NAD+ Energy, longevity, brain health anti-inflammatory Ray Griffiths MSc Clinical Education Associate Webinar Disclosure Webinars such as this are for educational purposes only and are intended for health care practitioners. These therapies are not substitutions for standard medical care. Practitioners are solely responsible for the care and treatment provided to their own patients. Rajman, L., Chwalek, K. and Sinclair, D.A., 2018. Therapeutic potential of NAD- boosting molecules: the in vivo evidence. Cell metabolism, 27(3), pp.529-547. Covered in this presentation: Energy production Sirtuins (SIRTs) our anti-ageing proteins Poly(ADP-ribose) polymerases (PARPs) – DNA repair CD38 – Immune cell surface marker which degrades NAD+ Enzymes - dehydrogenases NAD+ For energy NAD+ a vital part of the energy web of life Flow of energy largely determines the structure of ecosystems via food webs and taste sensors with appetite and quality controls, that avoid toxins but allow self- medication… …diet, along with domestication of microbes as gut symbionts, provide or manufacture vitamins, including nicotinamide/niacin. This vitamin has evolved to supply and translocate energy and information via NAD+ and NADH Williams, A.C., Hill, L.J. and Ramsden, D.B., 2012. Nicotinamide, NAD (P)(H), and methyl-group homeostasis evolved and became a determinant of ageing diseases: hypotheses and lessons from pellagra. Current gerontology and geriatrics research, 2012. Pellagra – in effect an NAD+ deficiency? Overt niacin or NAD+ deficiency is called pellagra Symptoms are dementia, depression, dermatitis, diarrhoea, and death But could subclinical pellagra be driving many chronic Western diseases? Williams, A.C., Hill, L.J. and Ramsden, D.B., 2012. Nicotinamide, NAD (P)(H), and methyl-group homeostasis evolved and became a determinant of ageing diseases: hypotheses and lessons from pellagra. Current gerontology and geriatrics research, 2012. The coenzyme NAD+ was first discovered by the British biochemists Arthur Harden and William John Young in 1906 NAD+ exists in two forms – oxidised and reduced Our mitochondria are effectively solar powered Energy from sunlight is used to remove electrons from water to synthesise plants. We eat the plants, to extract the high energy electrons, and then shuttle them via NADH to the mitochondrial electron transport chain. The high energy electrons are contained in the bond of NAD+ and H+ to form NADH Our mitochondria are effectively solar powered You would think that higher NADH levels are better for health? …but not so fast! When not carrying ‘energy bricks’ NAD+ has other vital roles to play The mitochondrial NAD+ pool is relatively distinct from that of the rest of the cell, while cytoplasmic NAD+/NADH ratios range between 60 and 700 in a typical eukaryotic cell, mitochondrial NAD+/NADH ratios are maintained at 7 to 8 These ratios decline as we age Zhu, X.H., Lu, M., Lee, B.Y., Ugurbil, K. and Chen, W., 2015. In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences. Proceedings of the National Academy of Sciences, p.201417921. Stein, L.R. and Imai, S.I., 2012. The dynamic regulation of NAD metabolism in mitochondria. Trends in Endocrinology & Metabolism, 23(9), pp.420-428. NAD + decreases as we age NADH increases as we age It’s estimated that by 40-50, most people will have half the NAD+ levels of their youth Zhu, X.H., Lu, M., Lee, B.Y., Ugurbil, K. and Chen, W., 2015. In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences. Proceedings of the National Academy of Sciences, p.201417921. Schultz, M.B. and Sinclair, D.A., 2016. Why NAD+ declines during aging: it’s destroyed. Cell metabolism, 23(6), pp.965-966. A lower NAD+/NADH ratio is strongly implicated in mitochondrial disorders and, age- related disorders including diaBetes, oBesity, neurodegeneration and cancer The NAD+/NADH ratio is in equilibrium with the pyruvate/lactate ratio Srivastava, S., 2016. Emerging therapeutic roles for NAD+ metabolism in mitochondrial and age-related disorders. Clinical and Translational Medicine, 5(1), pp.1-11. Mintun, M.A., Vlassenko, A.G., Rundle, M.M. and Raichle, M.E., 2004. Increased lactate/pyruvate ratio augments blood flow in physiologically activated human brain. Proceedings of the National Academy of Sciences, 101(2), pp.659-664. Parkinson’s patient organic acid results from Great Plains and Genova Same urine sample! Oxidative stress in schizophrenia The importance of the NAD+/NADH Ratio In the 1960s, psychiatrists Abraham Hoffer and Humphry Osmond gave as much as 17g of niacin to schizophrenic patients with impressive results Recent research has pointed to a dramatic drop in the NAD+/NADH Ratio during a patient’s first episode of schizophrenia. This fall in the ratio points to very high levels of oxidative stress within the central nervous system of the patient It is likely that Hoffer and Osmond were effectively increasing the NAD+/NADH ratio to support schizophrenic patients Carter, S., 2019. Origins of Orthomolecular Medicine. Integrative Medicine: A Clinician's Journal, 18(3), p.76. Kim, S.Y., Cohen, B.M., Chen, X., Lukas, S.E., Shinn, A.K., Yuksel, A.C., Li, T., Du, F. and Öngür, D., 2017. Redox dysregulation in schizophrenia revealed by in vivo NAD+/NADH measurement. Schizophrenia bulletin, 43(1), pp.197-204. NAD+ and caffeine to support motor neurons Green tea also supports Nmnat2 Zwilling, M., Theiss, C. and Matschke, V., 2020. Caffeine and NAD+ improve motor neural integrity of dissociated wobbler cells in vitro. Antioxidants, 9(6), p.46 Lau, C., 2008. Functional characterisation of three human nicotinamide mononucleotide adenylyltransferases. Human PD patient stem cell-derived dopaminergic neurons exhibit reduced NAD+ levels Fulleylove-Krause, B., Sison, S. and Ebert, A., 2020. Nicotinamide mononucleotide treatment increases NAD+ levels in an iPSC Model of Parkinsons Disease. bioRxiv. Parkinson’s disease is often linked with mitochondrial complex I dysfunction Complex I dysfunction is translated to an increased production of reactive oxygen species and a decreased energy supply NNAD+/NADH Tapias, V., McCoy, J.L. and Greenamyre, J.T., 2019. Phenothiazine normalizes the NADH/NAD+ ratio, maintains mitochondrial integrity and protects the nigrostriatal dopamine system in a chronic rotenone model of Parkinson's disease. Redox biology, 24, p.101164. Marella, M., Seo, B.B., Yagi, T. and Matsuno-Yagi, A., 2009. Parkinson’s disease and mitochondrial complex I: a perspective on the Ndi1 therapy. Journal of bioenergetics and biomembranes, 41(6), pp.493-497. NAD+ proteoxicity and AGEs Lowered NAD+ availability can lead to generation of methylglyoxal from glycolytic intermediates …which in turn can damage proteins (AGEs), promote generation of reactive oxygen species and induce mitochondrial dysfunction Methylglyoxal = AGEs Low NAD+ blocks glycolysis with catastrophic results Hipkiss, A.R., 2010. NAD+ and metabolic regulation of age-related proteoxicity: A possible role for methylglyoxal?. Experimental gerontology, 45(6), pp.395-399. So is oBesity really an NAD+ deficiency? Is it a desperate attempt to shunt excess energy into adipose tissue to regenerate vital NAD+? Williams, A.C., Hill, L.J. and Ramsden, D.B., 2012. Nicotinamide, NAD (P)(H), and methyl-group homeostasis evolved and became a determinant of ageing diseases: hypotheses and lessons from pellagra. Current gerontology and geriatrics research, 2012. Chronic alcohol binging injures the liver and other organs by reducing NAD+ levels French, S.W., 2016. Chronic alcohol binging injures the liver and other organs by reducing NAD+ levels required for sirtuin's deacetylase activity. Experimental and molecular pathology, 100(2), pp.303-306. Pau D’arco helps regenerate NAD+ from NADH β-lapachone from the herb Pau D’arco is a metabolite that modulates cellular NAD+ by conversion of NADH to NAD+ via the enzymatic action of NADH: quinone oxidoreductase 1 (NQO1) https://thegutclub.org/enduracell-sulforaphane/ Kim, H.J., Cao, W., Oh, G.S., Lee, S., Shen, A., Khadka, D., Lee, S.B., Sharma, S., Kim, S.Y., Choe, S.K. and Kwak, T.H., 2019. Augmentation of cellular NAD+ by NQO1 enzymatic action improves age-related hearing impairment. Aging cell, 18(5), p.e13016. Niacin Increases NAD+ Significantly – supports mitochondrial function NAD+ levels can be rescued by a potent NAD+ booster niacin. Niacin remarkably restores muscle and systemic NAD+ and provides metabolic and functional benefits for patients with mitochondrial myopathy Up to 1g a day of niacin was used for 4 months Pirinen, E., Auranen, M., Khan, N.A., Brilhante, V., Urho, N., Pessia, A., Hakkarainen, A., Kuula, J., Heinonen, U., Schmidt, M.S. and Haimilahti, K., 2020. Niacin cures systemic NAD+ deficiency and improves muscle performance in adult-onset mitochondrial myopathy. Cell metabolism, 31(6), pp.1078-1090. NAD+ can Be increased by exercise, calorie restriction and nutritional precursors Nutritional Ketosis Increases NAD+/NADH Ratio in the Human Brain Nutritional ketosis – blood levels 0.5 to 3 mg/dL Xin, L., Ipek, Ö., Beaumont, M., Shevlyakova, M., Christinat, N., Masoodi, M., Greenberg, N., Gruetter, R. and Cuenoud, B., 2018. Nutritional ketosis increases NAD+/NADH ratio in healthy human brain: an in vivo study by 31P-MRS. Frontiers in nutrition, 5, p.62. Poljsak, B. and Milisav, I., 2016. NAD+ as the link between oxidative stress, inflammation, caloric restriction, exercise, DNA repair, longevity, and health span. Rejuvenation research, 19(5), pp.406-413. Four ways to generate NAD + Plus don’t forget calorie restriction, exercise, healthy diet and not too much alcohol! Stein, L.R. and Imai, S.I., 2012. The dynamic regulation of NAD metabolism in mitochondria. Trends in Endocrinology & Metabolism, 23(9), pp.420-428. Supplements to generate NAD+ Nicotinamide Riboside Nicotinamide Dietary tryptophan Nicotinamide mononucleotide Niacin (extended release niacin may be preferable to avoid flushing) Some sources warn of the risk of liver toxicity when supplementing niacin/nicotinamide in excess of 3000mg per day Stein, L.R.