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NAD+ Vs. NADH: What’s The Difference?
General

NAD+ Vs. NADH: What’s The Difference?

NAD+ and NADH are two forms of a coenzyme called nicotinamide adenine dinucleotide (NAD). NAD is a coenzyme, which means that it works with enzymes to facilitate chemical reactions in the body. NAD plays a crucial role in many important biological processes, including the metabolism of carbohydrates, fats, and proteins, as well as DNA repair and signaling.

NAD is found in a variety of foods, including meat, fish, and dairy products, and can also be synthesized by the body from the amino acid tryptophan. NAD deficiency can lead to several health problems, including fatigue, muscle weakness, rashes, and impaired immune function.1

The Biochemistry

NAD+ is important for many cellular processes, including the production of energy through the process of cellular respiration. In this process, NAD+ accepts hydrogen atoms and electrons from the breakdown of glucose and other fuels and becomes reduced to NADH. The transfer of electrons from one molecule to another is called oxidation-reduction, or a redox reaction. The molecule that loses electrons is oxidized, and the molecule that gains electrons is reduced.

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NADH is important for synthesizing adenosine triphosphate (ATP), the energy currency of the cell. Through the process of oxidative phosphorylation, NADH donates its hydrogen atoms and electrons to the electron transport chain, where they are used to produce ATP.

There is a tight coupling between breaking down fats and glucose to reduce NAD+  to NADH and NADH reducing the first complex in the electron transport chain to produce ATP. NAD+ and NADH are constantly being interconverted in the cell, with NAD+ converted to NADH using energy from glucose metabolism and NADH converted back to NAD+ through the process of cellular respiration. Hydrogen ions move across the mitochondrial membrane, and oxygen accepts the electrons at the end of the electron transport chain. This balance is important for proper cell function.

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In summary, the major difference between NAD+ and NADH is the presence of an extra hydrogen atom. NAD+ is important for the breakdown of fuels to produce energy, while NADH is important for synthesizing ATP through oxidative phosphorylation.2

Does NAD+ Have More Energy Than NADH?

NAD+ and NADH are forms of nicotinamide adenine dinucleotide (NAD), which is an important molecule involved in energy metabolism in cells. NAD+ is the oxidized form of NAD, while NADH is the reduced form.

During energy metabolism, NAD+ is used as an electron acceptor in redox reactions, and it is converted to NADH when it gains electrons. NADH is a high-energy molecule. The oxidation of NADH (NADH + H+ ½O2 -> NAD+ + H2O) is highly exergonic, with a standard free energy change of -54 kcal/mol (7-fold greater than the standard free energy change for ATP hydrolysis of -7.3 kcal/mol).

In summary, NAD+ is the oxidized form of NAD and has less energy than NADH, which is the reduced form of NAD and contains more energy.

Is NAD+ Or NADH The Electron Carrier?

Both NAD+ and NADH are important electron carriers in the cell, but they play distinct roles in the electron transport chain. The electron transport chain is a series of proteins located in the inner membrane of the mitochondria that are responsible for the synthesis of ATP (the energy currency of the cell) through a process called oxidative phosphorylation.

NADH is the primary electron carrier in the electron transport chain. It donates its hydrogen atoms and electrons to the electron transport chain, where they are used to produce ATP. NADH is produced during the breakdown of glucose and other fuels through the process of cellular respiration.

NAD+ is also an electron carrier, but it plays a different role in the electron transport chain. It is produced when NADH donates its hydrogen atoms and electrons to the electron transport chain and is then used to accept hydrogen atoms and electrons during the process of cellular respiration.

Both NAD+ and NADH are important electron carriers, but NADH is the primary electron carrier in the electron transport chain, while NAD+ is involved in the process of cellular respiration.

What’s The Big Deal About NAD+ And NADH?

NAD+ and NADH were discovered over 100 years ago. Interest in their role in the cell increased about 20 years ago when Houtkooper et al. (2012) suggested that NAD+ is an essential substrate for sirtuins, a family of NAD+-dependent deacetylases that play an essential role in regulating energy metabolism and mitochondrial function.3 The poly (ADP-ribose) polymerase (PARP) protein family and the cyclic ADP-ribose (cADPr) synthases, including CD38 and CD157, were also found to be NAD+-consuming enzymes.1,2 More recently, sterile alpha and TIR motif-containing 1 (SARM1) has been identified as an enzyme with NAD+-cleavage activity in neurons, establishing a new family of NAD+-consuming enzymes.4

NAD+ production is tightly regulated. It can be produced de novo from tryptophan or via the salvage pathway from precursors and is broken down by NAD+-consuming enzymes. The de novo, Preiss-Handler, and NAD+ salvage pathways catalyze the formation of NAD (H), continuously counteracting the loss of NAD (H) by the three known families of NAD+-consuming enzymes.1 NAD balance is carefully maintained.

During the natural process of aging, NAD+ deficiency can occur. NAD+ depletion is detected in major neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, cardiovascular disease, and muscle atrophy.5 NAD+ deficiency has been identified in the skin and brain tissue, but the mechanisms leading to NAD+ deficiency are not fully understood.1  NAD+ supplementation can improve energy metabolism and insulin sensitivity in older individuals, as well as protect against neurodegeneration and improve cognitive function. However, more research is needed to fully understand the effects of NAD+ supplementation and to determine the optimal dosage and duration of treatment.

What Does NADH Do To The Brain?

Some studies have suggested that NADH may have several potential benefits for the brain, including improving mental clarity, reducing fatigue, and increasing alertness. Maintaining NAD+ levels seems to sustain a basal metabolic rate and health in neurons (brain cells). However, more research is needed to fully understand the effects of NADH on the brain and determine whether it is safe and effective for use as a supplement.

Brain neurons

Is It Better To Take NAD Or NADH?

Strategies to boost NAD+ levels fall into two categories: inhibiting NAD+ consumption and stimulating NAD+ biosynthesis. In preclinical trials, inhibiting NAD+ consumption was effective in raising NAD+ levels. Research interest in stimulating NAD+ synthesis by supplementing with NAD+ precursors has increased. Several clinical trials have been carried out with the NAD+ precursors NA, NAM, NR, and, to a much lesser extent, NMN. In one trial, NA supplementation restored NAD levels and improved muscle performance in patients with mitochondrial deficiency. NA supplementation induces a painful flushing reaction, which has increased interest in NMN and NR, molecules that do not cause this side effect.1

Although NR lowers circulating inflammatory cytokines,6 increases acetylcarnitine concentrations in skeletal muscle, and slightly increases the resting metabolic rate,7 it has no effects on overall activity, exercise performance, motor function, or mitochondrial bioenergetics. This lack of beneficial effects in humans may be in part related to the inability of NMN and NR to enhance NAD+ levels in human tissues.1

NADH supplements have been used as a treatment for conditions such as fatigue, depression, and Alzheimer’s disease. However, the evidence for the effectiveness of NADH supplements in these conditions is inconclusive, and more research is needed.

Sirtuins and PARPS control NAD+ balance and provide a link between metabolism, health, and lifespan. As researchers close in on better understanding this complex cellular metabolism, we are a step closer to understanding and treating the aging process.

“The potential preventive and therapeutic use of NAD+-boosting strategies requires an assessment of the bioavailability and effectiveness of various precursor doses in human therapy. In addition, new NAD+ boosters are welcomed since the side effects of niacin generally lead to poor compliance, despite its known efficacy in a myriad of diseases. Therefore, the dosing and safety of these new NAD+ boosters (e.g., NAD+ precursors, CD38 inhibitors, and PARP inhibitors) must be thoroughly assessed to translate these exciting insights into NAD+ biology toward human relevance.”2

Canto et al. 2015

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DISCLAIMER

While we strive to always provide accurate, current, and safe advice in all of our articles and guides, it’s important to stress that they are no substitute for medical advice from a doctor or healthcare provider. You should always consult a practicing professional who can diagnose your specific case. The content we’ve included in this guide is merely meant to be informational and does not constitute medical advice.

References

1. Zapata-Pérez R, Wanders RJA, van Karnebeek CDM, Houtkooper RH. NAD+ homeostasis in human health and disease. https://doi.org/10.15252/emmm.202113943. EMBO Molecular Medicine. 2021/07/07 2021;13(7):e13943. doi:https://doi.org/10.15252/emmm.202113943

2. Cantó C, Keir, Auwerx J. NAD+ Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus. Cell Metabolism. 2015;22(1):31-53. doi:10.1016/j.cmet.2015.05.023

3. Houtkooper RH, Pirinen E, Auwerx J. Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol. Mar 7 2012;13(4):225-238. doi:10.1038/nrm3293

4. Essuman K, Summers DW, Sasaki Y, Mao X, DiAntonio A, Milbrandt J. The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD(+) Cleavage Activity that Promotes Pathological Axonal Degeneration. Neuron. Mar 22 2017;93(6):1334-1343.e5. doi:10.1016/j.neuron.2017.02.022

5. Fang EF, Lautrup S, Hou Y, et al. NAD(+) in Aging: Molecular Mechanisms and Translational Implications. Trends Mol Med. Oct 2017;23(10):899-916. doi:10.1016/j.molmed.2017.08.001

6. Elhassan YS, Kluckova K, Fletcher RS, et al. Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD(+) Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures. Cell Rep. Aug 13 2019;28(7):1717-1728.e6. doi:10.1016/j.celrep.2019.07.043

7. Remie CME, Roumans KHM, Moonen MPB, et al. Nicotinamide riboside supplementation alters body composition and skeletal muscle acetylcarnitine concentrations in healthy obese humans. Am J Clin Nutr. Aug 1 2020;112(2):413-426. doi:10.1093/ajcn/nqaa072

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Published: Dec 19, 2022

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