NAD+ and Deficiency Diseases Georg Harald Mehlhorn NAD+ Functions and Deficiency Diseases GHM 27.04.2020 1 NAD+ and Deficiency Diseases Contents Summary ............................................................................................................................................3 Introduction ....................................................................................................................................3 Working Hypotheses .......................................................................................................................3 Deficiency Diseases .........................................................................................................................3 Conclusions .....................................................................................................................................3 Abbreviations/Registry .......................................................................................................................4 Introduction: NAD+ - Biosynthesis and-Metabolism .............................................................................5 Overview ........................................................................................................................................5 NAD+ Anabolism Biosynthesis and Catabolism .................................................................................9 Substrates/Anabolites .................................................................................................................9 Pathways I ................................................................................................................................. 10 Pathways II ................................................................................................................................ 11 Metabolism ............................................................................................................................... 13 Catabolites of NAD+ ...................................................................................................................... 14 Cofactors ...................................................................................................................................... 16 Catabolism of the NAD(P)(H) Pool and NAD+ Deficiency ............................................................ 16 Side Effects of NAD+ - Anabolites ...................................................................................................... 18 NA Flush ....................................................................................................................................... 19 Liver and Kidneys (all substrates) .................................................................................................. 20 NA ............................................................................................................................................. 20 NAM ......................................................................................................................................... 21 NR and NAR .............................................................................................................................. 21 Tolerable Upper Limits (UL) ....................................................................................................... 22 Interaction with Medications .................................................................................................... 22 Immunosuppressive Medications .............................................................................................. 23 Degenerated and Waste Products from Necrosis .......................................................................... 23 Dosages ........................................................................................................................................ 23 Outlook: What to do? ....................................................................................................................... 25 Thesis ........................................................................................................................................ 25 Diagnosis of NAD+ Deficiency .................................................................................................... 25 Appendix .......................................................................................................................................... 26 (1) A Case Study in the “Letters to the Editor” ............................................................................... 26 (2) More Case Studies ................................................................................................................... 27 (3) NAD+ and Tryptophan ............................................................................................................. 30 2 NAD+ and Deficiency Diseases Summary Introduction Nicotinamide Adenine Dinucleotide 1 (NAD+) is a coenzyme that is essential for energy balance and supply in every living being. It ensures the energy supply into the TCA-cycle from the respiratory chain in the mitochondria of all cells. Affected cells deteriorate and die without sufficient mitochondrial2 energy. The possible results could be diseases based on deficiency of NAD+. NAD+ deficiency arises when the energy use overwhelms humans, i.e. in competitive sports, viral and bacterial infections, parasites, stress, exposure to pollution, and last not least in pregnancy, at birth and during lactation - but always based on malnutrition and following deficiencies. Working Hypotheses 1. Eliminating deficiency in NAD+ is the prerequisite for successful therapies. 2. Eliminating of a NAD+ deficiency is not a therapy, but a diet. 3. Chronic deficiency of NAD+ creates chronic diseases. 4. NAD+- deficiency creates non-specific symptoms, which are characteristic for many diseases. Deficiency Diseases Lack of NAD+ inevitably means a lack of energy in the cells. This may lead to disorders, including • Fatigue illnesses, for example in CFS or ME3 and depression, • Many psychiatric disorders (for example schizophrenia and ADHD), Metabolic diseases, for example type 2 diabetes and metabolic syndrome, • Some prenatal genetic / chromosome disorders due to a defective methylation and DNA repair, some so-called inherited diseases, possibly the Down syndrome4 as well, • Cardiovascular diseases, • Changing stress response, necrosis instead of apoptosis /autophagy, Disruptions of the immune response and immune tolerance, autoimmune disorders, • Cancerous diseases that arise on the basis of a lack of cell energy, that is: a lack of NAD+5. The list is not exhaustive; it grows practically every day with new research. Conclusions Eliminating the NAD+ deficiency does not mean healing automatically, but it is the precondition of prevention, healing, or self-healing. The physician starts after the elimination of the NAD+ deficiency. Mostly several potential causes come together, i.e. previous illnesses and the life style (habits, diets, epigenetics), which must be known if effective help for a therapy shall be provided for. Refusal to apply a balancing of the NAD+ levels at the begin of a therapy is akin to the violation of the oath of Hippocrates. 1 https://www.ncbi.nlm.nih.gov/pubmed/29477227 2 The mitochondria probably do not attract a disease; they starve. 3 CFS and ME start in many cases with an infection causing a collapse of the immune system. The following symptoms may depend on the species of pathogens. After ramping up the NAD+ supply, all these following infections should be counteracted one by one. 4 Down syndrome was chosen as an example because the frequency of chromosomal defects in the child increases with the age of the mother - when the NAD+ level decreases due to mother’s age. Experience has shown that increasing the NAD+ level during pregnancy protects the infant from such syndromes. 5 https://www.ncbi.nlm.nih.gov/pubmed/29883761 3 NAD+ and Deficiency Diseases Abbreviations/Registry Abbreviation means/comment Page ADHD, ADHS Attention Deficit Hyperactivity Disorder (D = Disorder, S = Syndrom) 4;5;9;16 ADP AdeninosinDiPhosphat (Energy Transmitter in the TCA cycle) 5;16 ADPR Adenosine DiPhosphoRibose (activates the TRPM2 ion channel, DNA-repair) 14 ART ADP-ribosyltransferase, signals gene distortions to the PARPs 6;16 ATP AdeninosinTriPhosphat (Energy Transmitter in the TCA cycle) 15;18 Asp Aspartic acid 6;10 CNS Central Nervous System 7;9;15 CoA Coenzyme A 18 DNA Desoxyribonucleic Acid 4;6;7;16 DGE Deutsche Gesellschaft für Ernährung e.V. (German Association for Nutrition) 19 EFSA European Food Safety Authority 19 EBM Evidence based medicine. Denotes the introduction of statistical means as an interpretation method of results in medicinal research. 23;25 ER Extended Release (applies mostly to NAM) 19;25 FAD++ Flavin adenine dinucleotide, energy transfer into mitochondriae (similar to NAD+) 14;15;16 FADH2 FAD reduced, energy transfer into mitochondriae (similar to NAD+) 14;15;16 GTP Guanosintriphosphate 16;17 GDP Guanosindiphosphate 16;17 ICD International Statistical Classification of Diseases and Related Health Problems 6 IHN Inositol Hexanicotinate 10 MS Multiple Sclerosis 6;15 N-Me-2PYR N-methyl-2-pyridone-5-carboxamide 15 N-Me-4PYR N-methyl-4-pyridone3-carboxamide 15 NA Nicotinic Acid (synonymous Vitamin B3, niacin) 5ff NAD+ Nicotinamide Adenine Dinucleotide, extremely important coenzym in the 2ff energy supply to cells, oxidized NAD(H)(P) Pool of functional cofactors