NAD+ is the short form of nicotinamide adenine dinucleotide. The molecule consists of two mononucleotides that are connected to each other via a chemical bond. It is present in almost all of our cells and low NAD levels are a sign of ageing.
For this reason, a great deal of research is being carried out into how to keep levels as high as possible as we 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 on 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 together with an enzyme to initiate a chemical reaction. Imagine a co-pilot as an analogy. The 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.
A study has shown that NAD is required for over 500 of these enzymatic reactions in the organism. It therefore stands to reason that the sought-after co-pilot plays an important role in a number of biological processes. We'll explain exactly which biological processes these are in a moment. Before we look at the present, let's take a brief detour into the past.
NAD levels decrease dramatically over time - in both men and women!
Rückblick
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 both in the production of alcohol and in its degradation. 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 reaction partner releases electrons (negative charges) to another reaction partner. 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 a reality thanks to 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 gave high doses of niacin and thus lowered the cholesterol level. The development of today's statins or PCSK9 inhibitors only began much later.
In 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 this, however, but a seven-member gene family called sirtuins (SIRT1-7). Sirtuins are multifunctional enzymes that can regulate almost all cell functions and require NAD to function. Due to the flourishing optimism surrounding their role in recent longevity research, the scientific community quickly gave sirtuins the name longevity genes.
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, in particular SIRT1 . There are even entire diets that focus on activating sirtuins. The sirt food diet has become famous thanks to the singer Adele, among others. The Italian-American doctor Valter Longo also indirectly relies on the activation of sirtuins with his mock fasting diet.
Molecules such as glucosamine, berberine and spermidine capsules can support the fasting process at a molecular level.
NAD, NAD+ & NADH - who is who?
These three terms are sometimes used side by side and then again only in isolation in scientific papers. The term NAD is most frequently used for NAD+ or vice versa. The distinction between one molecule and another is often somewhat opaque. This sounds like a need for clarification, which we are now addressing.
Otto Warburg's discovery of NAD and its redox properties made a significant contribution to clarifying the term. He was the one who defined NAD as a "chemical backbone independent of charge". NAD+ is therefore the oxidized form (can accept electrons) and NADH is the reduced form (can donate electrons) of NAD. Together, chemistry refers to NAD+/NADH as a so-called redox pair.
The harmony of this relationship is incredibly important for energy production in the human body. NADH releases electrons to the respiratory chain in the mitochondria, the power plants of the cell, thereby enabling 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. Mitochondria can be strengthened , for example, by optimizing NAD levels.
NAD is then the general term to describe the redox couple and its reactions. For this reason, we have used the term NAD so far and will continue to do so in the following.
NAD metabolism - three paths to success
Little warning up front, once again we need to delve deeper into the physiology and biochemistry of our body. But don't worry, it will be worth it, because a deeper understanding of NAD metabolism will help you to better understand one of the most exciting molecules in longevity research.
By the end, you will understand when our body needs the molecule, how it is made and how it is broken down. At the end of this chapter, we show why, according to current scientific findings, the 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 certain period of time, but the molecule is actually completely reassembled, degraded or recycledin cells. On average, the occurrence of a person is around three grams.
The coenzyme is present in the body in two "states" - either as a free molecule or bound to proteins. The relationship between the two is known as the ratio, which varies in cells and tissues. With the exception of nerve cells, mammalian cells cannot import or absorb NAD.
As a result, the molecule must first be reassembled in the cell from different components. This de novo pathway ('de novo' lat. for "from new") is taken starting from the essential amino acid tryptophan or from other forms of vitamin B3 .
In order to maintain the NAD level within the cell, it is mainly "recycled" via the so-called salvage pathway. "salvage" comes from the English and means something like "salvage" or "rescue". The majority of nicotinamide adenine dinucleotide in our body is therefore recycled and not newly produced. There is also a third pathway to produce the molecule. In the "Preiss-Handler pathway", niacin forms the starting material. Niacin and tryptophan are contained in the NAD Regenerating Complex .
In the following graphic, the metabolic pathways mentioned are clearly illustrated again.
NAD can be produced in our body in three different ways. The most important pathway is the recycling pathway, which leads via NMN in the final step.
NAMPT - the key to obtaining NAD
In the production of NAD there is a speed-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 triggered by DNA damage or starvation. Genomic instability is also one of the Hallmarks of Aging.
Dismantling of NAD
Our body can break down NAD in various ways. One of the most important is the enzyme CD38. However, the "CD" does not stand for compact disc and the following number is not the volume of the BRAVO hits - CD in this case is the abbreviation for "cluster of differentiation".
These "clusters" are surface features on cells. Think of it as a kind of cell recognition feature. For example, patrolling immune cells can use these surface molecules to recognize whether they are intruders with "wrong" surface features. In addition to the pure recognition function, these molecules are also often enzymes. This means that they are responsible for biochemical reactions in our body. To date, around 400 of these characteristics are known.
Did you know For example, the discovery of increased expression of some of these distinguishing features on cancer cells has led to groundbreaking advances in cancer therapy. Researchers have developed antibodies that target certain CD. One example of this is CD20 in the context of lymphomas. The antibody binds to the CD molecule and thus marks the cell for the immune system, which can attack the tumor cell (and unfortunately also all healthy cells with the same surface feature).
This is what the "ectodomain fragment" of the CD38 enzyme looks like, greatly enlarged.
CD38
CD38 is not only found on some cells, but on all cells and ensures the degradation of NAD+ through its enzymatic function. This was discovered by genetically modifying mice so that they no longer have CD38. These experimental animals had significantly higher NAD levels.
Another molecule that has proven to be an effective CD-38 inhibitor in research is apigenin, which is found in nature, for example in parsley. Mice treated with apigenin had around 50% more NAD than the control group.
There is also a third scientific clue in this direction: In one study, CD38 was genetically "switched off" in old, 32-month-old mice. Thus, the NAD levels in the old mice increased 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 a high-fat diet such as fatty liver or glucose intolerance.
What does NAD do in the body?
Hundreds of NAD-dependent processes are found 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.
We now know that PARP1 and PARP2 play an important role in the repair of DNA and in translation. Scientists understand translation as the process in 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 in a "planned" manner.
But why does our body do this? The mechanism is actually quite clever. Damaged DNA can lead to malfunctions and diseases. Our body wants to get rid of such faulty cells as quickly as possible. The PARP1/NAD pathway is one of them. Incidentally, PARP1 behaves quite differently in healthy cells. It becomes a so-called low-turnover enzyme. This means that very little NAD is degraded by PARP1. Only when DNA damage occurs (which becomes more frequent with age) does PARP1 become active.
NAD+ plays a role in numerous processes in our organism.
Why does NAD decline with age?
Scientists have three possible explanations for this central question in aging research:
- NAD production decreases with age
- The degradation is increased (z.B. by CD38)
- A combination of both processes
To be able to categorize this more precisely, it helps to take another look at NAD research. We have summarized the most important points from the various studies so that you don't have to slog through pages of dry studies:
Decrease in NAMPT activity
Short refresher, NAMPT is the speed-determining enzyme in the recycling pathway - the most active NAD+ metabolic pathway in the organism. Perhaps an analogy here. In Formula 1, about ten mechanics need a good 2 seconds to change 4 tires on a car.
If you change the tires alone, you need significantly longer. In this case, the number of mechanics is the speed-determining step - the fewer people involved, the longer it will take. You can imagine this with NAMPT. As you get older, there is simply less of the enzyme present and your NAD synthesis slows down as a result.
Overactivation of the PARPs
The older we get, the more DNA damage accumulates. Our body becomes less effective at eliminating damaged cells and cell stress and inflammaging increase. The high level of DNA damage leads to an overactivation of PARP1 and thus to 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, the activity of CD38 also increases with age. Why is this the case?
It is now clear that CD38 activity is regulated in a very complex way. 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). Permanent inflammation upregulates CD38, which in turn consumes a lot of (and permanent) NAD.
Less NAD ultimately means less efficient energy supply and reduced functionality of dependent enzymes (see sirtuins and PARPs).
NAD can be increased through exercise, fasting & nutrition, as well as through NAD boosting and thus unfold its positive effects.
Can the decline be stopped?
Just as there are different hypotheses for age-related decline, there are also different approaches to maintaining NAD levels.
(1) Supplementation of precursors
The fact is that more NAD is consumed in old age. A logical idea would therefore be to increase production or support recycling. Taking NAD precursors for this purpose is actually a well-studied scientific approach to keeping levels high.
If we were to ingest NAD directly, it would do little good, as the molecule is "decomposed" in our stomach and there is no transporter for NAD in the cell membrane. This is why NAD infusions, which are usually very expensive, are discussed critically. Although the problem with stomach acid is avoided here, 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-knownnicotinamide riboside (NR) is also one of them. However, in 10 studies on humans with the precursor molecule NR the researchers did not find entirely consistent results. In some, it led to a strong increase in NAD and also to the hoped-for health benefits, but not in other studies.
One explanation for this is that NR is not the "optimal" precursor. Researchers found that other degradation products of NAD, such as MeNAM and Me2YP, increased after supplementation with NR, but not always NAD. This suggests that new NAD was simply broken down more quickly following NR supplementation.
NAD infusions are viewed critically by experts because the molecule is too large to enter the cells directly.
(2) Activation of enzymes that produce NAD
Another key player in NAD metabolism are the enzymes required to produce the molecule - including NAMPT and NMNAT. 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 percent 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 - 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 particular, inhibition of CD38 appears to be a promising pathway for NAD enhancement in animal studies. One molecule that is a potent CD38 inhibitor isapigenin . Both can increase cellular NAD+ levels and have also shown positive metabolic effects in one study.
What are the advantages of a high NAD level?
It has been scientifically proven that NAD levels fall with increasing age. It is also known that this has numerous negative consequences. But what are the specific advantages of a higher intracellular level?
How do you actually measure NAD? It is very likely that your GP will not be able to offer you a test for this - the evaluation is only possible in special laboratories . However, the determination is very important - for example, if you want to influence your NAD level
To date, MoleQlar has developed the only European NAD testin collaboration with Vilnius University. 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 that are active both during the day and at night make up our brain. It is probably one of the most fascinating structures in our body. Almost 120g of sugar, in the form of glucose, and around 20% of our daily oxygen requirements are accounted for by this organ, which weighs around 1.5kg.
The high energy requirement naturally requires a correspondingly high mitochondrial density. NAD as an important mitochondrial agent therefore has a hand in this . Studies have shown 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. An increased level improved the transmission of stimuli significantly . A study also shows thatvolume-induced hearing loss is reduced. And anyone who has ever heard everything muffled for a few hours after a concert knows how unpleasant this can be
Did you know? In addition to a 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 the Bayor College of Medicine showed that the regular intake of GlyNAC led to a measurable improvement in mitochondrial function .
Improved muscle function
It's not just our brain that relies on mitochondria, but also our muscle cells. We need ATP to contract our muscle fibers. The more ATP we can generate through our mitochondria, the stronger or more enduring we are.
In animal studies, it has been shown time and time again that higher NAD levels can contribute to improved muscle function. So is this a possible secret of how we can support our bodies to remain fit and agile in old age?
Effects on the cardiovascular system
When it comes to energy, the heart is indispensable. 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. This requires an incredible amount of mitochondria.
More than 30% of the cell mass is taken up by our cellular power plants and these all require NAD . And this is precisely why our central vital organ benefits from an increased supply of NAD . 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 proven to be inaccurate according to recent studies . Instead, the individual blood lipid values must be considered 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 levelsGuide in the magazine.
Entgiftungsbooster
In addition to muscle and nerve cells, there is a third cell type 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, very importantly, detoxifies our body. To do this, the liver has a large number 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 protection against infection
A study has looked at the immune defense in SARS-CoV-2 infections and found interesting results: NAD plays an important role in viral defense via the PARP enzyme.
But wasn't it said that PARP1 leads to the degradation of NAD? That's true, but there are various subclasses of the PARP family in addition to PARP1. Some of them are involved in the cellular immune defense against viruses. These PARP molecules (not PARP1) in turn require NAD to function better. While this study "only" found a direct correlation with SARS-CoV-2, it is possible that this is also transferable to other viral pathogens.
NAD - the fountain of youth?
In addition to all the performance-enhancing effects on the organs, the question arises as to why high NAD levels have been shown in so many studies to have a positive effect on health and longevity One explanation here is that NAD appears to affect all the molecular markers of ageing . Consequently, 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 appears to be a promising candidate that addresses as many ageing 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 a higher CD38 level is responsible for degradation in older people. High CD38 levels are associated with increased inflammation and DNA damage. But what comes first? Similar to the chicken and egg problem, we do not yet know exactly how the individual factors influence each other.
It will probably be some time before these complex questions are clarified - in any case, the NAD issue remains exciting! What is now very well established scientifically 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!
