Compositions and methods using combination of curcumin and an omega-3 fatty acid for cellular energy

Abstract

To provide methods and compositions that can treat or prevent a mitochondria-related disease, or a condition associated with altered mitochondrial function, or a reduced mitochondrial density.SOLUTION: The present invention provides a method of increasing antioxidant capacity, reducing oxidative stress, and / or enhancing mitochondrial function, the method comprising administering to an individual in need thereof an effective amount of a combination of curcumin and an omega-3 fatty acid.SELECTED DRAWING: None

Description

[Background technology]

[0001]

[0001] The present disclosure relates generally to compositions and methods that can treat or prevent mitochondrial-associated diseases or conditions associated with altered mitochondrial function or reduced mitochondrial density, in some embodiments in middle-aged or elderly individuals, for example, by improving antioxidant capacity, reducing oxidative stress, and / or improving mitochondrial function.

[0002]

[0002] Population ageing is a significant demographic phenomenon. As the growth of the elderly population exceeds the growth of the total population due to longer life spans, the proportion of the elderly population relative to the rest of the population has increased significantly, partly due to declining birth rates. For example, in the 1950s, one in every 12 people was aged 60 or over; by the end of the 2000s, one in every 10 people was aged 60 or over. It is projected that by the end of the 2050s, one in every five people worldwide will be aged 60 or over.

[0003]

[0003] Middle-aged and elderly people often suffer some degree of cognitive impairment, including a progressive decline in cognitive function with age, and age-related changes in brain morphology and cerebrovascular function are commonly observed. Cognitive decline has been reported in conjunction with aging in a wide range of cognitive domains, including processing speed, attention, episodic memory, spatial ability, and executive function. Brain imaging studies have shown that these normal age-related cognitive declines are associated with a decrease in both gray and white matter volume in the brain, with the fronto-striatal system being the most severely damaged with aging. This decrease in cortical volume may be due to many deleterious cellular processes involved in normal aging, such as the long-term accumulation of damage from free radicals resulting in oxidative damage, chronic low-grade inflammation, accumulation of homocysteine ​​(which, if increased, is a risk factor for cognitive impairment and dementia), and reduced mitochondrial function. In addition to direct cellular damage, the brain also suffers indirect damage from damage to the microvasculature. It is clear that the pathology of aging, and even dementia, involves a complex interplay between these interrelated factors. For example, mitochondrial dysfunction results in increased oxidative stress, which can trigger inflammation and vascular damage.

[0004]

[0004] Furthermore, cognitive decline is an early predictor of Alzheimer's disease and begins before the onset of dementia. In this case, a total cognitive score provides a reliable means of assessing cognitive decline that occurs before dementia. A large body of evidence suggests that maintaining brain health and preventing age-related cognitive decline can prevent or slow the progression of dementia due to Alzheimer's disease and other age-related neuropathologies.

[0005]

[0005] In recent years, nutrition, education, physical activity and cognitive exercises have been demonstrated as potential interventions to prevent age-related cognitive decline. A wealth of clinical, epidemiological and individual evidence supports the role of individual nutritional factors in reducing dementia risk and age-related neurodegeneration. However, formal trials of nutritional interventions have produced mixed results (Schmitt et al., Nutrition Reviews 68:S2-S5 (2010)).

[0006]

[0006] Furthermore, stress (generally an animal's reaction to changes that require physical, mental, or emotional regulation or response) can cause health problems in animals. Prolonged, uninterrupted, unexpected, and unmanageable stress is the most harmful type of stress.

[0007] There are known methods to affect stress and the symptoms and conditions caused by stress. Drugs such as antidepressants can be used to affect stress and its associated symptoms and conditions. Antidepressants such as Prozac, Deroxat, and Zoloft, or anti-anxiety drugs such as Xanax, Temesta, Lexomil, and Valium are prescribed to treat stress and affect the symptoms and conditions caused by stress. However, these methods often come with one or more side effects. Meditation, relaxation, hypnosis, exercise, counseling, and nutrition are known methods to affect stress and the symptoms and conditions caused by stress.

[0008]

[0008] Furthermore, the psychobiological characteristics of stress may be manifested as a manifestation of oxidative stress, i.e., an imbalance between the production and expression of reactive oxygen species and the ability of the living system to rapidly detoxify reactive intermediates or to rapidly repair the damage caused. When the normal redox state of tissues is disturbed, toxic effects can be caused by the production of peroxides and free radicals that damage all components of the cell, such as proteins, lipids, and DNA. Some reactive oxidative species can also act as messengers through a phenomenon called "redox signaling".

[0009]

[0009] In humans, oxidative stress is involved in many diseases, including atherosclerosis, Parkinson's disease, heart failure, myocardial infarction, Alzheimer's disease, schizophrenia, bipolar disorder, fragile X syndrome, and chronic fatigue syndrome.

[0010]

[0010] One source of ROS under normal conditions in humans is the leakage of ROS from mitochondria during oxidative phosphorylation. Other enzymes that can produce superoxide (O2-) include xanthine oxidase, NADPH oxidase, and cytochrome P450. Another strong oxidant, hydrogen peroxide, is produced by a variety of enzymes, including several oxidases. ROS plays an important role in the cellular signaling process called redox-dependent signaling. Therefore, a balance must be achieved between the production and consumption of ROS to maintain proper cellular homeostasis. Summary of the Invention

[0011]

[0011] In view of the experimental data disclosed hereinafter, the present inventors believe that curcumin and omega-3 fatty acids synergistically enhance the efficiency of mitochondrial energy production.

[0012] Thus, in a general embodiment, the present disclosure provides a method of improving antioxidant capacity, reducing oxidative stress, and / or improving mitochondrial function, the method comprising administering to an individual in need thereof an effective amount of a combination of curcumin and omega-3 fatty acids.

[0013] In another embodiment, the present disclosure provides a method of treating, reducing the incidence, and / or reducing the severity of a mitochondrial associated disease or a condition associated with altered mitochondrial function or reduced mitochondrial density, the method comprising orally administering to an individual in need thereof an effective amount of a combination of curcumin and omega-3 fatty acids.

[0014] In a further embodiment, there is provided a method of delaying the onset of metabolic decline, maintaining muscle mass, reducing oxidative stress, maintaining immune function, and / or maintaining cognitive function in a healthy middle-aged or elderly individual, the method comprising orally administering to the healthy middle-aged or elderly individual an effective amount of a combination of curcumin and omega-3 fatty acids.

[0015] The present invention also relates to a method of enhancing reactive oxygen species metabolism, improving glucose regulation, and / or improving muscle function in an individual having at least one of obesity or diabetes, the method comprising orally administering to the individual an effective amount of a combination of curcumin and an omega-3 fatty acid.

[0016] In another embodiment, the present disclosure provides: i) a method of improving mitochondrial function in an individual, comprising orally administering to the individual an effective amount of a combination of curcumin and omega-3 fatty acids; ii) a method for increasing metabolic rate comprising orally administering to an individual an effective amount of a combination of curcumin and omega-3 fatty acids; iii) a method of improving or maintaining cognitive function, comprising orally administering to an individual an effective amount of a combination of curcumin and omega-3 fatty acids; iv) a method of enhancing at least one of mental performance or muscular performance, comprising orally administering to an individual an effective amount of a combination of curcumin and an omega-3 fatty acid; 23. The method of claim 22, wherein v) the individual is a middle-aged individual, an elderly individual, or an ICU patient. vi) a method for weight management, comprising orally administering to an individual an effective amount of a combination of curcumin and omega-3 fatty acids; vii) a method of improving or maintaining mitochondrial function comprising administering to an individual an effective amount of a combination of curcumin and omega-3 fatty acids; to provide.

[0017] In further embodiments, the present disclosure relates to a composition in unit dosage form comprising a combination of curcumin and omega-3 fatty acids in an amount effective for at least one of: (i) treating, reducing the incidence, or reducing the severity of a mitochondrial-related disease or condition associated with altered mitochondrial function or reduced mitochondrial density; (ii) increasing metabolic rate; (iii) improving or maintaining cognitive function; (iv) enhancing mental performance; (v) enhancing muscular performance; (vi) weight management; or (vii) improving or maintaining mitochondrial function.

[0018] In another embodiment, the present disclosure provides a kit comprising curcumin and omega-3 fatty acids in one or more containers.

[0019] An advantage of one or more embodiments provided by the present disclosure is that they promote healthy aging of cells.

[0020] Another advantage of one or more embodiments provided by the present disclosure is that it helps combat the metabolic slowdown that accompanies aging.

[0021] Another advantage of one or more embodiments provided by the present disclosure is that they help increase fatty acid metabolism.

[0022] Yet another advantage of one or more embodiments provided by the present disclosure is that it helps the body metabolize fat and increase lean body mass.

[0023] An advantage of one or more embodiments provided by the present disclosure is that it helps maintain cardiac health.

[0024] Another advantage of one or more embodiments provided by the present disclosure is that they help maintain healthy LDL cholesterol and fatty acid concentrations in the blood.

[0025] Another advantage of one or more embodiments provided by the present disclosure is that it helps maintain healthy muscle mass.

[0026] Yet another advantage of one or more embodiments provided by the present disclosure is that they help reduce oxidative stress on the body.

[0027]

[0020] Additional features and advantages are described herein, and will be apparent from the drawings and detailed description that follow. [Brief description of the drawings]

[0028] 1-3 are graphs of data from the experimental examples disclosed herein. [Figure 1] Figure 1 shows the effect of curcumin (CUR), n-3 fatty acids (OM3), and a combination of curcumin and n-3 FA (CUR+OM3) on mitochondrial complex activity in aged rats. 20-month-old rats were fed either a control diet or a diet supplemented with curcumin and ad libitum n-3 FA for 1 month. Results are expressed as mean ± SEM. [Diagram 2]Figure 1 shows the effect of curcumin (CUR), n-3 fatty acids (OM3), and a combination of curcumin and n-3 FA (CUR+OM3) on the activity of citrate synthase in aged rats. Twenty-month-old rats were fed either a control diet or a diet supplemented with curcumin and ad libitum n-3 FA for one month. Results are expressed as mean ± SEM. [Diagram 3] Effect of curcumin (CUR), n-3 fatty acids (OM3), and the combination of curcumin and n-3 FA (CUR+OM3) on the MFN2 / DRP1 protein level ratio in aged rats. Twenty-month-old rats were fed either a control diet or a diet supplemented with curcumin and n-3 FA ad libitum for one month. Results are expressed as mean ± SEM. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029]

[0025] Definition

[0026] Some definitions are provided below. However, definitions may be found in the "Embodiments" section below, and the heading "Definitions" above does not imply that such disclosure in the "Embodiments" section is not a definition.

[0030]

[0027] All percentages set forth herein are by total weight of the composition unless otherwise indicated. As used herein, "about," "approximately," and "substantially" are understood to refer to numbers within a numerical range, e.g., within -10% to +10% of the referenced number, preferably within -5% to +5%, more preferably within -1% to +1% of the referenced number, and most preferably within -0.1% to +0.1% of the referenced number. All numerical ranges herein should be understood to include all integers or fractions within the range. Furthermore, these numerical ranges should be interpreted as supporting claims directed to any number or subset of numbers within the range. For example, a disclosure of 1 to 10 should be interpreted as supporting ranges such as 1 to 8, 3 to 7, 1 to 9, 3.6 to 4.6, 3.5 to 9.9, etc.

[0031]

[0028] As used in this disclosure and the appended claims, the singular forms "a," "an," and "the" include plural references unless otherwise indicated. Thus, for example, reference to "a component" or "the component" includes two or more components.

[0032]

[0029] The terms "comprise", "comprises", and "comprising" are to be interpreted inclusively, not exclusively. Similarly, the terms "include", "including", and "or" are all to be interpreted inclusively, unless such interpretation is clearly prevented by the context. However, the compositions disclosed herein may not include elements not specifically disclosed herein. Thus, disclosure of an embodiment using the term "comprising" includes disclosure of embodiments "consisting essentially of" and "consisting of" the specified component. A composition "consisting essentially of" means that the composition comprises 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.

[0033]

[0030] The term "and / or" used in the context of "X and / or Y" should be interpreted as "X" or "Y" or "X and Y". Similarly, "at least one of X or Y" should be interpreted as "X" or "Y" or "X and Y". For example, "at least one of mental performance or muscular performance" should be interpreted as "mental performance or muscular performance" or "muscular performance" or "both mental performance and muscular performance".

[0034]

[0031] As used herein, the terms "example" and "such as," especially when followed by a list of terms, are merely exemplary and explanatory and should not be considered as exclusive or exhaustive. As used herein, a condition "related to" or "associated with" another condition means that these conditions occur simultaneously, preferably that these conditions are caused by the same underlying condition, and most preferably that one of the specified conditions is caused by the other specified condition.

[0035]

[0032] The terms "food," "food product," and "food composition" refer to a product or composition intended for ingestion by an individual, such as a human, and providing at least one nutrient to such an individual. A food product typically comprises at least one of protein, lipid, carbohydrate, and optionally one or more vitamins and minerals. The compositions of the present disclosure, including the many embodiments described herein, can comprise, consist of, or consist essentially of the elements disclosed herein, as well as any additional or optionally present ingredients, components, or elements described or not described herein that are useful in the diet.

[0036]

[0033] As used herein, the term "isolated" means removed from one or more other compounds or components with which the compound may otherwise be found, e.g., in nature. Preferably, for example, "isolated" means that the specified compound is separated from at least a portion of the cellular material with which it is typically found in nature. In one embodiment, an isolated compound is pure, i.e., free of other compounds.

[0037]

[0034] As used herein, an "effective amount" is an amount that prevents a deficiency, treats a disease or medical condition of an individual, or more generally, alleviates symptoms, manages the progression of a disease, or provides a nutritional, physiological, or medical benefit to an individual. The relative terms "improved," "increased," "enhanced," and the like, refer to the effect of the compositions disclosed herein, i.e., compositions comprising a combination of curcumin and omega-3 fatty acids, compared to an otherwise identical composition that does not contain curcumin and omega-3 fatty acids. As used herein, "promoting" refers to enhancing or inducing compared to levels prior to administration of the compositions disclosed herein.

[0038]

[0035] The term "unit dosage form" as used herein refers to a physically discrete unit suitable as a unitary dosage for human and animal subjects, each unit containing a defined amount of the composition disclosed herein in an amount sufficient to produce the desired effect, preferably together with a pharma- ceutically acceptable diluent, carrier, or vehicle. The specifications of the unit dosage form depend on the specific compound used, the effect to be achieved, and the pharmacodynamics associated with each compound in the host. In some embodiments, the unit dosage form can be a defined amount of active compound in a serving of food product, a defined amount of active compound in a sachet, a defined amount of active compound in a capsule or tablet, or a defined amount of active compound in a defined amount of liquid, preferably a therapeutically or prophylactically effective amount, or a defined fraction of a therapeutically or prophylactically effective amount.

[0039]

[0036] A "subject" or "individual" is a mammal, preferably a human. The term "elderly" in the human context means a postnatal age of 60 years or more, preferably above 63 years, more preferably above 65 years, and most preferably above 70 years. The term "older adult" in the human context means a postnatal age of 45 years or more, preferably above 50 years, more preferably above 55 years, and includes elderly people.

[0040]

[0037] As used herein, "frailty" is defined as a clinically recognizable state of heightened vulnerability resulting from age-related declines in reserve and function across multiple physiological systems, resulting in impaired ability to cope with routine or acute stressors. The presence of one or two of these criteria identifies the pre-frailty stage as being at high risk for progression to frailty.

[0041] "Overweight" refers to a body mass index (BMI) between 25 and 30 kg / m 2 "Obesity" is defined in humans as a BMI of at least 30 kg / m 2 , for example 30 to 39.9 kg / m 2 "Weight loss / weight loss" is a reduction in total body weight. Weight loss can refer to a reduction in total body weight to improve one or more of, for example, health, fitness, or appearance.

[0042]

[0039] "Diabetes" encompasses both types I and II of the disease. Non-limiting examples of risk factors for diabetes include waist circumference greater than 40 inches for men or greater than 35 inches for women, blood pressure equal to or greater than 130 / 85 mmHg, triglycerides greater than 150 mg / dL, fasting blood glucose greater than 100 mg / dL, or high density lipoprotein less than 40 mg / dL for men or less than 50 mg / dL for women.

[0043]

[0040] 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, with prevalence increasing with age. Some studies suggest that the prevalence in the United States is estimated at 25% of the population. According to the International Diabetes Foundation's consensus worldwide definition (2006), metabolic syndrome is central obesity in combination with any two of the following:

[0041] Elevated triglycerides: greater than 150 mg / dL (1.7 mmol / L) or treatments directed at this lipid abnormality;

[0042] Lowering 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 treatments targeting this lipid abnormality;

[0043] Elevated blood pressure: systolic BP greater than 130 or diastolic BP greater than 85 mmHg, or treatment of previously diagnosed hypertension; and

[0044] Elevated fasting plasma glucose: (FPG) greater than 100 mg / dL (5.6 mmol / L) or previously diagnosed type 2 diabetes.

[0044]

[0045] As used herein, "neurodegenerative disease" or "neurodegenerative disorder" refers to any condition in the central nervous system that results in a gradual loss of functional neurons. In one embodiment, the neurodegenerative disease is associated with age-related cell death. 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 disease, Alpers disease, ataxia-telangiectasia, Batten disease, bovine spongiform encephalopathy (BSE), Canavan disease, corticobasal degeneration, Creutzfeldt-Jakob disease, dementia with Lewy bodies, fatal familial insomnia, prefrontal cortex syndrome, and pulmonary tuberculosis. These include temporotemporal lobar degeneration, Kennedy disease, Krabbe disease, Lyme disease, Machado-Joseph disease, multiple sclerosis, multiple system atrophy, neuroacanthocytosis, Niemann-Pick disease, Pick's disease, primary lateral sclerosis, progressive supranuclear palsy, Refsum disease, Sandhoff disease, diffuse myelinating sclerosis, spinocerebellar ataxia, subacute combined spinal degeneration, tabes dorsalis, Tay-Sachs disease, toxic encephalopathy, transmissible spongiform encephalopathy, and wobbly hedgehog syndrome.

[0045] As used herein, "cognitive function" refers to any mental process that involves symbolic activity, such as perception, memory, attention, speech comprehension, speech production, reading, imagery creation, learning, and reasoning, preferably at least memory.

[0046]

[0046] Methods for measuring cognitive function are well known and can include, for example, individual tests or battery tests for any aspect 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 such test is the Mini Mental State Exam (MMSE), which is designed to assess orientation to time and place, memorization, 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 stressor-related cognitive dysfunction" refers to stress-induced or stress-related cognitive dysfunction.

[0047]

[0047] As used herein, "mood disorder" (also known as affective disorder) refers to a disturbance 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, dysthymia, and bipolar disorder. "Stress-induced or stressor-related mood disorder" refers to a disturbance of emotional state that is stress-induced or stress-related. Such mood disorders are sometimes called reactive mood disorders and are distinguished from other mood disorders, such as "organic" mood disorders, which are due to a medical or health condition rather than a psychiatric illness.

[0048]

[0048] As used herein, "anxiety disorder" refers to a dysfunction of fear and anxiety, e.g., fear and anxiety that is out of proportion to the stressful situation or the anticipation 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 or stressor-related anxiety disorder" refers to a dysfunction of fear and anxiety that is stress-induced or stress-related. Such anxiety disorders are sometimes called reactive anxiety disorders and are distinguished from other anxiety disorders, e.g., "organic" anxiety disorders, which are caused by a medical or health condition rather than a psychiatric illness.

[0049]

[0049] Embodiment

[0001] The present disclosure provides a composition comprising a combination of curcumin and omega-3 fatty acids. In a preferred embodiment, the fatty acids include essential polyunsaturated fatty acids, i.e., linoleic acid (C18:2n-3) or alpha-linoleic acid (C18:3n-3), or long chain polyunsaturated fatty acids, such as eicosapentaenoic acid (C20:5n-3), docosahexaenoic acid (C22:6n-3), or any combination thereof. More preferably, the omega-3 fatty acid is eicosapentaenoic acid.

[0050]

[0002] Curcumin may be present in an amount of from about 0.01 mg to about 2.0 g per serving, preferably from about 0.1 mg to about 2.0 g per serving, and even more preferably from about 10.0 mg to about 1.0 g per serving.

[0051]

[0003] The omega-3 fatty acid may be at least about 10% by weight, preferably at least about 15% by weight, based on the total lipid content. In a preferred embodiment, the daily amount of omega-3 fatty acid is about 500 mg to about 5 g of omega-3 fatty acid per day, preferably 500 mg to 2.5 g of omega-3 fatty acid per day, more preferably about 1.5 g to about 2 g of omega-3 fatty acid per day. The omega-3 fatty acid preferably comprises eicosapentaenoic acid.

[0052]

[0050] Some embodiments of the compositions disclosed herein may include a plant extract, such as an extract of Curcuma longa (e.g., its root), that provides at least a portion of the curcumin. The plant extract may be rich in curcumin, for example, containing at least about 10% by weight of curcumin, preferably at least about 20% by weight of curcumin, more preferably at least about 30% by weight of curcumin, and most preferably at least about 50% by weight of curcumin. Additionally or alternatively, the portion of the curcumin may be isolated curcumin.

[0053]

[0051] In some embodiments of the compositions disclosed herein, at least a portion of the curcumin is highly bioavailable curcumin. Curcumin has poor absorption, biodistribution, metabolism, and bioavailability. Thus, continued research into curcumin has revealed several possibilities to overcome these problems. Various formulations, including nanoparticles, liposomes, micelles, and phospholipid complexes, have been developed to improve the bioavailability, longer circulation, better permeability, and resistance to metabolic processes of curcumin.

[0054] In addition to curcumin, one or more additional polyphenols may be included in the composition, such as flavonoids, such as isoflavones, anthocyanins, proanthocyanidins and anthocyanidins, flavans, flavonols, flavones and flavanones.Specific examples of bioflavonoids include catechins (catechin, epicatechin, gallocatechin, epigallocatechin, epicatechin gallate, epigallocatechin gallate), oleuropein, hesperidin, and genistein.

[0055]

[0053] Additional anti-inflammatory compounds or antioxidants may optionally be used in the composition. For example, additional antioxidants may be provided as antioxidant-rich food compositions or extracts thereof. An "antioxidant-rich" food composition has an ORAC (Oxygen Radical Absorbance Capacity) rating of at least 100 per 100 g of composition.

[0056]

[0054] Without wishing to be bound by theory, it is believed that various types of stress result in stress damage to mitochondria, thereby reducing the ability of mitochondria to perform many roles essential to overall cellular function. The methods disclosed herein may be useful for treating conditions involving stress damage to mitochondria. This damage may be manifested in any of a number of ways, including, but not limited to, mitochondrial diseases.

[0057]

[0055] Mitochondrial diseases are the result of either genetic or spontaneous mutations in mitochondrial or nuclear DNA, resulting in altered function of proteins or RNA molecules normally present in mitochondria. However, problems in mitochondrial function may only affect certain tissues due to factors occurring during development and growth that 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 in the clinic.

[0058]

[0056] Mitochondrial diseases result from damage to mitochondria, specialized compartments present in all cells of the body except red blood cells. Mitochondria are responsible for producing over 90% of the energy the body needs to sustain life and support development. When mitochondria stop functioning, less energy is produced in cells. Cells become damaged and even die. When this process is repeated throughout the body, the whole system begins to break down, and this breakdown severely threatens the person's life. Mitochondrial diseases primarily affect children, but adult onset is also becoming evident.

[0059]

[0057] Mitochondrial diseases appear to primarily damage cells of the brain, heart, liver, skeletal muscles, kidneys (eg, renal failure), and the endocrine and respiratory systems.

[0060] Many symptoms in mitochondrial disease are non-specific. Symptoms may also show a temporary course with periodic exacerbations. A review article on mitochondrial medicine mentions episodic migraine states, as well as myalgia, gastrointestinal symptoms, tinnitus, depression, chronic fatigue, and diabetes, among the various manifestations of mitochondrial disease. In patients with mitochondrial disease, clinical symptoms typically occur when energy demands are high in association with physiological stressors such as illness, hunger, excessive exercise, and extreme environmental temperatures. In addition, psychological stressors often trigger symptoms, perhaps due to the brain's energy demands being so high that the patient cannot perform sufficient ATP production.

[0061] Depending on which cells are affected, symptoms may include decreased mobility, muscle weakness and pain, gastrointestinal problems and swallowing problems, poor growth, heart disease, liver disease, diabetes, respiratory complications, seizures, visual / hearing problems (e.g., reduced vision or deafness), lactic acidosis, developmental delays, and susceptibility to infections.

[0062]

[0060] Mitochondrial diseases include, but are not limited to, Alper's disease, Barth syndrome, beta-oxidation disorders, 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 acidemia type 2, Kearns-Sayre syndrome, lactic acidosis, LCHAD (long-chain acyl-CoA dehydrogenase deficiency), Leber's hereditary optic neuropathy, Leigh disease, lethal infantile cardiomyopathy, and other conditions. cardiomyopathy, Luft's 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 dystrophies, myoclonic epilepsy and ragged-red fiber disease, myoneurogenic gastrointestinal encephalopathy, neuropathy, ataxia, retinitis pigmentosa, and ptosis, Pearson's syndrome, POLG mutations, pyruvate carboxylase deficiency, pyruvate dehydrogenase deficiency, SCHAD (short-chain acyl-CoA dehydrogenase deficiency), and very long-chain acyl-CoA dehydrogenase deficiency.

[0063]

[0061] Accordingly, one aspect of the present disclosure is a composition in unit dosage form comprising a combination of curcumin and omega-3 fatty acids in an amount effective for treating or preventing at least a symptom selected from the group consisting of stress (e.g., early life stress and / or its effects), obesity, reduced metabolic rate, metabolic syndrome, diabetes mellitus, hyperlipidemia, neurodegenerative disease, cognitive impairment, stress-induced or stressor-related cognitive dysfunction, mood disorder (e.g., stress-induced or stressor-related mood disorder), anxiety disorder (e.g., stress-induced or stressor-related anxiety disorder), and age-related neuronal cell death or dysfunction (e.g., age-related neuronal cell death or dysfunction not attributable to a specific neurodegenerative disease), trauma, infection (e.g., ICU), or cancer.

[0064] Another aspect of the present disclosure is a method for treating at least one condition selected from the group consisting of stress (e.g., early life stress and / or its effects), obesity, reduced metabolic rate, metabolic syndrome, diabetes mellitus, cardiovascular disease, hyperlipidemia, neurodegenerative disease, cognitive impairment, stress-induced or stressor-related cognitive dysfunction, mood disorder (e.g., stress-induced or stressor-related mood disorder), anxiety disorder (e.g., stress-induced or stressor-related anxiety disorder), and age-related neuronal cell death or dysfunction (e.g., age-related neuronal cell death or dysfunction not due to a specific neurodegenerative disease), trauma, infection (e.g., ICU), or cancer in an individual having at least one condition. The method includes administering to the individual a composition comprising a therapeutically effective amount of a combination of curcumin and omega-3 fatty acid.

[0065]

[0063] A further aspect of the present disclosure is a method for preventing at least one condition selected from the group consisting of stress, obesity, reduced metabolic rate, metabolic syndrome, diabetes mellitus, cardiovascular disease, hyperlipidemia, neurodegenerative disease, cognitive impairment, stress-induced or stressor-related cognitive dysfunction, mood disorder (e.g., stress-induced or stressor-related mood disorder), anxiety disorder (e.g., stress-induced or stressor-related anxiety disorder), and age-related neuronal cell death or dysfunction (e.g., age-related neuronal cell death or dysfunction not due to a specific neurodegenerative disease), trauma, infection (e.g., in an ICU), or cancer. The method comprises administering to an individual at risk of at least one condition a composition comprising a prophylactically effective amount of a combination of curcumin and omega-3 fatty acid.

[0066] In one embodiment of these methods, the hyperlipidemia treated or prevented comprises hypertriglyceridemia. In one embodiment of these methods, the hyperlipidemia treated or prevented comprises an increase in free fatty acids. In one embodiment of these methods, the age-related neuronal cell death or dysfunction treated or prevented is by administration of the composition to a middle-aged or elderly person, such as an elderly person.

[0067]

[0065] The stress to be treated or prevented can be early life stress, i.e., stress experienced during the period from birth to 5 years of age. Early life stress has been reported to have significant adverse effects on cognitive performance, including psychological parameters such as increased incidence or susceptibility to depression, anxiety, and abnormal risk-taking behavior. Higher incidence of attention deficit / hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), and major depression has been reported in individuals who have experienced early life stress.

[0068] Another aspect of the present disclosure is a method of delaying the onset of metabolic decline, maintaining muscle mass, reducing oxidative stress, maintaining immune function, and / or maintaining cognitive function in healthy middle-aged or older adults, comprising administering to the healthy middle-aged or older adults an effective amount of a combination of curcumin and omega-3 fatty acids.

[0069] Another aspect of the present disclosure is a method of improving mitochondrial function in an individual, such as a middle-aged or elderly individual, comprising administering to the individual an effective amount of a combination of curcumin and an omega-3 fatty acid.

[0070] Yet another aspect of the present disclosure is a method of enhancing reactive oxygen species metabolism, improving glucose regulation, and / or improving muscle function in an individual having at least one of obesity or diabetes, comprising administering to the individual an effective amount of a combination of curcumin and an omega-3 fatty acid.

[0071] Another aspect of the present disclosure is a method of improving mitochondrial function (preferably benefiting at least one of metabolism or muscle strength) in an individual, such as a middle-aged or elderly individual, comprising administering to the individual an effective amount of a combination of curcumin and omega-3 fatty acids.

[0072]

[0070] Yet another aspect of the present disclosure is a composition comprising curcumin and optionally omega-3 fatty acids in an amount effective for weight management. For adults (e.g., at least 18 years of age), "weight management" means that the individual has about the same body mass index BMI after 1 week of taking the composition, preferably after 1 month of taking the composition, more preferably after 1 year of taking the composition, compared to the BMI when the individual started taking the composition. For younger individuals, "weight management" means that the BMI is about the same percentile for individuals of the corresponding age after 1 week of taking the composition, preferably after 1 month of taking the composition, more preferably after 1 year of taking the composition, compared to the BMI percentile when the individual started taking the composition. In some embodiments, the individual undergoing weight management is an overweight individual who is preventing obesity.

[0073]

[0071] In a related embodiment, a method for managing weight in an individual comprises administering to the individual a composition comprising an effective amount of a combination of curcumin and omega-3 fatty acids.

[0074] Another aspect of the present disclosure is a composition in unit dosage form comprising an effective amount of a combination of curcumin and omega-3 fatty acids to improve at least one of muscle performance or mental performance (e.g., memory). In a related embodiment, a method of improving at least one of muscle performance or mental performance (e.g., memory) in an individual comprises administering to the individual a composition comprising an effective amount of a combination of curcumin and omega-3 fatty acids.

[0075]

[0073] With respect to muscle performance, the improvement in muscle performance can be one or more of improved muscle function, reduced decline in muscle function, improved muscle strength, improved muscle endurance, and improved muscle recovery. The composition can improve physical endurance (e.g., the ability to perform physical tasks such as exercise, physical labor, sports activities, etc.), inhibit or delay physical fatigue, improve blood oxygen levels, improve energy in healthy individuals, improve work capacity and endurance, reduce muscle fatigue, reduce stress, enhance cardiomyocyte function, improve sexual performance, increase muscle ATP levels, and / or reduce blood lactate. "Endurance" refers to the ability to increase the muscle ATP levels at a given workload, typically measured as V0. 2 It refers to the time to fatigue when exercising at an intensity less than 80% of max. In some embodiments, the composition is administered in an amount that increases mitochondrial activity, increases mitochondrial biogenesis, and / or increases mitochondrial mass. In some embodiments, the composition is administered in combination with exercise and / or an exercise regimen to improve muscle performance and / or muscle endurance.

[0076] In some embodiments, the combination of curcumin and omega-3 fatty acids is administered to individuals with reduced physical performance, reduced endurance, and / or reduced muscle function. Improved muscle function may be particularly effective in elderly subjects with reduced muscle cell function as a result of age-related conditions. For example, subjects who may experience reduced muscle function that may later lead to pre-frailty and frailty may benefit from improved muscle cell function. Such subjects do not necessarily experience muscle wasting in conjunction with reduced muscle function. Some subjects experience both muscle wasting and reduced muscle function. The combination of curcumin and omega-3 fatty acids can enhance muscle performance in subjects who are frail or pre-frail.

[0077]

[0075] Sports performance refers to the ability of an athlete's muscles to perform when participating in a sports activity. Enhanced sports performance, strength, speed, and endurance are measured by increasing the strength of muscle contraction, increasing the amplitude of muscle contraction, or shortening the muscle reaction time between stimulation and contraction. "Athlete" refers to an individual who participates in sports at any level and aims to improve strength, speed, or endurance in their performance, such as bodybuilders, cyclists, long-distance runners, and sprinters. Enhanced sports performance is manifested as the ability to overcome muscle fatigue, maintain activity for longer periods of time, and perform more effective workouts.

[0078]

[0076] The compositions and methods disclosed herein may also be effective in treating muscle-related pathological conditions, including neuromuscular diseases such as myopathies, Duchenne muscular dystrophy, and / or cachexia associated with burns, bed rest, limb immobilization, or major thoracic, abdominal, and / or orthopedic surgery.

[0079]

[0077] A further aspect of the present disclosure is a composition comprising a combination of curcumin and an omega-3 fatty acid in an amount effective to improve or maintain at least one of mitochondrial function or metabolic rate. In a related embodiment, a method of improving 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 a combination of curcumin and an omega-3 fatty acid.

[0080]

[0078] Yet another aspect of the present disclosure is a composition in unit dosage form comprising a combination of curcumin and omega-3 fatty acids in an amount effective to treat, prevent, or manage at least one of a mitochondrial-associated disease, a condition associated with altered mitochondrial function, or reduced mitochondrial density. In a related embodiment, a method of treating an individual having at least one of a mitochondrial-associated disease, a condition associated with altered mitochondrial function, or reduced mitochondrial density comprises administering to the individual a composition comprising an effective amount of a combination of curcumin and omega-3 fatty acids. In another related embodiment, a method of preventing at least one of a mitochondrial-associated disease, a condition associated with altered mitochondrial function, or reduced mitochondrial density in an individual at risk thereof comprises administering to the individual a composition comprising an effective amount of a combination of curcumin and omega-3 fatty acids.

[0081]

[0079] Another aspect of the present disclosure is a composition in unit dosage form comprising a combination of curcumin and omega-3 fatty acids in an amount effective to improve or maintain cognitive function. In a related embodiment, a method of improving or maintaining cognitive function in an individual comprises administering to the individual a composition comprising a combination of curcumin and omega-3 fatty acids.

[0082]

[0080] In one embodiment, the individual does not have a cognitive disorder. For example, the composition can enhance cognitive function in a subject with normal cognitive function.

[0083]

[0081] The compositions disclosed herein can also be used to treat any of a variety of additional diseases and conditions in which defective or reduced mitochondrial activity is involved in the pathophysiology of the disease or condition, or in which increased mitochondrial function produces a desired beneficial effect. Non-limiting examples of such conditions include male infertility associated with reduced sperm motility, hearing loss, macular degeneration, and other age-related and hereditary eye disorders, and hearing loss (e.g., age-related hearing loss).

[0084]

[0082] In each of the compositions and methods disclosed herein, the combination of curcumin and omega-3 fatty acids can be administered as a composition that is preferably a food product, including a food additive, food ingredient, functional food, dietary supplement, medical food, nutraceutical, or nutritional supplement.

[0085] In one embodiment, the composition further comprises a medium chain triglyceride, such as one or more of caproic acid, caprylic acid, capric acid, and lauric acid. In one embodiment, the composition further comprises a phospholipid, such as a phosphatidylcholine.

[0086] In one embodiment, the composition further comprises a protein source, preferably a purified protein (i.e. isolated from the natural food component in which the protein is produced). The protein content of the composition is preferably from 20 to 99% by weight of the composition, such as from 20 to 90% by weight of the composition, for example from 30 to 80% by weight of the composition, for example from 40 to 80% by weight of the composition, such as from 50 to 80% by weight, for example from 40 to 70% by weight of the composition.

[0087]

[0085] Non-limiting examples of proteins or sources thereof 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 source, such as milk (e.g., casein, whey), animal (e.g., meat, fish), grain (e.g., rice, corn), or vegetable (e.g., soy, pea). Combinations of sources or proteins may be used. Non-limiting examples of proteins or sources thereof 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 or calcium caseinate, whole milk, partially or fully skimmed milk, yogurt, soy protein isolate, and soy protein concentrate, and combinations thereof. Combinations of sources or proteins may be used. Preferred proteins include pea protein, whey protein, soy protein, and casein. Casein proteins may include, for example, sodium caseinate and calcium caseinate.

[0088]

[0086] The protein source may be provided by individual amino acids, polypeptides containing amino acids, or mixtures thereof. In many muscle growth, muscle maintenance, and / or muscle building treatments, the specific amino acids that are beneficial are, for example, L-arginine, L-glutamine, lysine, and branched chain amino acids (i.e., leucine, isoleucine, and valine; particularly leucine and isoleucine). These specific amino acids may be provided as a protein source or may be added to the main source of protein. Thus, the protein source in the composition may include 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 includes whey protein and / or casein protein together with one or more individual amino acids, for example, one or more (or all) of leucine, isoleucine, and L-arginine.

[0089] The composition may be administered at least 1 day per week, preferably at least 2 days per week, more preferably at least 3 or 4 days per week (e.g., every other day), and most preferably at least 5 days per week, 6 days per week, or 7 days per week. The administration period may be at least 1 week, preferably at least 1 month, more preferably at least 2 months, and most preferably at least 3 months, e.g., at least 4 months. In one embodiment, administration is at least daily, e.g., the subject may be administered one or more times per day. In some embodiments, administration continues for the remainder of the individual's life. In another embodiment, administration is administered until there is no detectable symptom of the medical condition. In certain embodiments, administration is administered until there is a detectable improvement in at least one symptom, and in further cases, administration is continued to maintain remission.

[0090]

[0088] The compositions disclosed herein may 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 by inhalation. Non-limiting examples of the form of the composition thus include whole foods, processed foods, natural fruit juices, concentrates and extracts, injections, microcapsules, nanocapsules, liposomes, plasters, inhalation forms, nasal sprays, nasal solutions, eye drops, sublingual tablets, and sustained release formulations.

[0091] The compositions disclosed herein may be used in any of a variety of formulations for therapeutic administration. More specifically, the pharmaceutical compositions may include suitable pharma- ceutically acceptable carriers or diluents and may be formulated as solid, semi-solid, liquid or gaseous formulations, such as tablets, capsules, powders, granules, ointments, liquids, suppositories, injections, inhalants, gels, microspheres, and aerosols. Thus, administration of the compositions may be accomplished in a variety of ways, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, and intratracheal administration. The active agent may be systemic after administration or may be localized by the use of topical administration, intramural administration, or the use of an implant that acts to retain an effective dose at the implantation site.

[0092]

[0090] In pharmaceutical dosage forms, the compounds may be administered as pharma- ceutically acceptable salts. They may also be used in appropriate association with other pharma- ceutical active compounds. The following methods and excipients are merely illustrative and in no way limiting.

[0093]

[0091] In oral formulations, the compounds may be used alone or in combination with suitable additives for producing tablets, powders, granules or capsules, for example with conventional additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, functional cellulose derivatives, gum arabic, corn starch or gelatin; with disintegrants such as corn starch, potato starch or sodium carboxymethylcellulose; with lubricants such as talc or magnesium stearate; and, if desired, with diluents, buffers, wetting agents, preservatives and flavouring substances.

[0094]

[0092] The compounds can be formulated as injectable preparations by dissolving, suspending or emulsifying in aqueous or non-aqueous solvents, such as vegetable oils or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids, or propylene glycol, together with conventional additives such as solubilizers, isotonicity agents, suspending agents, emulsifying agents, stabilizers, and preservatives, if desired.

[0095] The compounds can be utilized in aerosol formulations to be administered via inhalation. For example, the compounds can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, and nitrogen.

[0096]

[0094] Furthermore, the compound can be prepared as a suppository by mixing with various bases such as emulsifying bases or water-soluble bases. The compound can be administered rectally via a suppository. The suppository can include vehicles such as cocoa butter, carbowax, and polyethylene glycols, which melt at body temperature but solidify at room temperature.

[0097]

[0095] Unit dosage forms for oral or rectal administration, such as syrups, elixirs, and suspensions, may be provided, with each dosage unit, e.g., teaspoon, tablespoon, tablet, or suppository, containing a predetermined 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, saline, or another pharma- ceutically acceptable carrier, with each dosage unit, e.g., mL or L, containing a predetermined amount of a composition containing one or more of the compounds.

[0098]

[0096] The present disclosure also provides a kit comprising, in one or more containers, curcumin and omega-3 fatty acids, in some embodiments, one or more of these compounds may be isolated compounds.

[0099]

[0097] In one embodiment of the kit, the curcumin and omega-3 fatty acids may be provided together as one or more prepackaged unit dosage forms, for example, as separate containers each containing a dry powder, such that each container contains one prepackaged unit dosage form.

[0100] In another embodiment, the kit can include multiple compositions to be mixed together to form one or more of the compositions disclosed herein. For example, the kit can contain two or more dry powders in separate containers relative to each other, with each separate powder containing a portion of a final unit dosage form. As a non-limiting example of such an embodiment, the kit can include one or more first containers containing curcumin and can also include one or more second containers containing omega-3 fatty acids. The contents of one of the first containers can be mixed with one of the second containers to form at least a portion of a unit dosage form of the composition.

[0101]

[0099] Example

[0100] The following non-limiting examples present scientific data that develop and support the concept that administering a combination of curcumin and omega-3 fatty acids to increase cellular energy production improves the function of different tissues, such as muscle, that decline with age.

[0102] Aged rats are a good model for evaluating the effect of nutritional interventions on age-related decline. In this model used by the inventors, 20-month-old rats were fed for one month with either a normal diet or a similar diet supplemented with curcumin or n-3 fatty acids (n-3 FA), either alone or in combination. The activities of citrate synthase and mitochondrial respiratory chain complexes, measured by colorimetry, were synergistically enhanced in the curcumin and n-3 FA groups, suggesting better mitochondrial energy production. At the same time, in the same treatment groups, there was a synergistic increase in the MFN2 / DRP1 expression ratio (mitochondrial fusion / fission) measured by Western blot (Figures 1-3).

[0103]

[0102] Figure 1 shows the effect of curcumin (CUR), n-3 FA (OM3), and a combination of both (CUR+OM3) on mitochondrial complex activity in aged rats. 20-month-old rats were fed either a control diet or a similar diet supplemented with curcumin, n-3 FA, and a combination of both for 1 month. Results are expressed as mean ± standard error. CON: control diet. CUR: control diet with curcumin. OM3: control diet with n-3 fatty acids. CUR+OM3: control diet with curcumin and n-3 fatty acids.

[0104]

[0103] Figure 2 shows the effect of curcumin (CUR), n-3 FA (OM3), and a combination of both (CUR+OM3) on citrate synthase activity in aged rats. 20-month-old rats were fed either a control diet or a similar diet supplemented with curcumin, n-3 FA, and a combination of both for one month. Results are expressed as mean ± standard error. CON: control diet. CUR: control diet with curcumin. OM3: control diet with n-3 fatty acids. CUR+OM3: control diet with curcumin and n-3 fatty acids.

[0105]

[0104] Figure 3 shows the effect of curcumin (CUR), n-3 FA (OM3), and a combination of both (CUR+OM3) on the MFN2 / DRP1 expression ratio in aged rats. 20-month-old rats were fed either a control diet or a similar diet supplemented with curcumin, n-3 FA, and a combination of both for one month. Results are expressed as mean ± standard error. CON: control diet. CUR: control diet with curcumin. OM3: control diet with n-3 fatty acids. CUR+OM3: control diet with curcumin and n-3 fatty acids.

[0106]

[0105] 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 diminishing its intended advantages. It is therefore intended that such changes and modifications be covered by the appended claims.

Claims

1. 1. A method for improving antioxidant capacity, reducing oxidative stress, and / or improving mitochondrial function, comprising administering to an individual in need thereof an effective amount of a combination of curcumin and omega-3 fatty acids.

2. 10. The method of claim 1, wherein said combination is administered in an amount providing from about 500 mg to about 5 g of said omega-3 fatty acids per day.

3. 3. The method of claim 1 or 2, wherein the combination is administered in an amount providing from about 0.01 mg to about 2.0 g of the curcumin per day.

4. The method of any one of claims 1 to 3, wherein the combination is administered orally.

5. 5. The method of any one of claims 1 to 4, wherein the combination is administered as a food product comprising a plant extract that provides at least a portion of the curcumin.

6. The method according to any one of claims 1 to 5, wherein the individual is selected from the group consisting of middle-aged and elderly people.

7. The method of any one of claims 1 to 6, wherein the individual is an ICU patient.

8. 1. A method of treating, reducing the incidence, and / or reducing the severity of a mitochondrial associated disease, or a condition associated with altered mitochondrial function, or reduced mitochondrial density, comprising orally administering to an individual in need thereof an effective amount of a combination of curcumin and an omega-3 fatty acid.

9. 9. The method of claim 8, wherein the mitochondrial-related disease or condition is selected from the group consisting of stress, obesity, reduced metabolic rate, metabolic syndrome, diabetes mellitus, diabetic complications, hyperlipidemia, neurodegenerative disease, cognitive impairment, stress-induced or stressor-related cognitive dysfunction, mood disorder, anxiety disorder, age-related neuronal cell death or dysfunction, musculoskeletal disorder, frailty, pre-frailty, chronic kidney disease, renal failure, trauma, infection, cancer, hearing loss, macular degeneration, myopathy and dystrophies, and combinations thereof.

10. 10. The method of claim 8 or 9, wherein the mitochondrial-related disease or condition comprises early life stress and / or its effects.

11. The method of any one of claims 8 to 10, wherein the mitochondrial-related disease or condition comprises hyperlipidemia, including at least one of hypertriglyceridemia or high free fatty acids.

12. 12. The method of any one of claims 8 to 11, wherein the mitochondrial-related disease or condition comprises at least one of a stress-induced or stress-related mood disorder or a stress-induced or stress-related anxiety disorder.

13. The method according to any one of claims 8 to 12, wherein the mitochondrial-related disease or condition comprises age-related neuronal cell death or dysfunction not resulting from a specific neurodegenerative disease.

14. 1. A method for delaying the onset of metabolic decline, maintaining muscle mass, reducing oxidative stress, maintaining immune function, and / or maintaining cognitive function in a healthy middle-aged or older adult subject, comprising orally administering to said healthy middle-aged or older adult subject an effective amount of a combination of curcumin and omega-3 fatty acids.

15. 1. A method of enhancing reactive oxygen species metabolism, improving glucose regulation, and / or improving muscle function in an individual having at least one of obesity or diabetes, comprising orally administering to the individual an effective amount of a combination of curcumin and an omega-3 fatty acid.

16. 1. A method of improving, enhancing or maintaining mitochondrial function in an individual, comprising orally administering to said individual an effective amount of a combination of curcumin and an omega-3 fatty acid.

17. The method of any one of claims 1 to 16, wherein the individual is middle-aged or elderly.

18. The method of any one of claims 1 to 17, wherein the individual is an ICU patient.

19. A method for increasing metabolic rate, comprising orally administering to an individual an effective amount of a combination of curcumin and omega-3 fatty acids.

20. 1. A method for improving or maintaining cognitive function, comprising orally administering to an individual an effective amount of a combination of curcumin and an omega-3 fatty acid.

21. 21. The method of claim 20, wherein the cognitive function is selected from the group consisting of perception, memory, attention, speech comprehension, speech production, reading, imagery creation, learning, reasoning, and combinations thereof.

22. 21. The method of claim 20, wherein the individual does not have a cognitive impairment.

23. The method of any one of claims 20 to 22, wherein the individual is a middle-aged or elderly individual, an elderly individual, or an ICU patient.

24. 1. A method for enhancing at least one of mental or muscular performance, comprising orally administering to an individual an effective amount of a combination of curcumin and omega-3 fatty acids, optionally in combination with exercise or an exercise regimen.

25. 25. The method of claim 24, wherein the effective amount of the combination enhances mental performance, including memory.

26. 25. The method of claim 24, wherein the effective amount combination enhances muscle performance including at least one of strength, speed, or endurance.

27. 25. The method of claim 24, wherein the individual is middle-aged, elderly, or an ICU patient.

28. A method for weight management comprising orally administering to an individual an effective amount of a combination of curcumin and omega-3 fatty acids.

29. 1. A composition in unit dosage form comprising a combination of curcumin and omega-3 fatty acids in an amount effective for at least one of: (i) treating, reducing the incidence, or reducing the severity of a mitochondrial-associated disease, or a condition associated with altered mitochondrial function, or reduced mitochondrial density; (ii) increasing metabolic rate; (iii) improving or maintaining cognitive function; (iv) enhancing mental performance; (v) enhancing muscular performance; (vi) weight management; or (vii) improving or maintaining mitochondrial function.

30. 30. The composition of claim 29, wherein the combination of amounts is effective to treat, reduce the incidence, or reduce the severity of a mitochondrial associated disease or condition selected from the group consisting of stress, obesity, reduced metabolic rate, metabolic syndrome, diabetes mellitus, diabetic complications, hyperlipidemia, neurodegenerative disease, cognitive impairment, stress-induced or stressor-related cognitive dysfunction, mood disorder, anxiety disorder, age-related neuronal cell death or dysfunction, musculoskeletal disorder, sarcopenia, frailty, pre-frailty, chronic kidney disease, renal failure, trauma, infection, cancer, hearing loss, macular degeneration, myopathy and dystrophies, and combinations thereof.

31. The composition of any one of claims 29 to 30, which is a food product, a dietary supplement, or a nutraceutical.

32. A kit comprising, in one or more containers, curcumin and omega-3 fatty acids.

33. 33. The kit of claim 32, wherein the one or more containers include at least one first container containing the curcumin separately from the omega-3 fatty acids contained within at least one second container, and the kit further comprises instructions for combining the curcumin with the omega-3 into a unit dosage form.

34. 33. The kit of claim 32, wherein each of the one or more containers contains a unit dosage form of the combination of the curcumin and the omega-3 fatty acid.

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