosters increasing lifespan in lower organisms. Rodent studies are mixed as to lifespan. And there are certainly no clinical studies showing that replenishing NAD increases lifespan in humans. There are reasons to believe it might be so, but that belief would be an act of faith for now, and possibly for a long time. Although the jury is still out on living longer, your chances of living better are quite good.
READ More: Can NR Help Me Live Longer?
So Why Do You Recommend NR?
There is good evidence that NAD levels decline under many circumstances including chronic conditions like aging and inflammation, as well as episodic metabolic disturbances, like overeating, alcohol consumption, sun exposure, sleep disruption, viral infection, bright light, loud noise, pregnancy, postpartum, and more.
There is also no doubt that your cells need adequate NAD levels in order to manage their affairs, including mission-critical functions like DNA repair.
Would it be okay if your cells were inadequately powered for just an hour or a day or a week? It's hard to say. You can't go without oxygen even for four minutes. And the accumulation of problems at the cellular level may be the very definition of aging, even if one particular episode doesn't kill you, or even cause noticeable harm. So I don't miss a day (I am roughly 60 years old.)
Whether humans will benefit as much as mice do remains to be seen, but the human studies are certainly showing effect.
Right now, NR seems to be the best NAD precursor, because it is safe, available to every cell, bypasses steps that limit other precursors, and has the best safety profile.
Already, clinical trials are underway for many pharmaceutical uses for NAD boosters, including for heart disease, viral infection, and neurodegenerative diseases. Depending on the results, medical claims may be justified in the future.
Also in the future, improved pharmaceutical-grade NAD precursors will likely become available, such as NRH.
But for right now, NR appears to be state of the art.
Here is how the scientists say it:
NR is the main precursor of NAD+ in the central nervous system and the preferred precursor in mitochondria...NR is also the preferred precursor for supplementing NAD+ levels in animal models of heart failure and was shown to reduce cholesterol in obese mice. It has also been shown to exert a certain ameliorating effect on alcohol-induced liver disease and depressive behaviour and improve diabetic lesions and hepatic steatosis in mice with high-fat diet-induced obesity. NR can also ameliorate angiotensin Ⅱ-induced cerebral small vessel disease in mice and prevent noise-induced hearing loss. Similar to NMN, NR can also improve female fertility. NR is the only precursor that can prevent axon degeneration as well as the oxidative stress and organ damage caused by sepsis. Moreover, NR has been shown to exert a certain degree of therapeutic effect in the pathological progress of neurodegenerative diseases such as Alzheimer's Disease, Parkinson's Disease, aging, cerebral apoplexy, and hypertension and cardiovascular diseases. Numerous studies have shown that NR can increase the lifespan of all species tested so far, including mice...
Clinical studies on the short-term and long-term administration of NR have demonstrated the superior bioavailability and safety of NR. It is considered safe even when administered at a dose of 2000 mg a day for 12 weeks, and no adverse symptoms, such as nausea and vomiting, or undesirable skin flushing have been reported. Supplementation of NR neither inhibits NAD+-dependent enzymes nor causes side effects such as liver damage. A study indicated that with an increase in the NR level in tissues following NR administration, the activity of the enzyme sirtuin is significantly increased compared with NAM administration. Compared with other precursors, NR is gradually becoming a preferred candidate precursor because of its high bioavailability, safety, and ability to increase NAD+ levels. It offers many potential health benefits in diseases such as cardiovascular diseases, neurodegenerative diseases, and metabolic diseases. In summary, NR is a more effective precursor for synthesising NAD+ and increasing the activity of NAD+-dependent enzymes than NA and NAM...
Aging and Disease, December 1, 2021
Thanks for visiting -- I hope you enjoy the rest of the website. If I have made a convincing case, then please encourage your friends to care about their NAD levels, too. Just like exercise and healthy eating habits, sustaining your NAD levels can be important if yours are not where they need to be. If you might be interested in supporting our efforts at no additional cost to you, follow these links Tru Niagen or Amazon and check out what they are selling. And feel free to drop us a line!
Author / Editor
Science of NAD
1. Supplements Are Not Medicines. Health Supplements like nicotinamide riboside are not intended to cure or treat any disease, condition, or illness.
2. No Medical Advice. I am a lawyer, and a journalist, not a doctor, and I offer no medical advice. But I do follow the science, and I may be able to bring to your attention some interesting studies, and help clarify what the studies may may or may not be saying. And check with your physician -- your physician can look at this research, too.
3. Commercial Affiliations. I am a ChromaDex shareholder, and a marketing affiliate for Amazon and Rakuten. As a result, I will sometimes mention or recommend products that I endorse. I may earn a small commission from qualifying purchases if you were referred directly from this site and completed a purchase. [Thank you!] You can read more about our advertising, privacy, and data collection policies here.
Who Cares What I Think?
I am a lawyer, and I have led legal publishing businesses. I am functioning here is a journalist. But I am not a biochemist or a geneticist.
I happened upon the world of NAD after reading articles in 2016 that described apparent anti-aging properties of nicotinamide riboside, a molecule which, as Dr. Charles Brenner discovered in 2004, functions as a form of Vitamin B3 and can replenish intracellular NAD levels via a metabolic pathway that was previously unknown.
The effect of NR on me was significant, multi-faceted, and unexpected. So then I started paying a lot more attention, and I started reading the studies. With the help of some friendly biochemists, I even started understanding the studies.
My professional career (I am mostly retired now) was devoted to organizing legal information for lawyers, helping to bring order to the chaos resulting from millions of legal cases saying a variety of things that are sometimes the same, often similar, and sometimes conflicting.
During that work on legal research tools, I developed a certain affection for the techniques of organizing, indexing, and abstracting in order to prevent information overload without losing track of essential detail. Indeed, I even helped pioneer a few techniques.
In the years following Dr. Brenner's discovery of the vitamin function of NR, researchers published hundreds of papers documenting their collective explorations of the effects of the newly discovered metabolic pathways, and how they might impact the health of animals and humans with respect to a number of different situations, ranging from illnesses relating to specific organs, like the kidney, liver, and heart; general neurodegenerative diseases, like Alzheimer's, Parkinson's, and ALS; and more general conditions, like aging, pregnancy, and chronic inflammation.
Alas, having hundreds of such studies is nearly as unhelpful as having no such studies, because the results of the experiments can be the same, similar, or conflicting. And because they reliably deploy highly technical language to describe the results, it isn't easy to make sense of what's going on, unless you are willing to learn the science and read all the studies. That is, of course, exactly what the researchers in the field do. But it is quite challenging for lay people to do that.
Worse, the Internet's dark side has occasionally spawned sewers of inaccurate information and outright deception, which makes it that much harder for citizens and journalists to make sense of this rapidly developing domain of science that has the potential to help people immensely.
There is enough misinformation and half-truths surrounding NAD precursors that I thought there was an opportunity to provide a clear overview of the subject that was solidly rooted in the actual studies.
That means you don't have to believe anything I say -- you can click through to the underlying science and judge for yourself whether we are understanding it correctly.
I mentioned above that I own shares of ChromaDex, which is a small public company that has a number of patents on the manufacture and use of NAD precursors, including nicotinamide riboside, and which is the maker of Tru Niagen. However, I am not an investment advisor, and there is no investment advice here. Indeed, I have lost money on it, but I have gained health. So although I do not have any opinion about whether anyone should be a ChromaDex investor, I think there are real benefits to being a ChromaDex customer.
Here is an example of an NAD booster that contains NAD itself, not a precursor. Please do not click this link. I do not recommend NAD supplements that are not NAD precursors.
Where Can I Get It?
You can buy Niacin, Niacinamide, and NMN on amazon. But we buy Nicotinamide Riboside, and we get it directly from the source: Tru Niagen.