Homocysteine Control is a blend of folic acid, vitamin B6 and vitamin B12, Homocysteine Control

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1 Homocysteine Control Sustained Release Technical paper & product information Summary Homocysteine Control is a blend of folic acid, vitamin B6 and vitamin B12, formulated at precise levels shown by scientific studies to prevent and reduce elevated plasma homocysteine. Utilising a slow release delivery system and the most bioavailable forms of each ingredient, this formulation ensures optimal blood plasma levels are maintained throughout the day. Homocysteine is a natural by-product of the methylation cycle a process vitally important for the production of neurotransmitters, cell cycle regulation, synthesis of neuronal proteins and liver detoxification processes (Figure 1). Homocysteine is usually converted into essential proteins involved in processes such as sleep and mood regulation, or the powerful antioxidant glutathione. An accumulation of homocysteine represents poor conversion and thus blockage in numerous important health-promoting pathways. Elevated homocysteine levels are an extremely reliable independent risk factor for a number of life-threatening conditions including CVD, diabetes, dementia and depression. The methylation cycle relies heavily on folate, vitamin B6 and vitamin B12 to process and utilise homocysteine, with adequate levels of these nutrients required to prevent homocysteine accumulation and associated health risks. Understanding homocysteine When proteins are digested, they are broken down into individual amino acids, including the essential amino acid methionine, which is then broken down further via several methylation steps to produce homocysteine. To remove homocysteine the body reconverts it into methionine through a process called remethylation, or into the amino acid cysteine through a process called transulfuration, which leads to the production of the antioxidantt glutathione. These pathways involve a number of enzymes, in conjunction with several B-vitamin cofactors that function to maintain normal homocysteine levels within the body. [1, 2]

2 Step 1. Methionine receives an adenosine group giving rise to S-adenosyl methionine (SAMe). Step 2. SAMe then transfers the methyl group to an acceptor molecule (i.e., a protein or DNA), producing S-adenosyl homocysteine. SAMe is the direct precursor to neurotransmitter production (for mood regulation) and melatonin (for sleep regulation). Step 3. Adenosine is then hydrolysed from S-adenosyl homocysteine to yield homocysteine. Figure 1. Homocysteine cycling. Step 4. Homocysteine has two primary fates: conversion back into methionine by the addition of a methyl group requiring folate and vitamin B12 as cofactors; or conversion to cysteine, which is converted to the antioxidant glutathione of which both steps require vitamin B6. The methylation cycle Methylation is a fundamental process required for normal cell division and DNA repair. [3] The liver depends on methylation to perform the numerous enzymatic reactions and metabolic processes required for the efficient running of the detoxification process. The methylation cycle supplies methyl groups for a large number of methylation-dependent reactions, including those involved in the synthesis of substances including creatine, choline, carnitine, coenzyme Q10, melatonin and myelin proteins. Methylation is also used to metabolise the neurotransmitters dopamine and serotonin and to methylate phospholipids for transmission of signals through cell membranes. Poor methylation is due to either an insufficient supply of methyl groups necessary to the process, or a deficiency of the nutrients which facilitate the process notably folic acid, vitamin B6 and B12. If the detoxification process is impeded, or if DNA is not adequately repaired, mutations and strand breaks may occur, affecting the regulation of normal cell cycle. Compromised methylation is also implicated in accelerated ageing. Role and benefits of a healthy methylation cycle Neurotransmitter production: o Mood o Memory o Learning o Gut function Antioxidant activity: o Increased glutathione production o Reduced free radical production Cardioprotection: o Reduced risk of cardiovascular disease and stroke Detoxification: o Improved liver function o Increased energy o Improved sleep Neuroprotection Improves cell signalling Anti-inflammatory Normal cell cycle Reduced risk of bone loss and fracture Improved fertility Anti-ageing

3 Homocysteine and health Homocysteine is the by-product of the amino acid methionine, which must be remethylated back to methionine or converted to the amino acid cysteine. Folate, vitamin B6, and vitamin B12 play key roles in converting homocysteine into the essential amino acids methionine or cysteine. Deficiencies of these important nutrients and/or reduced enzyme activities inhibit the breakdown of homocysteine which, in severe cases, may lead to hyperhomocysteinemia. Such elevated homocysteine levels not only damage cells directly by promoting oxidative stress, but also impede the process of methylation, with profound implications for health. Homocysteine and cardiovascular health Elevated homocysteine risk factors Atherosclerosis Heart attack Stroke Compromised cell cycle control Diabetes Thyroid disease Neurodegenerative disease Depression/mood disorders Infertility Osteoporosis Low thyroid function IBD (inflammatory bowel disease) Chronic fatigue syndrome Pregnancy complications Cardiovascular disease is the leading cause of death worldwide, with ischaemic heart disease, stroke and congestive heart failure the most common contributors. Elevated levels of circulating total homocysteine levels are a well-documented risk factor for the development of cardiovascular disease. [4, 5] As levels of homocysteine in the blood are directly influenced by levels of the B-complex vitamins (folic acid, vitamin B6 and vitamin B12), [6] supplementation with these key nutrients offers preventive strategies for healthy people with low or high risk for developing cardiovascular disease (primary prevention), as well as those with an established cardiovascular disease (secondary prevention). Homocysteine and mood disorders There is an association between low folate, B6, B12 and elevated homocysteine in major depression [7] that appears to be related to low SAMe levels and a subsequent reduction in neurotransmitter production.[8, 9] Serotonin, dopamine and other brain chemicals require continuous methylation synthesis, so when homocysteine is not recycled to methionine the direct impact on SAMe levels will, in turn, impact neurotransmitter production (for mood regulation) and melatonin (for sleep regulation). Depressed people with the highest levels of homocysteine generally have the lowest levels of SAMe. Supplementation with folate, vitamin B6 and vitamin B12 helps restore homocysteine levels and regulates methylation and neurotransmitter metabolism and release [10]. Homocysteine and methylation Methylation is a process that is critical for human life. By acting as a switch that turns genes on and off (epigenetics), the process of methylation regulates cell division ensuring that cells divide at a healthy, balanced rate. As increased homocysteine is a precursor to decreased methylation, hyperhomocysteinemia has profound potential biological effects. Indeed, impaired methylation has been linked to a number of conditions including diabetes [11], multiple sclerosis [12] inflammatory

4 diseases,[13] diseases related to aberrant cell growth, [14] and increases the risk of neural tube birth defects, [15] amongst others (see table below). Therapeutic application for Homocysteine Control TM Cardiovascular disease o Heart attack o Stroke o Vascular disease o Atherosclerosis Mood disorders o Depression o Schizophrenia o Bipolar syndrome Neurodegenerative diseases o Huntington s disease o Parkinson s disease o Alzheimer s disease Neuromuscular diseases o Muscular dystrophy o Multiple sclerosis Migraine Cell cycle control Diabetes Liver disorders Thyroid disease/low thyroid function Infertility Low thyroid function Pregnancy complications Macular degeneration Chronic fatigue syndrome Supplementation and dosing Homocysteine Control contains a synergistic blend of bioavailable vitamins B6, B12 and folic acid at precise dosages for maintaining healthy homocysteine levels. Easy-to-swallow tablets utilise a sustained release delivery system and, combined with a split-dose treatment regime to overcome absorption issues associated with vitamin B12 (which decreases as the oral dose increases [16]), are designed to achieve optimal plasma levels throughout the day.

5 Product information Tablets per unit: 90 RRP: 9.99 Shelf life from manufacture: 730 days Commercial Highly bioavailable nutrients Easy to swallow tablets Split-dosing for optimal bioavailability Sustained release tablets for enhanced absorption & optimal tissue distribution Offers benefits for cardiovascular health, brain function and mood balance Product features Technical Lowers homocysteine levels Supports cardiovascular function Supports healthy mood Supports methylation pathways Supports neurotransmitter metabolism Supports red blood cell formation Supports neurological function Supports DNA and protein synthesis Nutritional information Serving size: 1 tablet Amount per tablet % RDA Vitamin B6 (as pyridoxal-5-phosphate) 8 mg 570% Vitamin B12 (as methylcobalamin) 300 µg 12,000% Folic acid 300 µg 150% Ingredients Bulking agent: calcium carbonate; emulsifier: microcrystalline cellulose; thickener: hydroxypropyl methylcellulose; vitamin B6 (pyridoxal-5-phosphate); anti-caking agents: magnesium stearate, stearic acid; folic acid; vitamin B12 (methylcobalamin); glycerol. Free from: Dairy Gluten Lactose Soya Yeast Artificial colourings & flavourings Not tested on animals Non-GMO Directions for use Adults and children aged 12 years and over should take 1 tablet 2-3 times daily. It is not advisable to exceed the above dose unless advised by a healthcare practitioner. Take Homocysteine Control with food for optimal absorption. Warnings and contraindications Pregnant or lactating women should consult their doctor before taking any food supplement. This product should not be used as a substitute for a balanced diet. Keep out of the reach of children and away from sunlight. There are no known drug or nutrient interactions associated with Homocysteine Control.

6 References 1. Scott JM, Weir DG: Folic acid, homocysteine and one-carbon metabolism: a review of the essential biochemistry. Journal of cardiovascular risk 1998, 5: Selhub J: Folate, vitamin B12 and vitamin B6 and one carbon metabolism. The journal of nutrition, health & aging 2002, 6: Crider KS, Yang TP, Berry RJ, Bailey LB: Folate and DNA methylation: a review of molecular mechanisms and the evidence for folate's role. Advances in nutrition 2012, 3: Wald DS, Law M, Morris JK: Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 2002, 325: Aronow WS, Ahn C: Increased plasma homocysteine is an independent predictor of new coronary events in older persons. The American journal of cardiology 2000, 86: Selhub J, Jacques PF, Wilson PW, Rush D, Rosenberg IH: Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA : the journal of the American Medical Association 1993, 270: Tiemeier H, van Tuijl HR, Hofman A, Meijer J, Kiliaan AJ, Breteler MM: Vitamin B12, folate, and homocysteine in depression: the Rotterdam Study. The American journal of psychiatry 2002, 159: Stanger O, Fowler B, Piertzik K, Huemer M, Haschke-Becher E, Semmler A, Lorenzl S, Linnebank M: Homocysteine, folate and vitamin B12 in neuropsychiatric diseases: review and treatment recommendations. Expert review of neurotherapeutics 2009, 9: Bottiglieri T: Homocysteine and folate metabolism in depression. Progress in neuropsychopharmacology & biological psychiatry 2005, 29: Bottiglieri T, Laundy M, Crellin R, Toone BK, Carney MW, Reynolds EH: Homocysteine, folate, methylation, and monoamine metabolism in depression. Journal of neurology, neurosurgery, and psychiatry 2000, 69: Yang M, Sun JZ, Sun YL, You W, Dai J, Li GS: [Association between leptin gene promoter methylation and type 2 diabetes mellitus]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 2012, 29: Kumagai C, Kalman B, Middleton FA, Vyshkina T, Massa PT: Increased promoter methylation of the immune regulatory gene SHP-1 in leukocytes of multiple sclerosis subjects. Journal of neuroimmunology 2012, 246: Ishida K, Kobayashi T, Ito S, Komatsu Y, Yokoyama T, Okada M, Abe A, Murasawa A, Yoshie H: Interleukin-6 gene promoter methylation in rheumatoid arthritis and chronic periodontitis. Journal of periodontology 2012, 83: Juergens RA, Rudin CM: Aberrant epigenetic regulation. American Society of Clinical Oncology educational book / ASCO American Society of Clinical Oncology Meeting 2013, 2013: Farkas SA, Bottiger AK, Isaksson HS, Finnell RH, Ren A, Nilsson TK: Epigenetic alterations in folate transport genes in placental tissue from fetuses with neural tube defects and in leukocytes from subjects with hyperhomocysteinemia. Epigenetics : official journal of the DNA Methylation Society 2013, 8: Carmel R: How I treat cobalamin (vitamin B12) deficiency. Blood 2008, 112: