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 lower NAD levels are a sign of aging.
For this reason, research is being carried out with great enthusiasm into 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 initiate a chemical reaction. As an analogy, imagine a co-pilot. This takes on important tasks to relieve the pilot so that they can both steer the aircraft safely. The situation is similar with NAD. It supports hundreds of processes in your body. This team effort enables molecules such as NAD to help determine the effects of enzymes.
According to a study, NAD is required for over 500 of these enzymatic reactions in the organism. First of all, it is obvious that the sought-after co-pilot plays an important role in a number of biological processes. We'll answer you exactly what biological processes these are. Before we deal with the present, let's take a brief detour into the past.
The NAD level decreases drastically over time - in both men and women!
Review
The molecule was first discovered in 1906 by the two scientists Arthur Harden and William Young as part of the alcoholic fermentation described. Interestingly, NAD plays a role in both the production of alcohol and the breakdown of it. 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 donates electrons (negative charges) to another reactant. This type of chemical barter plays a major role in combustion and metabolic processes, in detection reactions of certain substances and in technical production. Margarine, pyrotechnics and ammonia-based fertilizers, for example, only became reality through the redox reaction.
Did you know? Niacin, a precursor to NAD, was the first “drug” discovered that contains LDL Level could lower. In the 1950s, Rudolf Altschul gave high doses of niacin and thus lowered cholesterol levels. The development of today's statins or PCSK9 inhibitors only began much later.
In the 1960s, people thought they already 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, but rather 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. Because of the blossoming optimism surrounding their role in recent longevity research, science quickly gave the sirtuins the name longevity genes.
Did you know? Fasting is now known to have beneficial effects on aging. To a large extent, these effects occur through the activation of the Sirtuins, in particular SIRT1 . There are even entire diets that rely on activating sirtuins. The Sirtfood diet was made famous by the singer Adele, among others. The Italian-American doctor Valter Longo also relies indirectly on the activation of sirtuins with his pseudo-fasting diet.
molecules such as glucosamine, berberine and spermidine can support the fasting process on a molecular level.
MoleQlar's fasting bundle with glucosamine, berbersome and spermidine is intended to support the fasting process on a molecular level.
NAD, NAD+ & NADH – who is who?
These three terms are used side by side and then only in isolation in scientific treatises. The most common term is NAD for NAD+ or vice versa. The demarcation from the other molecules is often somewhat unclear. That 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. In summary, chemistry refers to NAD+/NADH as the 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 cell's power plant, thereby enabling us humans to produce the universal energy source: Adenosine triphosphate (ATP). What remains is NAD+ and its willingness to accept 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 so far and will continue to do so.
NAD metabolism – three paths to success
A little warning in advance, we must once again delve 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 one of the most exciting molecules in longevity research.
In the end you will understand when our body needs the molecule, how it produces it and how it is broken down. At the end of this chapter we will show why, according to current scientific knowledge, NAD metabolism is more complex than expected and why supplementing the precursors alone is probably not enough.
The amount of NAD may be measurable consistently over a certain period of time, but the molecule is actually constantly being reassembled, broken down or recycled in cells . On average, the occurrences of a person are around three grams.
The coenzyme exists in two “states” in the body – either as a free molecule or bound to proteins. The relationship to each other is called a ratio, which is expressed differently in cells and tissues. Mammalian cells, apart from nerve cells, cannot import NAD or to record
Consequently, the molecule must first be reassembled from different components in the cell. This de novo Path (‘de novo’ lat. for “again”) is based on 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 English and means something like “to rescue” or “to save”. The majority of nicotinamide adenine dinucleotide in our body is recycled and not newly produced. There is then also a third way to create the molecule. Niacin forms the starting material in the “Preiss-Handler pathway”. Niacin and tryptophan are contained in NAD Regenerating Complex (regeNAD) .
The metabolic pathways mentioned are clearly shown again in the following graphic.
NAD can be produced in our body in three different ways. The most important path is the recycling path, which leads via NMN in the last step.
NAMPT – the key to obtaining NAD
In the production of NAD there is a rate-determining step. This means that the synthesis takes place depending on an enzyme. If there is enough of the enzyme, a lot of the molecule can be produced - if the enzyme is missing, then production stops or is at least restricted.
The key enzyme is named 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 - meaning 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.
Degradation 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 – in this case CD is the abbreviation for “cluster of differentiation”.
These “clusters” are surface features on cells. Think of it as a kind of identifying feature of cells. Using these surface molecules, patrolling immune cells can, for example, detect whether there are intruders with “wrong” surface characteristics. In addition to the pure recognition function, these molecules are also often enzymes. This means they are responsible for biochemical reactions in our body. To date, around 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 CDs. An example of this is CD20 in the context of lymphoma. The antibody binds to the CD molecule and 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 how the “ectodomain fragment” of the CD38 enzyme looks greatly enlarged.
CD38
CD38 occurs not only on some but also on all cells and, through its enzymatic function, ensures the breakdown of NAD+. This was found out by genetically modifying mice so that they no longer had CD38. These experimental 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 approximately 50% more NAD than the control group.
There is also a third scientific pointer in this direction: in a study, CD38 was genetically “switched off” in old, 32-month-old mice. As a result, the NAD levels in the old mice increased again so much that they had the same level as their younger counterparts. In addition, these mice were resistant to the negative effects of a high-fat diet such as fatty liver disease 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 as telomere-protecting proteins in the mid-1980s. Today we know that they can do much more. They play an important role in mitochondrial metabolism, inflammation, cell division, autophagy processes, circadian rhythms and planned cell death (apoptosis).
While the Sirtuin 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 their understanding of it.
We now know that PARP1 and PARP2 play an important role in DNA repair and 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 illnesses. Our body wants to get rid of such faulty cells as quickly as possible. The PARP1/NAD pathway is one of them. By the way, PARP1 behaves completely differently in healthy cells. It becomes a so-called low-turnover enzyme. This means that very little NAD is broken down by PARP1. Only when there is DNA damage (which becomes more common with age) does PARP1 become active.
NAD+ plays a role in numerous processes in our organism.
Why does NAD decrease with age?
Scientists have three possible explanations for this central question in aging research:
- NAD production decreases with age
- The degradation is increased (e.g.b through CD38)
- A Combination of both processes
In order to be able to classify this more precisely, it helps to take another look at NAD research. So that you don't have to torture yourself through pages of dry studies, we have summarized the most important points from the various works for you:
Decrease in NAMPT activity
Short refresher, NAMPT is the rate-limiting enzyme in the recycling pathway – the most active NAD+- Metabolic pathway in the organism. Maybe an analogy to this. In Formula 1, around ten mechanics need a good 2 seconds to change 4 tires on a car.
If you change the tires alone, it will take you significantly longer. In this case, the number of mechanics is the speed-determining step - the fewer people involved, the longer it will take. This is how you can imagine it at NAMPT. As you get older, there is simply less of the enzyme available, which means your NAD synthesis slows down.
Overactivation of PARPs
The older we get, the more DNA damage accumulates. Our body no longer becomes as effective at eliminating broken cells and cell stress and inflammation increase. The large amount of DNA damage leads to 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 at all beneficial to inhibit PARP1.
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 manner. The seemingly 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). Due to the permanent inflammation, CD38 is upregulated, which in turn uses up a lot (and permanently) of NAD.
Less NAD ultimately means less efficient energy provision and reduced functionality of dependent enzymes (see sirtuins and PARPs).
NAD can be increased through exercise, fasting and diet, as well as through NAD boosting, thereby developing 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 used as we age. A logical idea would therefore be to increase production or to support recycling. Taking NAD precursors for this purpose is actually a well-studied scientific approach to keeping levels up.
If we were to consume 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. Therefore, NAD infusions, which are usually very expensive, are discussed critically. The problem with stomach acid is avoided here - 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 on humans using the precursor molecule NR the researchers found contradictory results. In some it led to a large increase in NAD and the hoped-for health benefits, but in other studies it did not.
One possible explanation for this is that NR is not the “optimal” precursor. Researchers found that although other breakdown products of NAD, such as MeNAM and Me2YP, increased after supplementation with NR, NAD did not always increase. This suggests that new NAD was simply broken down more quickly based on NR supplementation.
NAD infusions are viewed critically by experts because the molecule is too large to reach the cells directly.
(2) Activation of enzymes that produce NAD
Another adjustment screw in NAD metabolism are the enzymes required to produce the molecule - including NAMPT and NMNAT. The former catalyzes the important, rate-limiting reaction of nicotinamide(Nam) into nicotinamide mononucleotide (NMN). Without this enzyme, our body cannot produce NAD. Interestingly, in one study, exercise was able to lead 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) – is the most important ingredient of green tea – a promising booster from NMNAT.
Apart from special molecules, fasting could also be done. Caloric restriction has been shown to increase NAD levels in some studies. The physiological background is complex because a number of metabolic processes are involved. On the one hand, fasting leads to an activation of sirtuins and AMPK - on the other hand, there is a decrease in mTOR activity. As a result of evolution, our cells switch into a kind of resilience mode. Small side effect: Fasting also reduces inflammation levels in the body.
(3) Inhibition of degradation
We have already seen what a major role CD38 and PARP1 play in NAD degradation. In particular, inhibition of CD38 appears to be a promising way to increase NAD in animal studies. A molecule that represents 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 advantages of a high NAD level?
It is scientifically proven that NAD levels fall with increasing age. It is also known that this has numerous negative consequences. But what are the concrete advantages of a higher intracellular level?
How do you actually measure NAD? It is very likely that your family doctor will not be able to offer you a test for it - the evaluation is only possible in special laboratories. The determination is quite important - for example if you want to influence your NAD level.
Together with Vilnius University, MoleQlar has to date only European NAD test developed. This way you can find out where you stand and check which method has been proven to help you increase your levels.
MoleQlar's simple dried blood test shows you where you stand in terms of your NAD levels.
NAD and memory performance – more power for your nerve cells
Billions of nerve cells that are active both day and night make up our brain. It is probably one of the most fascinating facilities in our body. Almost 120g of sugar in the form of glucose and around 20% of the daily oxygen requirement 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 matter. Studies found that people with Alzheimer's disease had improved mitochondrial function by increasing NAD levels and their memory performance improved as a result.
The rest of our nervous system also benefits from the molecule. An increased level significantly improved stimulus transmission. In addition, a study shows that loudness-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 functional losses, our mitochondria also decrease in number as we age. One way to produce more mitochondria is to exercise. Regardless of whether it is strength or endurance – both promote the production of new cell power plants.
In addition, a study by the Bayor College of Medicine showed that the regular intake of GlyNAC to 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 ATP to contract our muscle fibers. The more ATP our mitochondria can generate, the stronger or more endurance we are.
It has been shown time and time again in animal studies that higher NAD levels can contribute to improved muscle function. So here lies a possible secret as to how we can support our bodies to remain fit and agile even as we get older?
Effects on the cardiovascular system
When it comes to energy, the heart is essential. No other muscle has as much endurance as our heart. It will beat more than 1 billion times over 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 cell power plants and they all require NAD. And that's exactly 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 that “good” and “bad” cholesterol has existed for many decades has been shown to be incorrect according to recent studies. Rather, you have to look at the individual blood lipid values side by side.
If you want to find out more about the individual blood lipid values and the egg myth, then read our large Blood lipid values Guide through the magazine.
Detox booster
In addition to muscle and nerve cells, there is a third cell type that has been proven to benefit from high NAD levels: Liver cells
Our liver has to carry out 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. The liver has a variety of different enzymes available for this purpose, which you can imagine as tools. However, these tools only work well if there is enough NAD available.
NAD as protection against infection?
A study looked at the immune defense in SARS-CoV-2 infections and found interesting results: NAD plays an important role in virus defense via the PARP enzyme.
But it didn't say that PARP1 leads to a breakdown of NAD? That's true, but in addition to PARP1 there are different subclasses of the PARP family. Some of them are involved in the cellular immune defense against viruses. These PARP molecules (not PARP1) in turn require NAD to function better. Although this study was “only” able to find a direct connection with SARS-CoV-2, it is possible that this can also be transferred to other viral pathogens.
NAD – the fountain of youth of life?
Aside from all the performance-enhancing effects on the organs, the question arises as to why high NAD levels have had a positive effect on health and longevity in so many studies? Here is an explanation that NAD appears to affect all molecular hallmarks of aging. Consistently, increasing NAD levels leads to an improvement in all Hallmarks.
This makes this molecule so interesting in longevity research. While many substances only address part of the problem, with NAD they seem to have found a promising candidate that addresses as many aging processes as possible at the same time.
We have seen that NAD metabolism is complex and depends on many factors. The breakdown of NAD also plays a larger role than initially thought. There are still a few questions to be answered here. For example, we know that in older people a higher CD38 level is responsible for the breakdown. High CD38 levels are associated with increased levels of inflammation and DNA damage. But what comes first? Similar to the chicken-and-egg problem, we don't yet know exactly how the individual factors influence each other.
It will probably take some time until these complex questions are clarified - the NAD topic remains exciting in any case! What is now very well scientifically proven is the fact that high levels of NAD Mirrors are beneficial for our body. For this reason, it can make sense for everyone to determine their own NAD level and the natural one through the combination of exercise, a healthy diet and appropriate boosters Counteract waste!
