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Nicotinamide Adenine Dinucleotide (NAD)

Nicotinamide Adenine Dinucleotide (NAD) is a metabolic co-enzyme and is has the important job of structuring, repairing, and remodelling every cell in the body. NAD requires constant replenishment in the body. Unfortunately, drug and alcohol abuse causes oxidative stress, triggering the brain to reorganise on a cellular level. This process, known as neuroadaptation, is directly responsible for addiction-related brain damage and depletion of neurotransmitters.


Supporting research & information

Supporting Research

Comparison of Oral Nicotinamide Adenine Dinucleotide (NADH) versus Conventional Therapy for Chronic Fatigue Syndrome

Maria L Santaella, MD;FACP, FAAAAI; Ivonne Font, MD; Orville M Disdier, MS
Department of Medicine, University of Puerto Rico

Results. The 12 patients who received NADH had a dramatic and statistically significant reduction of the mean symptom score in the first trimester.  However, symptom scores in the subsequent trimester of therapy were similar in both treatment groups.

Journal of Neural Transmission, Vienna Austria

No evidence from cognitive improvement from oral NAD in dementia

Nicotinic Acid, Nicotinamide, and Nicotinamide Riboside: A Molecular Evaluation of NAD+ Precursor Vitamins in Human Nutrition

Annual Review of Nutrition
Vol. 28: 115-130 (Volume publication date August 2008)
First published online as a Review in Advance on April 22, 2008
DOI: 10.1146/annurev.nutr.28.061807.155443
Katrina L. Bogan and Charles Brenner

Departments of Genetics and Biochemistry and the Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, New Hampshire 03756; email:charles.brenner@dartmouth.edu

Abstract:

Although baseline requirements for nicotinamide adenine dinucleotide (NAD+) synthesis can be met either with dietary tryptophan or with less than 20 mg of daily niacin, which consists of nicotinic acid and/or nicotinamide, there is growing evidence that substantially greater rates of NAD+ synthesis may be beneficial to protect against neurological degeneration, Candida glabrata infection, and possibly to enhance reverse cholesterol transport. The distinct and tissue-specific biosynthetic and/or ligand activities of tryptophan, nicotinic acid, nicotinamide, and the newly identified NAD+ precursor, nicotinamide riboside, reviewed herein, are responsible for vitamin-specific effects and side effects. Because current data suggest that nicotinamide riboside may be the only vitamin precursor that supports neuronal NAD+synthesis, we present prospects for human nicotinamide riboside supplementation and propose areas for future research.

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Nicotinic Acid, Nicotinamide, and Nicotinamide Riboside: A Molecular Evaluation of NAD+ Precursor Vitamins in Human Nutrition
Abstract

Although baseline requirements for nicotinamide adenine dinucleotide (NAD+) synthesis can be met either with dietary tryptophan or with less than 20 mg of daily niacin, which consists of nicotinic acid and/or nicotinamide, there is growing evidence that substantially greater rates of NAD+ synthesis may be beneficial to protect against neurological degeneration, Candida glabrata infection, and possibly to enhance reverse cholesterol transport. The distinct and tissue-specific biosynthetic and/or ligand activities of tryptophan, nicotinic acid, nicotinamide, and the newly identified NAD+ precursor, nicotinamide riboside, reviewed herein, are responsible for vitamin-specific effects and side effects. Because current data suggest that nicotinamide riboside may be the only vitamin precursor that supports neuronal NAD+synthesis, we present prospects for human nicotinamide riboside supplementation and propose areas for future research.

NAD+ metabolism and oxidative stress: the golden nucleotide on a crown of thorns  
In the twentieth century, NAD+ research generated multiple discoveries. Identification of the important role of NAD+ as a cofactor in cellular respiration and energy production was followed by discoveries of numerous NAD+ biosynthesis pathways. In recent years, NAD+ has been shown to play a unique role in DNA repair and protein deacetylation. As discussed in this review, there are close interactions between oxidative stress and immune activation, energy metabolism, and cell viability in neurodegenerative disorders and ageing. Profound interactions with regard to oxidative stress and NAD+ have been highlighted in the present work. This review emphasizes the pivotal role of NAD+ in the regulation of DNA repair, stress resistance, and cell death, suggesting that NAD+ synthesis through the kynurenine pathway and/or salvage pathway is an attractive target for therapeutic intervention in age-associated degenerative disorders. NAD+ precursors have been shown to slow down ageing and extend lifespan in yeasts, and protect severed axons from degeneration in animal models neurodegenerative diseases.

General Information

https://www.selfhacked.com/blog/nad-important-increase/

NAD+ has many important roles for health, including stimulating anti-aging activities of Sirtuins and the DNA damage repair enzymes.

High NAD+ is necessary for healthy metabolism and mitochondria. In addition, low NAD+ can contribute to fatigue and several diseases.

11 Harmful Effects of Low NAD+

First, it’s important to know why having low NAD+ is a problem.  That information will motivate you to increase this molecule.

4) Low NAD+ is Associated with Fatigue

Fatigue, low physical and mental energy are also signs of lower NAD+/SIRT1.

Levels of NAD+ largely control the “redox potential” because NAD+ has the ability to acquire electrons.

The higher the redox potential of the cell, the better the mitochondria work and the more it can fight infections and function the way a cell is supposed to function.

Supplementation of NADH, NAD+ or its cofactors helps with chronic fatigue syndrome and fibromyalgia [R, R2].

10) Low NAD+ Can Impair Brain Function

The brain has a high energy demand, so neurons contain a lot of mitochondria. Mitochondria dysfunction also contributes to many mental health and neurodegenerative diseases.

Treatment with NADH improves cognitive function of Alzheimer’s disease patients [R].

In a mouse model of Alzheimer’s disease, increasing NAD+ by supplementing with nicotinamide riboside restores cognitive function by increasing PGC-1alpha levels [R].

NADH has been used to treat Parkinson’s as NADH may increase the bioavailability of levodopa, the medication for Parkinson’s [R, R2].

In rats, NAD+ administration through the nose may decrease brain damage from oxygen deprivation (e.g. due to stroke) [R].

This is also why a lot of my clients claim to do better with niacin/nicotinamide in the short term: because it increases NAD+ [R].

My clients often claim to do better with amphetamine usage as well in the short term.  Amphetamines use up energy, ATP and also deplete dopaminein certain parts of the brain (striatum in rats) [R].

When rats were given niacinamide to increase NAD+ levels, the negative changes caused by amphetamines were reduced [R].

So we see that lower levels of NAD+ will decrease brain energy and dopamine, and people will start to need stimulants to keep up.

 

https://www.healthline.com/health-news/could-this-version-of-vitamin-b-3-slow-aging

Overview Information

NADH stands for "nicotinamide adenine dinucleotide (NAD) + hydrogen (H)." This chemical occurs naturally in the body and plays a role in the chemical process that generates energy. People use NADH supplements as medicine.

NADH is used for improving mental clarity, alertness, concentration, and memory; as well as for treating Alzheimer’s disease and dementia. Because of its role in energy production, NADH is also used for improving athletic performance and treating chronic fatigue syndrome (CFS).

Some people use NADH for treating high blood pressure, high cholesterol, jet lag, depression, and Parkinson’s disease; opposing alcohol’s effects on the liver; reducing signs of aging; and protecting against the side effects of an AIDS drug called zidovudine (AZT).

Healthcare providers sometimes give NADH by intramuscular (IM) or intravenous (IV) injection for Parkinson's disease and depression.

How does it work?

NADH produced by our bodies is involved in making energy in the body. While there is some evidence that suggests NADH supplements might reduce blood pressure, lower cholesterol, help chronic fatigue syndrome by providing energy, and increase nerve signals for people with Parkinson's disease, there isn't enough information to know for sure how or if these supplements work.

https://www.webmd.com/vitamins/ai/ingredientmono-1016/nadh

http://supplementpolice.com/nad/ 

NADH supplement health benefit, side effects 5 mg 10 mg and 20 mg tablets, which medical conditions is this nutrient used for by Ray Sahelian, M.D.
October 14, 2014

http://www.anti-aging-today.org/medicine/anti-aging/nadh.htm 

Short List of  NAD Studies 

Further Reading

The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways.
Houtkooper RH, Cantó C, Wanders RJ, Auwerx J.

Source
Ecole Polytechnique Fédérale de Lausanne, Laboratory for Integrative and Systems Physiology, Building AI, Station 15, CH-1015 Lausanne, Switzerland.

Abstract
A century after the identification of a coenzymatic activity for NAD(+), NAD(+) metabolism has come into the spotlight again due to the potential therapeutic relevance of a set of enzymes whose activity is tightly regulated by the balance between the oxidized and reduced forms of this metabolite. In fact, the actions of NAD(+) have been extended from being an oxidoreductase cofactor for single enzymatic activities to acting as substrate for a wide range of proteins. These include NAD(+)-dependent protein deacetylases, poly(ADP-ribose) polymerases, and transcription factors that affect a large array of cellular functions. Through these effects, NAD(+) provides a direct link between the cellular redox status and the control of signaling and transcriptional events. Of particular interest within the metabolic/endocrine arena are the recent results, which indicate that the regulation of these NAD(+)-dependent pathways may have a major contribution to oxidative metabolism and life span extension. In this review, we will provide an integrated view on: 1) the pathways that control NAD(+) production and cycling, as well as its cellular compartmentalization; 2) the signaling and transcriptional pathways controlled by NAD(+); and 3) novel data that show how modulation of NAD(+)-producing and -consuming pathways have a major physiological impact and hold promise for the prevention and treatment of metabolic disease.

Endocr Rev. 2010 Apr;31(2):194-223. Epub 2009 Dec 9.

NAD+ and NADH in cellular functions and cell death.
Ying W.

Source
Department of Neurology, University of California, San Francisco Veterans Affairs Medical Center, San Francisco, CA 94121, USA. Weihai.Ying@ucsf.edu

Abstract
Increasing evidence has indicated that NAD+ and NADH play critical roles not only in energy metabolism, but also in cell death and various cellular functions including regulation of calcium homeostasis and gene expression. It has also been indicated that NAD+ and NADH are mediators of multiple major biological processes including aging. NAD+ and NADH produce the biological effects by regulating numerous NAD+/NADH-dependent enzymes, including dehydrogenases, poly(ADP-ribose) polymerases, Sir2 family proteins (sirtuins), mono(ADP-ribosyl)transferases, and ADP-ribosyl cyclases. Of particular interest, NAD+-dependent generation of ADP-ribose, cyclic ADP-ribose and O-acetyl-ADP-ribose can mediate calcium homeostasis by affecting TRPM2 receptors and ryanodine receptors; and sirtuins and PARPs appear to play key roles in aging, cell death and a variety of cellular functions. It has also been indicated that NADH and NAD+ can be transported across plasma membranes of cells, and that extracellular NAD+ may be a new signaling molecule. Our latest studies have shown that intranasal NAD+ administration can profoundly decrease ischemic brain damage. These new pieces of information have fundamentally changed our understanding about NAD+ and NADH, suggesting novel paradigms about the metabolism and biological activities of NAD+ and NADH. Based on this information, it is tempted to hypothesize that NAD+ and NADH, together with ATP and Ca2+, may be four most fundamental components in life, which can significantly affect nearly all major biological processes. Future studies on NAD+ and NADH may not only elucidate some fundamental mysteries in biology, but also provide novel insights for interfering aging and many disease processes.

Front Biosci. 2006 Sep 1;11:3129-48.
PMID: 16720381 [PubMed - indexed for MEDLINE]

NAD+ and vitamin B3: from metabolism to therapies.
Sauve AA.

Source
Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA. aas2004@med.cornell.edu

Abstract
The role of NAD(+) metabolism in health and disease is of increased interest as the use of niacin (nicotinic acid) has emerged as a major therapy for treatment of hyperlipidemias and with the recognition that nicotinamide can protect tissues and NAD(+) metabolism in a variety of disease states, including ischemia/reperfusion. In addition, a growing body of evidence supports the view that NAD(+) metabolism regulates important biological effects, including lifespan. NAD(+) exerts potent effects through the poly(ADP-ribose) polymerases, mono-ADP-ribosyltransferases, and the recently characterized sirtuin enzymes. These enzymes catalyze protein modifications, such as ADP-ribosylation and deacetylation, leading to changes in protein function. These enzymes regulate apoptosis, DNA repair, stress resistance, metabolism, and endocrine signaling, suggesting that these enzymes and/or NAD(+) metabolism could be targeted for therapeutic benefit. This review considers current knowledge of NAD(+) metabolism in humans and microbes, including new insights into mechanisms that regulate NAD(+) biosynthetic pathways, current use of nicotinamide and nicotinic acid as pharmacological agents, and opportunities for drug design that are directed at modulation of NAD(+) biosynthesis for treatment of human disorders and infections.

J Pharmacol Exp Ther. 2008 Mar;324(3):883-93. doi: 10.1124/jpet.107.120758. Epub 2007 Dec 28.
PMID: 18165311 [PubMed - indexed for MEDLINE] Free full text

The new life of a centenarian: signalling functions of NAD(P).
Berger F, Ramírez-Hernández MH, Ziegler M.

Source
Institut für Biochemie, Freie Universität Berlin, Thielallee 63, 14195 Berlin, Germany.

Abstract
Since the beginning of the last century, seminal discoveries have identified pyridine nucleotides as the major redox carriers in all organisms. Recent research has unravelled an unexpectedly wide array of signalling pathways that involve nicotinamide adenine dinucleotide (NAD) and its phosphorylated form, NADP. NAD serves as substrate for protein modification including protein deacetylation, and mono- and poly-ADP-ribosylation. Both NAD and NADP represent precursors of intracellular calcium-mobilizing molecules. It is now beyond doubt that NAD(P)-mediated signal transduction does not merely regulate metabolic pathways, but might hold a key position in the control of fundamental cellular processes. The comprehensive molecular characterization of NAD biosynthetic pathways over the past few years has further extended the understanding of the multiple roles of pyridine nucleotides in cell biology.

Trends Biochem Sci. 2004 Mar;29(3):111-8.
PMID: 15003268 [PubMed - indexed for MEDLINE]

 

Emerging roles of NAD+ and its metabolites in cell signaling.
Koch-Nolte F, Haag F, Guse AH, Lund F, Ziegler M.

Source
Institute of Immunology, Diagnostic Department, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg, Germany. nolte@uke.de

Abstract
Nicotinamide adenine dinucleotide (NAD(+)) is the universal currency of energy metabolism and electron transfer. Recent studies indicate that apart from its role as a coenzyme, NAD(+) and its metabolites also function in cell signaling pathways; for example, they are substrates for nucleotide-metabolizing enzymes and ligands for extra- and intracellular receptors and ion channels. Moreover, the NAD(+) and NAD(+) phosphate metabolites adenosine 5'-diphosphoribose (ADP-ribose), cyclic ADP-ribose, and nicotinic acid adenine dinucleotide phosphate (NAADP) have emerged as key second messengers in Ca(2+) signaling. A symposium in Hamburg, Germany, brought together 120 researchers from various fields, who were all engaged in the molecular characterization of the key players of NAD(+) signaling (www.NAD2008.de).

Sci Signal. 2009 Feb 10;2(57):mr1. doi: 10.1126/scisignal.257mr1.
PMID: 19211509 [PubMed - indexed for MEDLINE]

Calcium signaling by cyclic ADP-ribose and NAADP. A decade of exploration.

Lee HC.

Source
Department of Physiology, University of Minnesota, Minneapolis 55455, USA. leehc@maroon.tc.umn.edu

Abstract
Ca2+ mobilization as a signaling mechanism has been placed on center stage with the discovery of the first Ca2+ messenger, inositol trisphosphate (IP3). This article focuses on two new Ca2+ release activators, which mobilize internal Ca2+ stores via mechanisms totally independent of IP3. They are cyclic ADP-ribose (cADPR) and nicotinic acid dinucleotide phosphate (NAADP), metabolites derived respectively from NAD and NADP. Major advances in the past decade in the understanding of these two novel signaling mechanisms are chronologically summarized.

Cell Biochem Biophys. 1998;28(1):1-17.
PMID: 9386889 [PubMed - indexed for MEDLINE]

Modulator and messenger functions of cyclic ADP-ribose in calcium signaling.
Lee HC.

Source
Department of Physiology, University of Minnesota, Minneapolis 55455, USA.

Abstract
Cyclic ADP-ribose (cADPR), a Ca+2 mobilizing cyclic nucleotide derived from NAD+, is emerging as an endogenous modulator of the Ca(+2)-induced Ca+2 release (CICR) mechanism in cells. cADPR was discovered because of the prominent delay in the initiation of Ca+2 release by NAD+ in sea urchin egg homogenates, which was due to enzymatic conversion to cADPR. In addition to the egg, an invertebrate cell, amphibian neurons, a variety of mammalian cells and plant vacuoles are found to be responsive to cADPR, indicating its generality. The cyclic structure of cADPR has been determined by X-ray crystallography. A series of analogs has been synthesized, which includes cyclic GDP-ribose, a fluorescent analog, a series of specific antagonists, a photoaffinity label and caged cADPR. The use of these analogs of cADPR has provided definitive evidence for the authenticity of its Ca+2 mobilizing activity and insights for understanding its mechanism and biological functions. Results show that its action requires a soluble protein which is identified as calmodulin. The effect of calmodulin is synergistic with cADPR and both act to sensitize CICR to Ca+2. Together, the Ca+2 sensitivity of CICR can be increased by several orders of magnitude. In addition to being a modulator of CICR. cADPR can also function as a messenger. Activation of its synthetic enzyme can lead to large increases in cellular concentrations of cADPR, which would sensitize CICR to such an extent that even basal levels of cellular Ca+2 are sufficient to trigger further release. This is operationally equivalent to being a Ca+2 messenger. Three types of enzymes are involved in the metabolism of cADPR, a soluble ADP-ribosyl cyclase; a bifunctional ecto-enzyme, CD38, which is also a lymphocyte antigen; and an intracellular enzyme activable by a cGMP-dependent process. The importance of two cysteine residues in the bifunctionality of CD38 has been shown by site-directed mutagenesis. Both ADP-ribosyl cyclase and CD38 can catalyze the exchange of the nicotinamide group in NADP+ with nicotinic acid, leading to the formation of another Ca+2 mobilizing metabolite, nicotinic acid dinucleotide phosphate (NAADP). Pharmacological and desensitization studies show that the NAADP-mechanism is totally independent of the cADPR- and inositol trisphosphate-mechanisms and the Ca+2 stores responsive to NAADP are separable from those sensitive to the other two Ca+2 agonists. Microinjection studies show that all three mechanisms are present and functional in cells. The emerging picture of multiplicity in Ca+2 signaling mechanisms underscores the versatility of Ca+2 in regulating diverse cellular functions.

Recent Prog Horm Res. 1996;51:355-88; discussion 389.

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