What is NAD?
Nicotinamide adenine dinucleotide (NAD) is a vital coenzyme that exists in every living cell and plays a central role in metabolism and cellular energy production. NAD's structure consists of two nucleotides connected through their phosphate groups. One nucleotide contains an adenine base while the other has nicotinamide. This molecule comes in two main forms: an oxidized form (NAD+) and a reduced form (NADH). These forms work together as a redox couple.
NAD works as an electron carrier in redox reactions. NAD+ oxidizes other molecules by accepting their electrons and transforms into NADH. NADH then acts as a reducing agent and gives these electrons to other reactions. NAD's electron-carrying ability lets it take part in over 400 enzymatic reactions throughout the body. Cells need NAD+'s electron-carrying capacity to turn food into adenosine triphosphate (ATP), which serves as energy currency for cell survival.
On top of that, NAD acts as a vital cofactor for many non-redox enzymes, including sirtuins, CD38, and poly(ADP-ribose) polymerases (PARPs). NAD+ influences these key cellular functions:
-
Energy metabolism: NAD+ takes part in glycolysis, the tricarboxylic acid cycle, and oxidative phosphorylation to produce ATP
-
DNA repair: NAD+ helps PARPs mark DNA damage sites to start repair mechanisms
-
Chromatin remodeling: Sirtuins need NAD+ to regulate gene expression through epigenetics
-
Cell signaling: NAD+ helps with intracellular calcium signaling and G-protein-coupled pathways
-
Immune function: NAD+ supports mono-ADP-ribosylation processes that boost immune response
NAD+ levels drop as we age across species, including humans. People at age 60 have less than half the NAD+ they had at 40. Scientists have seen this age-related decrease in human liver, skin, brain, plasma, skeletal muscle, and macrophages. Low NAD+ levels over time link to faster aging and age-related diseases.
NAD's molecular formula is C21H27N7O14P2 with a weight of 665.4 g/mol. Its structure provides a stable way to move electrons through reactive cellular environments. This setup lets NAD constantly gain and lose electrons, which makes it such an effective electron carrier.
NAD isn't a vitamin, but the body makes it from vitamin B3 (niacin) precursors like nicotinamide and nicotinic acid. The body can also create NAD through the de novo pathway using the essential amino acid tryptophan. Vitamin B3's relationship with NAD matters because proper vitamin B3 intake helps optimal NAD production.
Research shows NAD+'s most important role through studies where removing NAD+ biosynthetic enzymes NMNAT1 or NAMPT leads to embryonic death. Your body needs the right NAD+ levels to maintain tissue health and respond to stress throughout life.
Is NAD a vitamin or something else?
Image Source: Dreamstime.com
NAD isn't a vitamin but a coenzyme that your body combines from vitamin B3 precursors. People often link it with vitamin B3, but NAD is actually the bioactive form that vitamin B3 compounds must convert into before they can do their essential cellular work. Your body needs vitamin B3 mainly to keep adequate NAD+ levels.
Scientists know vitamin B3 (niacin) as a group of molecules that has precursors for NAD. These precursors include:
-
Nicotinic acid (NA)
-
Nicotinamide (NAM)
-
Nicotinamide mononucleotide (NMN)
-
Nicotinamide riboside (NR)
These forms need to change into NAD before they can work in your body. Each precursor takes slightly different paths in cells through specific enzyme reactions to become NAD.
The difference between NAD and vitamins becomes clear when you look at how they work in metabolism. Your body can't make enough vitamins by itself, so you need to get them from food. NAD, however, works like cellular currency in energy metabolism - instead of being used up, it cycles between its oxidized (NAD+) and reduced (NADH) forms during redox reactions.
NAD itself is the coenzyme - the active biochemical form. This makes it more like other coenzymes such as FAD (which comes from vitamin B2) than vitamins themselves.
Your NAD levels drop as you age. This decrease relates to many signs of aging, from less energy production to damaged DNA repair. Scientists are interested in ways to boost NAD+ levels, especially when you have to take supplements with NAD precursors.
NAD's importance shows up clearly in vitamin B3 deficiency cases. Not getting enough niacin in your diet leads to pellagra - you get dermatitis, diarrhea, and dementia - because of low NAD+ and NADP+ levels. This shows why vitamin B3 compounds are essential nutrients - they help make enough NAD.
NAD's connection to nutrition goes beyond vitamin B3. Your body can make NAD from the essential amino acid tryptophan through a de novo pathway that needs vitamin B6. This pathway shows why you need a well-laid-out diet with enough micronutrients to keep optimal NAD levels.
Your body ended up needing vitamins, particularly vitamin B3, to maintain NAD levels. Scientists agree that getting enough vitamin B3 matters because it keeps cellular NAD+ levels healthy. These levels support many vital processes from energy metabolism to DNA repair.
How is NAD made in the body?
Image Source: Nature
The body creates NAD through two main pathways: de novo synthesis from the amino acid tryptophan and salvage pathways that recycle vitamin B3 forms. These pathways are the foundations of maintaining adequate NAD levels and supporting essential cellular metabolism functions. People often ask if NAD is a vitamin. The synthesis pathways show how NAD depends on vitamin precursors yet remains biochemically distinct.
De novo synthesis from tryptophan
The kynurenine pathway serves as the only route to create NAD+ from dietary tryptophan. A complex biochemical process starts when either tryptophan-2,3-dioxygenase (TDO) or indoleamine 2,3-dioxygenase (IDO) transforms tryptophan into N-formylkynurenine. Several enzymatic steps produce quinolinic acid (QA). The enzyme quinolinate phosphoribosyltransferase (QPRT) then converts QA to nicotinic acid mononucleotide (NAMN).
Nicotinamide mononucleotide adenylyltransferases (NMNATs) adenylylate NAMN to create nicotinic acid adenine dinucleotide (NAAD). NAD synthase (NADSYN) then amidates NAAD to produce NAD+, with glutamine acting as a nitrogen donor.
The enzyme α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) can restrict NAD+ production. It converts ACMS to picolinic acid instead of allowing quinolinic acid formation. The human body can use the de novo pathway, but tryptophan alone cannot support physiological NAD+ concentrations. The liver mainly uses this pathway, while other tissues rely more on salvage mechanisms.
Salvage pathways using vitamin B3 forms
The body generates NAD+ through salvage pathways that recycle vitamin B3 forms. These include nicotinamide (NAM), nicotinic acid (NA), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN). These pathways are vital since cellular reactions constantly use NAD+ and generate salvageable NAM.
Nicotinic acid phosphoribosyltransferase (NAPRT) converts NA to NAMN through the Preiss-Handler pathway. This NAMN follows the same route as the de novo pathway to become NAD+. The NAM salvage pathway plays a fundamental role in maintaining NAD+ levels. Nicotinamide phosphoribosyltransferase (NAMPT) acts as the rate-limiting enzyme that transforms NAM to NMN. NAMPT shows remarkably high affinity for NAM (KM ~5 nM with ATP present). This allows it to detect and convert even tiny amounts of NAM to NMN.
Nicotinamide riboside kinases (NRK1 and NRK2) phosphorylate the nucleoside NR to form NMN. Scientists have discovered a specific NMN transporter, SLC12A8, that appears mostly in the small intestine. This suggests NMN provides direct entry into NAD+ biosynthetic pathways. NMNATs convert both NMN from the NAM salvage pathway and NR metabolism into NAD+.
Cell compartments affect where NAD+ synthesis occurs. NAM and other precursors can replenish mitochondrial NAD+ pools. The location of biosynthetic enzymes determines the site of NAD+ generation. Studies of cell viability show strong links between mitochondrial NAD+ levels and cell survival.
Mammals recycle most of their NAD+ rather than creating it from scratch. The salvage pathway's significance becomes clear when we see that blocking NAMPT kills mice. This highlights how essential NAD+ is and shows the body's dependence on vitamin B3 precursors for synthesis.
What does NAD do in the body?
Image Source: Nature
NAD works as a vital coenzyme, not a vitamin, and plays many significant roles in the human body. Learning about NAD's functions helps us understand why people often call it a vitamin by mistake. NAD isn't a vitamin itself, but its functions show why vitamin B3 precursors matter so much to our health.
Energy production and redox reactions
NAD+ works as a hydride acceptor in redox reactions, which makes it the cornerstone of energy metabolism. The oxidized form (NAD+) accepts electrons during catabolic processes and becomes reduced to NADH. This process supports many metabolic pathways, including glycolysis, the tricarboxylic acid (TCA) cycle, and fatty acid oxidation.
NADH moves electrons to the mitochondrial electron transport chain (ETC) during cellular respiration. Complex I (NADH:ubiquinone oxidoreductase) turns NADH back into NAD+. The electron flow through the ETC creates a proton gradient that powers ATP production through oxidative phosphorylation. Mouse skeletal muscle studies show mitochondrial NAD+ levels are about twice as high as in the rest of the cell.
NAD+ can turn into NADP+ through phosphorylation. NADP+ acts as a hydride acceptor to create NADPH—which we need for anabolic reactions and protection from oxidative stress. The NAD+/NADH ratio shows the cell's redox state and metabolic health. Healthy mammalian tissues typically have cytoplasmic ratios around 700:1.
DNA repair and cell signaling
NAD+ does more than handle redox functions. It serves as a vital substrate for three major enzyme families:
-
Sirtuins (SIRTs): NAD+-dependent deacetylases that remove acetyl groups from proteins and histones, regulating gene expression, metabolic pathways, and stress responses
-
Poly(ADP-ribose) polymerases (PARPs): Use NAD+ to attach ADP-ribose moieties to proteins at DNA damage sites, facilitating repair
-
NAD+ glycohydrolases: Enzymes like CD38, CD157, and SARM1 that generate calcium-mobilizing molecules for cell signaling
These interactions let NAD+ influence DNA repair mechanisms, chromatin remodeling, cellular senescence, and immune cell function. When DNA damage occurs, PARPs use NAD+ to make poly(ADP-ribose), which brings DNA repair proteins to damaged areas. Low NAD+ levels can lead to unstable genes and faster aging.
Role in aging and metabolism
NAD+ levels drop steadily as we age, and this happens in many organisms, including humans. People's NAD+ levels at age 60 fall to less than half of what they had at 40. Scientists have seen this decline in human liver, skin, brain, plasma, skeletal muscle, and macrophages.
Age-related NAD+ loss happens because:
-
CD38 expression increases in many tissues with age
-
DNA damage accumulation leads to more PARP activity
-
Long-term inflammation and oxidative stress take their toll
Lower NAD+ levels affect how mitochondria work, and cells switch from oxidative phosphorylation to glycolysis. This drop in NAD+ links to many age-related problems, from cognitive decline to metabolic disorders, heart disease, and weaker muscles.
The good news? Bringing NAD+ levels back up can slow or even reverse many aging-related diseases. Research shows that restoring NAD+ improves heart health, fixes metabolic conditions, strengthens muscles, boosts endurance, helps mitochondria work better, and even improves fertility in older mice.
How does NAD relate to Vitamin B3?
Vitamin B3 forms are the building blocks that create NAD in the human body. The body must convert all B3 vitamins to NAD+ before they can perform their vital biological functions. Vitamin B3 and NAD share a close connection but remain biochemically different. This relationship explains why NAD isn't a vitamin, even though vitamin precursors create it.
Nicotinamide and nicotinic acid as precursors
Several compounds make up Vitamin B3 and act as NAD precursors: nicotinic acid (NA), nicotinamide (NAM), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN). Each one follows its own enzymatic path to create NAD+:
-
Nicotinic acid pathway: The Preiss-Handler pathway converts NA to nicotinic acid mononucleotide (NAMN) using nicotinic acid phosphoribosyltransferase (NAPRT). NAMN then changes to nicotinic acid adenine dinucleotide (NAAD). Finally, NAD synthase uses glutamine as a nitrogen donor to create NAD+.
-
Nicotinamide pathway: This main salvage pathway uses nicotinamide phosphoribosyltransferase (NAMPT) to convert NAM to NMN. NAMPT limits the rate of NAD+ production. The process ends when nicotinamide mononucleotide adenylyltransferases (NMNATs) turn NMN into NAD+.
-
Nicotinamide riboside route: Nicotinamide riboside kinases (NRK1/NRK2) phosphorylate NR to create NMN, which then follows the salvage pathway.
Research shows that people need just 20 mg of niacin or its equivalents daily. Internal recycling systems maintain most tissue NAD+ levels through salvage routes.
Differences between NAD and niacin
NAD and niacin share a close bond but work differently. NAD acts as a bioactive coenzyme that directly helps cellular metabolism. Niacin forms need conversion before they become active.
Niacin forms do more than just create NAD+. Nicotinic acid (NA/niacin) causes blood vessels to dilate, creating the typical "niacin flush". NA also helps blood lipids by reducing harmful LDL cholesterol and boosting beneficial HDL cholesterol. These benefits don't come from NAD+ production.
Nicotinamide (NAM), also called niacinamide, doesn't affect blood vessels or lipids. High NAM levels can block sirtuin enzymes, which are NAD+-dependent deacetylases vital for cell health.
People need enough vitamin B3 mainly because it keeps cellular NAD+ at healthy levels. A severe lack of vitamin B3 leads to pellagra, which causes dermatitis, diarrhea, dementia, and possible death without treatment. These symptoms happen because of low NAD+ and NADP+ levels.
Can NAD supplements improve health?
Scientists are learning more about NAD supplementation and how it can reduce the natural drop in NAD+ levels as we age.
NAD+ injections and oral supplements
NAD+ supplements come in two main forms: injections and oral preparations. NAD+ injections go straight into the bloodstream and work faster since they skip the digestive process. You can also take oral supplements that contain NAD+ precursors like nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), nicotinic acid (NA), and nicotinamide (NAM). Each precursor has different absorption rates, with NR and NMN getting much attention from researchers.
Evidence from animal and human studies
Animal studies have shown remarkable results. These include longer lifespans, better heart function, improved muscle healing, and increased mitochondrial activity. Human trials look promising but show smaller improvements. Research proves that taking NAD+ precursor supplements boosts NAD+ levels in blood and tissues. A clinical trial found that middle-aged participants who took 1g of NR daily saw their NAD+ levels rise by about 60% in their blood cells.
Potential benefits and limitations
NAD+ supplements can boost heart health, insulin response, and fat metabolism. Research shows these supplements are safe for most people. Some challenges exist though. Absorption rates vary between people, optimal doses aren't clear yet, and human results aren't as dramatic as those seen in animals. Scientists haven't finished long-term safety studies on NR and NMN in humans.
Key Takeaways
Understanding NAD's true nature and relationship to vitamins reveals crucial insights about cellular health and aging:
FAQs
Q1. Is NAD the same as vitamin B3? NAD is not a vitamin itself, but rather a coenzyme synthesized in the body from vitamin B3 precursors. While closely related to vitamin B3, NAD is the bioactive form that directly participates in cellular metabolism, whereas vitamin B3 compounds must be converted to NAD before they can perform their essential functions.
Q2. How can I naturally increase my NAD levels? You can boost your NAD levels naturally through regular exercise, particularly interval training or aerobic exercise. These activities create energy stress in the body, which increases NAD+ production. Additionally, consuming foods rich in NAD precursors, such as turkey, cabbage, cucumber, and soybeans, can support NAD synthesis.
Q3. What are the potential benefits of NAD supplementation? NAD supplementation may offer several health benefits, including improved cardiovascular function, enhanced insulin sensitivity, and better lipid profiles. Some studies suggest it could also support muscle regeneration and mitochondrial activity. However, more research is needed to fully understand its long-term effects in humans.
Q4. Are there any side effects associated with NAD supplements? While NAD supplements are generally considered safe, some people may experience temporary side effects, particularly with intravenous administration. These can include mild nausea, stomach discomfort, or gastrointestinal issues. Most of these effects are short-lived and can often be mitigated by adjusting dosage or administration methods.
Q5. How does NAD contribute to cellular health and aging? NAD plays a crucial role in numerous cellular processes, including energy production, DNA repair, and cell signaling. As NAD levels naturally decline with age, it can impact these vital functions. Maintaining adequate NAD levels is thought to support overall cellular health and potentially slow some aspects of the aging process, though more research is needed to fully understand its impact on human aging.
