Compositions and methods using adenosylcobalamin

Abstract

To provide a method for restoring mitochondrial and other cellular function and / or increasing mitochondrial energy in one or more cells.SOLUTION: The present invention provides a method that comprises administering an effective amount of adenosylcobalamin to an individual in need thereof. Preferably, the amount of the adenosylcobalamin is from 1 to 10 μg up to 100 μg to 2000 μg per day, and the adenosylcobalamin is preferably administered orally.SELECTED DRAWING: None

Description

Technical Field

[0001] [Background Art]

[0001] The present disclosure generally relates to compositions and methods for increasing cellular energy and / or treating or preventing mitochondrial-related diseases or conditions by, for example, increasing ATP production in cells, reducing oxidative stress, and / or enhancing mitochondrial function in an individual.

[0002]

[0002] Adenosine triphosphate (ATP) is a complex organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, and chemical synthesis. ATP is found in all living organisms and is often referred to as the "energy currency of the living body" with respect to intracellular energy transfer. When consumed in metabolic processes, ATP is converted into either adenosine diphosphate (ADP) or adenosine monophosphate (AMP). ATP is also a precursor for DNA and RNA and is used as a coenzyme. ATP is also most commonly a substrate for adenylate cyclase in the G protein-coupled receptor signaling pathway and is converted into the second messenger cyclic AMP, which releases stored calcium in the cell to initiate a calcium signal. This form of signaling is involved in the regulation of various cellular processes and is particularly important in brain function.

[0003]

[0003] Mitochondria are the main source of aerobic energy production in mammalian cells and are important organelles involved in cellular energy production. A decrease in mitochondrial function can lead to excessive fatigue and other symptoms, which are common complaints in almost all chronic diseases. At the molecular level, a decrease in mitochondrial function can result in a decrease in the efficiency of oxidative phosphorylation and a decrease in the production of adenosine-5'-triphosphate (ATP). Clinical trials have shown that L-carnitine, alpha-lipoic acid, coenzyme Q 10The usefulness of using oral supplements such as NADH, membrane phospholipids, and other supplements has been shown. By combining these supplements, fatigue and other symptoms associated with chronic diseases can be significantly reduced, and mitochondrial function can be naturally restored even in long-term patients with intractable fatigue.

[0004]

[0004] Fatigue is a multidimensional sensation perceived as a decrease in overall energy in the body, and it is thought that even simple tasks cannot be performed without exertion. Mild fatigue can be caused by a number of conditions including depression and other psychological states, while moderate to severe fatigue involves the cellular energy system. At the cellular level, moderate to severe fatigue is associated with a decrease in mitochondrial function and a reduction in ATP production. Intractable fatigue (chronic fatigue) that persists for more than 6 months and does not recover with sleep is the most common complaint seen in patients visiting general medical clinics. Chronic fatigue is also an important secondary condition in many clinical diagnoses and often precedes the patient's primary diagnosis.

[0005]

[0005] Furthermore, as a result of aging and chronic diseases, the mitochondrial membrane is oxidatively damaged, impairing mitochondrial function. As an example, individuals with chronic fatigue syndrome show evidence of oxidative damage to DNA and lipids, such as oxidative blood markers and oxidized membrane lipids, which indicate excessive oxidative stress.

[0006] [Summary of the Invention]

[0006] The inventors consider that adenosylcobalamin (adenosyl B12), contrary to other B12 isomers, enhances the energy production efficiency of mitochondria by increasing the ATP-synthase-dependent component of respiration and strengthening the ATP production stimulated by epibatine.

[0007]

[0007] Thus, in general embodiments, the present disclosure provides a method of restoring mitochondrial function and other cellular functions and / or increasing mitochondrial energy in one or more cells, the method comprising administering an effective amount of adenosylcobalamin to an individual in need thereof, particularly by increasing ATP production and mitochondrial respiration.

[0008]

[0008] In one embodiment, the present disclosure provides a method of improving a physiological state associated with metabolic fatigue in one or more cells and / or reducing fatigue in an individual, the method comprising administering an effective amount of adenosylcobalamin to an individual in need thereof.

[0009]

[0009] In another embodiment, the present disclosure provides a method of treating, reducing the incidence of, and / or reducing the severity of a chronic disease, the method comprising administering an effective amount of adenosylcobalamin to an individual in need thereof.

[0010]

[0010] In one embodiment, at least a portion of the one or more cells is part of at least one body part selected from the group consisting of the liver, kidney, brain, heart, intestine, pancreas, immune cells, and skeletal muscle.

[0011]

[0011] In another embodiment, the present disclosure provides a method of treating, reducing the incidence of, and / or reducing the severity of a mitochondrial-related disease, a condition associated with a change in mitochondrial function, or a decrease in mitochondrial density, the method comprising orally administering an effective amount of adenosylcobalamin to an individual in need thereof.

[0012]

[0012] Mitochondrial-related diseases or conditions can be selected from the group consisting of stress, physiological aging, obesity, decreased metabolic rate, metabolic syndrome, type 2 diabetes, diabetic complications, hyperlipidemia, neurodegenerative diseases, cognitive impairment, stress-induced or stress factor-related cognitive dysfunction, mood disorders, anxiety disorders, age-related neuronal death or dysfunction, chronic kidney disease, renal failure, chronic heart failure, cardiac rehabilitation, orthopedic rehabilitation, wound healing, recovery from surgery, trauma, infections, cancer, hearing loss, macular degeneration, myopathy, and dystrophy, and combinations thereof.

[0013]

[0013] In a further embodiment, a method is provided for delaying the onset of metabolic decline, reducing oxidative stress, maintaining immune function, and / or maintaining cognitive function in healthy middle-aged and elderly individuals, the method comprising orally administering an effective amount of adenosylcobalamin to the healthy middle-aged and elderly individuals.

[0014]

[0014] This also relates to a method of enhancing the metabolism of reactive oxygen species and improving glucose control in an individual having at least one of obesity or diabetes, the method comprising orally administering an effective amount of adenosylcobalamin to the individual.

[0015]

[0015] An advantage of one or more embodiments provided by the present disclosure is to promote healthy aging of cells.

[0016]

[0016] Another advantage of one or more embodiments provided by the present disclosure is to help counteract the delay in metabolism associated with aging.

[0017]

[0017] Another advantage of one or more embodiments provided by the present disclosure is to help increase fatty acid metabolism.

[0018]

[0018] Yet another advantage of one or more embodiments provided by the present disclosure is to help the body metabolize fat and increase fat-free mass.

[0019]

[0019] An advantage of one or more embodiments provided by the present disclosure is to help maintain heart health.

[0020]

[0020] Another advantage of one or more embodiments provided by the present disclosure is to help maintain healthy LDL cholesterol and fatty acid concentrations in the blood.

[0021]

[0021] Yet another advantage of one or more embodiments provided by the present disclosure is to help reduce oxidative stress on the body.

[0022]

[0022] Further features and advantages are described herein and will become apparent from the following drawings and detailed description.

Brief Description of the Drawings

[0023]

[0023] Figures 1 - 4 are graphs of the data of the experimental examples disclosed herein.

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5-1

Figure 5-2

Figure 6

Mode for Carrying Out the Invention

[0024]

[0030] Definition

[0031] Several definitions are shown below. However, there may be cases where the definition is in the section "Embodiments" below, and the above heading "Definition" does not mean that such disclosure in the section "Embodiments" is not a definition.

[0025]

[0032] All percentages described in this specification are by weight in the total weight of the composition, unless otherwise indicated. As used herein, "about", "approximately", and "substantially" refer to numbers within a numerical range, e.g., within -10% to +10% of the reference number, preferably within -5% to +5% of the reference number, more preferably within -1% to +1% of the reference number, and most preferably within -0.1% to +0.1% of the reference number. All numerical ranges in this specification should be understood to include all integers or fractions within that range. Further, these numerical ranges should be construed to support claims directed to any number or subset of numbers within this range. For example, the disclosure of 1 to 10 should be construed to support ranges such as 1 to 8, 3 to 7, 1 to 9, 3.6 to 4.6, 3.5 to 9.9, etc.

[0026]

[0033] As used in this disclosure and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a component" or "the component" includes two or more components.

[0027]

[0034] The terms "comprise", "comprises", and "comprising" are to be construed as non-exclusive and capable of including other elements. Similarly, the terms "include", "including", and "or" are all to be construed as capable of including other elements as long as such construction is not clearly precluded by the context. However, the compositions disclosed herein may not include elements not specifically disclosed herein. Thus, the disclosure of embodiments using the term "comprising" includes the disclosure of embodiments "consisting essentially of" the specified components and embodiments "consisting of" the specified components. A "consisting essentially of" composition contains at least 50% by weight of the referenced component, preferably at least 75% by weight of the referenced component, more preferably at least 85% by weight of the referenced component, and most preferably at least 95% by weight of the referenced component.

[0028]

[0035] The term "and / or" as used in the context of "X and / or Y" is to be construed as "X" or "Y" or "X and Y". Similarly, "at least one of X or Y" is to be construed as "X" or "Y" or "X and Y". For example, "at least one of mental performance or muscle performance" is to be construed as "mental performance or muscle performance" or "muscle performance" or "both mental performance and muscle performance".

[0029]

[0036] As used herein, the terms "example" and "such as" are merely illustrative and explanatory, and should not be considered exclusive or exhaustive, particularly when followed by a list of terms. As used herein, another state "associated with" or "linked with" a state means that these states occur simultaneously, preferably that these states are caused by the same underlying condition, and most preferably that one of the specified states is caused by the other specified state.

[0030]

[0037] The terms "food", "food product", and "food composition" mean a product or composition intended for ingestion by an individual such as a human and providing at least one nutrient to such an individual. Food products typically contain at least one of protein, lipid, and carbohydrate, and optionally one or more vitamins and minerals. The compositions of the present disclosure, including many embodiments described herein, can comprise, consist of, or consist essentially of the elements disclosed herein, as well as any additional or optional raw materials, components, or elements described or not described herein that are useful in the diet.

[0031]

[0038] As used herein, the term "isolated" means separated from one or more other compounds or components that would be found together with the compound in its non-isolated state, for example in nature. Preferably, for example, "isolated" means that the specified compound is separated from at least a portion of the cellular material typically found together in nature. In one embodiment, the isolated compound is pure, i.e., does not contain other compounds.

[0032]

[0039] As used herein, "effective amount" means an amount that prevents deficiency, treats a disease or medical condition in an individual, or more generally, reduces symptoms, manages disease progression, or provides a nutritional, physiological or medical benefit to an individual. Relative terms such as "improved", "increased", "enhanced" etc. refer to the effects of the compositions disclosed herein. As used herein, "promoting" means enhancing or inducing as compared to the value prior to administration of the compositions disclosed herein.

[0033]

[0040] As used herein, the term "unit dosage form" refers to physically discrete units suitable as unit doses for administration to human and animal subjects, each unit containing a predetermined quantity of the composition disclosed herein in an amount sufficient to produce the desired effect, preferably together with a pharmaceutically acceptable diluent, carrier, or vehicle. The specification of the unit dosage form is determined by the particular compound used, the effect to be achieved, and the pharmacodynamics associated with each compound in the host body. In some embodiments, the unit dosage form can be a specified amount of an active compound in a food product for one meal, a specified amount of powder in a sachet, a specified amount of an active compound in a capsule or tablet, or a specified amount of an active compound in a specified volume of liquid, preferably a therapeutically effective amount or a prophylactically effective amount, or a defined portion of a therapeutically effective amount or a prophylactically effective amount.

[0034]

[0041] "Subject" or "individual" is a mammal, preferably a human. The term "elderly" in relation to humans means a postnatal age of at least 60 years, preferably more than 63 years, more preferably more than 65 years, and most preferably more than 70 years. The term "older adult" in relation to humans means a postnatal age of 45 years or more, preferably more than 50 years, more preferably more than 55 years, and includes elderly individuals.

[0035]

[0042] As used herein, "frail" is defined as a clinically recognizable state in which vulnerability has increased due to a decline in reserve capacity and function across multiple physiological systems with aging, and the ability to cope with daily or acute stressors is impaired. The pre-frail stage, in which one or two of these criteria are present, is identified as having a high risk of progressing to frailty.

[0036]

[0043] "Overweight" is defined, with respect to humans, as having a body mass index (BMI) of 25 to 30 kg / m 2 . "Obesity" is defined, with respect to humans, as having a BMI of at least 30 kg / m 2 , for example, 30 to 39.9 kg / m 2 . "Weight loss / reduction" is a decrease in total body weight. Weight loss can refer to a decrease in total body weight, for example, to improve one or more of health, fitness, or appearance.

[0037]

[0044] "Diabetes" includes both type I and type II of this disease. Non-limiting examples of risk factors for diabetes include a waistline of more than 40 inches in men or more than 35 inches in women, a blood pressure of 130 / 85 mmHg or higher, a triglyceride level of more than 150 mg / dL, a fasting blood glucose level of more than 100 mg / dL, or a high-density lipoprotein level of less than 40 mg / dL in men or less than 50 mg / dL in women.

[0038]

[0045] As used herein, the term "metabolic syndrome" refers to a combination of medical abnormalities that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. Metabolic syndrome affects one in five people in the United States, and the prevalence increases with age. Some studies indicate a prevalence of 25% of the population in the United States. According to the International Diabetes Foundation's consensus worldwide definition (2006), metabolic syndrome is defined as central obesity in combination with any two of the following:

[0046] Elevated triglycerides: greater than 150 mg / dL (1.7 mmol / L), or treatment for this lipid abnormality;

[0047] Reduced HDL cholesterol: less than 40 mg / dL (1.03 mmol / L) in men and less than 50 mg / dL (1.29 mmol / L) in women, or treatment for this lipid abnormality;

[0048] Elevated blood pressure: systolic BP greater than 130 or diastolic BP greater than 85 mmHg, or treatment for previously diagnosed hypertension; and

[0049] Elevated fasting plasma glucose: (FPG) greater than 100 mg / dL (5.6 mmol / L), or previously diagnosed with type 2 diabetes.

[0039]

[0050] As used herein, "neurodegenerative disease" or "neurodegenerative disorder" refers to any condition in which functional neurons in the central nervous system are gradually reduced. In one embodiment, the neurodegenerative disease is associated with cell death associated with aging. Non-limiting examples of neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (also known as ALS and Lou Gehrig's disease), AIDS dementia, adrenoleukodystrophy, Alexander's disease, Alpers' disease, ataxia telangiectasia, Batten disease, bovine spongiform encephalopathy (BSE), Canavan disease, corticobasal degeneration, Creutzfeldt-Jakob disease, Lewy body dementia, fatal familial insomnia, frontotemporal dementia, Kennedy disease, Krabbe disease, Lyme disease, Machado-Joseph disease, multiple sclerosis, multiple system atrophy, neuroacanthocytosis, Niemann-Pick disease, Pick disease, primary lateral sclerosis, progressive supranuclear palsy, Refsum disease, Sandhoff disease, diffuse myelinoclastic sclerosis, spinocerebellar ataxia, subacute combined degeneration of the spinal cord, tabes dorsalis, Tay-Sachs disease, toxic encephalopathy, transmissible spongiform encephalopathy, and the wobbly mouse syndrome.

[0040] As used herein, "cognitive function" refers to any mental process involving symbolic activities, such as perception, memory, attention, speech comprehension, speech production, reading comprehension, image creation, learning, and reasoning, preferably involving at least memory.

[0041]

[0051] Methods for measuring cognitive function are well known and can include, for example, individual tests or battery tests for any feature of cognitive function. One such test is the Prudhoe Cognitive Function Test by Margallo-Lana et al. (2003) J. Intellect. Disability Res. 47:488-492. Another test is the Mini Mental State Exam (MMSE), which is designed to evaluate orientation to time and place, registration, attention and calculation, recall, language use and comprehension, repetition, and complex commands. As used herein, "cognitive impairment" refers to any condition that reduces cognitive function. Non-limiting examples of cognitive impairment include delirium, dementia, learning disabilities, attention deficit disorder (ADD), and attention deficit hyperactivity disorder (ADHD). "Stress-induced or stress-related cognitive dysfunction" refers to a disruption of cognitive function induced by or related to stress.

[0042]

[0052] As used herein, "mood disorder" (also known as affective disorder) refers to a disruption of emotional state as described in the Diagnostic and Statistical Manual of Mental Disorders published by the American Psychiatric Association. Non-limiting examples of mood disorders include major depression, postpartum depression, mood swings, and bipolar disorder. "Stress-induced or stress-related mood disorder" refers to a disruption of emotional state induced by or related to stress. Such mood disorders are sometimes referred to as reactive mood disorders and are distinguished from other mood disorders, for example, "organic" mood disorders that result from a medical or health condition rather than a mental disorder.

[0043]

[0053] As used herein, "anxiety disorder" refers to a dysfunction of fear and anxiety, for example, fear and anxiety that are not proportional to a stressful situation or the prediction of a stressful situation. Non-limiting examples of anxiety disorders include generalized anxiety disorder, panic disorder, panic disorder with agoraphobia, agoraphobia, social anxiety disorder, obsessive-compulsive disorder, and post-traumatic stress disorder. "Stress-induced anxiety disorder or stress-related anxiety disorder" refers to a dysfunction of fear and anxiety induced by or related to stress. Such anxiety disorders may also be referred to as reactive anxiety disorders and are distinguished from "organic" anxiety disorders that result from a medical or health condition rather than another anxiety disorder, for example, a mental disorder.

[0044]

[0054] As used herein, "metabolic fatigue" means a decrease in mitochondrial function in one or more cells (e.g., one or more of the liver, kidney, brain, heart, intestine, pancreas, immune cells, or skeletal muscle cells).

[0045]

[0055] Embodiments Vitamin B12 (also known as cobalamin) is a group of water-soluble cobalt-containing vitamins that cannot be synthesized in the human body and thus must be obtained from food or synthesis by the gut microbiota. The group of vitamin B12 can refer to several chemical forms of vitamin B12 depending on the upper axial ligand of the cobalt ion. These are cyanocobalamin (R = -CN), hydroxocobalamin (R = -OH), methylcobalamin (R = -CH3), and adenosylcobalamin (R = -5'-deoxyadenosyl).

[0046]

[0056] The pool of vitamin B12 in the human body consists of several forms, namely, cyanocobalamin, which is inactive and requires conversion to obtain activity, and methylcobalamin and adenosylcobalamin, which are the metabolically active forms of vitamin B12.

[0047]

[0057] Two enzymes, methionine synthase and methylmalonyl-CoA mutase, are known to utilize vitamin B12 as a cofactor. Methionine synthase is an intracellular enzyme that utilizes methylcobalamin to convert homocysteine to methionine. Such an enzyme plays an important role in providing S-adenosylmethionine (SAM) as a methylation donor through this conversion and preventing the accumulation of homocysteine toxicity. At low SAM levels and high homocysteine levels observed due to severe vitamin B12 deficiency, myelination of the peripheral nerves and spinal cord is impaired. Methionine synthase also catalyzes the activation of 5-methyl-tetrahydrofolate to biologically active tetrahydrofolate, and this catalytic effect is required for one-carbon metabolism and DNA synthesis, and thus is effective in increasing red blood cells. Methylmalonyl-CoA mutase is a mitochondrial enzyme that utilizes adenosylcobalamin in converting methyl-malonyl-CoA to succinyl-CoA, and succinyl-CoA is subsequently incorporated into the TCA cycle. This is shown by the breakdown of branched-chain amino acids and odd-chain length fatty acids and is essential for the control of neurodevelopment during embryogenesis, but not essential in adulthood.

[0048]

[0058] The adenosylcobalamin of the present invention can be in the form of a semi-synthetic derivative.

[0049]

[0059] In another embodiment, the adenosylcobalamin can be hydroxocobalamin and / or cyanocobalamin that can be converted to adenosylcobalamin.

[0050]

[0060] Vitamin B12 deficiency

[0061] In one embodiment, the subject can be vitamin B12 deficiency.

[0051]

[0062] The Recommended Dietary Allowance (RDA) for adults in the United States was set at 2.4 μg per day by the Institute of Medicine, based on an average absorption of approximately 50% from food (National Academy of Sciences, Institute of Medicine (2000); Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin and Choline, Chapter 9, pp306 - 56). The daily requirement has been shown to vary according to body size.

[0052]

[0063] The likelihood of vitamin B12 deficiency in humans can be defined as follows according to the serum concentration of vitamin B12. Less than 148 picomol / L (less than 200 picogram / mL) indicates a possible deficiency, 148 - 258 picomol / L (201 - 350 picogram / mL) indicates a possible deficiency, and above 258 picomol / L (above 350 picogram / mL) indicates no likelihood of deficiency (BMJ, Best Practice, http: / / bestpractice.bmj.com / best - practice / monograph / 822 / basics.html). However, since there are no criteria for determining the relevance of complications regarding vitamin B12 levels as well as active and inactive vitamin B12, serum vitamin B12 assays are often combined with further biochemical assays or clinical evaluations based on main symptoms for diagnosing vitamin B12 deficiency.

[0053]

[0064] Additional assays that can be performed to provide further indicators of vitamin B12 deficiency include measuring the levels of holotranscobalamin, methylmalonic acid, and / or homocysteine in a sample isolated from the subject.

[0054]

[0065] Holotranscobalamin refers to vitamin B12 bound to its biologically active serum transporter, transcobalamin II. Holotranscobalamin levels can be measured using commercially available assays (e.g., ELISA assays). Low holotranscobalamin levels are associated with potential vitamin B12 deficiency.

[0055]

[0066] Methylmalonic acid (MMA) accumulates due to decreased activity of the vitamin B12-dependent enzyme methylmalonyl-CoA mutase. Therefore, high MMA levels are associated with vitamin B12 deficiency.

[0056]

[0067] In one embodiment, the individual has a high blood concentration of methylmalonic acid.

[0057]

[0068] Homocysteine accumulates due to decreased activity of the vitamin B12-dependent enzyme methionine synthase. Low / High levels of homocysteine are associated with vitamin B12 deficiency. However, assays of homocysteine levels can be confounded by folate deficiency.

[0058]

[0069] Adenosylcobalamin can be provided, for example, in the form of tablets, liquids (e.g., for oral ingestion, or for use in nasal drops or injections), or transdermal patches. For example, adenosylcobalamin can be available as a nutritional supplement, either by itself or in combination with other supplements.

[0059]

[0070] Oral supplementation typically involves administering 1 - 10 μg to a maximum of 100 μg - 2000 μg of adenosylcobalamin daily, depending on the form. When administered in the form of an oral nutritional supplement, the daily dose provides 1 - 10 μg, preferably 1 - 2 μg of adenosylcobalamin. When administered in the form of a supplement, the daily dose provides 100 μg - 2000 μg, preferably 250 μg - 1 mg of adenosylcobalamin.

[0060]

[0071] The present invention may involve administering to a subject a probiotic supplement comprising adenosylcobalamin-producing bacteria.

[0061]

[0072] The probiotic supplement can include any probiotic microorganism(s) that can beneficially affect a subject by improving the intestinal bacterial balance of the subject and enhancing vitamin B12 uptake. The probiotic microorganism can be selected from the group including the genus Bifidobacterium, the genus Lactobacillus, the genus Streptococcus, the genus Enterococcus, and the genus Saccharomyces, or a mixture thereof.

[0062]

[0073] Oral supplementation with adenosyl vitamin B12 can be in the form of a food or beverage product. The food or beverage product can include a probiotic supplement that includes other probiotics that can enhance vitamin B12-producing bacteria or existing microorganisms in the intestine that produce vitamin B12 in situ.

[0063]

[0074] Typically, a physician determines the actual dosage that would be most appropriate for an individual subject, and this dosage varies depending on the age, weight, and response of a particular patient. The dosage is sufficient to provide the required amount of active adenosyl vitamin B12.

[0064] Method

[0075] Without being bound by theory, it is thought that various types of stress cause mitochondrial stress damage, thereby reducing the ability of mitochondria to perform many roles essential for overall cell function. The methods disclosed herein may be useful for treating conditions associated with mitochondrial stress damage. This damage can manifest through any of a number of pathways including, but not limited to, mitochondrial diseases.

[0065]

[0076] Mitochondrial diseases are caused by a change in the function of proteins or RNA molecules normally present in mitochondria, due to either genetic mutations or spontaneous mutations in mitochondrial DNA or nuclear DNA. However, problems with mitochondrial function can affect only specific tissues due to factors that occur during development and growth, which are not yet fully understood. Even considering tissue-specific isoforms of mitochondrial proteins, it is difficult to explain the variable patterns of organ systems affected by mitochondrial disease syndromes seen clinically.

[0066]

[0077] Mitochondrial diseases are due to damage to mitochondria, a special compartment present in all cells of the body except red blood cells. Mitochondria are involved in generating more than 90% of the energy required by the body to support life and growth. When mitochondria stop functioning, the energy produced in cells decreases. The cells are damaged and may even lead to cell death. When this process is repeated throughout the body, the entire system begins to break down, severely threatening the person's life. Mitochondrial diseases mainly affect children, but adult onset has also become recognized.

[0067]

[0078] Mitochondrial diseases seem to cause the most damage to cells in the brain, heart, liver, skeletal muscle, kidneys, and the endocrine and respiratory systems.

[0068]

[0079] Many symptoms in mitochondrial diseases are nonspecific. The symptoms may also show a transient course with periodic exacerbations. Review papers in mitochondrial medicine mention transient migraine states, as well as muscle pain, gastrointestinal symptoms, tinnitus, depression, chronic fatigue, and diabetes among various manifestations of mitochondrial diseases. In patients with mitochondrial diseases, clinical symptoms typically occur when energy demand is high in relation to physiological stressors such as illness, fasting, excessive exercise, and extreme environmental temperatures. Furthermore, perhaps due to the large amount of brain energy requirements such that patients cannot produce sufficient ATP, psychological stressors often trigger symptoms.

[0069]

[0080] Depending on which cells are affected, the symptoms can include loss of motor control, muscle weakness and pain, gastrointestinal disorders and dysphagia, inadequate growth, heart disease, liver disease, diabetes, respiratory complications, seizures, visual / auditory problems, lactic acidosis, developmental delay, and susceptibility to infections.

[0070]

[0081] Mitochondrial diseases include, but are not limited to, Alzheimer's disease, Barth syndrome, abnormal beta-oxidation, carnitine deficiency, carnitine-acyl-carnitine deficiency, chronic progressive external ophthalmoplegia syndrome, coenzyme Q10 deficiency, complex I deficiency, complex II deficiency, complex III deficiency, complex IV deficiency, complex V deficiency, CPT I deficiency, CPT II deficiency, creatine deficiency syndrome, cytochrome c oxidase deficiency, glutaric aciduria type 2, Kearns-Sayre syndrome, lactic acidosis, LCHAD (long-chain acyl-CoA dehydrogenase deficiency), Leber hereditary optic neuropathy, Leigh disease, lethal infantile cardiomyopathy, Luft disease, MAD (medium-chain acyl-CoA dehydrogenase deficiency), mitochondrial cytopathy, mitochondrial DNA depletion, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like symptoms, mitochondrial encephalopathy, mitochondrial myopathy, mitochondrial recessive ataxia syndrome, muscular dystrophy, myoclonic epilepsy and ragged-red fiber disease, myoneurogenic gastrointestinal encephalopathy, neuropathy, ataxia, retinitis pigmentosa, and ptosis, Pearson syndrome, POLG mutation, pyruvate carboxylase deficiency, pyruvate dehydrogenase deficiency, SCHAD (short-chain acyl-CoA dehydrogenase deficiency), and very long-chain acyl-CoA dehydrogenase deficiency.

[0071]

[0082] Accordingly, one aspect of the present disclosure is a unit dosage form composition comprising adenosylcobalamin in an amount effective for the treatment or prevention of at least one condition selected from the group consisting of stress (e.g., childhood stress and / or its effects), obesity, decreased metabolic rate, metabolic syndrome, diabetes mellitus, hyperlipidemia, neurodegenerative diseases, cognitive impairment, stress-induced or stress factor-related cognitive dysfunction, mood disorders (e.g., stress-induced or stress factor-related mood disorders), anxiety disorders (e.g., stress-induced or stress factor-related anxiety disorders), and age-related neuronal death or dysfunction (e.g., age-related neuronal death or dysfunction not caused by a specific neurodegenerative disease), trauma, infections (e.g., ICU), or cancer.

[0072]

[0083] Another aspect of the present disclosure is a method of treating at least one condition selected from the group consisting of stress (e.g., childhood stress and / or its effects), obesity, decreased metabolic rate, metabolic syndrome, diabetes mellitus, cardiovascular diseases, hyperlipidemia, neurodegenerative diseases, cognitive impairment, stress-induced or stress factor-related cognitive dysfunction, mood disorders (e.g., stress-induced or stress factor-related mood disorders), anxiety disorders (e.g., stress-induced or stress factor-related anxiety disorders), and age-related neuronal death or dysfunction (e.g., age-related neuronal death or dysfunction not caused by a specific neurodegenerative disease), trauma, infections (e.g., ICU), or cancer in an individual having at least one such condition. The method comprises administering to the individual a composition comprising a therapeutically effective amount of adenosylcobalamin.

[0073]

[0084] A further aspect of the present disclosure is a method of preventing at least one condition selected from the group consisting of stress, obesity, decreased metabolic rate, metabolic syndrome, type 2 diabetes, cardiovascular disease, hyperlipidemia, neurodegenerative disease, cognitive impairment, stress-induced or stress factor-related cognitive dysfunction, mood disorder (e.g., stress-induced or stress factor-related mood disorder), anxiety disorder (e.g., stress-induced or stress factor-related anxiety disorder), and age-related neuronal death or dysfunction (e.g., age-related neuronal death or dysfunction not caused by a specific neurodegenerative disease), trauma, infection (e.g., in the ICU), or cancer. The method includes administering to an individual at risk of at least one condition a composition comprising a prophylactically effective amount of adenosylcobalamin.

[0074]

[0085] In one embodiment of these methods, the hyperlipidemia to be treated or prevented includes hypertriglyceridemia. In one embodiment of these methods, the hyperlipidemia to be treated or prevented includes an increase in free fatty acids. In one embodiment of these methods, the age-related neuronal death or dysfunction to be treated or prevented is by administration of the composition to middle-aged and elderly individuals such as the elderly.

[0075]

[0086] The stress to be treated or prevented can be childhood stress, i.e., stress experienced during the period up to 5 years of age. Childhood stress has been reported to have a significant adverse effect on cognitive abilities, including psychological parameters such as an increased incidence or susceptibility to the development of depression, anxiety, and abnormal risk-taking behavior. In individuals who have experienced childhood stress, an increased incidence of attention deficit / hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), and major depressive disorder has been reported.

[0076]

[0087] Another aspect of the present disclosure is a method of delaying the onset of metabolic decline, reducing oxidative stress, maintaining immune function, and / or maintaining cognitive function in healthy middle-aged and elderly individuals. The method includes administering to healthy middle-aged and elderly individuals an effective amount of adenosylcobalamin.

[0077]

[0088] Another aspect of the present disclosure is a method for improving mitochondrial function in an individual such as a middle-aged or elderly person. This method includes administering an effective amount of adenosylcobalamin to the individual.

[0078]

[0089] Yet another aspect of the present disclosure is a method for enhancing the metabolism of reactive oxygen species and improving glucose control in an individual having at least one of obesity or diabetes. This method includes administering an effective amount of adenosylcobalamin to the individual.

[0079]

[0090] Another aspect of the present disclosure is a method for improving mitochondrial function (preferably resulting in a benefit in at least one of metabolism or muscle strength) in an individual such as a middle-aged or elderly person. This method includes administering an effective amount of adenosylcobalamin to the individual.

[0080]

[0091] Yet another aspect of the present disclosure is a composition comprising adenosylcobalamin in an amount effective for weight management. "Weight management" for an adult (e.g., at least 18 years after birth) means that the individual has a body mass index (BMI) that is approximately the same as the BMI at the start of composition intake after one week of composition intake, preferably after one month of composition intake, more preferably after one year of composition intake. "Weight management" for a young individual means that the BMI percentile for an individual of the corresponding age is approximately the same as the BMI percentile at the start of composition intake after one week of composition intake, preferably after one month of composition intake, more preferably after one year of composition intake. In some embodiments, the individual undergoing weight management is an overweight individual preventing obesity.

[0081]

[0092] In related embodiments, a method for weight management in an individual includes administering to the individual a composition comprising an effective amount of adenosylcobalamin.

[0082]

[0093] The composition can improve physical endurance (e.g., the ability to perform physical tasks such as exercise, manual labor, sports activities, etc.), suppress or delay physical fatigue, increase blood oxygen concentration, enhance energy in healthy individuals, enhance work capacity and endurance, reduce muscle fatigue, improve recovery from exercise, reduce stress, enhance cardiomyocyte function, improve sexual ability, increase muscle ATP levels, and / or reduce lactic acid in the blood. "Endurance" refers to the time until fatigue when exercising at a constant workload, generally at an intensity of less than 80% of V02max. In some embodiments, the composition is administered in an amount that increases mitochondrial activity, increases mitochondrial biogenesis, and / or increases mitochondrial mass.

[0083]

[0094] A further aspect of the present disclosure is a composition comprising adenosylcobalamin in an amount effective to increase or maintain at least one of mitochondrial function or metabolic rate. In related embodiments, a method of increasing or maintaining at least one of mitochondrial function or metabolic rate in an individual comprises administering to the individual a composition comprising an effective amount of adenosylcobalamin.

[0084]

[0095] Yet another aspect of the present disclosure is a unit dosage form composition comprising adenosylcobalamin in an amount effective to treat, prevent, or manage at least one of mitochondrial-related diseases, conditions associated with changes in mitochondrial function, or a decrease in mitochondrial density. In related embodiments, a method of treating an individual having at least one of mitochondrial-related diseases, conditions associated with changes in mitochondrial function, or a decrease in mitochondrial density comprises administering to the individual a composition comprising an effective amount of adenosylcobalamin. In another related embodiment, a method of preventing at least one of mitochondrial-related diseases, conditions associated with changes in mitochondrial function, or a decrease in mitochondrial density in an individual at risk thereof comprises administering to the individual a composition comprising an effective amount of adenosylcobalamin.

[0085]

[0096] Another aspect of the present disclosure is a composition in unit dosage form comprising adenosylcobalamin in an amount effective to improve or maintain cognitive function. In related embodiments, a method of improving or maintaining cognitive function in an individual comprises administering to the individual a composition comprising adenosylcobalamin.

[0086]

[0097] In one embodiment, the individual does not have a cognitive disorder. For example, the composition can enhance cognitive function in a subject having normal cognitive function.

[0087]

[0098] The compositions disclosed herein can also be used for the treatment of any of a variety of additional diseases and conditions in which a defect or decrease in mitochondrial activity is involved in the pathophysiology of the disease or condition, or in which an increase in mitochondrial function results in a desired beneficial effect. Non-limiting examples of such conditions include male infertility associated with decreased sperm motility, macular degeneration, and other age-related and hereditary eye disorders and hearing loss (e.g., age-related hearing loss).

[0088]

[0099] In each of the compositions and methods disclosed herein, adenosylcobalamin can preferably be administered in a composition that is a food product, including a food additive, a food ingredient, a functional food, a dietary supplement, a medical food, a nutraceutical, or a nutritional supplement.

[0089] Dietary Interventions and Diet Products

[0100] The term "dietary intervention" refers to an external factor that is given to a subject and causes a change in the subject's diet. In one embodiment, the dietary intervention is a high-calorie diet. In another embodiment, the dietary intervention is a high-protein diet and / or a high-carbohydrate diet. In another embodiment, the dietary intervention is a diet supplemented with vitamins and minerals.

[0090]

[0101] In a preferred embodiment, the dietary intervention is a diet supplemented with adenosylcobalamin.

[0091]

[0102] In another preferred embodiment, the dietary intervention is a diet supplemented with hydroxocobalamin and / or cyanocobalamin that can be converted to vitamin B12, particularly adenosylcobalamin.

[0092]

[0103] The regular diet may be adjusted according to the initial weight of the subject.

[0093]

[0104] The dietary intervention may include administration of at least one regular diet product. The regular diet product may be, for example, a meal replacement product or a nutritional supplement product that can enhance the subject's appetite. The regular diet product may include food products, beverages, pet food products, dietary supplements, nutraceuticals, food additives, or nutritional formulations. Examples of oral nutritional supplements include Boost and Meritene of Nestle products.

[0094]

[0105] In one embodiment, the composition further includes one or more of medium-chain triglycerides, such as caproic acid, caprylic acid, capric acid, and lauric acid. In one embodiment, the composition further includes phospholipids, such as phosphatidylcholine.

[0095]

[0106] In one embodiment, the composition further includes a protein source, preferably a purified protein (i.e., isolated from the natural food components from which the protein was produced). The protein content of the composition is preferably 20 to 99% by weight of the composition, for example, 20 to 90% by weight of the composition, for example, 30 to 80% by weight of the composition, for example, 40 to 80% by weight of the composition, for example 50 to 80% by weight of the composition, for example, 40 to 70% by weight of the composition.

[0096]

[0107] Non-limiting examples of proteins or their raw materials suitable for use in the composition include hydrolyzed, partially hydrolyzed, or non-hydrolyzed proteins or protein sources. These may be derived from any known or other suitable raw materials such as milk (e.g., casein, whey), animals (e.g., meat, fish), grains (e.g., rice, corn), or vegetables (e.g., soybeans, peas). Raw materials or combinations of multiple proteins may be used. Non-limiting examples of proteins or their raw materials include intact pea protein, intact pea protein isolate, intact pea protein concentrate, milk protein isolate, milk protein concentrate, casein protein isolate, casein protein concentrate, whey protein concentrate, whey protein isolate, sodium caseinate or calcium caseinate, whole milk, partially or completely skimmed milk, yogurt, soy protein isolate, and soy protein concentrate, and combinations thereof. Raw materials or combinations of multiple proteins may be used. Preferred proteins include pea protein, whey protein, soy protein, and casein. Casein protein may include, for example, sodium caseinate and calcium caseinate.

[0097]

[0108] The protein source can be provided by each amino acid, polypeptide containing amino acids, or a mixture thereof. In many muscle growth, muscle maintenance, and / or muscle enhancement treatments, certain beneficial amino acids are, for example, L-arginine, L-glutamine, lysine, and branched-chain amino acids (i.e., leucine, isoleucine, and valine; especially leucine and isoleucine). These specific amino acids may be provided as a protein source or added to the main raw material of the protein. Therefore, the protein source in the composition may contain one or more branched-chain amino acids (leucine, isoleucine, and valine), one or both of L-arginine and L-glutamine, and lysine. In a preferred embodiment, the composition contains whey protein and / or casein protein together with one or more (or all) of each amino acid, for example, one or more of leucine, isoleucine, and L-arginine.

[0098]

[0109] The composition may be administered at least once a week, preferably at least twice a week, more preferably at least three or four times a week (e.g., every other day), most preferably at least five, six, or seven times a week. The administration period may be at least one week, preferably at least one month, more preferably at least two months, most preferably at least three months, for example, at least four months. In one embodiment, the administration is at least daily, for example, the subject may be administered more than once a day. In some embodiments, the administration is continued throughout the remaining life of the individual. In another embodiment, the administration is carried out until detectable symptoms of the medical condition disappear. In a particular embodiment, the administration is carried out until a detectable improvement is seen for at least one symptom and, in further cases, is continued to maintain remission.

[0099]

[0110] The compositions disclosed herein can be administered to a subject orally, enterally, or parenterally. Non-limiting examples of parenteral administration include intravenous, intramuscular, intraperitoneal, subcutaneous, intra-articular, intrasynovial, intraocular, intrathecal, topical, and inhalation. Thus, non-limiting examples of the form of the composition include natural foods, processed foods, natural fruit juices, concentrates and extracts, injection solutions, microcapsules, nanocapsules, liposomes, plasters, inhalation forms, nasal sprays, nasal drops, eye drops, sublingual tablets, and sustained release formulations.

[0100]

[0111] Any of a variety of formulations for therapeutic administration can be used with the compositions disclosed herein. More specifically, the pharmaceutical composition can include a suitable pharmaceutically acceptable carrier or diluent and can be formulated as a solid, semi-solid, liquid, or gaseous formulation such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Thus, administration of the composition can be accomplished by a variety of methods including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, and intratracheal administration. The active agent can be systemic after administration or can be localized by use of topical administration, use of intramural administration, or use of an implant that acts to maintain an effective dose at the site of implantation.

[0101]

[0112] In pharmaceutical dosage forms, the compounds may be administered as pharmaceutically acceptable salts. They may also be used in appropriate association with another pharmaceutically active compound. The following methods and additives are merely illustrative and are in no way limiting.

[0102]

[0113] In oral preparations, the compound can be used alone or in combination with suitable additives for manufacturing tablets, powders, granules or capsules, such as conventional additives like lactose, mannitol, corn starch or potato starch, binders like crystalline cellulose, cellulose functional derivatives, gum arabic, corn starch or gelatin, disintegrants like corn starch, potato starch or sodium carboxymethyl cellulose, lubricants like talc or magnesium stearate, and, if desired, in combination with diluents, buffers, wetting agents, preservatives and flavoring substances.

[0103]

[0114] The compound can be formulated as an injectable preparation by dissolving, suspending or emulsifying it in an aqueous or non-aqueous solvent, such as vegetable oil or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol, and, if desired, together with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.

[0104]

[0115] The compound can be utilized in aerosol preparations administered by inhalation. For example, the compound can be formulated in a pressurized acceptable propellant such as dichlorodifluoromethane, propane and nitrogen.

[0105]

[0116] Furthermore, the compound can be manufactured as a suppository by mixing it with various bases such as an emulsifying base or a water-soluble base. The compound can be administered rectally by suppository. The suppository can contain a vehicle that melts at body temperature but solidifies at room temperature, such as cocoa butter, carbowax and polyethylene glycol.

[0106]

[0117] Unit dosage forms for oral or rectal administration, such as syrups, elixirs, and suspensions, may be provided, and each dosage unit, for example, a tablespoon, a tablespoonful, a tablet, or a suppository, contains a specified amount of the composition. Similarly, unit dosage forms for injection or intravenous administration may contain the compound in a composition as a solution in sterile water, physiological saline, or another pharmaceutically acceptable carrier, and each dosage unit, for example, mL or L, contains a specified amount of the composition containing one or more of the compounds.

[0107]

[0118] [Examples]

[0119] The following non-limiting examples present scientific data that develop and support the concept that administration of adenosylcobalamin increases cellular energy production and thereby improves the function of various tissues.

[0108]

[0120] Example 1

[0121] Materials and Methods

[0122] To test the effects of adenosyl B12 and methyl B12 in human myotubes, the oxygen consumption rate and ATP production in human myotubes differentiated from primary adult myoblasts (HSMM) were measured. HSMM was purchased from Lonza (https: / / bioscience.lonza.com). HSMM was isolated from the muscle tissue of the upper arm or leg of healthy donors and used after the second passage. HSMM was seeded into SKM-M medium (ZenBio) in a 96-well plate at a cell density of 12,000 cells per well. The cells were grown for 4 days in DMEM / F-12 (Gibco) containing 2% horse serum to differentiate myotubes from HSMM. From the second day of growth, the medium was made B12-free.

[0109]

[0123] Oxygen consumption was measured using an XF96 machine (Seahorse Biosciences, North Billerica, MA, USA). After differentiation, the respiration rate was measured every 7 minutes at 37 °C. The myotubes were stimulated with 10 μM epibatidine. Then, oligomycin (2.5 μg / ml) was added to measure the ATP synthase-dependent component of respiration. Respiration dependent on ATP synthase was calculated as the difference in respiration rate before and after the addition of oligomycin.

[0110]

[0124] ATP measurements were performed using myotubes infected with an adenovirus expressing luciferase (from Sirion biotech). Luminescence was measured with a Cytation 3 cell imaging reader (Biotek). Forty-eight hours after infection, the relative change in ATP was measured with a luminometer in a standard medium containing 145 mM NaCl, 5 mM KCl, 1 mM MgCl2, 1 mM CaCl2, 10 mM glucose and 10 mM Hepes, pH 7.4. Luciferin (5 μM) was added to promote the ATP-dependent reaction and the basal luminescence was normalized to 100%. The addition of epibatidine stimulated ATP production in the myotubes.

[0111]

[0125] For treatment, the compound was added directly to the cell culture or myotube culture 3 hours (acute treatment) or 3 days (chronic treatment) before the measurement. Custom module analysis based on Excel (Microsoft) and GraphPad Prism 7.02 (GraphPad) software was used for quantification.

[0112]

[0126] Results

[0127] As shown in Figure 1, adenosyl B12 increases the ATP synthase-dependent component of respiration in myotubes of stimulated human skeletal muscle, while methyl B12 (Figure 2) does not increase the ATP synthase-dependent component of respiration in myotubes of stimulated human skeletal muscle.

[0113]

[0128] Similarly, as shown in FIG. 3, adenosyl B12 enhances ATP production stimulated by epibatine in human skeletal muscle myotubes during acute treatment, while methyl B12 does not enhance production.

[0114]

[0129] Also, chronic treatment of human skeletal muscle myotubes with adenosyl B12 enhances ATP production stimulated by epibatine, while chronic treatment with methyl B12 does not enhance it (FIG. 4).

[0115]

[0130] Example 2

[0131] Materials and Methods

[0132] Male Wistar rats at 3 months or 19 months of age were treated for 5 months by subcutaneous injection of adenosylcobalamin (adenosyl B12) or methylcobalamin (methyl-B12) at a dose of 1 mg / kg three times a week. Control animals were injected with the same amount of physiological saline. After 5 months of treatment, adult rats were defined as 8-month-old rats, and aged (senile) animals were defined as 24-month-old rodents.

[0116]

[0133] Total RNA was extracted from the extensor tibialis muscle using the Agencourt RNAdvance Tissue Kit. For gene set enrichment analysis and network analysis, the RNA amount was measured with Ribogreen, and the RNA quality was confirmed with a Fragment Analyzer using a standard sensitivity RNA analysis kit. All target cRNAs were synthesized using the IVT+ kit and fragmented according to the Affymetrix protocol based on the Eberwine T7 procedure. Briefly, 100 ng of total RNA was used to generate double-stranded cDNA, followed by in vitro transcription and biotin labeling of the cRNA. Gene set enrichment analysis (GSEA) of the skeletal muscle gene set shows significantly differentially expressed pathways (FIG. 5A). In network analysis (FIG. 5B), nodes with an interaction score > 0.9 are represented in different gray levels and are aggregated based on biological function.

[0117]

[0134] To measure muscle performance (Figure 6), coordinated movement was measured using a rotarod apparatus. Rats were placed on a rotating rod, and the rotational speed was gradually increased from 4 rpm to 40 rpm over 600 seconds until the rats could no longer cope with the rotation and fell onto a protective pad placed under the rod. The activity time on the rotarod was measured in seconds. Each animal was recorded three times with at least a 10-minute rest period between each test.

[0118]

[0135] Results

[0136] As shown in Figures 5-1 and 5-2, adenosyl B12 specifically shows the gene expression signature of the oxidative phosphorylation gene group in skeletal muscle. Enrichment plot analysis of the oxidative phosphorylation gene set (Panel 5A) comparing old rats treated with adenosyl B12 in vivo to old rats treated with methyl B12 shows that mitochondrial energy production is a strong transcriptional signature in skeletal muscle treated with adenosyl B12. Furthermore, network analysis of the regulated genes (Panel 5B) distinguished several clusters associated with mitochondrial respiratory chain complexes, oxidative phosphorylation, and mitochondrial function only in rats specifically treated with adenosyl B12.

[0119]

[0137] Also, when old rats are specifically treated with adenosyl B12 in vivo, the activity time on the rod significantly increases, indicating improved skeletal muscle performance.

[0120]

[0138] It should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the subject matter of the present invention and without sacrificing the intended advantages. Therefore, such changes and modifications are intended to be included within the scope of the appended claims.

[0121] Further embodiments of the present invention are as follows. [Embodiment 1] A method of restoring mitochondrial function and other cellular functions and / or increasing mitochondrial energy in one or more cells, the method comprising administering to an individual in need thereof an effective amount of adenosylcobalamin. [Embodiment 2] A method of improving a physiological state associated with metabolic fatigue in one or more cells and / or reducing fatigue in an individual, the method comprising administering to the individual in need thereof an effective amount of adenosylcobalamin. [Embodiment 3] The method according to Embodiment 2, which is a method of improving physical endurance, suppressing or delaying physical fatigue, increasing blood oxygen concentration, enhancing energy in a healthy individual, enhancing work ability and endurance, improving recovery from exercise, reducing muscle fatigue, reducing stress, and increasing muscle ATP levels. [Embodiment 4] A method of treating a chronic disease, reducing its incidence, and / or reducing its severity, the method comprising administering to an individual in need thereof an effective amount of adenosylcobalamin. [Embodiment 5] The method according to any one of Embodiments 1 to 4, wherein the one or more cells are part of at least one body part selected from the group consisting of the liver, kidney, brain, heart, intestine, pancreas, immune cells, and skeletal muscle. [Embodiment 6] The method according to any one of Embodiments 1 to 5, wherein the amount of adenosylcobalamin is from 1 to 10 μg per day up to a maximum of 100 μg to 2000 μg per day. [Embodiment 7] The method according to any one of Embodiments 1 to 6, wherein the adenylyl cobalamin is administered orally. [Embodiment 8] The method according to any one of Embodiments 1 to 7, wherein the individual has a high blood concentration of methylmalonic acid. [Embodiment 9] The method according to any one of Embodiments 1 to 8, wherein the individual is selected from the group consisting of middle-aged and elderly people, severely ill patients, or ICU patients. [Embodiment 10] A method for treating, reducing the incidence of, and / or reducing the severity of a mitochondrial-related disease, a condition related to a change in mitochondrial function, or a decrease in mitochondrial density, the method comprising orally administering an effective amount of adenosylcobalamin to an individual in need thereof. [Embodiment 11] The method according to embodiment 9, wherein the mitochondrial-related disease or condition is selected from the group consisting of stress, obesity, decreased metabolic rate, metabolic syndrome, type 2 diabetes, diabetic complications, hyperlipidemia, neurodegenerative diseases, cognitive impairment, stress-induced or stress factor-related cognitive dysfunction, mood disorders, anxiety disorders, age-related neuronal death or dysfunction, musculoskeletal disorders, frailty, pre-frailty, chronic kidney disease, chronic heart failure, cardiac rehabilitation, orthopedic rehabilitation, wound healing, recovery from surgery, trauma, infections, cancer, macular degeneration, and combinations thereof. [Embodiment 12] The method according to embodiment 9, wherein the mitochondrial-related disease or condition includes childhood stress and / or its effects. [Embodiment 13] The method according to embodiment 9, wherein the mitochondrial-related disease or condition includes hyperlipidemia including at least one of hypertriglyceridemia or an increase in free fatty acids. [Embodiment 14] The method according to embodiment 9, wherein the mitochondrial-related disease or condition includes at least one of stress-induced or stress factor-related mood disorder, or stress-induced or stress factor-related anxiety disorder. [Embodiment 15] The method according to embodiment 9, wherein the mitochondrial-related disease or condition includes age-related neuronal death or dysfunction not caused by a specific neurodegenerative disease. [Embodiment 16] A method for delaying the onset of metabolic decline, reducing oxidative stress, maintaining immune function, and / or maintaining cognitive function in healthy middle-aged and elderly individuals, said method comprising orally administering to said healthy middle-aged and elderly individuals an effective amount of adenosylcobalamin. [Embodiment 17] A method for increasing metabolic rate, said method comprising orally administering to an individual an effective amount of adenosylcobalamin. [Embodiment 18] A method for improving or maintaining cognitive function, said method comprising orally administering to an individual an effective amount of adenosylcobalamin. [Embodiment 19] The method according to Embodiment 18, wherein the cognitive function is selected from the group consisting of perception, memory, attention, speech comprehension, speech production, reading comprehension, image creation, learning, inference, and combinations thereof. [Embodiment 20] A method for enhancing at least one of mental performance, said method comprising orally administering to an individual an effective amount of adenosylcobalamin.

Claims

**Claim 1** A method for restoring mitochondrial function and other cellular functions and / or increasing mitochondrial energy in one or more cells, the method comprising administering an effective amount of adenosylcobalamin to an individual in need thereof. **Claim 2** A method for improving a physiological state associated with metabolic fatigue in one or more cells and / or reducing fatigue in an individual, the method comprising administering an effective amount of adenosylcobalamin to the individual in need thereof. **Claim 3** The method according to claim 2, which is for improving physical endurance, suppressing or delaying physical fatigue, increasing blood oxygen concentration, enhancing energy in a healthy individual, enhancing work ability and endurance, improving recovery from exercise, reducing muscle fatigue, reducing stress, and increasing muscle ATP levels. **Claim 4** A method for treating, reducing the incidence of, and / or reducing the severity of a chronic disease, the method comprising administering an effective amount of adenosylcobalamin to an individual in need thereof. **Claim 5** The method according to any one of claims 1 to 4, wherein the one or more cells are part of at least one body part selected from the group consisting of the liver, kidney, brain, heart, intestine, pancreas, immune cells, and skeletal muscle. **Claim 6** The method according to any one of claims 1 to 5, wherein the amount of adenosylcobalamin is from 1 to 10 μg per day up to a maximum of 100 μg to 2000 μg. **Claim 7** The method according to any one of claims 1 to 6, wherein the adenylyl cobalamin is administered orally. **Claim 8** The method according to any one of claims 1 to 7, wherein the individual has a high blood concentration of methylmalonic acid. **Claim 9** The method according to any one of claims 1 to 8, wherein the individual is selected from the group consisting of middle-aged and elderly individuals, severely ill patients, or ICU patients. **Claim 10** A method for treating, reducing the incidence of, and / or reducing the severity of a mitochondrial-related disease, a condition associated with a change in mitochondrial function, or a decrease in mitochondrial density, the method comprising orally administering an effective amount of adenosylcobalamin to an individual in need thereof. **Claim 11** The method according to claim 9, wherein the mitochondrial-related disease or condition is selected from the group consisting of stress, obesity, decreased metabolic rate, metabolic syndrome, type 2 diabetes, diabetic complications, hyperlipidemia, neurodegenerative diseases, cognitive impairment, stress-induced or stress factor-related cognitive dysfunction, mood disorders, anxiety disorders, age-related neuronal death or dysfunction, musculoskeletal disorders, frailty, pre-frailty, chronic kidney disease, chronic heart failure, cardiac rehabilitation, orthopedic rehabilitation, wound healing, recovery from surgery, trauma, infectious diseases, cancer, macular degeneration, and combinations thereof.

12. The method according to claim 9, wherein the mitochondrial-related disease or condition includes childhood stress and / or its effects.

13. The method according to claim 9, wherein the mitochondrial-related disease or condition includes hyperlipidemia including at least one of hypertriglyceridemia or increased free fatty acids.

14. The method according to claim 9, wherein the mitochondrial-related disease or condition includes at least one of stress-induced or stress factor-related mood disorder or stress-induced or stress factor-related anxiety disorder.

15. The method according to claim 9, wherein the mitochondrial-related disease or condition includes age-related neuronal death or dysfunction not caused by a specific neurodegenerative disease.

16. A method for delaying the onset of metabolic decline, reducing oxidative stress, maintaining immune function, and / or maintaining cognitive function in healthy middle-aged and elderly individuals, the method comprising orally administering an effective amount of adenosylcobalamin to the healthy middle-aged and elderly individuals.

17. A method for increasing metabolic rate, the method comprising orally administering an effective amount of adenosylcobalamin to an individual.

18. A method for improving or maintaining cognitive function, the method comprising orally administering an effective amount of adenosylcobalamin to an individual.

19. The method according to claim 19, wherein the cognitive function is selected from the group consisting of perception, memory, attention, speech comprehension, speech production, reading comprehension, image creation, learning, reasoning, and combinations thereof.

20. A method for enhancing at least one of mental performance, the method comprising orally administering an effective amount of adenosylcobalamin to an individual.

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