NAD is the short form of Nicotinamide Adenin Dinnucleotide. The molecule consists of two mononucleotides that are linked 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, great research is being carried out into how to keep the level as high as possible as we age. In this overview, you will learn everything you need to know about NAD. We will travel through the past, present and future of the molecule and present you with the most important studies on the longevity molecule.
What is NAD?
NAD is a coenzyme, which is found in almost every cell of an organismA 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 fly the plane safely. NAD works in a similar way. It supports hundreds of processes in your body. This team effort enables molecules such as NAD to influence the action of enzymes.
According to a study, NAD is required for over 500 of these enzymatic reactions in the organism. It is obvious that the co-pilot in question plays an important role in a number of biological processes. We will answer exactly what these biological processes are in a moment. Before we deal with the present, let's take a short detour into the past.
NAD levels decrease dramatically over time - in both men and women!
retrospective
The molecule was first discovered 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 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 reactant gives 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 and 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 to LDL level could be lowered. In the 1950s, Rudolf Altschul gave high doses of niacin and thus lowered cholesterol levelsThe development of today's statins or PCSK9 inhibitors began much later.
In the 1960s, everyone 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.
However, the reason for the molecule’s current popularity in scientific circles is not this, 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. Due to the flourishing optimism surrounding their role in recent longevity research, science has given the sirtuins the name longevity genes.
Did you know? Fast is now known to have beneficial effects on aging. To a large extent, these effects occur through the Activation of the sirtuins, especially SIRT1 There are even entire diets that focus on the activation of sirtuins. Sirtfood diet has become famous thanks to the singer Adele, among others. The Italian-American doctor Valter Longo With its pseudo-fasting diet, it indirectly relies on the activation of sirtuins.
Molecules such as glucosamine, berberine and spermidine can support the fasting process at the molecular level.
MoleQlar’s fasting bundle with glucosamine, berbersome and spermidine is designed to support the fasting process on a molecular level.
NAD, NAD+ & NADH – who is who?
These three terms are used sometimes side by side and sometimes only in isolation in scientific papers. The most common term is NAD for NAD+ or vice versaThe distinction between the other molecules is often somewhat unclear. This sounds like there is a need for clarification, which we are now addressing.
Otto Warburg's discovery of NAD and its redox properties contributed significantly to the clarification of the term. He was the one who NAD as a “chemical backbone independent of charge”. NAD+ is therefore the oxidized form (can absorb electrons) and NADH the reduced Form (can release electrons) of NAD. In summary, chemistry refers to NAD+/NADH as so-called redox couple.
The harmony of this relationship is incredibly important for the production of energy in the human body. NADH releases electrons to the respiratory chain in the mitochondrion, the power plant of the cell, and thus enables the production of the universal energy carrier for us humans: adenosine triphosphate (ATP). What remains is NAD+ and its ability to absorb electrons again.
NAD is then the general term to describe the redox pair 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 once again have 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 better understand one of the most exciting molecules in longevity research.
In the end you understand, when our body needs the molecule, how it produces it and how it is broken downAt the end of this chapter, we show why, according to current scientific findings, NAD metabolism is more complex than assumed and why supplementing the precursors alone is probably not enough.
The amount of NAD may be constantly measurable over a certain period of time, but in reality the molecule is constantly reassembled, dismantled or recycledOn average, the occurrence of a person to about three grams.
The coenzyme exists in the body in two "states" - either as a free molecule or bound to proteins. The relationship between them is called 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 reassembled in the cell from different components. This de novo path (‚de novo' Latin for "again“) is produced from the essential amino acid tryptophan or from other forms of vitamin B3 taken.
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 also a third way to create the molecule. In the “price handler pathway“ Niacin is the starting material. Niacin and tryptophan are found in NAD Regenerating Complex (regeNAD) contain.
The following graphic clearly shows the metabolic pathways mentioned above.
NAD can be produced in our body in three different ways. The most important way is the recycling pathway, which in the last step leads via NMN.
NAMPT – the key to obtaining NAD
In the production of NAD there is a rate-determining stepThis means that the synthesis depends 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 limited.
The key enzyme is named NAMPT and supports the first step in the recycling path, where nicotinamide (Nam) in nicotinamide mononucleotide (NMN) The amount of NAMPT is highly dynamic – it can adapt very quickly to the changing NAD requirements in the cell. These changing conditions include cell stress caused 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 CD38However, the “CD” does not stand for compact disc and the number that follows 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. Imagine the whole thing as a kind of recognition feature of cells. These surface molecules can be used, for example, by patrolling immune cells to recognize whether there are intruders with "wrong" surface features. In addition to their pure recognition function, these molecules are also often enzymesThis means that they are responsible for biochemical reactions in our body. To date, around 400 of these characteristics are known.
Did you know? The discovery of an 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. One example is CD20 in lymphomas. 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 what the "ectodomain fragment" of the CD38 enzyme looks like when greatly enlarged.
CD38
CD38 is found not only on some cells, but on all cells and, through its enzymatic function, causes the breakdown of NAD+. This was discovered by genetically modifying mice so that they no longer have 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 in nature, for example in parsley. Mice treated with apigenin had about 50% more NAD than the control group.
There is also a third scientific indication 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 rose so much that they had the same level as their younger counterpartsIn 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 sirtuin family has “only” seven members, the PARP family is significantly larger. However, not all subclasses have been researched equally well.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 DNA repair and translationScientists understand translation to be 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 then "plannedly" die later.
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 defective cells as quickly as possible. The PARP1/NAD pathway is one of them. In healthy cells, PARP1 behaves completely differently. It becomes a so-called low-turnover enzyme. This means that only very little NAD is broken down by PARP1. PARP1 only becomes active when DNA damage occurs (which becomes more common with age)..
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:
- The NAD production decreases with age
- The degradation is increased (e.g. by CD38)
- One combination from both processes
To understand this more clearly, 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 studies:
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. Perhaps 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 that case, the number of mechanics is the speed-determining step - the fewer people involved, the longer it will take. That's how you can imagine NAMPT. As you get older, there is simply less of the enzyme and your NAD synthesis slows down.
overactivation of PARPs
The older we get, the more DNA damage accumulates. Our body becomes less effective at eliminating damaged cells and cell stress and inflammation increase. The large amount of DNA damage leads to an overactivation of PARP1 and thus to an increased consumption of NAD. However, the research results on PARP1 inhibition are still very vague. Here we cannot tell you exactly whether it is beneficial at all to inhibit PARP1.
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). The persistent inflammation causes CD38 to be upregulated, which in turn consumes a lot (and permanently) 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 & diet, as well as through NAD boosting and thus develop 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 as we age. A logical idea would therefore be to increase production or support recycling. Taking NAD precursors for this purpose is actually a well-researched scientific approach to keep levels high.
If we were to take NAD directly, it would have little effect, because on the one hand the molecule is “broken down” in our stomach and on the other hand there is no transporter for NAD in the cell membrane. This is why NAD infusions, which are usually very expensive, are being discussed quite criticallyHere, the problem with stomach acid is avoided – 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 included. In 10 Human studies with the precursor molecule NR However, the researchers found contradictory results. In some studies, it led to a strong increase in NAD and also to the hoped-for health benefits, but in other studies it did not.
One possible explanation for this isthat NR is not the “optimal” precursorResearchers found that although other NAD breakdown products, such as MeNAM and Me2YP, increased after NR supplementation, NAD did not always increase. This suggests that new NAD was simply broken down more quickly following NR supplementation.
NAD infusions are viewed critically in professional circles because the molecule is too large to enter the cells directly.
(2) Activation of enzymes that produce NAD
Another key factor in NAD metabolism are the enzymes required to produce the molecule – including NAMPT and NMNATThe former catalyzes the important, rate-limiting reaction of nicotinamide(Nam) in 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 NMNATIt 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 of the green teas – 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 a Activation of sirtuins and AMPK – on the other hand, to a decrease in mTOR activityAs a result of evolution, our cells switch to a kind of resilience mode. A small side effect: fasting also reduces 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 seems to be a promising way to increase NAD in animal studies. A 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 high NAD levels?
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? 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. Determination is certainly important – for example, if you want to influence your NAD levels.
Together with Vilnius University, MoleQlar has developed the only European NAD test This way you can find out where you stand and check which method has been proven to help you increase your level.
MoleQlar's simple dry blood test shows you where you stand in terms of your NAD levels.
NAD and memory performance – more power for your nerve cells
Our brain is made up of billions of nerve cells that are active both day and night. It is probably one of the most fascinating structures in our body. This organ, which weighs around 1.5 kg, processes almost 120g of sugar in the form of glucose and about 20% of our daily oxygen requirements.
The high energy requirement naturally requires a correspondingly high mitochondrial density. NAD as an important mitochondrial agent therefore has a hand in thisStudies have shown that people with Alzheimer's disease had improved mitochondrial function and memory performance by increasing NAD levels.
The rest of our nervous system also benefits from the molecule. Through an increased level the transmission of stimuli improved significantly. 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 functional losses, our mitochondria also decrease in number as we age. One way to produce more mitochondria is 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
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 and more enduring we are.
Animal studies have shown time and time again that higher NAD levels can contribute to improved muscle function. So could this be a possible secret to helping our bodies stay fit and agile as we age?
Effects on the cardiovascular system
When it comes to energy, the heart is also 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 new cells being formed. To do this, it needs an incredible amount of mitochondria.
More than 30% of the cell mass is taken up by our cell power plants and they all require NADAnd that is exactly why our central vital organ benefits from an increased NAD supplyThe 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 incorrect according to recent studiesRather, the individual blood lipid values must be considered side by side.
If you want to learn more about the individual blood lipid values and the egg myth, then read our large blood lipid levels Guide in the magazine.
detoxification booster
In addition to muscle and nerve cells, there is a third type of cell that has been proven 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, it detoxifies our body. The liver has a variety of different enzymes at its disposal for this purpose, 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 examined the immune defense against 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 breakdown of NAD? That's true, but in addition to PARP1 there are various 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 is also transferable to other viral pathogens.
NAD – the fountain of youth of life?
In addition to all the performance-enhancing effects on the organs, the question arises: why have high NAD levels had a positive effect on health and longevity in so many studies? One explanation here is that NAD appears to affect all molecular hallmarks of agingConsequently, 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, NAD seems to be 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 degradation of NAD also plays a larger role than initially thoughtThere are still some 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 inflammation and DNA damage. But which 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 take some time until these complex questions are clarified – but the NAD topic remains exciting! What is now scientifically well established is the fact that high NAD levels are beneficial for our bodyFor this reason, it can be useful for everyone to to determine one's own NAD level and counteract the natural waste through the combination of exercise, a healthy diet and appropriate boosters!
