WO2016179097A1

WO2016179097A1 - Methods for treating mitochondrial damage diseases

Info

Publication number: WO2016179097A1
Application number: PCT/US2016/030422
Authority: WO
Inventors: Brian BROOKOVER
Original assignee: Stella Maris
Priority date: 2015-05-04
Filing date: 2016-05-02
Publication date: 2016-11-10

Abstract

The present invention provides compositions comprising therapeutic combinations of Vitamin A, thiamine, pyridoxine, L-methylfolate, methylcobalamin, cholecalciferol, magnesium, Acetyl-L-carnitine, quercetin, D-ribose, coenzyme Q10, riboflavin, biotin, ascorbic acid, potassium, malic acid, astaxanthin, and/or curcuminoids purified from turmeric. Compositions of the invention can be used for the treatment of a subject with a mitochondrial damage disease (MDD).

Description

METHODS FOR TREATING MITOCHONDRIAL DAMAGE DISEASES

CROSS REFERENCE TO RELATED APPLICATIONS

[0001 ] This application claims the priority of U.S. provisional application number 62/156,824, filed May 4, 2015, U.S. provisional application number 62/156,825, filed May 4, 2015, U.S. provisional application number 62/156,826, filed May 4, 2015, U.S. provisional application number 62/156,827, filed May 4, 2015, U.S. provisional application number 62/156,828, filed May 4, 2015, U.S. provisional application number 62/156,829, filed May 4, 2015, U.S. provisional application number 62/156,830, filed May 4, 2015, U.S. provisional application number 62/262,573, filed December 3, 2015, U.S. provisional application number 62/192,595, filed July 15, 2015, U.S. provisional application number 62/175,533, filed June 15, 2015, and U.S. provisional application number 62/175,495, filed June 15, 2015, each of which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

[0002] The present invention provides compositions comprising combinations of Vitamin A, thiamine, pyridoxine, L-methylfolate, methylcobalamin, cholecalciferol, magnesium, Acetyl-L-carnitine, quercetin, D-ribose, coenzyme Q10, riboflavin, biotin, ascorbic acid, potassium, malic acid, astaxanthin, and/or curcuminoids purified from turmeric. Compositions of the invention can be used for the treatment of a subject with a mitochondrial damage disease (MDD).

BACKGROUND OF THE INVENTION

[0003] There remains a need in the art for an effective treatment for the symptoms of mild cognitive impairment (MCI), Alzheimer's disease (AD), autism, myalgic encephalomyelitits /chronic fatigue syndrome (ME/CFS), diabetes, metabolic syndrome, or schizophrenia. SUMMARY OF THE INVENTION

[0004] In an aspect, the present disclosure encompasses a method to improve one or more symptoms of a mitochondrial damage disease (MDD) in a subject with a MDD, as compared to the same subject at an earlier time or a healthy control subject. The method comprises orally administering to the subject a composition comprising a combination listed in Table B, Table C, Table D, Table E, Table F, or Table G, and optionally one or more additional ingredients from Table A.

[0005] In an aspect, the present disclosure encompasses a method to improve one or more symptoms of a mitochondrial damage disease (MDD) in a subject with a MDD, as compared to the same subject at an earlier time or a healthy control subject. The method comprises orally administering to the subject a composition comprising a two or more ingredients from Table A.

[0006] In another aspect, the present disclosure encompasses a method to prevent an increase in the severity of, or frequency in, one or more symptoms of a MDD in a subject with a MDD, as compared to the same subject at an earlier time or a healthy control subject. The method comprises orally administering to the subject a composition comprising a combination listed in Table B, Table C, Table D, Table E, Table F, or Table G, and optionally one or more additional ingredients from Table A.

[0007] In another aspect, the present disclosure encompasses a method to prevent an increase in the severity of, or frequency in, one or more symptoms of a MDD in a subject with a MDD, as compared to the same subject at an earlier time or a healthy control subject. The method comprises orally administering to the subject a composition comprising a two or more ingredients from Table A.

[0008] In another aspect, the present disclosure encompasses a method to improve one or more symptoms of mild cognitive impairment (MCI) in a subject with MCI, as compared to the same subject at an earlier time or a healthy control subject. The method comprises orally administering to the subject a composition comprising a combination listed in Table B, Table C, Table D, Table E, Table F, or Table G, and optionally one or more additional ingredients from Table A. [0009] In another aspect, the present disclosure encompasses a method to improve one or more symptoms of mild cognitive impairment (MCI) in a subject with MCI, as compared to the same subject at an earlier time or a healthy control subject. The method comprises orally administering to the subject a composition comprising a two or more ingredients from Table A.

[0010] In another aspect, the present disclosure encompasses a method to prevent an increase in the severity of, or frequency in, one or more symptoms of MCI in a subject with MCI, as compared to the same subject at an earlier time or a healthy control subject. The method comprises orally administering to the subject a composition comprising a combination listed in Table B, Table C, Table D, Table E, Table F, or Table G, and optionally one or more additional ingredients from Table A.

[001 1 ] In another aspect, the present disclosure encompasses a method to prevent an increase in the severity of, or frequency in, one or more symptoms of MCI in a subject with MCI, as compared to the same subject at an earlier time or a healthy control subject. The method comprises orally administering to the subject a composition comprising a two or more ingredients from Table A.

[0012] In another aspect, the present disclosure encompasses a method to improve one or more symptoms of Alzheimer's disease (AD) in a subject with AD, as compared to the same subject at an earlier time or a healthy control subject. The method comprises orally administering to the subject a composition comprising a combination listed in Table B, Table C, Table D, Table E, Table F, or Table G, and optionally one or more additional ingredients from Table A.

[0013] In another aspect, the present disclosure encompasses a method to improve one or more symptoms of Alzheimer's disease (AD) in a subject with AD, as compared to the same subject at an earlier time or a healthy control subject. The method comprises orally administering to the subject a composition comprising a two or more ingredients from Table A.

[0014] In another aspect, the present disclosure encompasses a method to prevent an increase in the severity of, or frequency in, one or more symptoms of AD in a subject with AD, as compared to the same subject at an earlier time or a healthy control subject. The method comprises orally administering to the subject a composition comprising a combination listed in Table B, Table C, Table D, Table E, Table F, or Table G, and optionally one or more additional ingredients from Table A.

[0015] In another aspect, the present disclosure encompasses a method to prevent an increase in the severity of, or frequency in, one or more symptoms of AD in a subject with AD, as compared to the same subject at an earlier time or a healthy control subject. The method comprises orally administering to the subject a composition comprising a two or more ingredients from Table A.

[0016] In another aspect, the present disclosure provides a composition comprising a combination listed in Table B, Table C, Table D, Table E, Table F or Table G. The compositions may further comprise one or more ingredients listed in Table A. The compositions can be formulated as a capsule, a table, a dry powder, a liquid, or a ready-to-drink beverage.

[0017] In another aspect, the present disclosure provides a composition comprising a combination listed in Table B, Table C, Table D, Table E, Table F or Table G, without any additional nutritional ingredients. The compositions can be formulated as a capsule, a table, a dry powder, a liquid, or a ready-to-drink beverage.

[0018] In another aspect, the present disclosure provides a composition comprising a combination listed in Table B, Table C, Table D, Table E, Table F or Table G, without any additional nutritional ingredients. The compositions can be formulated as a capsule, a table, a dry powder, a liquid, or a ready-to-drink beverage.

[0019] In other aspect, the present disclosure provides a composition comprising a two or more ingredients listed in Table A. The compositions can be formulated as a capsule, a table, a dry powder, a liquid, or a ready-to-drink beverage

[0020] Other aspects and iterations of the invention are described more thoroughly below.

DETAILED DESCRIPTION

[0021 ] Applicant has discovered a therapeutic combination of vitamins and nutrients that improves mitochondrial function and reduces mitochondrial oxidative stress. Accordingly, compositions comprising a therapeutic combination of the invention can be used for the treatment of mitochondrial damage diseases (MDD). Mitochondrial damage diseases (MDDs) are the consequence of a positive feedback system in which oxidative stress and mitochondrial damage and dysfunction result from (either directly or indirectly), and amplify, an insult (e.g. a genetic predisposition for a disease and/or environmental stress). For example, mitochondrial damage can cause oxidative stress, which in turn causes further mitochondrial damage. The cycle continues unnoticed and unchecked until outward signs of disease develop. Exemplary MDDs include, but are not limited to, mild cognitive impairment (MCI), Alzheimer's disease (AD), autism, myalgic encephalomyelites /chronic fatigue syndrome (ME/CFS), diabetes, metabolic syndrome, or schizophrenia.

[0022] Other aspects of the invention are described more thoroughly below.

I. DEFINITIONS

[0023] The following terms have the meanings ascribed to them unless specified otherwise.

[0024] When introducing elements of the present disclosure or the preferred aspects(s) thereof, the articles "a", "an", "the" and "said" are intended to mean that there are one or more of the elements. The terms "comprising", "including" and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[0025] As used herein, the term "enteral administration" refers to any method of administration that uses the gastrointestinal (Gl) tract to deliver part or all of a person's dietary requirements (e.g. calories, vitamins, minerals, carbohydrates, protein, fat, electrolytes, etc.). It can include a normal oral diet, the use of liquid, solid, semi-solid or powdered supplements, or delivery of part or all of the daily requirements by use of a tube (tube feeding).

[0026] As used herein, the term "medical food" refers to a food which is formulated to be consumed or administered enterally under the supervision of a physician. A medical food is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements are established by medical evaluation. Medical foods are distinguished from the broader category of foods for special dietary use and from foods that make health claims by the requirement that medical foods be intended to meet distinctive nutritional requirements of a disease or condition, used under medical supervision, and intended for the specific dietary management of a disease or condition. Medical foods are not those simply recommended by a physician as part of an overall diet to manage the symptoms or reduce the risk of a disease or condition, and all foods fed to sick patients are not medical foods. Instead, medical foods are foods that are specially formulated and processed (as opposed to a naturally occurring foodstuff used in a natural state) for a patient who is seriously ill or who requires use of the product as a major component of a disease or condition's specific dietary management.

[0027] As used herein, the term "subject" refers to a mammal, preferably a human. Subjects may be a control subject or a subject with a MDD. A "control subject," also referred to as a "healthy control" or a "normal control," refers to a subject who is generally healthy. A "subject with a MDD" refers to a subject that has a disease characterized by mitochondrial damage. Subjects with a MDD include, but are not limited to, subjects diagnosed with Acute Lymphoblastic Leukemia, Alcohol-related diseases of the nervous system, Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS), Angina pectoris, Anxiety Disorder, Asperger syndrome, Asthma, Atherosclerosis, Atopic Dermatitis, Attention Deficit Disorder (ADD), Attention Deficit Hyperactivity Disorder (ADHD), Autism or an Autism Spectrum Disorder, Autoimmune Uveitis, Beta-Thalassemia, Bipolar Disorder, Cancer, Cardiovascular Disease, Cataracts, Celiac Disease, Cerebral edema, Cerebral Ischemia, Chronic Obstructive Pulmonary Disease, Chronic Spontaneous Urticaria, Chronic Traumatic Brain Injury, Chronic Traumatic Encephalopahty, Colitis, Coronary Artery Disease, Creutzfeldt-Jakob disease, Crohn's Disease, Dementia with Lewy bodies, Depression, Dermatitis, Diabetes mellitus, Diabetic nephropathy, Diabetic retinopathy, Epilepsy, Esophageal Cancer, Excessive exposure to copper, Fibromyalgia, Fragile X syndrome, Friedreich's ataxia, Frontotemporal dementia, Grey hair, Gulf War Syndrome, Heart Failure, Human monocytic ehrlichiosis, Huntington's disease, Hypertension, Hypertension, Insulin Resistance, Irritable Bowel Syndrome, Kidney Stones, Lichen planus, Liver disease, Lyme Disease, Macular degeneration, Male and female infertility, Metabolic Syndrome, Mild Cognitive Impairment (MCI), Mild traumatic brain injury, Mixed dementia, Multiple Sclerosis (MS), Myalgic Encephalomyelites /Chronic Fatigue Syndrome (ME/CFS), Myocardial Infarction, Nephropathy, Non-alcoholic fatty liver disease, Normal pressure hydrocephalus, Obesity, Osteoarthritis, Parkinson's disease, Periodontitis, Peripheral artery disease, Post-Traumatic Stress Disorder, Psoriasis, Psychosis, Pulmonary hypertension, Reflux esophagitis, Retinal degeneration, Retinitis Pigmentosa, Rheumatoid Arthritis, Schizophrenia, Sickle-cell disease, Sleep apnea, Stroke, Systemic Lupus Erythematosus, Temporomandibular Joint Diseases, Thrombosis, Tinnitus, Urolithiasis, Vascular Dementia, Vitiligo, Wernicke-Korsakoff Syndrome, or Wilson's Disease. "A subject with a MDD" also refers to a subject with genetic predispositions of human leukocyte antigen-D related polymorphism biomarkers, receptor for advanced glycation end products polymorphism biomarkers, inborn errors of metabolism, glutathione-S-transferase genetic polymorphisms or methylenetetrahydrofolate reductase polymorphisms. Methods for diagnosing the above diseases are well known in the art.

[0028] As used herein, the term "symptom" refers to any subjective or objective evidence of disease. Symptoms of MDD include, but are not limited to, amyloid beta plaques, an increase in CSF Αβ42 concentration, an increase in CSF Αβ42/Αβ40 ratio, oxidative stress, hypoxia, vitamin/nutrient deficiency, pruritus, blurred vision, excessive thirst, excessive urination, fatigue, myalgia, joint hypermobility, visual contrast sensitivities, cognitive impairment (e.g. difficulties with memory, attention, concentration, language, abstract thought, creativity, judgment, name recall, planning, executive function, planning, and organization, as well as misplacing objects), functional capacity impairment, behavior impairment (e.g. changes in personality, physical or verbal aggression, impulsivity, decreased inhibition, apathy, decreased initiation, changes in personality, social withdrawal, sleep disturbances, abuse of alcohol, tobacco or drugs, and other addiction-related behaviors), a decline in general physical health, a decline in quality of life, a deviation of electric power measured at one or more electrode by quantitative electroencephalography (qEEG) while performing a standardized test, mitochondrial damage and dysfunction, aggressive behavior, autoimmune disorders, brain region hypo perfusion, elevated levels of pro-inflammatory cytokines, elevated MMP-9 levels, increased lactic acid levels, P2X7 upregulation, elevated aluminum, low melatonin levels, depression, decreased glutathione levels, gluten sensitivity, headaches, insulin resistance, impaired fasting glucose, impaired insulin resistance, irritable bowel syndrome, low serotonin, elevated levels of anti-serotonin antibodies, sleep disorders (e.g. sleep apnea, narcolepsy, hypersomnia, cataplexy, circadian rhythm sleep disorders, etc.), elevated triglycerides, and epilepsy. Additionally, symptoms include adrenal insufficiency or irregularities involving cerebral imaging, dopamine levels, GABA/glutamate, gut biome, methylation pathways, hypothalamic- pituitary-adrenal axis, insulin-like growth factor 1 , nicotinic cholinergic system, nitric oxide, platelet derived growth factor, thyroid function, C4a or C4b biomarkers, corticotropin levels, VEGF levels, vasopressin levels, HGH/IGF-1 levels, and transsulfuration metabolism.

[0029] As used herein, the terms "treat," "treating," or "treatment" include prevention, attenuation, reversal, or improvement in at least one symptom or sign of a MDD. Treatment can be achieved by dietary management (e.g. administering a nutritional supplement or medical food as a component of a subject's diet) or by pharmaceutical intervention (e.g. administering a pharmaceutical drug).

[0030] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this invention belongs.

II. COMPOSITIONS OF THE INVENTION

[0031 ] The present invention provides compositions comprising combinations of Vitamin A, thiamine, pyridoxine, L-methylfolate, methylcobalamin, cholecalciferol, magnesium, Acetyl-L-carnitine, quercetin, D-ribose, coenzyme Q10, riboflavin, biotin, ascorbic acid, potassium, malic acid, astaxanthin, and/or curcuminoids purified from turmeric. In preferred embodiments, all the components of the composition are classified by the U.S. Food and Drug Association (hereinafter, "FDA") as "Generally Recognized as Safe" (hereinafter, "GRAS"). Astaxanthin is described at least in the FDA GRAS Notice No. 294, which is hereby incorporated by reference in its entirety. Curcuminoids are described at least in the FDA GRAS Notice No. 460, which is hereby incorporated by reference in its entirety. Quercetin is described in the FDA GRAS Notice No. 341 , which is hereby incorporated by reference in its entirety. D-Ribose is described at least in the FDA GRAS Notice No. 243, which is hereby incorporated by reference in its entirety.

(a) Composition A

[0032] One aspect of the invention is a composition comprising a combination of Vitamin A, thiamine (Vitamin B1 ), pyridoxine (Vitamin B6), L-methylfolate (Vitamin B9), Methylcobalamin (Vitamin B12), cholecalciferol (Vitamin D3), magnesium, Acetyl-L-carnitine, quercetin, D-ribose, and coenzyme Q10. Another embodiment of the invention further comprises riboflavin (Vitamin B2), biotin (Vitamin B7), Ascorbic Acid (Vitamin C), Potassium, Malic Acid, Astaxanthin, Curcuminoids purified from turmeric, or any combination thereof. Preferably, a composition comprises a therapeutic combination of Vitamin A, thiamine (Vitamin B1 ), pyridoxine (Vitamin B6), L-methylfolate (Vitamin B9), Methylcobalamin (Vitamin B12), cholecalciferol (Vitamin D3), magnesium, Acetyl-L-carnitine, quercetin, D-ribose, and coenzyme Q10.

[0033] A preferred embodiment of the invention comprises Vitamin A in an amount of at least about 350 meg, more preferably at least about 500 meg of Vitamin A, more preferably at least about 750 meg of Vitamin A, still more preferably at least about 1 ,000 meg of Vitamin A. Alternatively, another preferred embodiment includes between about 350 meg and about 3,000 meg of Vitamin A, preferably between about 500 meg and about 2,500 meg of Vitamin A, more preferably between about 750 meg and about 2,000 meg of Vitamin A. In still another alternative, a preferred embodiment includes between about 1 ,000 meg and about 2,000 meg of Vitamin A. In yet another alternative, a preferred embodiment includes between about 750 meg and about 1 ,500 meg of Vitamin A, between about 1 ,000 meg and about 1 ,750 meg of Vitamin A, or between about 1 ,250 meg and about 2,000 meg of Vitamin A. [0034] A preferred embodiment of the invention further comprises thiamine in an amount of at least about 125 meg, more preferably at least about 12.5 mg of thiamine, more preferably at least about 125 mg of thiamine, more preferably at least about 500 mg of thiamine, more preferably at least about 750 mg of thiamine, still more preferably at least about 1 ,000 mg of thiamine. Alternatively, another preferred embodiment includes between about 125 meg and about 1 ,500 mg of thiamine, between about 1 .25 mg and about 1 ,500 mg of thiamine, between about 12.5 mg and about 1 ,500 mg of thiamine, or between about 125 mg and about 1 ,500 mg of thiamine. Alternatively, another preferred embodiment includes between about 125 mg and about 1 ,500 mg of thiamine, between about 250 mg and about 1 ,500 mg of thiamine, between about 500 mg and about 1 ,500 mg of thiamine, or between about 750 mg and about 1 ,500 mg of thiamine. In still another alternative, a preferred embodiment includes between about 500 mg and about 1 ,250 mg of thiamine, or between about 750 mg and about 1 ,500 mg of thiamine. In yet another alternative, a preferred embodiment includes between about 750 mg and about 1 ,250 mg of thiamine, or between about 1 ,000 mg and about 1 ,500 mg of thiamine.

[0035] A preferred embodiment of the invention further comprises pyridoxine in an amount of at least about 125 meg, more preferably at least about 250 meg of pyridoxine, more preferably at least about 500 meg of pyridoxine, more preferably at least about 1 mg of pyridoxine, more preferably at least about 2.5 mg of pyridoxine, still more preferably at least about 5 mg of pyridoxine. Alternatively, another preferred embodiment includes between about 125 meg and about 1 ,500 mg of pyridoxine, between about 125 meg and about 150 mg of pyridoxine, or between about 125 meg and about 15 mg of pyridoxine. Alternatively, another preferred embodiment includes between about 500 meg and about 1 ,500 mg of pyridoxine, between about 500 meg and about 150 mg of pyridoxine, or between about 500 meg and about 15 mg of pyridoxine. Alternatively, another preferred embodiment includes between about 1 mg and about 1 ,500 mg of pyridoxine, between about 1 mg and about 150 mg of pyridoxine, or between about 1 mg and about 15 mg of pyridoxine. In yet another alternative, a preferred embodiment includes between about 1 mg and about 1000 mg of pyridoxine, between about 1 mg and about 100 mg of pyridoxine, or between about 1 mg and about 10 mg of pyridoxine. In still another alternative, a preferred embodiment includes between about 125 meg and about 12.5 mg of pyridoxine, or between about 500 meg and about 50 mg of pyridoxine.

[0036] A preferred embodiment of the invention further comprises L- methylfolate in an amount of at least about 25 meg, more preferably at least about 50 meg of L-methylfolate, more preferably at least about 75 meg of L-methylfolate, still more preferably at least about 100 meg of L-methylfolate, still more preferably at least about 250 meg of L-methylfolate, even more preferably at least about 500 meg of L- methylfolate. Alternatively, another preferred embodiment includes between about 35 meg and about 2,000 meg of L-methylfolate, preferably between about 100 meg and about 1 ,500 meg of L-methylfolate, more preferably between about 200 meg and about 1 ,000 meg of L-methylfolate. In still another alternative, a preferred embodiment includes between about 100 meg and about 1 ,100 meg of L-methylfolate, between about 250 meg and about 1 ,250 meg of L-methylfolate, or between about 500 meg and about 1 ,500 meg of L-methylfolate. In yet another alternative, a preferred embodiment includes between about 250 meg and about 750 meg of L-methylfolate, between about 350 meg and about 850 meg of L-methylfolate, between about 450 meg and about 950 meg of L-methylfolate, or between about 550 meg and about 1 ,500 meg of L- methylfolate. In yet another alternative, a preferred embodiment includes between about 250 meg and about 750 meg of L-methylfolate, between about 500 meg and about 1 ,000 meg of L-methylfolate, or between about 750 meg and about 1 ,250 meg of L- methylfolate.

[0037] A preferred embodiment of the invention further comprises methylcobalamin in an amount of at least about 125 meg, more preferably at least about 250 meg of methylcobalamin, more preferably at least about 500 meg of methylcobalamin, more preferably at least about 750 meg of methylcobalamin, more preferably at least about 1 mg of methylcobalamin, still more preferably at least about 5 mg of methylcobalamin. Alternatively, another preferred embodiment includes between about 125 meg and about 15 mg of methylcobalamin, between about 250 meg and about 15 mg of methylcobalamin, between about 500 meg and about 15 mg of methylcobalamin, or between about 1 mg and about 15 mg of methylcobalamin. In still another alternative, a preferred embodiment includes between about 125 meg and about 10 mg of methylcobalamin, between about 250 meg and about 10 mg of methylcobalamin, between about 500 meg and about 10 mg of methylcobalamin, or between about 1 mg and about 10 mg of methylcobalamin. In yet another alternative, a preferred embodiment includes between about 1 mg and about 15 mg of methylcobalamin, between about 1 mg and about 10 mg of methylcobalamin, between about 5 mg and about 15 mg of methylcobalamin, or between about 5 mg and about 10 mg of methylcobalamin.

[0038] A preferred embodiment of the invention further comprises cholecalciferol in an amount of at least about 5 meg of cholecalciferol, more preferably at least about 10 meg of cholecalciferol, more preferably at least about 20 meg of cholecalciferol, still more preferably at least about 30 meg of cholecalciferol. Alternatively, another preferred embodiment includes between about 5 meg of cholecalciferol and about 125 meg of cholecalciferol or more preferably between about 10 meg of cholecalciferol and about 50 meg of cholecalciferol.

[0039] A preferred embodiment of the invention further comprises magnesium in an amount of at least about 100 mg, more preferably at least about 150 mg of magnesium, still more preferably at least about 200 mg of magnesium, still more preferably at least about 250 mg of magnesium, still more preferably at least about 300 mg of magnesium. Alternatively, another preferred embodiment includes between about 100 mg and about 450 mg of magnesium, more preferably between about 150 mg and about 400 mg of magnesium, more preferably between about 200 mg and about 350 mg of magnesium. In still another alternative, a preferred embodiment includes between about 250 mg and about 350 mg of magnesium, between about 300 mg and about 400 mg of magnesium, or between about 350 mg and about 450 mg of magnesium. Suitable magnesium salts, complexes and chelates are known in the art. A skilled artisan will be able to determine the appropriate amount of the salt, complex or chelate, such that a preferred amount of magnesium is provided. Non-limiting examples of suitable forms of magnesium include magnesium carbonate, magnesium chloride, magnesium hydroxide, magnesium oxide, magnesium phosphate dibasic, magnesium phosphate tribasic, magnesium stearate, magnesium sulfate, magnesium L-threonate, magnesium gluconate, magnesium citrate, magnesium aspartate, magnesium glycinate, magnesium malate, magnesium orotate, magnesium taurate, and magnesium pidolate. In an exemplary embodiment, magnesium is provided as magnesium carbonate. In another exemplary embodiment, magnesium is provided as magnesium L-threonate.

[0040] A preferred embodiment of the invention further comprises acetyl-L- carnitine in an amount of at least about 200 mg, more preferably at least about 500 mg of acetyl-L-carnitine, more preferably at least about 1 ,000 mg of acetyl-L-carnitine, more preferably at least about 2,000 mg of acetyl-L-carnitine, still more preferably at least about 2,000 mg of acetyl-L-carnitine, still more preferably at least about 3,000 mg of acetyl-L-carnitine. Alternatively, another preferred embodiment includes between about 200 mg and about 4,000 mg of acetyl-L-carnitine, between about 500 mg and about 4,000 mg of acetyl-L-carnitine, between about 1 ,000 mg and about 4,000 mg of acetyl- L-carnitine, between about 2,000 mg and about 4,000 mg of acetyl-L-carnitine, or between about 3,000 mg and about 4,000 mg of acetyl-L-carnitine. In still another alternative, a preferred embodiment includes between about 1 ,500 mg and about 3,000 mg of acetyl-L-carnitine, between about 2,000 mg and about 3,500 mg of acetyl-L- carnitine, or between about 2,500 mg and about 4,000 mg of acetyl-L-carnitine. In yet another alternative, a preferred embodiment includes between about 2,500 mg and about 3,000 mg of acetyl-L-carnitine, between about 3,000 mg and about 3,500 mg of acetyl-L-carnitine, or between about 3,500 mg and about 4,000 mg of acetyl-L-carnitine.

[0041 ] A preferred embodiment of the invention further comprises quercetin in an amount of at least about 50 mg, more preferably at least about 100 mg of quercetin, more preferably at least about 200 mg of quercetin, more preferably at least about 300 mg of quercetin, still more preferably at least about 350 mg of quercetin. Alternatively, another preferred embodiment includes between about 50 mg and about 2,000 mg of quercetin, between about 50 mg and about 1 ,000 mg of quercetin, between about 50 mg and about 750 mg of quercetin, or between about 50 mg and about 500 mg of quercetin. In still another alternative, a preferred embodiment includes between about 100 mg and about 2,000 mg of quercetin, between about 100 mg and about 1 ,000 mg of quercetin, between about 100 mg and about 750 mg of quercetin, or between about 100 mg and about 500 mg of quercetin. In yet another alternative, a preferred embodiment includes between about 100 mg and about 600 mg of quercetin, between about 200 mg and about 700 mg of quercetin, or between about 300 mg and about 800 mg of quercetin.

[0042] A preferred embodiment of the invention further comprises D-ribose in an amount of at least about 1 ,000 mg, more preferably at least about 1 ,500 mg of D- ribose, still more preferably at least about 2,000 mg of D-ribose, still more preferably at least about 2,500 mg of D-ribose, still more preferably at least about 3,000 mg of D- ribose. Alternatively, another preferred embodiment includes between about 250 mg and about 15,000 mg of D-ribose, more preferably between about 500 mg and about 7,500 mg of D-ribose, more preferably between about 1 ,000 mg and about 5,000 mg of D-ribose. In still another alternative, a preferred embodiment includes between about 1 ,000 mg and about 5,000 mg of D-ribose, between about 1 ,500 mg and about 5,500 mg of D-ribose, between about 2,000 mg and about 6,000 mg of D-ribose, between about 2,500 mg and about 6,500 mg of D-ribose, between about 3,000 mg and about 7,000 mg of D-ribose. In yet another alternative, a preferred embodiment includes between about 1 ,000 mg and about 3,000 mg of D-ribose, between about 2,000 mg and about 4,000 mg of D-ribose, or between about 3,000 mg and about 5,000 mg of D- ribose.

[0043] A preferred embodiment of the invention further comprises Coenzyme Q10 in an amount of at least about 50 mg, more preferably at least about 100 mg of Coenzyme Q10, still more preferably at least about 150 mg of Coenzyme Q10, still more preferably at least about 200 mg of Coenzyme Q10, still more preferably at least about 250 mg of Coenzyme Q10. Alternatively, another preferred embodiment includes between about 50 mg and about 500 mg of Coenzyme Q10, more preferably between about 100 mg and about 500 mg of Coenzyme Q10, more preferably between about 150 mg and about 500 mg of Coenzyme Q10, more preferably between about 200 mg and about 500 mg of Coenzyme Q10. Alternatively, another preferred embodiment includes between about 50 mg and about 500 mg of Coenzyme Q10, more preferably between about 50 mg and about 450 mg of Coenzyme Q10, more preferably between about 50 mg and about 400 mg of Coenzyme Q10, more preferably between about 50 mg and about 350 mg of Coenzyme Q10. In still another alternative, a preferred embodiment includes between about 100 mg and about 250 mg of Coenzyme Q10, between about 150 mg and about 300 mg of Coenzyme Q10, between about 200 mg and about 350 mg of Coenzyme Q10, or between about 250 mg and about 400 mg of Coenzyme Q10. Coenzyme Q10 is also known as ubiquinone, ubidecarenone, ubiquinol, and CoQ10. There are three, redox states of Coenzyme Q10: fully oxidized (ubiquinone), semiquinone (ubisemiquinone), and fully reduced (ubiquinol). In certain embodiments, Coenzyme Q10 is provided as ubiquinone. In certain embodiments, Coenzyme Q10 is provided as ubisemiquinone. In certain embodiments, Coenzyme Q10 is provided as ubiquinol. As described herein, ubiquinol is a preferred form.

(b) Composition B

[0044] Another aspect of the invention is a composition comprising a combination of thiamine (Vitamin B-1 ), riboflavin (Vitamin B-2), pyridoxine (Vitamin B-6), and biotin (Vitamin B-7). Preferably, the composition comprises a therapeutic combination of thiamine, riboflavin, pyridoxine, and biotin. Another aspect of the invention is a composition comprising a combination of thiamine, riboflavin, pyridoxine, and biotin and further comprising methylfolate (Vitamin B-9), methylcobalamin (MeCbl, Vitamin B-12) and/or hydroxocobalamin (HOCbl, Vitamin B-12). Preferably the composition comprises a therapeutic combination of thiamine, riboflavin, pyridoxine, and biotin and further comprising methylfolate, methylcobalamin and/or hydroxocobalamin.

[0045] A preferred embodiment of the invention comprises thiamine (Vitamin B-1 ) in the amount of at least about 125 meg, more preferably at least about 250 meg of thiamine (Vitamin B-1 ), still more preferably at least about 500 meg of thiamine (Vitamin B-1 ). Alternatively, another preferred embodiment includes between about 125 meg and about 1 ,500 mg of thiamine (Vitamin B-1 ) or more preferably between about 250 meg and about 750 mg of thiamine (Vitamin B-1 ). [0046] A preferred embodiment of the invention comprises riboflavin (Vitamin B-2) in the amount of at least about 125 meg, more preferably at least about 250 meg of riboflavin (Vitamin B-2), still more preferably at least about 500 meg of riboflavin (Vitamin B-2). Alternatively, another preferred embodiment includes between about 125 meg and about 40 mg of riboflavin (Vitamin B-2) or more preferably between about 250 meg and about 20 mg of riboflavin (Vitamin B-2).

[0047] A preferred embodiment of the invention comprises pyridoxine (Vitamin B-6) in the amount of at least about 250 meg more preferably at least about 500 meg of pyridoxine (Vitamin B-6), still more preferably at least about 1 mg of pyridoxine (Vitamin B-6). Alternatively, another preferred embodiment includes between about 250 meg and about 1 ,500 mg of pyridoxine (Vitamin B-6) or more preferably between about 500 meg and about 750 mg of pyridoxine (Vitamin B-6).

[0048] A preferred embodiment of the invention comprises biotin (Vitamin B-7) in the amount of at least about 2.5 meg, more preferably at least about 5 meg of biotin (Vitamin B-7), still more preferably at least about 10 meg of biotin (Vitamin B-7). Alternatively, another preferred embodiment includes between about 2.5 meg and about 300 meg of biotin (Vitamin B->7) or more preferably between about 5 meg and about 150 meg of biotin (Vitamin B-7).

[0049] A preferred embodiment of the invention further comprises L- methylfolate (Vitamin B-9) in the amount of at least about 25 meg, more preferably at least about 50 meg of L-methylfolate (Vitamin B-9), still more preferably at least about 100 meg of L-methylfolate (Vitamin B-9). Alternatively, another preferred embodiment includes between about 25 meg and about 2 mg of L-methylfolate (Vitamin B-9) or more preferably between about 50 meg and about 1 mg of L-methylfolate (Vitamin B-9).

[0050] A preferred embodiment of the invention further comprises Vitamin B-12 methylcobalamin (MeCbl) in the amount of at least about 125 mg, more preferably at least about 250 mg of Vitamin B-12 methylcobalamin (MeCbl), still more preferably at least about 500 mg of Vitamin B-12 methylcobalamin (MeCbl). Alternatively, another preferred embodiment includes between about 125 mg and about 2,000 mg of Vitamin B-12 methylcobalamin (MeCbl) or more preferably between about 250 mg and about 1 ,000 mg of Vitamin B-12 methylcobalamin (MeCbl).

[0051 ] A preferred embodiment of the invention further comprises Vitamin B-12 hydroxocobalamin (HOCbl) in the amount of at least about 250 meg, more preferably at least about 500 meg of Vitamin B-12 hydroxocobalamin (HOCbl), still more preferably at least about 1 mg of Vitamin B-12 hydroxocobalamin (HOCbl). Alternatively, another preferred embodiment includes between about 250 meg and about 10 mg of Vitamin B-12 hydroxocobalamin (HOCbl) or more preferably between about 500 meg and about 5 mg of B-12 hydroxocobalamin (HOCbl).

(c) Composition C

[0052] Another aspect of the invention is a composition comprising a combination of D-Ribose, magnesium, ascorbic acid, cholecalciferol, potassium citrate, and malic acid. Preferably the composition comprises a therapeutic combination of D- Ribose, magnesium, ascorbic acid, cholecalciferol, potassium citrate, and malic acid.

[0053] One embodiment of the invention is a formulation for the treatment of a patient with a mitochondrial damage disease comprising a therapeutic combination D-ribose, magnesium in one or more forms, ascorbic acid (Vitamin C) and cholecalciferol (Vitamin D3). A preferred embodiment of the invention further comprises a therapeutically beneficial amount of potassium citrate and/or malic acid.

[0054] A preferred embodiment of the invention comprises D-ribose in the amount of at least about 250 mg, more preferably at least about 500 mg of D-ribose, still more preferably at least about 1 ,000 mg of D-ribose. Alternatively, another preferred embodiment includes between about 250 mg and about 15,000 mg of D-ribose or more preferably between about 500 mg and about 7,500 mg of D-ribose.

[0055] A preferred embodiment of the invention further comprises magnesium in the amount of at least about 25 mg , more preferably at least about 50 mg of magnesium, still more preferably at least about 100 mg of magnesium. Alternatively, another preferred embodiment includes between about 25 mg and about 450 mg of magnesium or more preferably between about 50 mg and about 225 mg of magnesium. Suitable magnesium salts, complexes and chelates are known in the art. A skilled artisan will be able to determine the appropriate amount of the salt, complex or chelate, such that a preferred amount of magnesium is provided. Non-limiting examples of suitable forms of magnesium include magnesium carbonate, magnesium chloride, magnesium hydroxide, magnesium oxide, magnesium phosphate dibasic, magnesium phosphate tribasic, magnesium stearate, magnesium sulfate, magnesium L-threonate, magnesium gluconate, magnesium citrate, magnesium aspartate, magnesium glycinate, magnesium malate, magnesium orotate, magnesium taurate, and magnesium pidolate. In an exemplary embodiment, magnesium is provided as magnesium carbonate. In another exemplary embodiment, magnesium is provided as magnesium L-threonate.

[0056] A preferred embodiment of the invention comprises ascorbic acid (Vitamin C) in the amount of at least about 25 mg, more preferably at least about 50 mg of ascorbic acid (Vitamin C), still more preferably at least about 100 mg of ascorbic acid (Vitamin C). Alternatively, another preferred embodiment includes between about 25 mg and about 2,000 mg of ascorbic acid (Vitamin C) or more preferably between about 50 mg and about 1 ,000 mg of ascorbic acid (Vitamin C).

[0057] A preferred embodiment of the invention comprises cholecalciferol (Vitamin D3) in the amount of at least about 5 meg, more preferably at least about 10 meg of cholecalciferol (Vitamin D3), still more preferably at least about 20 meg of cholecalciferol (Vitamin D3). Alternatively, another preferred embodiment includes between about 5 meg and about 500 meg of cholecalciferol (Vitamin D3) or more preferably between about 50 meg and about 250 meg of cholecalciferol (Vitamin D3).

[0058] A preferred embodiment of the invention further comprises potassium citrate in the amount of at least about 62.5 mg, more preferably at least about 125 mg of potassium citrate, still more preferably at least about 250 mg of potassium citrate. Alternatively, another preferred embodiment includes between about 62.5 mg and about 5,000 mg of potassium citrate or more preferably between about 125 mg and about 2,500 mg of potassium citrate.

[0059] A preferred embodiment of the invention further comprises malic acid in the amount of at least about 150 mg, more preferably at least about 300 mg of malic acid, still more preferably at least about 600 mg of malic acid. Alternatively, another preferred embodiment includes between about 150 mg and about 2,400 mg of malic acid or more preferably between about 300 mg and about 1 ,200 mg of malic acid.

(d) Composition D

[0060] Another aspect of the invention is a composition comprising a combination of acetyl-L-carnitine, coenzyme Q10, astaxanthin, curcuminoids purified from turmeric, and quercetin. Preferably the composition comprises a therapeutic combination of acetyl-L-carnitine, coenzyme Q10, astaxanthin, curcuminoids purified from turmeric, and quercetin.

[0061 ] A preferred embodiment of the invention comprises acetyl-L- carnitine in the amount of at least about 50 mg, more preferably at least about 100 mg of acetyl-L-carnitine, still more preferably at least about 200 mg of acetyl-L-carnitine. Alternatively, another preferred embodiment includes between about 50 mg and about 4,000 mg of acetyl-L-carnitine or more preferably between about 100 mg and about 2,000 mg of acetyl-L-carnitine.

[0062] A preferred embodiment of the invention further comprises coenzyme Q10 in the amount of at least about 12.5 mg, more preferably at least about 25 mg of coenzyme Q10, still more preferably at least about 50 mg of coenzyme Q10. Alternatively, another preferred embodiment includes between about 12.5 mg and about 500 mg of coenzyme Q10 or more preferably between about 25 mg and about 250 mg of coenzyme Q10. Coenzyme Q10 is also known as ubiquinone, ubidecarenone, and CoQ10. There are three redox states of Coenzyme Q10: fully oxidized (ubiquinone), semiquinone (ubisemiquinone), and fully reduced (ubiquinol). As described herein, the substantially reduced form of coenzyme Q10 is the preferred form for use in the formulation.

[0063] A preferred embodiment of the invention comprises astaxanthin in the amount of at least about 250 pg of astaxanthin, more preferably at least about 500 pg of astaxanthin, still more preferably at least about 1000 pg of astaxanthin. Alternatively, another preferred embodiment includes between about 250 pg and about 10 mg of astaxanthin or more preferably between about 500 pg and about 5 mg of astaxanthin. [0064] A preferred embodiment of the invention comprises curcuminoids purified from turmeric in the amount of at least about 12.5 mg, more preferably at least about 25 mg of curcuminoids purified from turmeric, still more preferably at least about 50 mg of curcuminoids purified from turmeric. Alternatively, another preferred embodiment includes between about 12.5 mg and about 2,000 mg of curcuminoids purified from turmeric or more preferably between about 25 mg and about 1 ,000 mg of curcuminoids purified from turmeric.

[0065] A preferred embodiment of the invention further comprises quercetin in the amount of at least about 12.5 mg, more preferably at least about 25 mg of quercetin, still more preferably at least about 50 mg of quercetin. Alternatively, another preferred embodiment includes between about 12.5 mg and about 2,000 mg of quercetin or more preferably between about 25 mg and about 1 ,000 mg of quercetin.

(e) Additional Ingredients

[0066] In another aspect of the invention, compositions of the invention may further comprise one or more additional ingredients. For example, compositions of the invention may further comprise 1 , 2, 3, 4, or 5 additional ingredients. Compositions of the invention may also comprise 6, 7, 8, 9, or 10 additional ingredients. Alternatively, compositions of the invention may further comprise 1 1 , 12, 13, 14, or 15 additional ingredients. Still other compositions of the invention may further comprise 16, 17, 18, 19 or 20 additional ingredients. Yet other compositions of the invention may further comprise more than 20, more than 30 or more than 40 additional ingredients. Compositions of the invention may also comprise between 1 and 20 additional ingredients, between 1 and 15 additional ingredients, or between 1 and 10 additional ingredients. The additional ingredients may be a vitamin, a mineral, a probiotic, an active pharmaceutical ingredient, or any combination of vitamins, minerals, a probiotics, and/or active pharmaceutical ingredients. Exemplary ingredients include, but are not limited to, those provided in Table A.

[0067] In another aspect of the invention, a composition of the invention may comprise two or more ingredients listed in Table A. For example, a composition of the invention may comprise 1 , 2, 3, 4, or 5 ingredients listed in Table A. Compositions of the invention may also comprise 6, 7, 8, 9, or 10 ingredients listed in Table A. Alternatively, compositions of the invention may comprise 1 1 , 12, 13, 14, or 15 ingredients listed in Table A. Still other compositions of the invention may comprise 16, 17, 18, 19 or 20 ingredients listed in Table A. Yet other compositions of the invention may further comprise more than 20, more than 30 or more than 40 ingredients listed in Table A. Compositions of the invention may comprise each ingredient listed in Table A Compositions of the invention may also comprise between 1 and 20 ingredients listed in Table A, between 1 and 15 ingredients listed in Table A, or between 1 and 10 ingredients listed in Table A. A composition of the invention comprising two or more ingredients from Table A may further comprise one or more additional ingredients. The additional ingredients may be a vitamin, a mineral, a probiotic, an active pharmaceutical ingredient not listed in Table A, or any combination of vitamins, minerals, a probiotics, and/or active pharmaceutical ingredients not listed in Table A.

Table A:

INGREDIENT / NUTRIENT DAILY DOSAGE RANGE

Alpha glyceryl phophoryl choline 30 to 600 mg

Ashwagandha extract 25 to 250 mg

Blueberry extract 150 to 750 mg

Caffeine 20 to 500 mg

Carnosine 50 to 3000 mg

Choline 100 to 800 mg

Curcumin 400 to 800 mg

Dehydroepiandrosterone (DHEA) 10 to 50 mg

Fish Oil - DHA 100 to 1000 mg

Fish Oil - EPA 200 to 1400 mg

Fish Oil - Gamma-linolenic acid 100 to 1000 mg

Ginkgo biloba 25 to 250 mg

Green tea extract 200 to 1500 mg

Huperzine A 100 to 800 meg

Inositol 200 to 8000 mg

Melatonin 0.5 to 10 mg

N-acetylcysteine (NAC) 200 to 1800 mg

Panax ginseng 100 to 1000 mg

Pantothenic Acid (Vitamin B5) 2 to 1200 mg

Phosphatidylcholine (Lecithin) 5 to 100 mg Phosphatidylserine 5 to 200 mg

Pregnenolone 2 to 20 mg

Pycnogenol 20 to 300 mg

Pyrroloquinoline quinone (PQQ) 10 to 20 mg

Resveratrol 25 to 250 mg

R-Lipoic acid 240 to 480 mg

S-Adenosyl methionine (SAMe) 200 to 1600 mg

Selenium 10 to 100 meg

Tryptophan 200 to 4000 mg

Uridine monophosphate 100 to 1000 mg

Vinpocetine 10 to 30 mg

Vitamin C 100 to 1000 mg

Vitamin E 100 to 2000 mg

Vitamin K1 1000 to 9000 meg

Vitamin K2 100 to 1000 meg

Whole Grape extract 10 to 150 mg

GABA 50 to 800 mg

Inositol 100 to 10000 mg

L-Tyrosine 200 to 4000 mg

Pregnenolone 1 to 100 mg

Resveratrol 10 to 500 mg

Uridine-5'-Monophosphate 100 to 1000 mg

Adenosylcobalamin 500 to 2000 mg

Hydroxocobalamin 1 to 10 mg

Methylcobalamin 0.125 to 15 mg

Folinic Acid 0.1 to 2 mg

Tetrahydrobiopterin 200 to 2400 mg

L-carnitine fumarate 500 to 2000 mg

Alpha Lipoic Acid 100 to 1800 mg

Magnesium orotate 100 to 450 mg

Nicotinamide adenine dinucleotide 5 to 20 mg

Probiotic (L rhamnosus, L.

salivarus, B. bifidum, B. infantis) 100 to 800 mg

Dietary fiber (insoluble and soluble

lignin) 10,000 to 40,000 mg

Vasoactive intestinal peptide 1 -4 nasal sprays daily

Chlorella 5000 to 20,000 mg

Niacinamide 50 to 2000 mg

Bioflavanoids 100 to 1200 mg

Cocoa Extract Flavanols 100 to 1200 mg

Thiamine 500 to 1500 mg

Riboflavin 500 to 40 mg Biotin 2.5 to 500 meg

St. John's Wort extract - tetrahydrohyperforin (5%

hyperforin) 100 to 900 mg

Luteolin 50 to 1500 mg

Rutin 30 to 1000 mg

Astaxanthin 1 to 10 mg

Oleocanthal - Olive oil 5 to 100 g

Piperin 1 to 20 mg

Pantothenic Acid 2 to 20 mg

Curcuminoids purified from

Turmeric 50 to 2000 mg

Malic acid 600 to 2400 mg

Potassium citrate 250 to 3500 mg

D-ribose 2000 to 10,000 mg

Ascorbic acid 100 to 2000 mg

Acetyl l-carnitine 200 to 4000 mg

Quercetin 50 to 2000 mg

Pyridoxine 0.125 to 5000 mg

L-methylfolate 25 to 2000 mg

Ubiquinol Coenzyme Q10 50 to 500 mg

Cholecalciferol 5 to 125 meg

Dimethylaminoethanol (DMAE) 100 to 1000 mg

(f) Formulations comprising a composition of the invention

[0068] Each of the compositions described above or a mixture thereof may be formulated into a dosage form suitable for administration orally, parenterally, rectally, intradermally, transdermal^, or topically. Formulations of the various embodiments above may include the composition of the invention and one or more excipient. Non- limiting examples of excipients include binders, diluents (fillers), disintegrants, effervescent disintegration agents, preservatives (antioxidants), flavor-modifying agents, lubricants and glidants, dispersants, coloring agents, pH modifiers, chelating agents, antimicrobial agents, release-controlling polymers, and combinations of any of these agents. In certain embodiments, a formulation may comprise a composition described above, calcium phosphate, silicon dioxide, and citric acid, and may optionally contain a sweetener, a natural flavor, and/or an artificial flavor. In preferred embodiments, the sweetener is sucralose,

[0069] Non-limiting examples of binders suitable for the formulations of various embodiments include starches, pregelatinized starches, gelatin, polyvinylpyrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, Ci₂-Ci₈ fatty acid alcohols, polyethylene glycol, polyols, saccharides, oligosaccharides, polypeptides, oligopeptides, and combinations thereof. The polypeptide may be any arrangement of amino acids ranging from about 100 to about 300,000 Daltons.

[0070] In one embodiment, the binder may be introduced into the mixture to be granulated in a solid form including but not limited to a crystal, a particle, a powder, or any other finely divided solid form known in the art. In another embodiment, the binder may be dissolved or suspended in a solvent and sprayed onto the mixture in a granulation device as a binder fluid during granulation.

[0071 ] Non-limiting examples of diluents (also referred to as "fillers" or "thinners") include carbohydrates, inorganic compounds, and biocompatible polymers, such as polyvinylpirrolydone (PVP). Other non-limiting examples of diluents include dibasic calcium sulfate, tribasic calcium sulfate, starch, calcium carbonate, magnesium carbonate, microcrystalline cellulose, dibasic calcium phosphate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, talc, modified starches, saccharides such as sucrose, dextrose, lactose, microcrystalline cellulose, fructose, xylitol, and sorbitol, polyhydric alcohols; starches; pre-manufactured direct compression diluents; and mixtures of any of the foregoing.

[0072] Disintegrents may be effervescent or non-effervescent. Non-limiting examples of non-effervescent disintegrants include starches such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, micro-crystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pecitin, and tragacanth. Suitable effervescent disintegrants include but are not limited to sodium bicarbonate in combination with citric acid, and sodium bicarbonate in combination with tartaric acid. [0073] Non-limiting examples of preservatives include, but are not limited to, ascorbic acid and its salts, ascorbyl palmitate, ascorbyl stearate, anoxomer, N- acetylcysteine, benzyl isothiocyanate, m-aminobenzoic acid, o-aminobenzoic acid, p- aminobenzoic acid (PABA), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), caffeic acid, canthaxantin, alpha-carotene, beta-carotene, beta-caraotene, beta- apo-carotenoic acid, carnosol, carvacrol, catechins, cetyl gallate, chlorogenic acid, citric acid and its salts, clove extract, coffee bean extract, p-coumaric acid, 3,4- dihydroxybenzoic acid, N,N'-diphenyl-p-phenylenediamine (DPPD), dilauryl thiodipropionate, distearyl thiodipropionate, 2,6-di-tert-butylphenol, dodecyl gallate, edetic acid, ellagic acid, erythorbic acid, sodium erythorbate, esculetin, esculin, 6- ethoxy-1 ,2-dihydro-2,2,4-trimethylquinoline, ethyl gallate, ethyl maltol, ethylenediaminetetraacetic acid (EDTA), eucalyptus extract, eugenol, ferulic acid, flavonoids (e.g., catechin, epicatechin, epicatechin gallate, epigallocatechin (EGC), epigallocatechin gallate (EGCG), polyphenol epigallocatechin-3-gallate), flavones (e.g., apigenin, chrysin, luteolin), flavonols (e.g., datiscetin, myricetin, daemfero), flavanones, fraxetin, fumaric acid, gallic acid, gentian extract, gluconic acid, glycerine, glycine, gum guaiacum, hesperetin, alpha-hydroxybenzyl phosphinic acid, hydroxycinammic acid, hydroxyglutaric acid, hydroquinone, N-hydroxysuccinic acid, hydroxytryrosol, hydroxyurea, rice bran extract, lactic acid and its salts, lecithin, lecithin citrate; R-alpha- lipoic acid, lutein, lycopene, malic acid, maltol, 5-methoxy tryptamine, methyl gallate, monoglyceride citrate; monoisopropyl citrate; morin, beta-naphthoflavone, nordihydroguaiaretic acid (NDGA), octyl gallate, oxalic acid, palmityl citrate, phenothiazine, phosphatidylcholine, phosphoric acid, phosphates, phytic acid, phytylubichromel, pimento extract, propyl gallate, polyphosphates, quercetin, trans- resveratrol, rosemary extract, rosmarinic acid, sage extract, sesamol, silymarin, sinapic acid, succinic acid, stearyl citrate, syringic acid, tartaric acid, thymol, tocopherols (i.e., alpha-, beta-, gamma- and delta-tocopherol), tocotrienols (i.e., alpha-, beta-, gamma- and delta-tocotrienols), tyrosol, vanilic acid, 2,6-di-tert-butyl-4-hydroxymethylphenol (i.e., lonox 100), 2,4-(tris-3',5'-bi-tert-butyl-4'-hydroxybenzyl)-mesitylene (i.e., lonox 330), 2,4,5-trihydroxybutyrophenone, ubiquinone, tertiary butyl hydroquinone (TBHQ), thiodipropionic acid, trihydroxy butyrophenone, tryptamine, tyramine, uric acid, vitamin K and derivates, vitamin Q10, wheat germ oil, zeaxanthin, or combinations thereof. In an exemplary embodiment, the preservatives are an antioxidant, such as a-tocopherol or ascorbate, and antimicrobials, such as parabens, chlorobutanol or phenol.

[0074] Suitable flavor-modifying agents include flavorants, taste-masking agents, sweeteners, and the like. Flavorants include, but are not limited to, synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits, and combinations thereof. Other non-limiting examples of flavors include cinnamon oils, oil of wintergreen, peppermint oils, clover oil, hay oil, anise oil, eucalyptus, vanilla, citrus oils such as lemon oil, orange oil, grape and grapefruit oil, fruit essences including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, fruit punch, and apricot.

[0075] Taste-masking agents include but are not limited to cellulose hydroxypropyl ethers (HPC) such as Klucel®, Nisswo HPC and PrimaFlo HP22; low- substituted hydroxypropyl ethers (L-HPC); cellulose hydroxypropyl methyl ethers (HPMC) such as Seppifilm-LC, Pharmacoat®, Metolose SR, Opadry YS, PrimaFlo, MP3295A, Benecel MP824, and Benecel MP843; methylcellulose polymers such as Methocel® and Metolose®; Ethylcelluloses (EC) and mixtures thereof such as E461 , Ethocel®, Aqualon@-EC, Surelease; Polyvinyl alcohol (PVA) such as Opadry AMB; hydroxyethylcelluloses such as Natrosol®; carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) such as Aualon@-CMC; polyvinyl alcohol and polyethylene glycol co-polymers such as Kollicoat IR@; monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as Eudragit® EPO, Eudragit® RD100, and Eudragit® E100; cellulose acetate phthalate; sepifilms such as mixtures of HPMC and stearic acid, cyclodextrins, and mixtures of these materials. In other embodiments, additional taste-masking agents contemplated are those described in U.S. Pat. Nos. 4,851 ,226, 5,075,1 14, and 5,876,759, each of which is hereby incorporated by reference in its entirety. [0076] Non-limiting examples of sweeteners include glucose (corn syrup), dextrose, invert sugar, fructose, and mixtures thereof (when not used as a carrier); saccharin and its various salts such as the sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcone compounds, glycyrrhizin; Stevia rebaudiana (Stevioside); chloro derivatives of sucrose such as sucralose; sugar alcohols such as sorbitol, mannitol, sylitol, hydrogenated starch hydrolysates and the synthetic sweetener 3,6- dihydro-6-methyl-1 ,2,3-oxathiazin-4-one-2,2-dioxide, particularly the potassium salt (acesulfame-K), and sodium and calcium salts thereof. In an exemplary embodiment, the sweetener is sucralose.

[0077] A lubricant may be utilized to lubricate ingredients that form a composition. As a glidant, a lubricant facilitates removal of solid dosage forms during the manufacturing process. Non-limiting examples of lubricants and glidants include magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oils, sterotex, polyoxyethylene monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and light mineral oil. The composition will generally comprise from about 0.01 % to about 10% by weight of a lubricant. In some embodiments, the composition will comprise from about 0.1 % to about 5% by weight of a lubricant. In a further embodiment, the composition will comprise from about 0.5% to about 2% by weight of a lubricant.

[0078] Dispersants may include but are not limited to starch, alginic acid, polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose as high hydrophilic-lipophilic balance (HLB) emulsifier surfactants.

[0079] Depending upon the embodiment, it may be desirable to include a coloring agent. Suitable color additives include but are not limited to food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C). These colors or dyes, along with their corresponding lakes, and certain natural and derived colorants may be suitable for use in various embodiments. [0080] Non-limiting examples of pH modifiers include citric acid, acetic acid, tartaric acid, malic acid, fumaric acid, lactic acid, phosphoric acid, sorbic acid, benzoic acid, sodium carbonate and sodium bicarbonate.

[0081 ] A chelating agent may be included as an excipient to immobilize oxidative groups, including but not limited to metal ions, in order to inhibit the oxidative degradation of the morphinan by these oxidative groups. Non-limiting examples of chelating agents include lysine, methionine, glycine, gluconate, polysaccharides, glutamate, aspartate, and disodium ethylenediaminetetraacetate (Na2EDTA).

[0082] An antimicrobial agent may be included as an excipient to minimize the degradation of the compound according to this disclosure by microbial agents, including but not limited to bacteria and fungi. Non-limiting examples of antimicrobials include parabens, chlorobutanol, phenol, calcium propionate, sodium nitrate, sodium nitrite, Na2EDTA, and sulfites including but not limited to sulfur dioxide, sodium bisulfite, and potassium hydrogen sulfite.

[0083] Release-controlling polymers may be included in the various embodiments of the solid dosage compositions incorporating compounds according to this disclosure. In one embodiment, the release-controlling polymers may be used as a tablet coating. In other embodiments, including but not limited to bilayer tablets, a release-controlling polymer may be mixed with the granules and other excipients prior to the formation of a tablet by a known process including but not limited to compression in a tablet mold. Suitable release-controlling polymers include but are not limited to hydrophilic polymers and hydrophobic polymers.

[0084] Suitable hydrophilic release-controlling polymers include, but are not limited to, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose ethers, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, nitrocellulose, crosslinked starch, agar, casein, chitin, collagen, gelatin, maltose, mannitol, maltodextrin, pectin, pullulan, sorbitol, xylitol, polysaccharides, ammonia alginate, sodium alginate, calcium alginate, potassium alginate, propylene glycol alginate, alginate sodium carmellose, calcium carmellose, carrageenan, fucoidan, furcellaran, arabicgum, carrageensgum, ghaftigum, guargum, karayagum, locust beangum, okragum, tragacanthgum, scleroglucangum, xanthangum, hypnea, laminaran, acrylic polymers, acrylate polymers, carboxyvinyl polymers, copolymers of maleic anhydride and styrene, copolymers of maleic anhydride and ethylene, copolymers of maleic anhydride propylene or copolymers of maleic anhydride isobutylene), crosslinked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone, diesters of polyglucan, polyacrylamides, polyacrylic acid, polyamides, polyethylene glycols, polyethylene oxides, poly(hydroxyalkyl methacrylate), polyvinyl acetate, polyvinyl alcohol, polyvinyl chloride, polystyrenes, polyvinylpyrrolidone, anionic and cationic hydrogels, and combinations thereof.

[0085] In a preferred embodiment, compositions provided herein may be formulated as a dosage form suitable for oral administration. Suitable dosage forms include a tablet, including a suspension tablet, a chewable tablet, an effervescent tablet or caplet; a pill; a powder such as a sterile packaged powder, a dispensable powder, and an effervescent powder; a capsule including both soft or hard gelatin capsules; a lozenge; a sachet; a sprinkle; a reconstitutable powder or ready-to-drink shake or other drink; a troche; pellets; granules; liquids; suspensions; emulsions; or semisolids and gels. Alternatively, the compositions may be incorporated into a food product or powder for mixing with a liquid, or administered orally after only mixing with a non-foodstuff liquid. In certain embodiments, compositions provided herein may be formulated as a capsule or tablet. Capsule and tablet formulations may further comprise binders, lubricants, diluents, flavor-modifying agents, taste-masking agents, pH modifiers, and coloring agents. Tablets may be coated according to methods well known in the art. In certain embodiments, compositions provided herein may be formulated as an aqueous suspension. Aqueous suspension formulations may further comprise pH modifiers, dispersants, flavor-modifying agents, taste-masking agents, and coloring agents. In certain embodiments, compositions provided herein may be formulated as a powder. Powder formulations may further comprise fillers, diluents, pH modifiers, flavor- modifying agents, taste-masking agents, and coloring agents. In an exemplary embodiment, compositions provided herein may be formulated as a nutritional supplement, a medical food, or a pharmaceutical composition. [0086] Compositions provided herein may also be formulated as a liquid formulation including, but not limited to, an aqueous or oily suspension, a solution, an emulsion, a syrup, and an elixir. The compositions may also be formulated as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain additives including, but not limited to, suspending agents, emulsifying agents, nonaqueous vehicles and preservatives. Suspending agent include, but are not limited to, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel, and hydrogenated edible fats. Emulsifying agents include, but are not limited to, lecithin, sorbitan monooleate, and acacia. Nonaqueous vehicles include, but are not limited to, edible oils, almond oil, fractionated coconut oil, oily esters, propylene glycol, and ethyl alcohol. Preservatives include, but are not limited to, methyl or propyl p- hydroxybenzoate and sorbic acid.

[0087] Compositions provided herein may also be formulated as suppositories. In these embodiments, the composition may include a suitable non- irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Non-limiting examples of suitable excipients for rectal suppository embodiments include cocoa butter, beeswax, and polyethylene glycols

[0088] Compositions provided herein may also be formulated for parenteral administration including, but not limited to, by injection or continuous infusion. Formulations for injection may be in the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents including, but not limited to, suspending, stabilizing, and dispersing agents. The composition may also be provided in a powder form for reconstitution with a suitable vehicle including, but not limited to, sterile, pyrogen-free water.

(f) Exemplary Compositions

[0089] An exemplary composition of the invention comprises a therapeutic combination of Vitamin A, thiamine, pyridoxine, L-methylfolate, methylcobalamin, cholecalciferol, magnesium carbonate, Acetyl-L-carnitine, quercetin, D-ribose, and coenzyme Q10 in the amounts shown in Table B. Another exemplary composition of the invention comprises a therapeutic combination of Vitamin A, thiamine, pyridoxine, L- methylfolate, methylcobalamin, cholecalciferol, magnesium carbonate, Acetyl-L- carnitine, quercetin, D-ribose, and coenzyme Q10 in the amounts shown in Table C. Another exemplary composition of the invention comprises a therapeutic combination of Vitamin A, thiamine, pyridoxine, L-methylfolate, methylcobalamin, cholecalciferol, magnesium carbonate, Acetyl-L-carnitine, quercetin, D-ribose, and coenzyme Q10 in the amounts shown in Table D. Exemplary compositions of the invention may further comprise one or more additional ingredients, as described in Section ll(e). The exemplary compositions may further comprise one or more excipient, and may be formulated into a dosage form suitable for administration orally, parenterally, or rectally. In certain embodiments, the exemplary compositions may be formulated as a capsule or tablet. Capsule and tablet formulations may further comprise binders, lubricants, diluents, flavor-modifying agents, taste-masking agents, pH modifiers, and coloring agents. Tablets may be coated according to methods well known in the art. In certain embodiments, the exemplary compositions may be formulated as an aqueous suspension. Aqueous suspension formulations may further comprise pH modifiers, dispersants, flavor-modifying agents, taste-masking agents, and coloring agents. In certain embodiments, the exemplary compositions provided herein may be formulated as a powder. Powder formulations may further comprise fillers, diluents, pH modifiers, flavor-modifying agents, taste-masking agents, and coloring agents. In certain embodiments, the composition may be a nutritional supplement, a medical food, or a pharmaceutical composition. Preferred dry powder formulations may comprise calcium phosphate, silicon dioxide, and citric acid, and may optionally contain a sweetener, a natural flavor, and/or an artificial flavor. In certain embodiments, the sweetener is sucralose.

Table B. Combination A1

Vitamin A 350 meg 3,000 meg

Thiamine 125 meg 1 ,500 mg

Pyridoxine 125 meg 1 ,500 mg

L-methylfolate 25 meg 2,000 meg

Methylcobalamin 125 meg 15 mg

Cholecalciferol 5 meg 125 meg

Magnesium (as magnesium 100 mg 450 mg carbonate)

Acetyl-L-carnitine 200 mg 4,000 mg

Quercetin 50 mg 2,000 mg

D-Ribose 1 ,000 mg 15,000 mg

Coenzyme Q10 50 mg 500 mg

Table C. Combination A2

Table D. Combination A3

Vitamin A 1000 meg

Thiamine 1000 mg

Pyridoxine 5 mg

L-methylfolate 500 meg

Methylcobalamin 8 mg

Cholecalciferol 25 meg

Magnesium 300 mg carbonate

Acetyl-L-carnitine 3,000 mg

Quercetin 350 mg

D-Ribose 3000 mg

Ubiquinol Coenzyme 250 mg Q10

Table E. Combination B

D-Ribose 1 ,000 mg 15,000 mg

Ascorbic Acid 100 mg 2,000 mg

Potassium citrate (optional) 250 mg 3,500 mg

Malic acid (optional) 600 mg 2,400 mg

Table G. Combination D

Minimum Maximum

Nutrient preferred preferred

amount amount

Acetyl-L-carnitine 200 mg 4,000 mg

Quercetin (optional) 50 mg 2,000 mg

Coenzyme Q10 50 mg 500 mg

Astaxanthin (optional) 1 mg 10 mg

Curcuminoids purified from 50 mg 2,000 mg

Turmeric (optional)

III. METHODS OF USE

[0090] Another aspect of the invention is a method to address the metabolic disturbances associated with a MDD in a subject with the MDD by administering to the subject a composition of the invention, such as Composition A, Composition B, Composition C, or Composition D, or mixtures thereof. The method comprises administering to the subject a composition of the invention. Preferably, the composition is administered once or twice daily. Alternatively, the composition may be administered on a less frequent basis, for example, once or twice a week, or every second, third, fourth or fifth day. Compositions of the invention are described in detail in Section II. In certain embodiments, the composition comprises a combination listed in Table B, Table C or Table D, and optionally comprises one or more additional ingredients from Table A. In other embodiments, the composition comprises a combination listed in Table E, Table F, or Table G, and optionally comprises one or more additional ingredients from Table A. In alternative embodiments, the composition consists essentially of a combination listed in Table B, Table C, Table D, Table E, Table F, or Table G. In different embodiments, the composition comprises two more ingredients from Table A.

[0091 ] Another aspect of the invention is a method to treat a MDD in a subject with the MDD by administering to the subject a composition of the invention. The term "treat" includes prevention, attenuation, reversal, or improvement in at least one symptom or sign of a MDD. The method comprises administering to the subject a composition of the invention. Preferably, the composition is administered once or twice daily. Alternatively, the composition may be administered on a less frequent basis, for example, once or twice a week, or every second, third, fourth or fifth day. Compositions of the invention are described in detail in Section II. In certain embodiments, the composition comprises a combination listed in Table B, Table C, Table D, Table E, Table F, or Table G, and optionally comprises one or more additional ingredients from Table A. In other embodiments, the composition consists essentially of a combination listed in Table B, Table C, Table D, Table E, Table F, or Table G. In different embodiments, the composition comprises two more ingredients from Table A.

[0092] Another aspect of the invention is a method to improve one or more symptoms of a MDD in a subject with the MDD, as compared to the same subject at an earlier time or a healthy control subject. The method comprises administering to the subject a composition of the invention. Preferably, the composition is administered once or twice daily. Alternatively, the composition may be administered on a less frequent basis, for example, once or twice a week, or every second, third, fourth or fifth day. Compositions of the invention are described in detail in Section II. In certain embodiments, the composition comprises a combination listed in Table B, Table C, Table D, Table E, Table F, or Table G, and optionally comprises one or more additional ingredients from Table A. In other embodiments, the composition consists essentially of a combination listed in Table B, Table C, Table D, Table E, Table F, or Table G. In different embodiments, the composition comprises two more ingredients from Table A.

[0093] Another aspect of the invention is a method to prevent an increase in the severity of and/or frequency in one or more symptoms of a MDD in a subject with the MDD, as compared to the same subject at an earlier time or a healthy control subject. The method comprises administering to the subject a composition of the invention. Preferably, the composition is administered once or twice daily. Alternatively, the composition may be administered on a less frequent basis, for example, once or twice a week, or every second, third, fourth or fifth day. Compositions of the invention are described in detail in Section II. In certain embodiments, the composition comprises a combination listed in Table B, Table C, Table D, Table E, Table F, or Table G, and optionally comprises one or more additional ingredients from Table A. In other embodiments, the composition consists essentially of a combination listed in Table B, Table C, Table D, Table E, Table F, or Table G. In different embodiments, the composition comprises two more ingredients from Table A.

[0094] The term "MDD" is defined above in Section I. In some embodiments, a subject with a MDD is a subject diagnosed with mild cognitive impairment (MCI), Alzheimer's disease (AD), autism, myalgic encephalomyelites /chronic fatigue syndrome (ME/CFS), diabetes, metabolic syndrome, or schizophrenia. In other embodiments, a subject with a MDD is a subject diagnosed with autism or an autism spectrum disorder. In other embodiments, a subject with a MDD is a subject diagnosed with angina pectoris, atherosclerosis, cardiovascular disease, coronary artery disease, heart failure, hypertension, myocardial infarction, peripheral artery disease, pulmonary hypertension, sleep apnea, stroke, or thrombosis. In other embodiments, a subject with a MDD is a subject diagnosed with diabetes mellitus, insulin resistance, metabolic syndrome, obesity. In other embodiments, a subject with a MDD is a subject diagnosed with acute lymphoblastic leukemia, esophageal cancer, or other forms of cancer. In other embodiments, a subject with a MDD is a subject diagnosed with alcohol-related disease of the nervous system, Alzheimer's disease (AD), amyotrophic lateral sclerosis, cerebral edema, cerebral ischemia, chronic traumatic brain injury, chronic traumatic encephalopathy, Creutzfeld-Jakob disease, dementia with lewy bodies, diabetic neuropathy, epilepsy, Friedreich's ataxia, multiple sclerosis, frontotemporal dementia, Huntington's disease, mild cognitive impairment, mild traumatic brain injury, mixed dementia, nephropathy, normal pressure hydrocephalus, Parkinson's disease, or vascular dementia. In additional embodiments, a subject with a MDD is a subject diagnosed with an anxiety disorder, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), bipolar disorder, depression, Gulf War Syndrome, post-traumatic stress disorder, or psychosis. In still other embodiments, a subject with a MDD is a subject diagnosed with beta thalassemia, fibromyalgia, myalgic encephalomyelites /chronic fatigue syndrome (ME/CFS), Sickle- cell disease, Systemic Lupus Erythematosus, Osteoarthritis, Rheumatoid Arthritis, or a Temporomandibular Joint Disorder. In other embodiments, a subject with a MDD is a subject diagnosed human monocytic ehrlichiosis or Lyme disease. In yet other embodiments, a subject with a MDD is a subject diagnosed with Celiac Disease, colitis, Crohn's Disease, Wernicke-Korsakoff Syndrome, Wilson's Disease, Kidney Stones, reflux esophagitis, or Urolithiasis. In alternative embodiments, a subject with a MDD is a subject diagnosed with autoimmune uveitis, cataracts, diabetic retinopathy, macular degeneration, retinal degeneration, or retinitis pigmentosa. In further embodiments, a subject with a MDD is a subject diagnosed with atopic dermatitis or other forms of dermatitis, chronic spontaneous urticarial, lichen planus, psoriasis, or vitiligo. In other embodiments, a subject with a MDD is a subject diagnosed with asthma or chronic obstructive pulmonary disease. In other embodiments, a subject with a MDD is a subject diagnosed with male or female infertility. In other embodiments, a subject with a MDD is a subject diagnosed with or experiencing tinnitus. In other embodiments, a subject with a MDD is a subject diagnosed with non-alcoholic fatty liver disease or another form of liver disease. In other embodiments, a subject with a MDD is a subject diagnosed with periodontitis. In other embodiments, a subject with a MDD is a subject exposed to excessive levels of copper. In other embodiments, a subject with a MDD has genetic predispositions of human leukocyte antigen-D related polymorphisms biomarkers, glutathione S-transferase polymorphisms, and/or receptor for advanced glycation end products polymorphism biomarkers. In other embodiments, a subject with MDD has methylene tetrahydrofolate reductase polymorphisms.

[0095] Another aspect of the invention is a method to treat mild cognitive impairment or Alzheimer's disease in a subject with mild cognitive impairment or Alzheimer's disease, respectively. The term "treat" includes prevention, attenuation, reversal, or improvement in at least one symptom or sign of mild cognitive impairment or Alzheimer's disease. The method comprises administering to the subject a composition of the invention. Preferably, the composition is administered once or twice daily. Alternatively, the composition may be administered on a less frequent basis, for example, once or twice a week, or every second, third, fourth or fifth day. Compositions of the invention are described in detail in Section II. In certain embodiments, the composition comprises a combination listed in Table B, Table C, Table D, Table E, Table F, or Table G, and optionally comprises one or more additional ingredients from Table A. In other embodiments, the composition consists essentially of a combination listed in Table B, Table C, Table D, Table E, Table F, or Table G. In other embodiments, the composition comprises two more ingredients from Table A. Methods for identifying subjects with mild cognitive impairment and Alzheimer's disease are known in the art. Guy M. McKhann et al. "The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging - Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease." Alzheimer's & Dementia: The Journal of the Alzheimer's Association 201 1 ;7(3):263 - 269. Marilyn S. Albert et al. "The diagnosis of mild cognitive impairment due to Alzheimer's disease: Recommendations from the National Institute on Aging - Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease." Alzheimer's & Dementia: The Journal of the Alzheimer's Association 201 1 ;7(3):270 - 279. Reisa A. Sperling et al. "Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging - Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease." Alzheimer's & Dementia: The Journal of the Alzheimer's Association 201 1 ;7(3):280 - 292.

[0096] Another aspect of the invention is a method to improve one or more symptoms of mild cognitive impairment or Alzheimer's disease in a subject with mild cognitive impairment or Alzheimer's disease, as compared to the same subject at an earlier time or a healthy control subject. The method comprises administering to the subject a composition of the invention. Preferably, the composition is administered once or twice daily. Alternatively, the composition may be administered on a less frequent basis, for example, once or twice a week, or every second, third, fourth or fifth day. Compositions of the invention are described in detail in Section II. In certain embodiments, the composition comprises a combination listed in Table B, Table C, Table D, Table E, Table F, or Table G, and optionally comprises one or more additional ingredients from Table A. In other embodiments, the composition consists essentially of a combination listed in Table B, Table C, Table D, Table E, Table F, or Table G. In other embodiments, the composition comprises two more ingredients from Table A. Methods for identifying subjects with mild cognitive impairment and Alzheimer's disease are known in the art. Guy M. McKhann et al. "The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging - Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease." Alzheimer's & Dementia: The Journal of the Alzheimer's Association 201 1 ;7(3):263 - 269. Marilyn S. Albert et al. "The diagnosis of mild cognitive impairment due to Alzheimer's disease: Recommendations from the National Institute on Aging - Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease." Alzheimer's & Dementia: The Journal of the Alzheimer's Association 201 1 ;7(3):270 - 279. Reisa A. Sperling et al. "Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging - Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease." Alzheimer's & Dementia: The Journal of the Alzheimer's Association 201 1 ;7(3):280 - 292.

[0097] Another aspect of the invention is a method to treat a subject with a polymorphism in the MTHFR gene associated with a cell's inability to convert folic acid to 6(S)-5-MTHF7. Methylenetetrahydrofolate reductase (MTHFR) is an enzyme that catalyzes the conversion of dietary folic acid into its bioactive form 6(S)-5- Methyltetrahydrofolate, (6(S)-5-MTHF). This converted form of folate is in turn used in many biochemical pathways, most importantly in the recycling of homocysteine back into methionine. It is well established that certain genetic variations (called single nucleotide polymorphisms, or SNPs) in MTHFR gene result in a cell's inability to convert folic acid to 6(S)-5-MTHF7. It is known in the art that there are direct associations between polymorphisms in the MTHFR gene and elevated levels of homocysteine. Numerous conditions have been associated with polymorphisms of MTHFR genes and hyperhomocysteinemia, including cardiovascular disease, migraines, age-related macular degeneration, brain atrophy and Alzheimer's disease. Non-limiting examples of polymorphisms in the MTHFR gene associated with a cell's inability to convert folic acid to 6(S)-5-MTHF7 include the C677T polymorphism, the C677Y polymorphism, and the A1298C polymorphism. Non-limiting examples of polymorphisms in the MTHFR gene associated with Alzheimer's disease or vascular dementia include the C677T polymorphism, the C677Y polymorphism, and the A1298C polymorphism. The term "treat" includes prevention, attenuation, reversal, or improvement in at least one symptom or sign associated with the polymorphism. The method comprises administering to the subject a composition of the invention. Preferably, the composition is administered once or twice daily. Alternatively, the composition may be administered on a less frequent basis, for example, once or twice a week, or every second, third, fourth or fifth day. Compositions of the invention are described in detail in Section II. In certain embodiments, the composition comprises a combination listed in Table B, Table C, Table D, Table E, Table F, or Table G, and optionally comprises one or more additional ingredients from Table A. In other embodiments, the composition consists essentially of a combination listed in Table B, Table C, Table D, Table E, Table F, or Table G. In other embodiments, the composition comprises two more ingredients from Table A.

[0098] Another aspect of the invention is a method to prevent an increase in the severity of, and/or frequency in, one or more symptom of mild cognitive impairment or Alzheimer's disease in a subject with mild cognitive impairment or Alzheimer's disease, as compared to the same subject at an earlier time or a healthy control subject. The method comprises administering to the subject a composition of the invention. Preferably, the composition is administered once or twice daily. Alternatively, the composition may be administered on a less frequent basis, for example, once or twice a week, or every second, third, fourth or fifth day. Compositions of the invention are described in detail in Section II. In certain embodiments, the composition comprises a combination listed in Table B, Table C, Table D, Table E, Table F, or Table G, and optionally comprises one or more additional ingredients from Table A. In other embodiments, the composition consists essentially of a combination listed in Table B, Table C, Table D, Table E, Table F, or Table G. In other embodiments, the composition comprises two more ingredients from Table A. Methods for identifying subjects with mild cognitive impairment and Alzheimer's disease are known in the art. Guy M. McKhann et al. "The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging - Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease." Alzheimer's & Dementia: The Journal of the Alzheimer's Association 201 1 ;7(3):263 - 269. Marilyn S. Albert et al. "The diagnosis of mild cognitive impairment due to Alzheimer's disease: Recommendations from the National Institute on Aging - Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease." Alzheimer's & Dementia: The Journal of the Alzheimer's Association 201 1 ;7(3):270 - 279. Reisa A. Sperling et al. "Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging - Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease." Alzheimer's & Dementia: The Journal of the Alzheimer's Association 201 1 ;7(3):280 - 292.

[0099] In each of the above aspects of the invention, a composition of the invention is administered to a subject. Administration is preferably oral. Compositions may be taken one or more times daily. Alternatively compositions may be taken less frequently than once a day, for example every second, third, fourth or fifth day. In still another alternative, a composition may be administered once a week, or even once a month. Compositions of the invention may be administered with or without food. For example, compositions may be taken before, during or after meals. Compositions of the invention may be divided into one or more doses for administration. A composition may be administered for varying durations of time. For example, a composition may be administered for a duration of at least one week, at least one month, at least three months, at least 6 months, or more. [00100] In each of the above aspects of the invention, a composition of the invention is administered to a subject with a MDD to treat the MDD. As stated above, the term "treat" includes prevention, attenuation, reversal, or improvement in at least one symptom of a MDD. An "improvement" in a symptom refers to a measurable change in the symptom in a subject over time, preferably a statistically significant change, more preferably a statistically significant change that is also clinically significant. In some embodiments, a method of the invention improves at least one symptom. For example, a method of the invention may improve 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more symptoms. In certain embodiments, a subject with MDD has experienced or is experiencing a vitamin deficiency and/or a nutrient deficiency. Alternatively, or in addition, a subject with MDD may have experienced or be experiencing chronic fatigue, depression, headaches, migraines, myalgia, and/or joint hypermobility. A subject with MDD may also have experienced or be experiencing an autoimmune disorder, epilepsy, gut biome irregularities and/or thyroid irregularities. A subject with MDD may also have experienced or be experiencing gluten sensitivity, insulin resistance, and/or elevated triglycerides. A subject with MDD may also have experienced or be experiencing hypoxia, pruritus, blurred vision, visual contrast sensitivity impairment, excessive thirst, and/or excessive urination. A subject with MDD may also have experienced or be experiencing a sleep disorder (e.g. sleep apnea, narcolepsy, hypersomnia, cataplexy, a circadian rhythm sleep disorder, etc.) A subject with MDD may also have experienced or be experiencing cognitive impairment (e.g. difficulties with memory, attention, concentration, language, abstract thought, creativity, judgment, name recall, planning, executive function, planning, and organization, as well as misplacing objects), functional capacity impairment, changes in behavior (e.g. changes in personality, physical or verbal aggression, impulsivity, decreased inhibition, apathy, decreased initiation, changes in personality, social withdrawal, sleep disturbances, abuse of alcohol, tobacco or drugs, and other addiction- related behaviors), a decline in general physical health, and/or a decline in quality of life. A subject with MDD may also have experienced or be experiencing circadian rhythm disturbance. In certain embodiments, a subject with MDD has experienced or is experiencing platelet derived growth factor irregularities and/or irregularities of the nicotinic cholinergic system. In certain embodiments, a subject with MDD has experienced or is experiencing brain region hypoperfusion, even more preferably in the brainstem. In certain embodiments, a test or analysis of a subject with MDD, when compared to normal values for the subject's cohort, has shown oxidative stress, mitochondrial dysfunction, low glutathione levels, elevated lactic acid levels, C4a or C4b biomarker irregularities, activation of toll like receptor 4, hypothalamic- pituitary-adrenal axis and/or Cortisol irregularities, nicotinic cholingergic system irregularities, human growth hormone irregularities, insulin-like growth factor-1 irregularities, autonomic nervous system irregularities, immune system irregularities, platelet derived growth factor irregularities, adrenal insufficiency, GABA or glutamate irregularities, low serotonin levels, elevated serotonin antibodies, dopamine level irregularities, abnormal levels of vascular endothelial growth factor, abnormal levels of a-melanocyte-stimulating hormone, abnormal levels of adrenocorticotropic hormone, abnormal levels of melatonin, abnormal levels of coenzyme Q1 0, abnormal levels of nitric oxide, abnormal levels of transsulfuration metabolism, abnormal levels of vasopressin, elevated levels of proinflammatory cytokines, P2X7 upregulation, elevated MMP-9 levels, and/or abnormal levels of aluminum. In certain embodiments, a subject with MDD has experienced or is experiencing irregularities involving cerebral imaging (including, but not limited to, amyloid beta deposition, metabolic activity and/or perfusion).

[00101 ] In certain embodiments, at least one symptom is a deviation of electric power measured at one or more electrode by quantitative electroencephalography (qEEG). In other embodiments, at least one symptom is a deviation of electric power measured at one or more electrode by quantitative electroencephalography (qEEG) and one or more additional symptom is selected from oxidative stress, vitamin/nutrient deficiency, fatigue, cognitive impairment, a decline in general health, changes in behavior, a decline in quality of life, gluten sensitivity, elevated triglycerides, and insulin resistance. In other embodiments, at least one symptom is a deviation of electric power measured at one or more electrode by quantitative electroencephalography (qEEG) and one or more additional symptom is selected from vitamin/nutrient deficiency, fatigue, cognitive impairment, a decline in general health, changes in behavior, and a decline in quality of life. In other embodiments, at least one symptom is a deviation of electric power measured at one or more electrode by quantitative electroencephalography (qEEG) and one or more addition symptom is selected from vitamin/nutrient deficiency, gluten sensitivity, elevated triglycerides, and insulin resistance. Cognitive impairment may include, but is not limited to, difficulties with memory, attention, concentration, language, abstract thought, creativity, judgment, name recall, planning, executive function, planning, and organization, as well as misplacing objects. Changes in behavior may include, but is not limited to, changes in personality, physical or verbal aggression, impulsivity, decreased inhibition, apathy, decreased initiation, social withdrawal, sleep disturbances, abuse of alcohol, tobacco or drugs, and other addiction-related behaviors. In other embodiments, at least one symptom is a deviation of electric power measured at one or more electrode by quantitative electroencephalography (qEEG) and one or more addition symptom is abnormal regulation of Glycogen Synthase Kinase and Protein Phosphatase 2A. Vitamin deficiencies have been implicated in the abnormal regulation of Glycogen Synthase Kinase and Protein Phosphatase 2A, both of which are associated with Amyloid beta and neurofibrillary tangles formation in MCI and AD. In exemplary embodiments, the subject is a subject with cognitive impairment, dementia, Alzheimer's disease, and/or a polymorphism in the MTHFR gene associated with Alzheimer's disease or vascular dementia.

[00102] In certain embodiments, at least one symptom is vitamin/nutrient deficiency. In other embodiments, at least one symptom is vitamin/nutrient deficiency and one or more addition symptom is selected from oxidative stress, fatigue, cognitive impairment, a decline in general health, changes in behavior, a decline in quality of life, gluten sensitivity, elevated triglycerides, insulin resistance, and a deviation of electric power measured at one or more electrode by quantitative electroencephalography (qEEG). In other embodiments, at least one symptom is vitamin/nutrient deficiency and one or more addition symptom is selected from fatigue, cognitive impairment, a decline in general health, changes in behavior, a decline in quality of life, gluten sensitivity, elevated triglycerides, insulin resistance. Cognitive impairment may include, but is not limited to, difficulties with memory, attention, concentration, language, abstract thought, creativity, judgment, name recall, planning, executive function, planning, and organization, as well as misplacing objects. Changes in behavior may include, but is not limited to, changes in personality, physical or verbal aggression, impulsivity, decreased inhibition, apathy, decreased initiation, changes in personality, social withdrawal, sleep disturbances, abuse of alcohol, tobacco or drugs, and other addiction-related behaviors. In other embodiments, at least one symptom is vitamin/nutrient deficiency and one or more addition symptom is abnormal regulation of Glycogen Synthase Kinase and Protein Phosphatase 2A. Vitamin deficiencies have been implicated in the abnormal regulation of Glycogen Synthase Kinase and Protein Phosphatase 2A, both of which are associated with Amyloid beta and neurofibrillary tangles formation in MCI and AD. In exemplary embodiments, the subject is a subject with cognitive impairment, dementia, Alzheimer's disease, and/or a polymorphism in the MTHFR gene associated with a cell's inability to convert folic acid to 6(S)-5-MTHF7.

[00103] Methods for measuring these symptoms are known in the art. For example, methods for measuring triglycerides, pro-inflammatory cytokines, anti- serotonin antibodies, serotonin, dopamine, insulin resistance, vitamin/nutrient deficiency and thyroid function are well known in the art, and may employ saliva, urine, or blood tests, among other forms of testing. Symptoms including, but not limited to, fatigue, myalgia, cognitive impairment, functional capacity impairment, changes in behavior (e.g. increased aggression, etc.), a decline in quality of life, depression may be measured by standardized assessment tools. Typically, a standardized assessment tool is administered to a subject, a subject's caregiver, and/or a subject's family. Suitable, validated assessment tools are known in the art. See, for example, the PROQOLID database (www.proqolid.com). Non-limiting examples of suitable assessment tools are also listed in Table H below. Table H

capacity Daily Living (IADL), Physical Self-Maintenance Scale (PSMS), and impairment Progressive Deterioration Scale (PDS)

Myalgia Pain Quality Assessment Scale (PQAS), Revised Pain Quality

Assessment Scale (PQAS-R)

Sleep Insomnia Severity Index Questionnaire (ISI), Parkinson's Disease Sleep

(abnormal / Scale 2 (PDSS-2), Pittsburgh Sleep Quality Index (PSQI), McGill Pain disrupted / Questionnaire Short Form (SF-MPQ), Short-form McGill Pain impaired, Questionnaire (SF-MPQ-2),

etc.)

Quality of Assessment of Quality of Life (AQoL), Centers for Disease Control and life Prevention Health Related Quality of Life 4 item or 14 item measure

(CDC HRQOL-4 or CDC HRQOL-14), Wisconsin Quality of Life Index (W-QIL), Quality of Life Index for Adults (A-QLI), The Family Quality of Life Index (F-QLI), Activity and Affect Indicators of QOL, EuroQol, Short Form -36 (SF-36), Short Form-12 (SF-12)

Dementia specific assessment tools: DEMQOL, Quality of Life in Alzheimer's Disease (QOL-AD), Quality of Life in Late-Stage Dementia (QUALID), Alzheimer's Disease-Related Quality of Life (ADRQL)

[00104] Oxidative stress is mediated by reactive oxygen species. However, the short half-life of these species makes their measurement difficult. In this regard, changes in biomarkers of oxidative stress may be measured as an alternative - e.g. DNA, lipids, proteins and carbohydrates that change in amount and/or are modified in response to oxidative stress. Non-limiting examples of biomarkers of oxidative stress include isoprostanes, products of lipid peroxidation (e.g. malondialdehyde, 4-hydroxy-2- noneal (HNE), and 2-propenal (acrolein)), nitrotyrosine formation on proteins, S- glutathionylation, myeloperoxidase function, oxidation and/or glycation of LDL, oxidation and/or glycation of phospholipids, oxidation of bases in DNA, and net antioxidant capacity of serum. See, for example, Dalle-Donne et al. Clinical Chemistry, 2006, pp. 601 -623, Vol. 52, No. 4; or Ho et al. Redox Biology, 2013, pp. 483-491 , Vol. 1 ; or Palmeri et al. European Review for Medical and Pharmacological Sciences, 2007, pp. 309-342, Vol. 1 1 .

[00105] Hypoxia indicates that blood, tissue or an organ has insufficient oxygen. Methods for measuring blood oxygen levels are known in the art. Alternatively, an approximate of blood oxygen level can be estimated using a pulse oximeter. Methods for measuring hypoxia in tissues or organs are also known in the art. For example, many methods developed to measure oxygen levels in tumors may be applied. See, e.g., Hammond et al. Clinical Oncology, 2014, pp. 277-288, Vol. 25, No. 5. Hypoxia is also known to be associated with the stabilization of hypoxia inducible factor- 1 (HIF-1 ), which may be used as a biomarker for hypoxia. Methods for imaging hypoxic tissue are also known in the art and include, but are not limited to, Cu-ATSM PET.

[00106] Methods for imaging changes in brain size, mass and perfusion are known in the art. For example, MRI and/or PET may be used to measure atrophy and/or hypoperfusion across different regions of the brain. Brain perfusion can also be measured by a SPECT scan. Abnormal metabolic activity can also be detected and imaged, for example, by FDG-PET.

[00107] Biomarkers for pre-clinical and clinical forms of Alzheimer's disease, and the dementia and cognitive impairment associated therewith, are also known in the art. See, for example, Sperling et al. "Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging- Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease," 201 1 , Alzheimer's & Dementia, pp. 280-292, Vol. 7; McKhann et al. "The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease," 201 1 , Alzheimer's & Dementia, pp. 263-269, Vol. 7; or Albert et al. "The diagnosis of mild cognitive impairment due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease," 201 1 , Alzheimer's & Dementia, pp. 270-279, Vol. 7. [00108] Oxidative stress and mitochondrial damage may also result in a deviation of electric magnitude or power measured at one or more electrode by quantitative electroencephalography (qEEG). qEEG is a field concerned with the numerical analysis of electroencephalography data and associated behavioral correlates. Without wishing to be bound by theory, distinct mental operations are believed to present distinct EEG profiles, which are reproduced reliably whenever a task or mental state occurs. These assumptions lay the foundation for qEEG assessment in subjects with a MDD. Briefly, qEEG recordings are obtained from a subject while resting (e.g. eyes open for an amount of time and staring at a blank wall or fixed point on a dark monitor, and/or eyes closed for an amount of time) and while performing one or more mental task. The mental task is often presented to the subject in the form a psychometric test. Non-limiting examples of psychometric tests include aptitude tests, memory tests, verbal reasoning tests, numerical reasoning tests, abstract reasoning tests, mechanical reasoning tests, and situational reasoning tests. When compared to normal controls, the recordings of electric magnitude or power from a subject with a MDD, obtained at rest and/or during the mental tasks, can deviate from a normal control. Recordings obtained from the same subject performing the same task can also deviate over time, indicating a change in the disease.

[00109] A qEEG assessment typically measures electrical activity from electrodes placed on the scalp of a subject for multiple frequency bands: delta (1 .25- 4.50 Hz), theta (4.75-6.75 Hz), alphal (7.00-9.50 Hz), alpha2 (9.75-12.50 Hz), betal (12.75-18.50 Hz) and beta2 (18.75-35.00 Hz). Electrodes may be positioned on the scalp and labeled according to the International 10-20 system, or other systems known in the art. In referential recordings, all electrodes are paired to the same physical reference such as vertex (site Cz) or the ears. In bipolar recordings, electrodes are paired together in series and there is no common reference across pairings (e.g., site F3 is linked to C3; C3 to P3, P3 to O1 ). Data may be reported as means, percent change from another condition, or as statistical database comparisons. These data may be presented in numerical tables or line graphs (spectral plots, topometrics), brain maps, or functional connectivity maps. The frequency analysis may be based on absolute spectral power values or on relative spectral power values.

[001 10] A deviation of electric power or magnitude may occur in one or more than one frequency range. For example, a deviation may occur only in one frequency range selected from delta, theta, alphal , alpha2, betal , and beta2. Alternatively, a deviation may occur in any combination of frequency ranges selected from delta, theta, alphal , alpha2, betal , and beta2. A deviation of electric power or magnitude may occur in one or more than one lobe of the brain. For example, a deviation may occur only in the frontal lobe, the parietal lobe, the central region, the temporal lobe, and the occipital lobe. Alternatively, a deviation may occur in any combination of regions selected from the frontal lobe, the parietal lobe, the central region, the temporal lobe, and the occipital lobe. It will be appreciated that many combinations of frequency range(s) and region(s) of the brain are possible.

[001 1 1 ] Whether a deviation is measured in a one or more region of the brain will depend, in part, on the task being performed while the obtaining the EEG recording. Non-limiting examples of deviations in electrical power measured by qEEG for a subject with mild cognitive impairment and/or dementia when performing memory tests or numerical reasoning tests, as compared to normal controls, includes (1 ) higher values of electric power at single electrodes during the "eyes open" resting condition, (2) higher global median values at all electrode positions during the "eyes open" resting condition, (3) lower global median values in the delta and theta frequency range during psychometric testing, taking the "eyes open" as reference (100%), (4) lower increase in parietal, frontal and/or fronto-temporal delta power during psychometric testing, taking the "eyes open" as reference (100%), (5) lower increase in parietal, frontal and/or fronto-temporal theta power during psychometric testing, taking the "eyes open" as reference (100%), and/or (6) greater decrease in parietal alpha power during psychometric testing, taking the "eyes open" as reference (100%).

[001 12] Methods of using the compositions of the invention may further comprise [001 13] The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent techniques discovered by the inventors to function well in the practice of the invention. Those of skill in the art should, however, in light of the present disclosure, appreciate that changes may be made in the specific embodiments that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention. Therefore, all matter set forth or shown in the accompanying drawings is to be interpreted as illustrative and not in a limiting sense.

EXAMPLES

[001 14] The following examples illustrate various iterations of the invention.

Example 1. Preparation of a formulation comprising Combination A3.

[001 15] A supplement comprising Combination A3, prepared as a dry powder formulation, was produced by methods known in the art, and packaged in a bottle. Each bottle contained 30 servings.

SUPPLEMENT FACTS:

Serving Size: 14 grams

Servings per Container: 30

Ingredient Amount

Vitamin A 1,000 meg

Thiamine (Vitamin B-l) 1,000 mg

Pyridoxine (Vitamin B-6) 5 mg

L-Methylfolate (Vitamin B-9) 500 meg

Methylcobalamin MeCbl (B-12) 8 mg

Cholecalciferol (Vitamin D-3) 25 meg

Magnesium carbonate 300 mg

Acetyl-L-Carnitine 3,000 mg

Quercetin 350 mg

D- ibose 3,000 mg

Ubiquinol Coenzyme Q.10 250 mg Other Optional Ingredients: calcium phosphate, silicon dioxide, citric acid, sucralose, and natural and artificial flavors.

Example 2. Pharmaco-EEG trials

[001 16] Compositions of the invention provide a therapeutic combination of Vitamin A, thiamine, pyridoxine, L-methylfolate, methylcobalamin, cholecalciferol, magnesium\, Acetyl-L-carnitine, quercetin, D-ribose, and coenzyme Q10. To measure the therapeutic effect of compositions of the invention in subjects with mitochondrial damage diseases, the following pharmacoelectroencephalography (pharmaco-EEG) clinical trial design was developed. Generally speaking, the trial is designed to measure changes in electric power (at approximately day 30, approximately day 90, approximately day 120, approximately, day 150 , approximately 1 80, as compared to baseline) of six defined frequency ranges (i.e. delta, theta, alphal , alpha2, betal and beta2) with respect to 99 electrode positions (17 real and 18 virtual) during quantitative- topographic EEG performed in combination with psychometric testing, after daily administration of a composition of the invention (treatment arm) or placebo (control arm).

[001 17] Briefly, after obtaining informed consent, baseline screening of subjects is performed. Baseline screening includes an initial qEEG experimental series (see Table 2), and baseline symptom evaluation using validated assessment tools known in the art. Inclusion and exclusion criteria for the trial are also confirmed, and vital signs and ECG recordings obtained. Randomization into the treatment arm or control arm of the study occurs on the first study day (Day A). Study procedures on each study day are the same - e.g. Day A (day 0), Day B (approximately day 30) and Day C (approximately day 90) are the same. In certain instances, the duration of the trial may extend beyond 90 days. For example, it may be desirable to extend the study to 120 days, 180 days, or even longer. On each study day, subjects take a breath alcohol test and then receive a standardized breakfast. Following breakfast, vital signs are recorded and a baseline qEEG experimental series is obtained (t= 0 hours; see Table 2). The study composition is then administered (treatment or control), and additional qEEG experimental series are recorded at t=1 hour and t= 3 hours. Symptom(s) associated with the mitochondrial damage disease are also evaluated using one or more validated assessment tool known in the art. To evaluate changes in symptoms compared to enrollment/screening, the same assessment tool is used throughout the clinical study (i.e. from screening to follow-up).

Table 2. Experimental series - qEEG recording

[001 18] EEG is recorded bipolarly from 17 surface electrodes placed according to the International 10/20-system with Cz as physical reference electrode using an electrocap. Subjects sit in a quiet, separate room with dimmed light and a comfortable chair. Test conditions are standardized and have been validated {see Dimpfel, Advances in Alzheimer's Disease, 2014, Vol. 3). Automated EEG processing is performed with CATEEM® (Computer aided topographical electroencephalometry). Using the original EEG signals and an interpolation algorithm (e.g. Lagrange Interpolation), signals from 82 additional virtual electrodes are calculated to provide high-resolution topographical maps. The signals of 99 electrode positions (17 real and 82 virtual) undergo Fast Fourier Transformation (FTT) based on 4-second sweeps of data epochs (Hanning window). Data are analyzed from 1 .25 to 35 Hz using six frequency bands: delta (1 .25-4.50 Hz), theta (4.75-6.75 Hz), alphal (7.00-9.50 Hz), alpha2 (9.75-12.50 Hz), betal (12.75-18.50 Hz) and beta2 (18.75-35.00 Hz). This frequency analysis is based on absolute spectral power values. Color coding of the maps is achieved by transforming the content of the power spectrum into spectral colors with resolution of 0.25 Hz segments giving 140 frequency ranges. Additive mixture of these segments results in the final color display in the maps. Thus, frequency dependent focal changes of electric power results in local changes of color mixture.

[001 19] Data acquisition and analysis are carried out simultaneously and provide topographical maps, which are displayed on-line on the computer screen. The maps show the relative, time averaged, changes of electric brain activity of each specific recording condition in comparison to the reference period.

[00120] Using this approach it is possible to visualize spectral frequency changes taking place during the performance of mental tasks in comparison to the reference period. For example, the absolute power values under the recording condition "eyes open" can be used as reference values and set to 100% when psychometric tests are performed. Thus, possible physiological changes during test performance are given in % of these reference values. In this way, a differential map can be calculated which shows the changes in frequency content at all electrode positions, including the virtual ones. A rather complete analysis can be given from electric changes, represented by spectral color, which are related to a specific task (memory, attention, etc.). They represent the true proportions of frequency changes with respect to topographical distribution.

Example 3. Use of formulation comprising Combination A3 to treat Alzheimer's disease or mild cognitive impairment.

[00121 ] A formulation comprising Combination A3, in particular the supplement described in Example 1 , can be evaluated in a double-blind, randomized, placebo-controlled trial to measure changes in psychometric testing and/or quantitative- topographic EEG (qEEG) recordings following daily or twice daily administration of a formulation comprising Combination A3 or placebo in subjects with mild cognitive impairment or dementia. Briefly, a suitable trial will enroll a mixture of male and female healthy subjects aged 50-80 years (inclusive) with mild cognitive impairment or dementia, and subjects will be randomized to treatment or control arms (n > 20 per arm). Subjects will be screened for mild cognitive impairment (MCI) and dementia using the DemTect Scale (MCI = 9-12 points; dementia < 8 points). Alternative cognitive assessment tools (e.g. Mini-Mental State Examination, Addenbrooke's Cognitive Examination, Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), etc.) and/or scoring methodologies (e.g. item response theory, analysis-of-covariance, etc.) may also be used. Exclusion criteria for the trial includes chronic disease; use of CNS-active medication during the two weeks preceding enrollment; major deviations from EEG recording or bad quality of recording; artefact-free screening-EEG < 30% of total recording; known allergic reactions; abuse of caffeine nicotine, alcohol or any drugs; participation in a clinical trial within the last 60 days; pregnancy; and annulation of informed consent.

[00122] Psychometric testing and qEEG recordings will be performed at screening, on day 0, and on day 30 and day 90 (approximately), as described in Example 2. Additional screening may also occur on day 60, day 120, day 150 and/or day 180. Subjects will also be administered at least one standardized assessment tool to evaluate cognition at screening and on each study day (e.g. Alzheimer's Disease Assessment Scale, cognitive subsection (ADAS-Cog), MMSE, or similar test) and, optionally, a standardized assessment tool to evaluate functional capacity, behavior, general physical health, and/or quality of life. Safety signals will also be recorded throughout the study.

[00123] Compared to normal controls, subjects with mild cognitive impairment and dementia may have (1 ) higher values of electric power at single electrodes during the "eyes open" condition, (2) higher global median values at all electrode positions during the "eyes open" condition, (3) lower global median values in the delta and theta frequency range during psychometric testing, taking the "eyes open" as reference (100%), (4) lower increase in parietal, frontal and/or fronto-temporal delta power during psychometric testing, taking the "eyes open" as reference (100%), (5) lower increase in parietal, frontal and/or fronto-temporal theta power during psychometric testing, taking the "eyes open" as reference (100%), and/or (6) greater decrease in parietal alpha power during psychometric testing, taking the "eyes open" as reference (100%). Example 4. Preparation of a formulation comprising Combination A3.

[00124] A ready-to-drink beverage comprising Combination A3 was produced by methods known in the art, and packaged in a bottle. Bottles are stored at 15-30 °C,

BEVERAGE FACTS:

Serving Size: 16 oz

Servings per Container: 1

Ingredient Amount % D.V.

Vitamin A 1,000 meg 59%

Thiamine (Vitamin B-l) 1,000 mg 66,667%

Pyridoxine (Vitamin B-6) 5 mg 250%

L-Methylfolate (Vitamin B-9) 500 meg 125%

Methylcobalamin MeCbl (B-12) 8 mg 133,333%

Cholecalciferol (Vitamin D-3) 25 meg 250%

Magnesium (as 300 mg magnesium 123 mg 31%

carbonate)

Acetyl-L-Carnitine 3,000 mg *

Quercetin 350 mg *

D- ibose 3,000 mg *

Ubiquinol Coenzyme Q10 250 mg *

Other Ingredients: purified water, citric acid, calcium phosphate, xanthan gum, natural & artificial berry flavors, sodium benzoate, potassium benzoate, potassium sorbate, sucralose, and silica.

Claims

CLAIMS What is claimed is:

1 . A method to improve one or more symptoms of a mitochondrial damage disease, or to prevent an increase in the severity of or frequency in one or more symptoms of a mitochondrial damage disease, in a subject with a mitochondrial damage disease, as compared to the same subject at an earlier time or a healthy control subject, the method comprising orally administering to the subject a composition comprising a combination listed in Table B, Table C, Table D, Table E, Table F, or Table G, and optionally one or more additional ingredients from Table A, or a composition comprising two or more ingredients listed in Table A.

2. The method of claim 1 , wherein the mitochondrial damage disease is selected from myalgic encephalomyelitis / chronic fatigue syndrome, autism, diabetes, metabolic syndrome, schizophrenia, mild cognitive impairment, and Alzheimer's disease (AD).

3. The method of claim 1 or claim 2, wherein the symptom is selected from oxidative stress, hypoxia, vitamin/nutrient deficiency, fatigue, myalgia, joint hypermobility, circadian rhythm disturbance, cognitive impairment, functional capacity impairment, behavior impairment, a decline in general physical health, a decline in quality of life, a deviation of electric power measured at one or more electrode by quantitative electroencephalography (qEEG), or a combination thereof.

4. The method of claim 1 or claim 2, wherein at least one symptom is a deviation of electric power measured at one or more electrode by qEEG.

5. The method of claim 3 or claim 4, wherein the deviation of electric power is measured at rest, during cognitive performance, or a combination thereof.

6. The method of any one of claims 3 to 5, wherein the deviation occurs within a frequency range selected from delta, theta, alphal , alpha2, betal , beta2, or a combination thereof.

7. The method of claim 6, wherein the deviation occurs within a frequency range selected from delta, theta, alphal , and combination thereof.

8. The method of any one of claims 3 to 7, wherein the deviation is measured in a region of the brain of the subject with mitochondrial damage disease selected from fronto-temporal region, centro-parietal region, and fronto-central region.

9. The method of any one of claims 3 to 5, wherein the deviation (a) occurs within a frequency range selected from delta, theta, alphal , and combination thereof, and (b) is measured in a region of the brain of the subject with mitochondrial damage disease selected from fronto-temporal region, centro-parietal region, and fronto-central region.

10. The method of any one of claims 3 to 5, wherein the deviation (a) occurs within a frequency range selected from delta, theta, and combination thereof, and (b) is measured in a region of the brain of the subject with mitochondrial damage disease selected from fronto-temporal region, centro-parietal region, and fronto-central region.

1 1 . The method of any one of claims 3 to 10, wherein the electric power is measured at two or more electrodes.

12. The method of any one of claims 3 to 1 1 , wherein the electric power is measured at three or more electrodes, at four or more electrodes, at five or more electrodes, at six or more electrodes, at seven or more electrodes, at eight or more electrodes, at nine or more electrodes, at ten or more electrodes, at eleven or more electrodes, at twelve or more electrodes, at thirteen or more electrodes, at fourteen or more electrodes, at fifteen or more electrodes, at sixteen or more electrodes, at seventeen or more electrodes.

13. The method of any one of the preceding claims, wherein the composition comprises a combination listed in Table C or Table D, and optionally one or more additional ingredients from Table A.

14. The method of any one of the preceding claims, wherein the composition consists essentially of a combination listed in Table C or Table D.

15. The method of any one of the preceding claims, wherein the composition further comprises binders, diluents, fillers, disintegrants, effervescent disintegration agents, preservatives, antioxidants, flavor-modifying agents, lubricants, glidants, dispersants, coloring agents, pH modifiers, chelating agents, antimicrobial agents, release-controlling polymers, and combinations of any of these agents.

16. The method of any one of the preceding claims, wherein the composition is formulated as a dry powder, a tablet, a capsule, a liquid, a gel, a semi-solid, or a food product.

17. The method of any one of the preceding claims, wherein the composition is a medical food.

18. The method of any one of the preceding claims, wherein the composition is a nutritional supplement.

19. The method of any one of the preceding claim, wherein the composition is a pharmaceutical composition.

20. The method of any one of the preceding claims, wherein the composition is administered once daily or twice daily.

21 . The method of any one of the preceding claims, wherein the composition is administered for a duration of at least one week, at least two weeks, at least three weeks, at least four weeks, or more.

22. A method to improve one or more symptom of a mitochondrial damage disease, or to prevent an increase in the severity of or frequency in one or more symptoms of a mitochondrial damage disease, in a subject with mild cognitive impairment or Alzheimer's disease, as compared to the same subject at an earlier time or a healthy control subject, the method comprising orally administering to the subject a composition comprising a combination listed in Table B, Table C, Table D, Table E, Table F or Table G, and optionally one or more additional ingredients from Table A, or a composition comprising two or more ingredients listed in Table A.

23. The method of claim 22, wherein the symptom is selected from oxidative stress, hypoxia, vitamin/nutrient deficiency, fatigue, myalgia, joint hypermobility, circadian rhythm disturbance, cognitive impairment, functional capacity impairment, behavior impairment, a decline in general physical health, a decline in quality of life, a deviation of electric power measured at one or more electrode by quantitative electroencephalography (qEEG), and a combination thereof.

24. The method of claim 23, wherein at least one symptom is cognitive impairment and the standardized assessment tool is selected from Alzheimer's Disease Assessment Scale - cognitive subsection (ADAS-Cog), Blessed Information-Memory- Concentration Test (BIMC), Clinical Dementia Rating Scale (CDR), Mini-Mental State Examination (MMSE), Addenbrooke's Cognitive Examination (ACE), Addenbrooke's Cognitive Examination-Revised (ACE-R), Modified Mini Mental Exam (3MS), Psychogeriatric Assessment Scale (PAS), Montreal Cognitive Assessment (MoCA), DemTect, General Practitioner Assessment of Cognition (GPCOG), AD8, and Mini-Cog.

25. The method of claim 23, wherein at least one symptom is functional capacity impairment and the standardized assessment tool is selected from Functional Assessment Questionnaire (FAQ), Instrumental Activities of Daily Living (IADL), Physical Self-Maintenance Scale (PSMS), and Progressive Deterioration Scale (PDS).

26. The method of claim 23, wherein at least one symptom is a deviation of electric power measured at one or more electrode by qEEG.

27. The method of claim 23, wherein the symptoms are (a) a deviation of electric power measured at one or more electrode by qEEG, and (b) at least one additional symptom selected from oxidative stress, hypoxia, vitamin/nutrient deficiency, fatigue, myalgia, joint hypermobility, circadian rhythm disturbance, cognitive impairment, functional capacity impairment, behavior impairment, a decline in general physical health, a decline in quality of life.

28. The method of any one of claims 23 to 27, wherein the deviation of electric power is measured at rest, during cognitive performance, or a combination thereof.

29. The method of any one of claims 23 to 28, wherein the deviation occurs within a frequency range selected from delta, theta, alphal , alpha2, betal , beta2, and a combination thereof.

30. The method of claim 29, wherein the deviation occurs within a frequency range selected from delta, theta, alphal , and a combination thereof.

31 . The method of any one of claims 23 to 30, wherein the deviation is measured in a region of the brain of the subject with mitochondrial damage disease selected from fronto-temporal region, centro-parietal region, and fronto-central region.

32. The method of any one of claims 23 to 28, wherein the deviation (a) occurs within a frequency range selected from delta, theta, alphal , and combination thereof, and (b) is measured in a region of the brain of the subject with mitochondrial damage disease selected from fronto-temporal region, centro-parietal region, and fronto-central region.

33. The method of any one of claims 23 to 28, wherein the deviation (a) occurs within a frequency range selected from delta, theta, and combination thereof, and (b) is measured in a region of the brain of the subject with mitochondrial damage disease selected from fronto-temporal region, centro-parietal region, and fronto-central region.

34. The method of any one of claims 23 to 33, wherein the electric power is measured at two or more electrodes.

35. The method of any one of claims 23 to 34, wherein the electric power is measured at three or more electrodes, at four or more electrodes, at five or more electrodes, at six or more electrodes, at seven or more electrodes, at eight or more electrodes, at nine or more electrodes, at ten or more electrodes, at eleven or more electrodes, at twelve or more electrodes, at thirteen or more electrodes, at fourteen or more electrodes, at fifteen or more electrodes, at sixteen or more electrodes, at seventeen or more electrodes.

36. The method of any one of claims 23 to 35, wherein the composition comprises a combination listed in Table C or Table D, and optionally one or more additional ingredients from Table A.

37. The method of any one of claims 23 to 36, wherein the composition consists essentially of a combination listed in Table B, Table C or Table D.

38. The method of any one of claims 23 to 37, wherein the composition further comprises binders, diluents, fillers, disintegrants, effervescent disintegration agents, preservatives, antioxidants, flavor-modifying agents, lubricants, glidants, dispersants, coloring agents, pH modifiers, chelating agents, antimicrobial agents, release-controlling polymers, and combinations of any of these agents.

39. The method of any one of claims 23 to 38, wherein the composition is formulated as a dry powder, a tablet, a capsule, a liquid, a gel, a semi-solid, or a food product.

40. The method of any one of claims 23 to 39, wherein the composition is a medical food.

41 . The method of any one of claims 23 to 40, wherein the composition is a nutritional supplement.

42. The method of any one of claims 23 to 41 , wherein the composition is a pharmaceutical composition.

43. The method of any one of claims 23 to 42, wherein the composition is administered once daily or twice daily.

44. The method of any one of claims 23 to 43, wherein the composition is administered for a duration of at least one week, at least two weeks, at least three weeks, at least four weeks, or more.

45. A composition comprising a combination listed in Table B, Table E, Table F or Table G.

46. The composition of claim 45, wherein the composition comprises a combination listed in Table C.

47. The composition of claim 46, wherein the composition comprises a combination listed in Table D.

48. The composition of any one of claims 45-47 further comprising one or more ingredients from Table A.

49. A composition comprising two or more ingredients from Table. A.

50. A composition comprising three, four, or five or more ingredients from Table A.

51 . The composition of any one of claims 45-50, wherein the composition is formulated as a tablet.

52. The composition of any one of claims 45-50, wherein the composition is formulated as a capsule.

53. The composition of any one of claims 45-50, wherein the composition is formulated as a dry powder.

54. The composition of any one of claims 45-50, wherein the composition is formulated as a liquid.

55. The composition of any one of claims 45-50, wherein the composition is a ready-to-drink formulation.

54. The composition of any one of claims 45-47, without any additional nutritional ingredients.

55. A composition consisting of a combination listed in Table B, Table C, Table D, Table E, Table F or Table G.