NAD+ is the abbreviation for nicotinamide adenine dinucleotide. The molecule essentially consists of two mononucleotides that are chemically bonded together. It is present in almost all of our cells and lower NAD levels are a sign of aging.
For this reason, there is great enthusiasm in researching how to maintain the level as high as possible in old age. In this overview, you will learn everything you need to know about NAD. We will journey 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 that can be 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. Imagine a co-pilot as an analogy. They take on important tasks to relieve the pilot, allowing both to safely steer the airplane. Similarly, NAD acts as a support in hundreds of processes in your body. This teamwork enables molecules like 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 therefore obvious that the sought-after co-pilot plays an important role in a number of biological processes. We will answer which biological processes these are shortly. Before we deal with the present, let's take a brief detour into the past.
The NAD level decreases drastically over time - both in men and women!
Overview
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 its breakdown. 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 exchange plays a significant 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 through the redox reaction.
Did you know? Niacin, a precursor of NAD, was the first discovered "medication" that could lower the LDL levels. In the 1950s, Rudolf Altschul administered high doses of niacin and thereby lowered cholesterol levels.
In the 1960s, it was believed that everything about NAD and its functions was already known 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 has given research new momentum.
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. Science quickly dubbed the sirtuins "longevity genes" due to the flourishing optimism surrounding their role in recent longevity research. Langlebigkeitsgene.
Did you know? Fasting is now known to have beneficial effects on aging.A large part of these effects occurs through the activation of the sirtuins, especially SIRT1 . There are even entire diets that focus on the activation of sirtuins. The Sirtfood diet has become famous, among other things, through the singer Adele. The Italian-American doctor Valter Longo also indirectly relies on the activation of sirtuins with his fasting mimicking diet.
Molecules such as glucosamine, berberine , and spermidine capsules can support the fasting process at the molecular level.
NAD, NAD+ & NADH – who is who?
These three terms are used side by side and then again only in isolation in scientific papers. The term NAD is most commonly used for NAD+ or vice versa. The distinction from the other molecules is often somewhat opaque. This sounds like a need for clarification, which we will now address.
The clarification of terms was significantly contributed to by the discovery of Otto Warburg regarding NAD and its redox properties. He was the one who NAD defined as "chemical backbone independent of charge". NAD+ is therefore the oxidized form (can accept electrons) and NADH the reduced form (can donate electrons) of NAD.In summary, 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 donates electrons to the electron transport chain in the mitochondria, the powerhouses of the cell, thereby enabling the production of the universal energy carrier for us humans: adenosine triphosphate (ATP). What remains is NAD+ and its readiness to accept electrons again. Mitochondria can be strengthened for example by an optimized NAD level.
NAD is then the general term for describing the redox pair and its reactions. For this reason, we use the term NAD so far and will continue to do so.
NAD metabolism – three pathways to success
A small warning in advance, we need to dive deeper into the physiology and biochemistry of our body once again. But don't worry, it will be worth it, as 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 point out why, according to current scientific findings, NAD metabolism is more complex than previously thought and why sole supplementation of the precursors is likely not sufficient.
The amount of NAD may be measurable as constant over a certain period, but in reality, the molecule is constantly being reassembled, broken down, or recycled. 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 between them is referred to as the ratio, which varies in cells and tissues. Mammalian cells, apart from nerve cells, cannot import or take up NAD.
Consequently, the molecule must first be reassembled in the cell from different components. This de novo path (‘de novo’ lat. for "anew") is based on the essential amino acid Tryptophan or from other forms of Vitamin B3 is taken.
To maintain the intracellular NAD level, it is mainly "recycled" through the so-called salvage pathway. "salvage" comes from English and translates to "recover" or "save". 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 serves as the starting material. Niacin and tryptophan are included in the NAD Regenerating Complex .
The following graphic provides a clear representation of the mentioned metabolic pathways.
NAD can be produced in our body through three different pathways. The most important pathway is the recycling path, which ultimately leads through NMN.
NAMPT – the key to NAD production
In the production of NAD, there is a rate-limiting step. This 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 lacking, then production is halted or 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 – it can quickly adapt to the changing NAD demand in the cell. These changing conditions also include cellular stress, which is triggered by DNA damage or starvation. Genomic instability is also one of the hallmarks of aging.
Degradation of NAD
Our body can degrade NAD through various pathways. One of the most important is the enzyme CD38.The "CD" does not stand for compact disc, and the following number is not the volume of the BRAVO Hits – CD is in this case the abbreviation for "cluster of differentiation".
These "clusters" are surface markers on cells. Imagine it as a kind of identification feature of cells. Through these surface molecules, for example, patrolling immune cells can recognize whether there are intruders with "false" surface markers. In addition to their pure recognition function, these molecules are often also enzymes. This means they are responsible for biochemical reactions in our body. To date, about 400 of these markers are known.
Did you know? The discovery of an increased expression of some of these distinguishing features on cancer cells has, for example, led to groundbreaking advances in cancer therapy. Researchers have developed antibodies that target certain CDs. One example is CD20 in the context of lymphomas. The antibody binds to the CD molecule and marks the cell for the immune system, which can then 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 highly magnified.
CD38
CD38 is not only present on some, but on all cells and, through its enzymatic function, is responsible for the breakdown of NAD+.It was discovered by genetically modifying mice so that they no longer possess CD38. These test animals had significantly higher NAD levels.
Another molecule that has proven to be an effective CD-38 inhibitor in research is apigenin, which can be 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 mice, 32 months old. This led to a significant increase in NAD levels in the old mice, bringing them to the same level as their younger counterparts.Additionally, 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?
NAD-dependent processes can be found in hundreds in our body. Two of the most important signaling protein families for longevity research are the Sirtuins and the PARPs. Sirtuins, also referred to as longevity genes, were described in the mid-80s as telomere-protecting proteins. Today we know that they can do much more. They play an important role in mitochondrial metabolism, in inflammation, cell division, autophagy processes, the circadian rhythm, and programmed cell death (apoptosis).
While the Sirtuin family has "only" seven representatives, the PARP family is significantly larger.However, not all subclasses are equally well researched yet. This basic research is very complex and extensive, which is why much work still awaits researchers to improve the understanding of it accordingly.
We now know that PARP1 and PARP2 play an important role in DNA repair and in translation. Scientists understand translation as 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, there is an overactivation of PARP1, which in turn causes the NAD levels 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? 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 quickly as possible. The PARP1/NAD pathway is one of them. In healthy cells, PARP1 behaves quite differently. It becomes what is known as a low-turnover enzyme. This means that only a very small amount of NAD is broken down by PARP1. Only in the case of DNA damage (which becomes more frequent with age) does PARP1 become active. NAD+ plays a role in numerous processes of our organism. Why does NAD decrease with age? For this central question of aging research, scientists have three possible explanations: The NAD production decreases with age. The breakdown is increased.through CD38)
To better understand this, a renewed look at NAD research is helpful. So you don't have to struggle through pages of dry studies, we have summarized the key points from 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. Perhaps an analogy here. In Formula 1, about ten mechanics need around 2 seconds to change 4 tires of a car.
If you change the tires alone, it takes you 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 it like this with NAMPT. With age, there is simply less of the enzyme available, and as a result, 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 cellular stress and inflammaging increase. Due to the many DNA damages, there is an overactivation of PARP1, leading to increased NAD consumption. However, the research findings on PARP1 inhibition are still very vague. Here we cannot tell you exactly whether inhibiting PARP1 is beneficial 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 manner. The seemingly most important connection is between CD38 and chronic inflammatory processes. This silent "inflammation" has been linked to disease processes in aging in numerous studies (Inflammaging). Due to the persistent inflammation, CD38 is upregulated, which in turn consumes a significant (and permanent) amount of NAD.
Less NAD ultimately means a less efficient energy supply and reduced functionality of dependent enzymes (see sirtuins and PARPs).
NAD can be increased through exercise, fasting &and nutrition, as well as through NAD-boosting, thereby unleashing its positive effects.
Can one stop the decline?
Just as there are different hypotheses for age-related decline, there are also various approaches to maintain NAD levels.
(1) Supplementation of precursors
The fact is that more NAD is consumed with age. A logical thought would therefore be to increase production or support recycling. The intake of NAD precursors for this purpose is indeed a well-researched scientific approach to keep levels high.
If we were to take NAD directly, it would not be very effective, as on 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. Therefore, the usually very expensive NAD infusions are indeed discussed critically. Here, the problem with stomach acid is circumvented – but the molecule is still "too large" to enter the cells directly.
NAD precursors are usually various forms of Vitamin B3 such as nicotinamide, niacin, or tryptophan. The well-known Nicotinamide Riboside (NR) is also included. In 10 studies on humans with the precursor molecule NR , however, researchers found not entirely consistent results.In some cases, it led to a significant increase in NAD and also to the hoped-for health benefits, while in other studies it did not.
A possible explanation for this is that NR is not the "optimal" precursor. Researchers found that while other breakdown products of NAD, such as MeNAM and Me2YP, increased after supplementation with NR, NAD did not always do so. This suggests that new NAD based on NR supplementation was simply broken down faster.
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 adjustment in NAD metabolism is the required enzymes for the production of 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, exercise in a study could 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) – the most important ingredient of green tea – is a promising booster of NMNAT.
Aside from specific molecules, fasting or caloric restriction in some studies could also increase NAD levels.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, there is a decrease in the mTOR activity. As a result, our cells evolutionarily switch to a kind of resilience mode. A small side effect: Fasting also lowers inflammation levels in the body.
(3) Inhibition of degradation
We have already seen the significant role that CD38 and PARP1 play in NAD degradation. In particular, the inhibition of CD38 seems 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 a study.
What are the benefits of a high NAD level?
It is scientifically proven that NAD levels decrease 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 family doctor will not be able to offer you a test for this – the evaluation is only possible in specialized laboratories. However, determining it is quite important – for example, if you want to influence your NAD levels.
Together with the University of Vilnius, MoleQlar has developed the only European NAD test to date. This way, you can find out where you stand and check which method can help you increase your levels.
NAD and memory performance – more power for your nerve cells
Billion of nerve cells that are active both day and night make up our brain. It is arguably one of the most fascinating organs in our body. Almost 120g of sugar, in the form of glucose, and about 20% of the daily oxygen requirement are attributed to this approximately 1.5kg heavy organ.
The high energy demand naturally requires a correspondingly high density of mitochondria. NAD, as an important mitochondrial agent, therefore has a role to play here. Studies have shown that people with increased NAD levels had improved mitochondrial function and their memory performance improved as a result.
Our entire nervous system also benefits from the molecule. With an increased level the signal transmission improved significantly. Additionally, a study shows that noise-induced hearing loss is reduced. And anyone who has experienced muffled hearing for several hours after a concert knows how uncomfortable that can be.
Did you know? In addition to functional impairments, our mitochondria also decrease in number as we age.One way to produce more mitochondria is through exercise. Whether strength or endurance – both promote the production of new cellular power plants.
Additionally, a study from the Baylor College of Medicine showed that the regular intake of GlyNAC led to a measurable improvement in mitochondrial function.
Improved muscle function
Not only does our brain rely on mitochondria, but so do 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 repeatedly shown that higher NAD levels can contribute to improved muscle function. Is there a possible secret here on how we can support our bodies to remain fit and agile even 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 over the course of our lives without new cells being formed. For this, it requires an incredible amount of mitochondria.
More than 30% of cell mass is occupied by our cellular power plants, and they all require NAD. And that is 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 long-standing assumption of "good" and "bad" cholesterol has been shown to be incorrect according to recent studies. Rather, one must consider the individual blood lipid levels side by side.
If you want to learn more about the individual blood lipid levels and the egg myth, then read our comprehensive blood lipid levels guide in the magazine.
Detox Booster
In addition to muscle and nerve cells, there is a third type of cell that clearly benefits from high NAD levels: Liver cells
Our liver has to perform a multitude of tasks every day. It stores energy in the form of glucagon, produces important proteins for our coagulation system, and very importantly: it detoxifies our body. For this purpose, the liver has a variety of different enzymes available, which you can imagine as tools. However, these tools only work well when sufficient NAD is available.
NAD as infection protection?
A study has investigated immune defense in SARS-CoV-2 infections and found interesting results: NAD plays an important role in virus defense through the PARP enzyme.
But wasn't it said that PARP1 leads to a degradation of NAD? That's true, however, there are various subclasses of the PARP family besides PARP1. Some of these are involved in the cellular immune defense against viruses. These PARP molecules (not PARP1) require NAD to function better. Although this study could "only" 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 as to why high NAD levels have had a positive impact on health and longevity in so many studies? One explanation here is that NAD seems to affect all molecular hallmarks of aging. Consequently, an increase in 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, it seems that NAD has been found to be a promising candidate that tackles as many aging processes as possible simultaneously.
We have seen that the NAD metabolism is complex and depends on many factors. The breakdown of NAD also plays a larger role than initially thought. There are still some questions to clarify 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 markers and DNA damage. But what comes first? Similar to the chicken-and-egg problem, we still do not 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 scientifically well established is the fact that high NAD levels are beneficial for our body.For this reason, it can be beneficial for everyone to determine their own NAD levels and to counteract the natural decline through a combination of exercise, a healthy diet, and appropriate boosters!
Sources
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The images were acquired under license from Canva.
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