CoenzymeCoenzyme QQ1010 Ubiquinone-10 and Ubiquinol-10 Nano-colloid delivery system enhances absorption & increases bioavailability

Coenzyme Q10 The Q Cycle & Thermogenin Physiological Indications for Ubiquinol

Coenzyme Q10 (CoQ10) is a naturally occurring compound that is synthesized endogenously in humans, and is found in some foods.1 Dietary sources Ubiquinol is the predominant form of CoQ10 in the human body and should make up at least 92% to 93% of the total plasma CoQ10 concentration 9,26,27 G3PDH H H 43,75 are relatively low, with an estimated dietary intake of less than 10 mg a day, the majority of which is derived from meat and poultry. CoQ10 has H Mitochondrial in adults, such that the ratio of ubiquinol to ubiquinone can be as high as 50 to 1. The ratio of ubiquinol to ubiquinone can change with age as G3P 43,77,78 a broad range of functions in the human body, which are all very dependent on adequate levels of CoQ10. DHAP Intermembrane well as various disease states. Assessing the ubiquinol to ubiquinone ratio may be used for both a biomarker of condition associated oxidative FAH+ UCP1 78-80 Space stress and as a biomarker of aging. 1. Energy Production: CoQ10 is required to convert energy from food into ATP, the carrier of chemical FA- energy that can be used by every cell in the body. It does this by supporting the transport of Age Associated Decline in Ubiquinol to Ubiquinone Ratio 50 1,5-9 electrons within mitochondria, the energy producing organelles inside cells. It is now widely recognized that during aging there is a pro-oxidizing shift in the cellular redox Ubiquinone QH 2. Antioxidant Protection: CoQ10 is a powerful fat soluble antioxidant that prevents the generation of Q QH Q state, accompanied by an accrual of the amounts of molecules damaged by oxidative stress, 40 Q free radicals and protects fats, DNA and other proteins from oxidative damage.2,10-12 and subsequent progression of senescence.76 As a powerful lipophilic antioxidant, ubiquinol plays CoQ10 Pool Vitamin E Dihydrolipoic 3. Antioxidant Regeneration: Vitamin E, vitamin C and lipoic acid are all dependent on CoQ10 to be CoQ10 Pool a critical role in decreasing oxidative stress. However, the ratio of reduced CoQ10 (ubiquinol) to 30 Inner Acid Inner 43,77 regenerated after they protect the body from oxidative damage.2,13,14 oxidized CoQ10 (ubiquinone) can adversely change with age. The age associated increase Membrane a-tocopherol Membrane QH Q QH 20 Mitochondrial Mitochondrial QH Q in oxidative stress can best be demonstrated by observing the age dependent drop in the a-tocotrienol 4. Heart Protection: Often described as “cardioprotective”, CoQ10 protects both the blood vessels 15-17 ubiquinol to ubiquinone ratio; a phenomenon considered evidence of increased oxidative stress that feed the heart, and the heart muscle itself, from damage. 43,76-79 10 Ubiquinol in both aging and in disease states. While the ubiquinol to ubiquinone ratio only drops slightly Ubiquinol : Ubiquinone Ratio 5. Nerve Protection: CoQ10 is required to protect the brain and other nerve tissues from free radical NAD+ between younger children and older children, the average drop increases in adulthood and E LA 18-20 Fumarate Mitochondrial damage. This “neuroprotective” ability is in large part due to its antioxidant properties. NADH 43,77 Dehydroascorbate continues with age. 0 Vitamin C Radical Succinate Matrix 0.2 - 7.6 10.4 - 17.4 20 - 39 40 - 59 60 & over 6. Anti-inflammatory: CoQ10 exerts anti-inflammatory properties by decreasing the secretion of pro- 100% 21-23 Complex I Complex II Complex III H Age Related Drop in Ubiquinol : Ubiquinone Ratio inflammatory cytokines, chemical messengers that affect immune system function. 90% compiled from Miles, 2004 & Wada, 2007 C % QH Male % QH Female Condition Associated Decline of Ubiquinol 7. Promotes Thermogenesis: By supporting the function of thermogenin, a protein that derives energy Vitamin E Vitamin E 80% The percentage of ubiquinol to total CoQ10 (ubiquinol %) is another method of assessing CoQ10 Radical Radical 24-26 Ascorbate from fatty acids, CoQ10 generates body heat, and helps maintain ideal body weight. The Q Cycle is a series of reactions within the electron transport chain that involve sequential oxidation and reduction of the lipophilic electron 70% Vitamin C function. Health conditions often have a significant effect on the percentage of ubiquinol 8. Cellular Communication & Gene Expression: CoQ10 improves the ability of cells to receive carrier, ubiquinol-ubiquinone (Coenzyme Q) in a cyclical fashion that ultimately results in the pumping of protons across a lipid bilayer, such as a cell 60% (ubiquinol %). Subjects (60) with fasting glucose (FG) less than 99 mg/dl had normal ubiquinol messages and influences how some genes respond to those messages.2 membrane or the membrane of a cell organelle.14,39 The citric acid cycle, not shown in this graphic, donates electrons to the Q-cycle through NADH Antioxidant Regeneration by CoQ10 50% % (male 93%, female 95%), while subjects with and FG of 100 to124 had a significant drop of Compiled from Packer, 1997, Hyun, 2006 & Turunen, 2004 9. Supports Organ Metabolism: The concentration of CoQ10 varies greatly among different organs, & succinate.39 ubiquinol % (male 43%, female 41%), and subjects with Type 2 diabetes (and FG >124) were 40% with higher amounts found in tissue with increased metabolic activity such as the heart, kidney The cyclical oxidation and reduction of CoQ10 is required for oxidative phosphorylation, which is the metabolic pathway that uses energy released noted has to have severely low ubiquinol % (male 24%, female 29%).103 The lower ubiquinol % 30% and liver tissue, and lower amounts found in lung tissue.14,27 by the oxidation/reduction of nutrients to produce adenosine triphosphate (ATP), the molecule required for intracellular energy transfer.39 More levels are recognized as a sign of increased oxidative stress, which may be responsible for the 20% 79 2 specifically, CoQ10 interacts with a series of protein complexes within mitochondria that act as enzymes to create a proton gradient across the inner increased observance of vascular and micro-vascular co-morbidity seen in Type 2 diabetes. 10. Healthy Cell Growth: CoQ10 promotes cell growth and inhibits cell death in healthy tissues. 40,49,50 mitochondrial membrane into the matrix. The concentration gradient drives ATP synthase to convert ADP to ATP. 10% It is the low percentage of ubiquinol levels, not the total CoQ10 levels, that are recognized as 14 While intracellular transport of CoQ10 may be ATP dependant, ATP synthase (not shown in this graph) does not depend on CoQ10 to function. The 0% clinically relevant in a number of conditions that have increased oxidative stress as a component Endogenous Production of CoQ10 protein three complexes that depend upon the Q Cyle include Complex, I, Complex II & Complex III, which are three of the four complexes in the Normal Glucose Tolerance Impaired Fasting Glucose Type 2 Diabetes Mellitus of their pathology, including various neurological, cardiovascular, pulmonary, genetic 14,39,40,49,50 Decreased % of Ubiquinol in Dysglycemias 57,78-87 electron transport chain. Though not directly used by ATP synthase, ubiquinone and ubiquinol both drive the electron transport chain that based on Lim, 2006 mitochondrial, and hepatic disorders, as well as the dysglycemic disorders. creates the protonic gradient which is used by ATP synthase to produce ATP. CoQ10 is a ubiquitous quinone that is synthesized within human cells, where the Q refers to the Acetyl-CoA The Q Cycle also supports the function of glyceraldehyde 3-phosphate dehydrogenase (G3PDH), a glycolysis enzyme required to convert glucose benzoquinone “head”, and the 10 refers to the “tail” which consists of 10 isoprenyl subunits. The Research & Observations on CoQ10 to create energy.39 In addition, the Q Cycle supports the function of Thermogenin (UCP1), an uncoupling protein in the mitochondrial membrane quinone portion of CoQ10 is synthesized from tyrosine and indispensably requires vitamins B2, B3, B5, 3-hydroxy-3-methylglutaryl-CoA that removes protons from fatty acids in the intermembrane space and moves the protons to the matrix to create heat instead of converting ADP B6, B12, folic acid, tetrahydrobiopterin and vitamin C.28 The isoprenyl side chain is synthesized from Since its discovery in 1957, coenzyme Q10 (CoQ10) has been the subject of about 9,000 published studies, with over 2,500 of those studies focused (HMG-CoA) to ATP.24 Thermogenin requires oxidized CoQ10 (ubiquinone) to subtract H+ from fatty acids and deliver them to the H+ acceptor group of UCP1.25,26 acetyl-CoA through the mevalonate pathway, which also requires zinc.29 The mevalonate pathway on the direct affect that ubiquinone and/or ubiquinol have on human health and disease. Almost 200 papers focus on the role that ubiquinone/ Proper thermogenin function is required for lipolysis and optimal fatty acid metabolism, healthy body weight and ideal utilization of glucose. is also involved in cholesterol biosynthesis. ubiquinol has on congestive heart failure. While ubiquinone and ubiquinol both play very significant roles in antioxidant, bioenergetics, cell signaling Reduction of Ubiquinone to Ubiquinol takes place in Complex I, Complex II, G3PDH & UPC1 Oxidation of Ubiquinol to Ubiquinone takes place in Complex III The mevalonate pathway may be inhibited by as much as 40% by statins (HMG-CoA reductase HMG-CoA Reductase Inhibitors and gene expression which affect the health and function of every body system, it is notable that ubiquinol is the preeminent antioxidant in the inhibitors) most frequently prescribed to lower cholesterol.30 Statins block production of farnesyl human body which is why ubiquinone/ubiquinol may have applications in so many health conditions. pyrophosphate, an intermediate in the synthesis of ubiquinone (CoQ10).31 Giving CoQ10 Bioavailability of CoQ10 Mevalonate CoQ10 may have a beneficial effect on neurological conditions marked by supplementation with statins has been proposed.32 Other medications which can adversely affect CoQ10 levels are decreased in both the plasma and the brain tissue in patients with neurological conditions associated with progressive, irreversible degeneration of the brain cells and severe loss of CoQ10 levels include propranolol, diazoxide, hydrochlorothiazide, hydralazine, and clonidine.33,34 As a fat soluble bioactive molecule, CoQ10 has pronounced hydrophobic & lipophilic properties Isopentenyl progressive loss of dopaminergic neurons in the substantia memory by supporting healthy mitochondrial function which resists beta- Inborn errors of metabolism may result in very rare and serious mitochondrial or metabolic disorders and therefore exhibits poor water solubility but high membrane permeability, which makes 88-90 pyrophosphate nigra. These, and other neuronal changes cause complex and amyloid production caused by oxidative stress. Ubiquinol percentage in which patients are not capable of producing enough CoQ10.35,36 7.5 CoQ10 a class II compound in the Biopharmaceutical Classification System (BCS).51 The poor 7.0 variable motor and nonmotor symptoms. Supplementation may be considerably lower in some neurological conditions that involve Nano-colloidal CoQ 52 120 6.5 10 water solubility of Class II BCS bioactive compounds traditionally limits their bioavailability. Even # with CoQ10 (with ubiquinol producing the largest increases degeneration of upper and lower motor neurons. CoQ10 may improve Famesyl Solubulized CoQ 1 53 6.0 10 taking CoQ10 with food only causes a very modest increase in bioavailability. 82,108 Lung Pryophosphate in plasma concentrations) may provide neuroprotection the mitochondrial function in these cases. 5.5 oil based CoQ formulation 100 10 8 5.0 and decrease dopaminergic dysfunction by supporting Solubulized CoQ #2 CoQ10 reduces cochlear oxidative stress induced by acoustic Heart Squalene Ubiquinone 4.5 10 7 Increasing bioavailability has a proper mitochondrial function. CoQ10 may also support overstimulation and can preserve cochlear hair cell by promoting 80 4.0 6 direct affect on the tissue and supranuclear mitochondrial function in other neurological 3.5 Serum Myocardium Mitochondria recovery from damage in auditory hairs as well as preventing Spleen Cholesterol 5 mitochondrial levels of CoQ10. A 90,104-107 3.0 conditions. mitochondrial damage.110-112 Chronic ringing in the ears may be 60 2.5 4 3.8 times increase in serum levels(ug/ 109 Liver Age Specific Changes in Tissue Levels CoQ10 levels in the retina can decline by approximately improved if low CoQ10 levels are increased by supplementation. 2.0 3 ml) resulted in a 2.5 times increase 1.5 40% with age, which may be linked to the progressive CoQ10 can support the health of the periodontium (the 40 While CoQ10 is found in most living cells in humans, there is a in myocardial tissue(ug/g) CoQ10 Kidney 1.0 2 38 degeneration of the macula (the central retina which tissues that surround and support the teeth), most probably large variation in CoQ10 distribution during development. The 0.5 levels and a 2.4 times increase 1 91 113-115 Plasma Concentration Coenzyme Q10 [ug/ml] 0.0 provides vision for fine work and reading). The by decreasing the oxidative stress in those tissues.

mg ubiquinone-10/gram tissue, wet weight Pancreas highest tissue concentrations of CoQ10 are reached at about in the CoQ10 levels of cardiac 20 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 54 antioxidant properties of CoQ10 are considered to be 20 years of age in the heart, kidneys and liver, while CoQ10 Time [h] Nano-Colloid Solubilizate 1 Oil Based Solubilizate 2 mitochondrial protein(ug/mg). Ubiquinol percentage is significantly lower in pulmonary Adrenal 92,93 levels peak in adrenal and pancreatic tissue at approximately Differences in Bioavailability of Different Ubiquinone Formulations Relative Concentrations in Serum, Myocardium & Mitochondria the mechanism of action in retinal protection. 78 0 based on Liu, 2009 & Rosenfel, 2005 conditions which have some degree of chronic obstruction. 27 based on Liu, 2009 1 - 3 days 0.7 - 2 years 19 - 21 years 39 - 43 years 77 - 81 years one year of age. After tissues achieve their respective peak CoQ10 can support healthy sight by preserving the Clinical outcomes are dependent on increased bioavailability. Increased clinical improvement in congestive heart failure (CHF) patients is only CoQ10 can improve muscular energy metabolism when there Age Related Change in CoQ10 Concentrations based on Kelen, 1989 concentrations, their levels progressively decrease with aging. function of the retinal ganglion cells that may be 116 seen with plasma CoQ10 levels of at least 2.5 ug/ml.5 Therapeutic plasma levels in CHF are now considered to be greater than 3.5 ug/ml.56,57 The is low blood oxygen levels at rest and/or during exercise. compromised by high intraocular pressure.94-96 CoQ10 greatest benefit for Parkinson disease patients was seen at CoQ10 dosages that achieved plasma CoQ10 levels of at least 3.5 ug/ml.58 Similarly, the Chronic inflammatory conditions of the respiratory system may also provide cardio-protection when beta-blockers progressive spread of breast disease to the liver was decreased when blood levels of CoQ10 were maintained in the 3.34 to 3.77 range.59 As the are associated with lower concentrations of CoQ10 with a Two Forms of CoQ10 are used to address high intraocular pressure.97 “Difference in Bioavailability” graph indicates, increased bioavailability is critical to achieve and maintain these levels. concomitant antioxidant imbalance that may be ameliorated 117 As the “Difference in Bioavailability” graph indicates, there is a significant difference in bioavailability between various brands and formulations of CoQ10 levels are lower in both the serum and the heart with CoQ10 supplementation. CoQ10 supplementation may also CoQ10 supplements.1,61 Suspension, solubilizates, oil based formulations and even micro-emulsions are not able to achieve and maintain therapeutic tissue of patients with heart muscle disorders with decreased support a decreased dependency on corticosteroids in chronic 118 levels of CoQ10 that are readily achieved by nano-colloidal delivery systems.51,53 A nano-colloidal delivery system is a lipid based formulation that heart function.98 Ubiquinol was able to dramatically increase inflammatory conditions of the respiratory system. upon contact with an aqueous fluid self-assembles into millions of tiny droplets that are in cryo-electron micrograph of plasma CoQ10 levels in patients with decreased heart Ubiquinol percentage is lower in seminal fluid of idiopathically the size range of less than and around 100 nm in diameter. A nano-colloidal CoQ10 delivery function, even after supplementation with ubiquinone infertile males, which is believed to be due to the impaired function Ubiquinone: The fully oxidized form of CoQ10 is ubiquinone-10, Ubiquinol: The fully reduced form of CoQ10 is ubiquinol-10, or simply ubiquinol, nano-colloidal formulation system has been developed, which is able to significantly improve the bioavailability of failed to reach therapeutic goals.57 The ubiquinol intake was of protective antioxidant activity.119-121 or simply ubiquinone, and is often represented as “Q”. and is represented as “QH”. Ubiquinol is an effective antioxidant that protects CoQ10.60,61 This nano-colloidal CoQ10 delivery system releases nano droplets with a well associated with improvement in ejection fraction, a measure Ubiquinone is a required coenzyme of the Q cycle and is also vitamin E, and is required for function of Complex III within the electron transport 99 Clinical trials have demonstrated a considerable variation in the 39,25 10,40 41,14,38,42 defined average diameter of 70 to 75 nm, as observed in the cryo-electron micrograph of of heart function. involved in glycolysis and lipolysis. A full representation shows chain. Ubiquinol levels are higher than ubiquinone levels in humans. A the nano-colloidal formulation used in the above graph.51,62-65 decrease of CoQ10 levels on patients taking different HMG-CoA all 10 ubiquinone isoprenyl subunits. The chemical structure full representation shows all 10 ubiquinol isoprenyl subunits. The chemical structure Ubiquinol percentage is lower in hyperlipidemic patients that reductase inhibitors (statins), ranging from 26% to 57% drops of total may be represented by showing the oxidized quinone head may be represented by showing the reduced hydroquinol (reduced quinone) have high blood pressure compared to subjects without CoQ10.122-125 It has also been observed that ubiquinol levels may attached to a bracketed isoprenyl subunit with a 10 subscript. head attached to a bracketed isoprenyl subunit with a 10 subscript. high blood pressure.86 CoQ10 supplementation supports the drop by 20% to 43%.123,126 Genetic predisposition may be associated Nano-Colloid Delivery of CoQ10 body’s natural blood pressure regulatory mechanisms with with the intolerance and risks associated with HMG-CoA reductase a normalizing affect on both systolic and diastolic values.100 CoQ10 inhibitor use.128,129 may also normalize the elevated blood pressure associated with Mucus maintains an unstirred water layer adjacent to the intestinal epithelial cells Genetic CoQ10 deficiency conditions that affect nerve, muscle, 66 metabolic syndrome by attenuating the increase of oxidative stress (enterocytes) despite the shearing actions of intestinal peristalsis. The tenacious properties kidney and heart function may be due to mutations in ubiquinone and nitrative stress markers and inflammatory markers typically seen in of mucus prevent most particles from penetrating to the epithelial surface, including some biosynthetic genes or mutations in genes not directly related to CoQ10 51,67 Lumen that syndrome.101 nano-particles. biosynthesis.35 They have been associated with autosomal recessive The nano-colloidal CoQ10 delivery system is able to effectively increase bioavailability of Ubiquinol percentage of total CoQ10 is significantly lower in the neurological disorders that are responsive to CoQ10 supplementation.130 Predominance of Ubiquinol 51 Unstirred CoQ10 by penetrating the mucus mesh and easily diffusing across the unstirred water layer. presence of metabolic conditions accompanied by high and very These conditions typically manifest during infancy and childhood, but The mucus mesh barrier can be crossed by the fluid nano-colloid CoQ10 droplets with sizes of Layer high blood sugar levels, such that the very high blood sugar levels, such 120 some patients have presented with adult-onset cerebellar ataxia or less than 75 nm, that are created with precise ratios of food grade nonionic emulsifiers and that patients with very high blood sugar levels may have ubiquinol 36,130,131 Ubiquinol is the predominant form of CoQ10 in the human body.43 In adults, 92% to 98% myopathy. A significantly lowerubiquinol percentage and total dietary triglycerides / fatty acids.51,62 Due to the nonionic nature of the nano-colloid CoQ10 percentages as low as 24% in males and 29% in females.79 The change of total CoQ10 is in its reduced form as ubiquinol, while the percentage may be from CoQ10 observed in children with trisomy 21 (Down syndrome), were both 100 droplets, they do not interact with mucin and are capable of diffusing freely through the 43 in ubiquinol %, reveals increased oxidative stress which may contribute increased twelve fold, with a majority of them achieving normal ratios, 93% to 100% for people less than 18 years of age. Tissues with a higher percentage of 68 Ubiquinol mucus matrix. Penetration of the nano-colloidal CoQ10 droplets through the mucus mesh to increased risk of cardiovascular disorders.102,103 when supplemented with ubiquinol.83 ubiquinol than ubiquinone include the kidney, liver, muscles, pancreas, spleen, thyroid, and across the unstirred water layer delivers CoQ10 to the surface of the enterocytes. enterocyte 80 intestines and colon.14,38 A little less than 50% of heart CoQ10 is ubiquinol, while slightly Ubiquinone less than 25% of brain and lung CoQ10 is ubiquinol. It should be noted that even Once the nano-colloid delivers CoQ10 to the surface of the enterocyte, the high membrane chylomicrons Improvement of Biomarkers though the percentage of ubiquinol to ubiquinone in the heart is less than 50%, the 60 permeability of CoQ10 allows passive diffusion of CoQ10 molecule into the enterocytes.51,52 amount of ubiquinol per gram of heart tissue is actually higher in the heart than the lymph vessels Condition Associated Superiority of Ubiquinol for Improving Biomarkers of Health 8 45 14 The binding and transfer of the lipophilic CoQ10 molecules between the intracellular lipid amount found in other tissues. 7 40 40 surfaces, and its transport through the enterocyte, is mediated by proteins such as saposin B, a Ubiquinol showed superiority over ubiquinone for improvement of biomarkers of cardiac function in a As the predominant form of CoQ10 in the human body, ubiquinol can be regenerated 35 glycoprotein that also binds and transfers gamma tocopherol, other lipids and phospholipids.69-71 group of patients with heart muscle disorders. When patients were switched from average daily dosage 6 ug/g of tissue, wet weight at the cellular level by various enzymes. This regeneration of ubiquinol from the 30 5 42 The enterocytes incorporate CoQ10 into chylomicrons that are carried to the lateral surface of of 450 mg of ubiquinone to 580 mg of ubiquinol, plasma levels of CoQ10 increased from an average 20 oxidized form ubiquinone is essential to the maintenance of its antioxidant function. 57 25 the enterocytes for exocytosis into the extracellular space, which drains into lymph vessels and is of 1.6 ug/ml to 6.5 ug/ml, revealing a four-fold increase in levels with only a 28% increase in dosage. 4 Enzymes involved in this regenerative process include lipoamide dehydrogenase, 20 42,44,45 then taken up by liver cells and associated with lipoproteins such as VLDL & LDL to be distributed Their average ejection fraction improved from an average of 22% to 39%. On ubiquinone, their average 3 glutathione reductase, and thioredoxin reductase. All three enzymes can also 72-74 15 0 to tissues throughout the body. NYHA classification was IV (severe limitations with symptoms at rest), but after switching to ubiquinol they 2 reduce lipoic acid to its antioxidant form dihydrolipoic acid, which can reduce 57 10 Liver Lung Brain improved to NYHA Class II (slight limitations during ordinary activity and mild symptoms). The increased Heart

Colon 14,46 Kidney Spleen Thyroid Muscle ubiquinone to ubiquinol. Another enzyme involved in reducing ubiquinone is 1 5 Intestine Nano-colloid droplets passing through intestinal edema that is associated with diminished cardiac function may be responsible for the decreased Pancrease DT-diaphorase, which also protects ubiquinol from being oxidized.47,48 Amount of Ubiquinol per gram of tissue in Humans mucin matrix in unstirred layer ubiquinone absorption seen in these patients.57,132,133 0 0 based on Turunen, 2003 & Aberg, 1993 Ubiquinone Ubiquinol based on Langsjoen, 2008

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