What Is So Interesting About NAD+?
Nicotinamide adenine dinucleotide, otherwise known as NAD+, has been all the rage recently. However, what actually is it? NAD+ is a very critical coenzyme that is necessary for the proper functioning of hundreds of enzymes throughout the body. Furthermore, it is found in every cell of the body and plays a crucial role in energy production and metabolism. In fact, a highly prominent NAD+ researcher, Dr. David Sinclair, has often proclaimed that without NAD+ in our bodies, we would be dead in 30 seconds! That’s quite a claim. It’s also very much true, which highlights the sheer importance of NAD+.
Due to its presence in all of our cells, it is quite clear that maintaining adequate NAD+ levels are crucial to our overall health. The problem is that NAD+ levels decline as we age. Due to this, NAD+ has often been touted as one of the best longevity supplements out there. Replenishing NAD+ levels as we age can help enhance our energy levels, circadian rhythms, metabolism, cognitive function, and even healing! Even in younger individuals, elevating NAD+ levels could prove to be effective. This is because NAD+ levels can also decline due to various stressors, such as increased oxidative stress and increased body weight. Ensuring your body has adequate NAD+ levels is not only reserved for people in old age!
How is NAD+ made?
We can synthesize our own NAD+ in our bodies, and there are various different pathways which can lead to NAD+ production. The first pathway is the kynurenine pathway otherwise known as the de novo pathway. This pathway utilizes the dietary amino acid L-tryptophan as the starting material for NAD+ production. The path to generating NAD+ in the kynurenine pathway is quite lengthy and complex, and due to this is also not the most efficient pathway for NAD+ production.
The next pathway is the Preiss-Handler pathway which uses dietary nicotinic acid (vitamin B3) to generate NAD+. This pathway appears to be a lot more efficient, and indeed, low dietary intake of vitamin B3 can in fact cause NAD+ deficiencies. That being said, supplementing with nicotinic acid, while good at preventing deficiencies, is not the most efficient way of generating NAD+. For this, we must look towards the next pathway, the salvage pathway!
In the salvage pathway, nicotinamide mononucleotide, otherwise known as NMN, gets directly converted into NAD+ in just a single step! Within this pathway, nicotinamide riboside (NR), is also utilized and serves as a precursor to NMN. With this in mind, the most efficient way to raise NAD+ levels is to supplement with either NMN or NR. Thus, it is no surprise that this is by far the most utilized strategy for those looking to enhance their NAD+ status.
This does raise the question: which is better, NMN or NR? If you are simply looking to enhance NAD+, nothing beats NMN. NAD+ contains a large phosphate group, and this same phosphate group is already present in NMN, but is not present in NR. This is problematic, due to the fact that phosphate chemistry is not easy, and thus requires quite a bit of energy. This means that while NR is a great NAD+ precursor, NMN is better due to being much more efficient. That being said, NR does have some very unique properties within the brain. NR is contained in the axons of neurons, and higher levels of NR in these axons appears to exert a robust neuroprotective effect.
NAD+ Production In Response To Calorie Restriction
NAD+ is also a major metabolic regulator, and responds quite strongly to calorie restriction. This is one of the reasons why fasting can have major health benefits. When we fast, our bodies production of NAD+ is greatly upregulated. This is mainly to act as a protective factor. This is one of the reasons why enhancing NAD+ levels is highly desirable, as it helps make our bodies and brains more resilient.
In addition to fasting, simple calorie restriction also works well to enhance NAD+ production. This is also why being in a caloric surplus and gaining a lot of body weight can have major negative effects on our health, because our NAD+ production greatly slows down. In fact, it has been shown that in general, individuals who are overweight tend to have lower levels of NAD+. With this in mind, simply restricting our caloric intake and allowing ourselves to feel hungry is a great strategy for maintaining NAD+ levels. Pair this with a great NAD+ precursor like NMN or NR, and then you’re really elevating your NAD+ levels!
NAD+ Production In Response To Circadian Rhythms
NAD+ production is also under strict circadian control, but more interestingly, NAD+ also helps entrain our circadian rhythms. It has been found that NAD+ production is highest in the mornings, which makes perfect sense as NAD+ has an energizing effect. This also means that supplementing with NMN or NR makes the most amount of sense first thing in the morning, since that is when NAD+ synthesis is most efficient. This is also the time when you will likely welcome the increased energy!
In addition to this, NAD+ helps set and control our circadian rhythms. Thus, enhancing NAD+ levels even further in the morning with NMN or NR should have a positive effect later in the day on sleep. In fact, we have heard from many individuals that taking NAD+ enhancing supplements in the morning has helped enhance their sleep. We have also personally noticed these effects, and would recommend taking NMN or NR early in the morning whenever possible due to this!
Other Factors Which Influence NAD+ Production
So far, we have discussed some direct mechanisms for enhancing NAD+ production, such as supplementing with NMN and/or NR, restricting calories, fasting and taking NAD+ precursors early in the morning. However, there are a few more strategies that can be employed. The first of which is inhibiting an enzyme called CD38. CD38 can degrade NAD+ quite efficiently, and thus will be a roadblock when trying to elevate NAD+ levels. Luckily this enzyme can quite easily be inhibited and this has been shown to have a great effect on enhancing NAD+ status. We like to use apigenin for this purpose, and this has been a favorite amongst many people who are interested in enhancing their NAD+ status. Another compound which influences CD38 is a flavonoid called quercetin, and this is also a popular choice for enhancing NAD+ levels.
One important thing to remember about NAD+, is that a lot of its functions depend on it forming a redox couple with NADH, the reduced version of NAD+. NAD+ and NADH are constantly switching back and forth within this redox couple relationship, in a single step. In addition to this NADH has its own transporters within cells called the malate/aspartate shuttle, so it can even be taken orally (unlike NAD+ itself). When taken orally, NADH functions as an incredibly efficient NAD+ precursor as it is even more efficiently turned into NAD+ than NMN!
Where Do The Sirtuins Factor In?
If you are familiar with NAD+ already, and especially if you have paid attention to David Sinclair in the last few years, then you have probably also heard of sirtuins. Sirtuins are a class of highly important signaling proteins that require NAD+ to function. This means that if there is no NAD+ around, the sirtuins can’t exert their essential functions, such as their deacylase activity. Sirtuins also play a major role in metabolic health and circadian rhythms, and in fact, a lot of the NAD+ benefits are actually coming from its sirtuin activity stimulating effects. This means that without sirtuins we cannot take advantage of NAD+ benefits. This is where supplements such as Quercetin also shine, as they help upregulate sirtuin activity, in addition to enhancing NAD+ levels by inhibiting CD38.
Most famously, resveratrol is taken alongside NAD+ precursors as it has profound effects on the sirtuins. This has been made famous by David Sinclair over the years. However, an unfortunate side effect of this popularity is that we are hyper focused on resveratrol now. This is a shame, because there are lots of incredibly beneficial sirtuin modulators out there that are not resveratrol. At Noo-tropics.eu we actually carry quite a few. These are our current favorites:
● White Jelly Mushroom
● Rhodiola Rosea/Salidrosol
● Magnolia Bark
Bringing It All Together
✔ Significantly Increases NAD+ Levels*
✔ Enhances Cellular Energy*
✔ Supports Healthy Aging*
✔ Promotes Circadian Rhythms*
After really diving into the world of NAD+ over the last few years, we decided it was time to condense all of our knowledge into a stack designed for achieving the most efficient path to NAD+ production. We took all of the concepts discussed so far throughout this blog, and turned this into a multi-faceted approach to increasing NAD+ levels.
We start with a very solid base of two of the most important NAD+ precursors, NMN and NR. While NMN is the more efficient NAD+ precursor of the two, we also are very interested in the unique neuroprotective effects of NR. In addition to this, we discovered that subjectively a combination of both NMN and NR was better at dialing in our energy levels. This really got pushed over the edge when we added in NADH. When we first added NADH to the mix, we all proclaimed “this is rocket fuel!”. The NADH, likely due to the fact that it plays a very important role in ATP production, and is a very efficient way at enhancing NAD+ levels, took the energy and mood effects to the next level. When we took the NADH out, and tried just NMN and NR together, something was clearly missing.
Now that we had our NAD+ precursor base dialed in, it was time to move onto the synergistic components. For this we chose a combination of apigenin and quercetin. Apigenin acts as a great CD38 inhibitor, and quercetin also exerts this same effect. In addition to this, quercetin also helps modulate the sirtuins, which make it a great pairing with the NAD+ precursors.
Last but not least, we decided to add in trimethylglycine, a very good methyl donor. This turns out to be important when we are very significantly raising our NAD+ levels, because higher levels of NAD+ production also mops up quite a lot of the methyl groups in our body. For this reason, it has recently become popular to supplement trimethylglycine with NMN or NR. Adding trimethylglycine into the OptiNAD+ stack was the final cherry on top, just to make sure everything runs like a well oiled machine when you take OptiNAD+!
Sirtuin Focused Stack Ideas
With OptiNAD+, we were after one primary goal: raising NAD+ levels as much as possible, while slightly modulating the sirtuins. However, we did not want to overcomplicate it, and we wanted to keep the dosage and price reasonable. With that in mind, OptiNAD+ works even better when it is also taken alongside a few sirtuin modulators.
There are quite a few to choose from, each one having their own unique auxiliary effects such as stimulation, relaxation or skin health promotion. With this in mind, below are a few goal specific complimentary stacks which focus on OptiNAD+ as the base of the stack.