What is NAD (nicotinamide adenine dinucleotide)?

NAD is the short form of nicotinamide adenine dinucleotide. The molecule consists, mutatis mutandis, of two mononucleotideslinked together by a chemical bond. It is present in almost all of our cells and lower NAD levels are a sign of aging.

For this reason, research is being conducted with great zeal on how to keep the level as high as possible in old age. In this overview, you will learn everything you need to know about NAD. We travel through the past, present and future of the molecule and introduce you to the most important studies of the longevity molecule.

What is NAD?

NAD is a coenzyme that is found in almost every cell of an organism. A coenzyme is a small organic molecule, such as vitamins, that works with an enzyme to start a chemical reaction. As an analogy, imagine a co-pilot. This co-pilot takes on important tasks to relieve the pilot so that they can both steer the plane safely. The situation is similar with NAD. It supports hundreds of processes in your body. This team effort enables molecules like NAD to help determine the action of enzymes.

According to one study, NAD is needed for over 500 of these enzymatic reactions in the organism. It is therefore obvious that the sought-after co-pilot plays an important role in a number of biological processes. We'll tell you exactly which biological processes these are in a moment. Before we look at the present, let's take a brief detour into the past.

Review

The molecule was first described in 1906 by the two scientists Arthur Harden and William Young in the context of alcoholic fermentation. Interestingly, NAD plays a role in both the production of alcohol and the breakdown thereof. Three decades later, Otto Warburg successfully demonstrated that NAD plays a role in redox reactions in the body. Redox stands for reduction-oxidation and describes a type of chemical reaction in which one reactant gives up electrons (negative charges) to another reactant. This type of chemical exchange plays a major role in combustion and metabolic processes, in detection reactions of certain substances and in technical production. Margarine, pyrotechnics or ammonia-based fertilizers, for example, only became reality through the redox reaction.

Did you know? Niacin, a precursor of NAD, was the first "drug" discovered that could lower LDL levels. In the 1950s, Rudolf Altschul administered high doses of niacin to lower cholesterol levels. The development of today's statins or PCSK9 inhibitors did not begin until much later.

By the 1960s, people thought they knew everything about NAD and its functions when a new discovery made waves. The molecule plays a role in PARylation, a DNA repair process. PARPs are enzymes that require NAD as a cofactor. This knowledge gave new impetus to research.

The reason for the molecule's current popularity in scientific circles is not that, however, but a seven-member gene family called sirtuins (SIRT1-7). Sirtuins are multifunctional enzymes that can regulate almost all cellular functions and require NAD to function. Science unceremoniously gave the sirtuins the name longevity genes because of the flourishing optimism surrounding their role in recent longevity research.

Did you know? Fasting is now known to have beneficial effects on ageing. To a large extent, these effects occur through the activation of sirtuins, especially SIRT1. There are even entire diets that focus on activating sirtuins. The Sirtfood diet has become famous thanks to the singer Adele, among others. The Italian-American doctor Valter Longo also relies indirectly on the activation of sirtuins with his mock fasting diet.

Molecules such as glucosamine, berberine and spermidine can support the fasting process on a molecular level.

NAD, NAD+ & NADH - who is who?

These three terms are once used side by side and then again only in isolation in scientific papers. The most common term is NAD for NAD+ or vice versa. The distinction between these and the other molecules is often somewhat obscure. This sounds like a need for clarification, which we will now address.

The discovery of Otto Warburg around NAD and its redox properties contributed significantly to the clarification of the term. He was the one who defined NAD as a "chemical backbone independent of charge". Accordingly, NAD+ is the oxidized form (can accept electrons) and NADH is the reduced form (can donate electrons) of NAD. When viewed together, chemistry refers to NAD+/NADH as a so-called redox couple.

The harmony of this relationship is incredibly important for energy production in the human body. NADH releases electrons to the respiratory chain in the mitochondrion, the powerhouse of the cell, and thus enables the production of the universal energy source for us humans: Adenosine triphosphate(ATP). What remains is NAD+ and its willingness to take up electrons again.

NAD is then the general term to describe the redox couple and its reactions. For this reason, we have used the term NAD up to now and also in the further course.

NAD metabolism - three paths to success

Small warning up front, we will once again have to dive deeper into the physiology and biochemistry of our bodies. But don't worry, it will be worth it, because a deeper understanding of NAD metabolism will help you better understand arguably one of the most exciting molecules in longevity research.

By the end, you'll understand when our body needs the molecule, how it makes it, and how it is broken down. At the end of this chapter we show why, according to current scientific findings, NAD metabolism is more complex than assumed and why supplementation of the precursors alone is probably not sufficient.

The amount of NAD may be constantly measurable over a period of time, but in fact the molecule is constantly being reassembled, degraded or recycled in cells. On average, a person's occurrences amount to about three grams.

The coenzyme exists in the body in two "states" - either as a free molecule or bound to proteins. The ratio to each other is known as the ratio, which varies in cells and tissues. Mammalian cells, apart from nerve cells, cannot import or absorb NAD.

Consequently, the molecule must first be newly assembled in the cell from different components. This de nov o pathway ('de novo' Latin for "anew") is followed starting from the essential amino acid tryptophan or from other forms of vitamin-B3.

In order to maintain the NAD level internally in the cell, it is mainly "recycled" via the so-called salvage pathway. "salvage" comes from the English language and means something like "salvage" or "save". So the majority of nicotinamide adenine dinucleotide in our bodies is recycled and not newly manufactured. There is then also a third pathway to create the molecule. In the "price-handler pathway," niacin forms the starting material. Niacin and tryptophan are combined in the NAD Regenerating Complex (regeNAD) contained.

In the following graphic, the mentioned metabolic pathways are again clearly shown.

NAMPT - the key to obtaining NAD

In the production of NAD, there is a rate-determining step. This means that the synthesis is dependent on an enzyme. If there is enough of the enzyme, a lot of the molecule can be produced - if the enzyme is missing, production stops or is at least restricted.

The key enzyme is called NAMPT and supports the first step in the recycling pathway, where nicotinamide (Nam) is converted into nicotinamide mononucleotide (NMN). The amount of NAMPT is highly dynamic - i.e. it can adapt very quickly to the changing NAD requirements in the cell. These changing conditions also include cell stress, which is triggered by DNA damage or starvation.

NAD degradation

Our body can break down NAD via various pathways. One of the most important of these is the enzyme CD38. However, the "CD" does not stand for compact disc and the number following it is not the volume of BRAVO hits - CD in this case is the abbreviation for "cluster of differentiation".

These "clusters" are surface features on cells. Think of the whole thing as a kind of recognition feature of cells. These surface molecules can be used, for example, by patrolling immune cells to detect whether they are invaders with "wrong" surface features. In addition to their pure recognition function, these molecules are also often enzymes at the same time. This means that they are responsible for biochemical reactions in our body. To date, about 400 of these features are known.

Did you know? The discovery of increased expression of some of these distinguishing features on cancer cells, for example, has led to groundbreaking advances in cancer therapy. Researchers have developed antibodies that target certain CD. One example is CD20 in the context of lymphoma. The antibody binds to the CD molecule and thus marks the cell for the immune system, which can attack the tumor cell (and, unfortunately, all healthy cells with the same surface feature).

CD38

CD38 is present not only in some cells, but in all cells, and its enzymatic function ensures the degradation of NAD+. This was discovered by genetically modifying mice so that they no longer possessed CD38. These test animals had significantly higher NAD levels.

Another molecule that has been shown in research to be an effective CD-38 inhibitor is apigenin, which is found naturally in parsley, for example. Mice treated with apigenin had about 50% more NAD than the control group.

There is also a third scientific hint in this direction: In one study, CD38 was genetically "switched off" in old, 32-month-old mice. As a result, the NAD levels in the old mice rose again to such an extent that they had the same level as their younger conspecifics. In addition, these mice were resistant to the negative effects of high-fat diets such as fatty liver or glucose intolerance.

What does NAD do in the body?

There are hundreds of NAD-dependent processes in our body. Two of the most important signaling protein families for longevity research are the sirtuins and the PARPs. Sirtuins, also known as longevity genes, were described in the mid-1980s as telomere-protecting proteins. Today we know that they can do much more. They play an important role in mitochondrial metabolism, inflammation, cell division, autophagy processes, the circadian rhythm and planned cell death (apoptosis).

While the Sirtuine family has "only" seven representatives, the PARP family is significantly larger. However, not all subclasses have been equally well researched. This basic research is very complex and extensive, which is why researchers still have a lot of work to do to improve our understanding of it accordingly.

We now know that PARP1 and PARP2 play an important role in DNA repair and translation. By translation, scientists mean the process by which our genetic code is translated into an effective "protein.

What role does NAD play in this process? If our DNA is damaged, PARP1 is overactivated, which in turn causes the NAD level in our cells to drop. This is one of the reasons why cells later die "planned".

But why does our body do that? In fact, the mechanism is quite clever. Damaged DNA can lead to malfunctions and diseases. Our body wants to get rid of such faulty cells as soon as possible. The PARP1/NAD pathway is one of them. By the way, PARP1 behaves quite differently in healthy cells. It becomes a so-called low-turnover enzyme. This means that only very little NAD is degraded by PARP1. Only in the case of DNA damage (which becomes more frequent with age) does PARP1 become active.

Why does NAD decrease with age?

Scientists have three possible explanations for this central question in aging research:

1. NAD production decreases with age
2. Degradation is increased (e.g. by CD38)
3. A combination of both processes

To be able to classify this more precisely, it helps to take another look at NAD research. So that you don't have to trudge through pages and pages of dry studies, we have summarized the most important points from the various studies:

Decrease in NAMPT activity

Brief refresher, NAMPT is the rate-determining enzyme in the recycling pathway - the most active NAD+ metabolic pathway in the organism. Perhaps an analogy to this. In Formula 1, about ten mechanics need a good 2 seconds to change 4 tires of a car.

If you change the tires on your own, it will take you much longer. In that case, the number of mechanics is the speed-determining step - the fewer people involved, the longer it will take. Here's how you can think of it with NAMPT. As you age, there's simply less of the enzyme, and so your NAD synthesis slows down.

Overactivation of PARPs

The older we get, the more DNA damage accumulates. Our body becomes less effective at eliminating broken cells and cell stress and inflammaging increase. All this DNA damage leads to over-activation of PARP1 and thus increased NAD consumption. However, the research results on PARP1 inhibition are still very vague. Here we cannot tell you exactly whether it is beneficial to inhibit PARP1 at all.

CD38 - a possible "culprit?"

In addition to PARPs, CD38 activity also increases with age. Why is this the case?

It is now clear that CD38 activity is regulated in a very complex manner. The apparently most important connection is between CD38 and chronic inflammatory processes. This silent "inflammation" has been linked in numerous studies to disease processes in old age (inflammaging). Persistent inflammation upregulates CD38, which in turn neatly (and permanently) consumes NAD.

Less NAD then ultimately means less efficient energy provision and reduced functionality of dependent enzymes (see sirtuins and PARPs).

Is it possible to stop the decline?

Just as there are different hypotheses for age-related decline, there are also different approaches to maintain NAD levels.

(1) Supplementation of precursors

The fact is that more NAD is consumed in old age. A logical thought would therefore be to increase production or support recycling. Taking NAD precursors for this purpose is actually a well-studied scientific approach to keep levels high.

If we were to take NAD directly, it would be of little use, since on the one hand the molecule is "decomposed" in our stomach and on the other hand there is no transporter for NAD in the cell membrane. That is why NAD infusions, which are usually very expensive, are discussed critically. Here, the problem with the stomach acid is circumvented - but the molecule is still "too big" to get directly into the cells.

NAD precursors are usually different vitamin B3 variants such as nicotinamide, niacin or tryptophan. The well-known nicotinamide riboside (NR) is also one of them. However, in 10 studies in humans using the precursor molecule NR , researchers found conflicting results. In some, it led to a strong NAD increase and also to the hoped-for health benefits, but in other studies it did not.

One explanation is that NR is not the "optimal" precursor. Indeed, researchers found that while other degradation products of NAD, such as MeNAM and Me2YP, increased after supplementation with NR, NAD did not always. This suggests that new NAD was simply degraded faster based on NR supplementation.

(2) Activation of enzymes that produce NAD.

The enzymes required for the production of the molecule - including NAMPT and NMNAT- are another key factor in NAD metabolism. The former catalyzes the important, rate-determining reaction of nicotinamide(Nam) into nicotinamide mononucleotide (NMN). Without this enzyme, our body cannot produce NAD. Interestingly, in one study, exercise led to a 127% increase in NAMPT.

The second important enzyme is NMNAT. It enables the very last step in the production of NAD - namely the transfer of ATP to NMN. In this context, epigallocatechin gallate (EGCG) - the most important ingredient in green tea - is a promising booster of NMNAT.

Apart from specific molecules, fasting or caloric restriction has also been shown to increase NAD levels in some studies. The physiological background is complex, as a number of metabolic processes are involved. On the one hand, fasting leads to an activation of sirtuins and AMPK - and on the other hand to a decrease in mTOR activity. As a result, our cells switch to a kind of resilience mode for evolutionary reasons. A small side effect: fasting also lowers inflammation levels in the body.

(3) Inhibition of degradation

We have already seen the major role that CD38 and PARP1 play in NAD degradation. In animal studies, the inhibition of CD38 in particular appears to be a promising way to increase NAD. One molecule that is a potent CD38 inhibitor is apigenin . Both can increase cellular NAD+ levels and have also shown positive metabolic effects in one study.

What are the benefits of a high NAD level?

It is scientifically proven that NAD levels fall with age. It is also known that this has numerous negative consequences. But what are the concrete benefits of a higher intracellular level?

How do you actually measure NAD? In all probability, your family doctor will not be able to offer you a test for this - the evaluation is only possible in special laboratories. However, the determination is quite important - for example, if you want to influence your NAD level.

Together with Vilnius University, MoleQlar has developed the only European NAD test to date. This allows you to find out where you stand and check which method has been proven to help you increase your levels.

NAD and memory performance - more power for your nerve cells

Billions of nerve cells, active both during the day and at night, make up our brain. It is probably one of the most fascinating facilities of our body. Almost 120g of sugar, in the form of glucose and about 20% of the daily oxygen requirement go on the bill of this organ weighing about 1.5kg.

The high energy requirement naturally presupposes a correspondingly high mitochondrial density. NAD as an important mitochondrial agent therefore has its fingers in the pie here. Studies showed that people with Alzheimer's disease had improved mitochondrial function due to an increase in NAD levels and that their memory performance improved as a result.

The rest of our nervous system also benefits from the molecule. Increased levels significantly improved the transmission of stimuli. In addition, a study shows that volume-induced hearing loss is reduced. And anyone who has ever heard everything muffled for a few hours after a concert knows how unpleasant that can be.

Did you know? In addition to loss of function, our mitochondria also become fewer in number as we age. One way to produce more mitochondria is to exercise. Whether strength or endurance - both promote the production of new cellular power plants.

In addition, a study by Bayor College of Medicine showed that the regular intake of GlyNAC led to a measurable improvement in mitochondrial function.

Improved muscle function

Not only our brain depends on mitochondria, but also our muscle cells. We need the ATP to contract our muscle fibers. The more ATP we can generate through our mitochondria, the stronger or the more endurance we have.

Animal studies have shown time and time again that higher NAD levels can contribute to improved muscle function. So is this a possible secret to helping our bodies stay fit and agile as we age?

Effects on the cardiovascular system

When it comes to energy, it's hard to imagine life without the heart. No other muscle is as enduring as our heart. It will beat more than 1 billion times in the course of our lives without forming new cells. For this, it needs an incredible amount of mitochondria.

More than 30% of the cell mass is taken up by our cellular power plants and these all need NAD. And this is exactly why our central vital organ benefits from an increased NAD supply. The result: more powerful heart cells and increased pumping power.

Did you know? One of the most important factors for cardiovascular health is your blood lipid levels. The assumption of "good" and "bad" cholesterol, which has existed for many decades, has been shown to be inaccurate according to recent studies. Instead, you need to look at the individual blood fat levels side by side.

If you want to find out more about the individual blood lipid levels and the egg myth, read our big blood lipid values guide in the magazine.

Detox booster

In addition to muscle and nerve cells, there is a third type of cell that has been shown to benefit from high NAD levels: Liver cells

Our liver has to perform a whole host of tasks every day. It stores energy in the form of glucagon, produces important proteins for our coagulation system and, most importantly, detoxifies our body. To do this, the liver has a variety of different enzymes at its disposal, which you can think of as tools. However, these tools only work well if sufficient NAD is available.

NAD as infection control?

One study looked at immune defense in SARS-CoV-2 infections and found interesting results: NAD plays an important role in virus defense via the PARP enzyme.

But wasn't it said that PARP1 leads to a degradation of NAD? That is true, however, there are several subclasses of the PARP family besides PARP1. Some of these are involved in cellular immune defense against viruses. These PARP molecules (not PARP1) in turn require NAD to function better. While this study was "only" able to find a direct link with SARS-CoV-2, it is possible that this could also be applicable to other viral pathogens.

NAD - the fountain of youth of life?

In addition to all the performance-enhancing effects on organs, why have high NAD levels been shown in so many studies to have a positive effect on health and longevity? One explanation here is that NAD seems to affect all the molecular hallmarks of aging. Consistently, an increase in NAD levels leads to an improvement in all hallmarks.

This is what makes this molecule so interesting in longevity research. While many substances only address one part of the problem, NAD seems to be a promising candidate that addresses as many aging processes as possible simultaneously.

We have seen that NAD metabolism is complex and depends on many factors. The degradation of NAD also plays a greater role than initially thought. There are still some questions to be answered here. For example, we know that higher CD38 levels are responsible for degradation in the elderly. High CD38 levels are associated with increased inflammation and DNA damage. But which comes first? Similar to the chicken-and-egg problem, we don't yet know exactly how the individual factors interact with each other.

It will probably take some time before these complex questions are clarified - in any case, the NAD topic remains exciting! What is now scientifically very well established is the fact that high NAD levels are beneficial for our body. For this reason, it can be useful for everyone to determine their own NAD level and to counteract the natural decline through a combination of exercise, a healthy diet and appropriate boosters!