How the Body Makes and Maintains NAD+

Your body acts like an efficient factory to keep the coenzyme NAD+ active throughout your life. Here’s how it works and how you can help the body make more NAD+.

Key Takeaways:

• The body makes and maintains NAD+ by converting NAD+ precursors into NAD+. Sources of NAD+ precursors include food and by-products of cellular reactions that use NAD+. 
• Cells use several pathways involving different NAD+ precursors to create NAD+. Some of these pathways are more efficient than others. 
• As we age, NAD+ levels in our body decline. Supplementation with NAD+ precursors like NR and NMN can help to replace the NAD+ lost with age. 

Related Products:

• Basis: Contains the NAD+ precursor NR and pterostilbene, which work together to target cellular aging and support healthy DNA by increasing NAD+ levels and activating SIRT1.
• Signal: Contains the NAD+ precursor NMN, honokiol, and viniferin. These ingredients work together to target metabolic aging and support mitochondrial function by increasing NAD+ levels and activating SIRT3.

NAD+, nicotinamide adenine dinucleotide, is a critical coenzyme found in every cell of your body. It's involved in hundreds of metabolic processes, but levels of this essential molecule decline with age. The impact of supplements designed to increase NAD+ on the aging process is still being studied.
NAD+ has earned its reputation by playing a role in the body’s central cellular functions. For example, NAD+ is essential in the production of cellular energy and also works throughout the body to support mitochondrial function.
Your body already makes and maintains NAD+ in various ways, specifically by converting food in your diet to NAD+. It’s important to understand that you can increase your levels in other ways, too. Here’s what you need to know about how the body makes and maintains NAD+.

The Link Between NAD+ Precursors and the Diet

When you’re driving a car, you’re probably not thinking about how it was made. But imagine the steps at play in an automotive factory: At the start, it’s simply a handful of separate parts — metal, headlights, radiators, and more — that, when put together with leather and stitching, become a fully functioning car. Each part goes through a series of steps that transform it until ultimately, the car is in its final state: gassed up, shined, and ready to hit the road.

The body’s function in making and maintaining NAD+ is a similar process. Your cells take certain raw materials—in this case, a specific set of molecules that are NAD+ precursors—which go through a series of chemical transformations that turn them into NAD+ the body can put to work. Just as there are multiple ways to manufacture a vehicle that can hit the road, there are many ways NAD+ can be manufactured, too.

NAD+ precursors are the raw materials from which your body makes NAD+. Each NAD+ precursor follows a pathway made up of steps that chemically convert the precursors to NAD+. Some pathways are more efficient than others, some provide more NAD+, and some provide less, but all of them lead to the same thing: NAD+.

It’s not entirely known why NAD+ declines, but what’s suspected is that NAD+-consuming enzymes, which provide various benefits to the body’s biological function, essentially “use up” NAD+.

Scientists believe it’s possible that we get a sufficient amount of NAD+ precursors from our diet to support the NAD+ biosynthesis required for normal functioning, but not to replace the NAD+ lost with age. This is where supplementation with NAD+ precursors can help.

 The five predominant NAD+ precursors are:

• Nicotinic acid, also called niacin, or NA for short
• Nicotinamide, or Nam for short
• Nicotinamide riboside, or NR for short
• Nicotinamide mononucleotide, or NMN for short 
• Tryptophan

NA, Nam, and NR are each a variation of vitamin B3. Vitamins are organic compounds that the body needs to function and can access through whole foods, fortified processed foods, or supplementation. For example, vitamin B — of which there are eight types — is a vitamin we get from our diets in foods like beef, milk, eggs, yeast, lentils, spinach, and salmon.

Look at the label of any regular baking flour, and you'll likely find niacin, or NA, listed as an ingredient. The U.S. government and international governments mandate that enriched flours include NA. This dates back to the early 1900s, when a fatal disease called pellagra was plaguing the American south. It was eventually mitigated by doctors who identified poor diets, specifically lacking vitamin B3s, were to blame.

While the three vitamin B3 precursors to NAD+ each provide their own benefits and all eventually get made into NAD+, one is thought to be highly efficient: NR.

A 2016 study tested all three of these precursors in mice, concluding that NR was the most efficient of the three precursors. Additional research is needed to confirm a similar effect in humans. The efficacy of each precursor can be attributed to the pathway each takes to get to NAD+. NR simply has the most direct route to NAD+, whereas Nam and NA take less productive pathways to become NAD+.

If these pathways were the conveyor belts inside an automotive factory, each one producing the same car but with different steps, then NR’s pathway would be the conveyor belt that uses the least amount of machinery and electricity to get the most amount of cars.

There is another NAD+ precursor which is actually one step closer to NAD+: NMN. In fact, NR has to be converted to NMN before it becomes NAD+. NMN is not a vitamin B3 but its molecular structure is almost identical to NR—NMN has an added phosphate group which makes it slightly larger than NR. Scientists use to believe that NMN was too large to cross cellular membranes and must convert to NR before entering cells, where it would then revert back to NMN and subsequently to NAD+. However, studies now show that there is an NMN-specific transporter (Slc12a8), expressed on cell surfaces that may aid in its cellular entry. Indeed, human clinical trials, including our own study on Basis, demonstrate that oral supplementation with NMN or NR both result in significant increases in plasma NAD+ levels. Interestingly, the NMN transporter was shown in mice to be unequally distributed throughout the body, suggesting that different tissues and organs may utilize the various precursors in distinct ways.

Tryptophan is another NAD+ precursor, but it’s the least efficient one, having to go through the most complex pathway before transforming into NAD+. Tryptophan is an amino acid that might sound familiar because it’s in turkey and is often mistakenly touted for making people tired after Thanksgiving dinner. 

NAD+ Pathways in the Body

Once you do consume something with an NAD+ precursor in it, be it through diet or supplementation, it works its way through the body on one of the pathways.

The "de novo pathway" works with the NAD+ precursor tryptophan, converting it into another molecule called quinolinic acid that eventually merges with one of the other NAD+ pathways, the "Preiss-Handler pathway". The Preiss-Handler pathway, named after scientists Jack Preiss and Philip Handler who discovered it in 1958, converts NA into NAD+, but it also consolidates the tryptophan-turned-quinolinic acid to create NAD+ as well.

There’s also the "salvage pathway", which can lead to NAD+ in a variety of ways. There’s a lot happening in the salvage pathway at once. This pathway is the route for NR and Nam, both of which convert to NMN before turning into NAD+. They go through different reactions, however. NR bypasses what’s called the rate-limiting step in the pathway, which Nam has to go through. The rate-limiting step limits the rate at which NAD+ can be produced.

The salvage pathway also has a recycling element. NAD+-dependent enzymes, like sirtuins, use NAD+ by breaking off what they need of NAD+ and sending the rest — Nam — through the pathway to be recycled back into NAD+.

If this part of the pathway were one of the conveyor belts in the automotive factory, it’d be like taking a car apart and breaking down the parts to make something else, then reusing the leftover parts to make another car.

Other Ways to Get More NAD+

You may be wondering why you can’t just take a pill made up of NAD+, and that’s because NAD+ is not bioavailable, meaning it can’t be taken orally and still survive the digestion process. It’s also very large, twice as large as NMN. With the possible exception of certain neurons, human cells cannot import NAD+.

Other ways to boost NAD+, like caloric restriction and exercise, have also been studied but require more research. In the meantime, supplementing with NAD+ precursors like NR and NMN has been proven in human clinical trials to safely and effectively boost NAD+ levels in the body.

Regardless of how the body is acquiring its NAD+ supply, our cells are hard at work making, using, and maintaining NAD+.

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