Compositions and methods using combinations of fisetin and quercetin for cellular energy

Abstract

A composition is provided that comprises a combination of fisetin or a derivative thereof and quercetin or a derivative thereof. The composition can be an oral nutritional composition, such as a nutritional supplement, an oral nutritional supplement, a food product, a food for special medical purposes (FSMP). The composition can be administered to an individual in need thereof for (i) improving a physiological state associated with metabolic fatigue in one or more cells, (ii) increasing mitochondrial energy and mitochondrial calcium uptake in one or more cells, and (iii) enhancing antioxidant capacity, reducing oxidative stress and / or enhancing mitochondrial function, (iv) treating or preventing calcium deficiency / depletion disorders in an individual. Additionally or alternatively, by the present method, mitochondrial-related diseases or conditions associated with changes in mitochondrial function can be treated or prevented in individuals in need of such treatment or at risk thereof.

Description

Technical Field

[0001]

[0001] The present disclosure generally relates to compositions and methods for managing energy at the cellular level using a combination of fisetin or its derivatives and quercetin or metabolites. In some embodiments, the compositions and methods can enhance mitochondrial function, increase bioenergetics by activating the mitochondrial calcium uniporter, and thereby promote cellular activation in adults or the elderly.

Background Art

[0002]

[0002] The aging of the population is a remarkable event in terms of population dynamics. As the increase in the elderly population exceeds the increase in the total population due to the extension of lifespan, the ratio of the elderly population to other populations has increased significantly due to the decline in the birth rate as well. For example, in the 1950s, one in twelve people was over 60 years old, but by the end of the 2000s, one in ten people was over 60 years old. By the end of the 2050s, it is predicted that one in five people worldwide will be over 60 years old.

[0003]

[0003] In middle-aged and elderly people, it is common to develop a certain degree of cognitive impairment including a decline in physical function and / or cognitive function that progresses with aging, and changes due to aging in brain morphology and cerebrovascular function are generally observed. The decline in cognitive function has consistently been reported in conjunction with the aging of a wide range of cognitive domains including processing speed, attention, episodic memory, spatial ability, and executive function. Brain imaging analysis has shown that these normal age-related declines in cognitive function are associated with a decrease in the volume of both gray and white matter in the brain, and it has been found that the fronto-striatal system is the most severely damaged with aging. Such a decrease in cortical volume may be due to, for example, the accumulation of long-term damage caused by free radicals that cause oxidative damage, chronic low-grade inflammation, the accumulation of homocysteine (which, when the accumulation increases, becomes a risk factor for cognitive impairment and dementia), and many other harmful cellular processes associated with normal aging such as a decline in mitochondrial function. In addition to direct cell damage, the brain also suffers indirect damage from injury to the microvascular structure. It is clear that aging, and furthermore the pathology of dementia, encompasses complex interactions between these factors that are related to each other. For example, mitochondrial dysfunction results in an increase in oxidative stress, and oxidative stress can trigger inflammation and vascular damage.

[0004]

[0004] Mitochondria are the main source of aerobic energy production in mammalian cells, and also maintain a large Ca2+ gradient across the inner membrane and provide the signaling potential of the molecule. Furthermore, mitochondrial Ca2+ may play a role in the regulation of ATP production in mitochondria and contribute to the orchestration of cellular metabolic homeostasis. (Glancy, B. et al. (2012). "Role of mitochondrial Ca2+ in the regulation of cellular energetics." Biochemistry 51(14):2959-2973). Changes in mitochondrial Ca2+ homeostasis have been associated with various pathological conditions and are important in the etiology of some human diseases (Arduino et al. Journal Physiol. 2018 Jul;596(14):2717-2733).

[0005]

[0005] In recent years, nutritional intake, education, exercise, and cognitive exercise have been demonstrated as intervention methods that can prevent the decline of physical and cognitive functions due to aging. Abundant clinical, epidemiological, and individual evidence has confirmed that individual nutritional factors can reduce the risk of dementia and age-related neurodegeneration. However, the results obtained from official tests on nutritional interventions are complex (Schmitt et al., Nutrition Reviews 68:S2-S5 (2010)). In addition, efforts have been made to utilize the mitochondrial Ca2+ transport mechanism for therapeutic intervention, but there are currently no pharmacological compounds that can induce and selectively regulate mitochondrial Ca2+ homeostasis.

Summary of the Invention

[0006]

[0006] Considering the experimental data disclosed later in this specification, the inventors believe that the combination of fisetin and quercetin can improve the energy production efficiency of mitochondria.

[0007]

[0007] Therefore, in a general embodiment, the present disclosure provides a composition comprising a combination of fisetin and / or a derivative and quercetin and / or a derivative in a therapeutically effective amount for (i) improving a physiological state associated with metabolic fatigue in one or more cells, (ii) increasing mitochondrial energy and mitochondrial calcium uptake in one or more cells, and (iii) enhancing antioxidant capacity, reducing oxidative stress, and / or enhancing mitochondrial function, and (iv) use in the treatment or prevention of calcium deficiency / depletion disorders in an individual.

[0008] In another embodiment, the present disclosure provides a composition comprising a combination of fisetin and / or its derivatives and quercetin and / or its derivatives in a therapeutically effective amount for delaying the onset of metabolic decline, maintaining muscle mass and / or muscle function, reducing oxidative stress, maintaining immune function, and / or maintaining cognitive function in healthy adults or middle-aged and elderly individuals.

[0009]

[0009] In a further embodiment, the present disclosure also i) enhancing at least one of mental performance or muscle performance in an individual, or ii) providing a composition comprising a combination of fisetin and / or its derivatives and quercetin and / or its derivatives in a therapeutically effective amount for improving or maintaining cognitive function in an individual.

[0010]

[0010] In another embodiment, the present invention provides a unit dosage form comprising a combination of a combination of fisetin and / or its derivatives and quercetin and / or its derivatives in an effective amount for at least one of (i) treating a mitochondrial-related disease or a condition associated with altered mitochondrial function, reducing its incidence, or reducing its severity, (ii) improving a physiological condition associated with metabolic fatigue in one or more cells, (iii) increasing mitochondrial energy and mitochondrial calcium uptake in one or more cells, and (iv) treating or preventing a calcium deficiency / depletion disorder, (v) increasing the metabolic rate, (vi) improving or maintaining cognitive function, (vii) enhancing or maintaining mitochondrial function.

[0011]

[0011] In another embodiment, the present invention provides a kit comprising a combination of a combination of fisetin and / or its derivatives and quercetin and / or its derivatives in one or more containers.

Advantages of the Invention

[0012]

[0012] Advantages and additional features will become apparent from the following drawings and detailed description.

Brief Description of the Drawings

[0013]

Figure 1

[0013] Represents the chemical structures of fisetin (A) and quercetin (B).

Figure 2

[0014] It is a graph showing that the effect of the combination of fisetin and quercetin is greater than the effect of fisetin or quercetin alone on the activation of mitochondria by the increase in mitochondrial Ca2+ in HeLa cells. The bar graph shows the effects of fisetin (3 μM, black), quercetin (3 μM, gray), and a combination of 3 μM fisetin + 3 μM quercetin on the integrated mitochondrial calcium rise induced by 100 μM histamine. The results are presented as the mean ± SEM of n = 6 experiments. * indicates a statistically significant difference at P < 0.05 (one-way ANOVA test) regarding the difference between the measured and theoretical values in mitochondrial calcium.

Figure 3

[0015] It is a graph showing that in HeLa cells, fisetin synergistically acts with quercetin to activate mitochondria by the increase in mitochondrial Ca2+. To quantify the synergistic effect of the combination of quercetin and fisetin on mitochondrial activation, the predicted theoretical effect (the sum of the fisetin effect and the quercetin effect, extracted from the data in Figure 2) was compared with the actually measured effect of the combination (fisetin + quercetin, extracted from the data in Figure 2). The results are presented as the mean ± SEM of n = 6 experiments. * indicates a statistically significant difference at P < 0.05 (Student's t-test) regarding the difference between the measured and theoretical values in mitochondrial calcium.

Mode for Carrying Out the Invention

[0014]

[0016] Definitions

[0017] The following presents several definitions. However, there may be cases where the definition is in the "Embodiments" section below, and the above heading "Definitions" does not mean that such disclosure in the "Embodiments" section is not a definition.

[0015]

[0018] All percentages described in this specification are based on the total weight of the composition unless otherwise specified. As used herein, "about", "approximately", and "substantially" refer to numbers within a numerical range, for example, within a range of -10% to +10% of the reference number, preferably within a range of -5% to +5% of the reference number, more preferably within a range of -1% to +1% of the reference number, and most preferably within a range of -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 interpreted as supporting claims directed to any number or subset of numbers within this range. For example, the disclosure of 1 to 10 should be interpreted as corresponding to ranges such as 1 to 8, 3 to 7, 1 to 9, 3.6 to 4.6, 3.5 to 9.9, etc.

[0016]

[0019] 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, references to "(a) metabolite" or "(the) metabolite" include one metabolite but also include two or more metabolites.

[0017]

[0020] 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 unless such construction is 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.

[0018]

[0021] As used herein, "a composition consisting essentially of at least one fisetin or a derivative thereof" and "a composition consisting essentially of calcium and at least one fisetin or a derivative thereof" do not include any additional compounds that affect mitochondrial calcium transport other than at least one fisetin or a derivative thereof and optional calcium. In certain non - limiting embodiments, the composition consists of an excipient, at least one fisetin or a derivative thereof, and optionally calcium.

[0019]

[0022] The term "and / or" when 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 "both X and Y". For example, "at least one fisetin or a derivative thereof" means "fisetin" or "a derivative of fisetin" or "both fisetin and its derivatives".

[0020]

[0023] As used herein, the terms "example" and "such as" are merely illustrative and explanatory, especially when followed by a list of terms, and should not be construed as exclusive or inclusive. As used herein, "associated with" and "linked with" mean occurring simultaneously, preferably caused by the same underlying condition, and most preferably, one of the specified conditions is caused by another specified condition.

[0021]

[0024] 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. The compositions of the disclosure, including many of the embodiments described herein, may include, consist of, or consist essentially of the elements disclosed herein, as well as any additional or optional raw materials, components, or elements described herein or not described herein that are useful in a diet.

[0022]

[0025] As used herein, the terms "treating" and "treatment" mean administering to a subject having a condition, for the purpose of reducing, lessening or ameliorating at least one symptom associated with the condition and / or for the purpose of delaying, reducing or preventing the progression of the condition, a composition disclosed herein. The terms "treatment" and "treating" include both prophylactic or preventive treatment (treatment that prevents and / or delays the onset or progression of a targeted pathological condition or disorder) and curative, therapeutic, or disease-modifying treatment, for example, therapeutic means for the cure, delay, symptom alleviation, and / or arrest of progression of a diagnosed pathological condition or disorder, and treatment of patients at risk of developing, or suspected of having developed, and patients in poor health, or patients diagnosed with a disease or medical condition. The terms "treatment" and "treating" do not necessarily mean treating until the subject is cured. The terms "treatment" and "treating" also refer to maintaining and / or enhancing the health of an individual who is not suffering from a disease but is susceptible to developing an unhealthy condition. The terms "treatment" and "treating" are also intended to include the synergistic action, or otherwise potentiation, of one or more primary prophylactic or therapeutic means. By way of non-limiting example, treatment can be effected by a patient, caregiver, physician, nurse, or another medical professional.

[0023]

[0026] Treatment of both humans and animals is within the scope of the present disclosure. Preferably, at least one fisetin or a derivative thereof is administered in a serving or unit dosage form that provides a therapeutically effective amount or a prophylactically effective amount.

[0024]

[0027] The terms "prevent" and "prevention" mean administering to a subject that does not exhibit any symptoms of the condition a composition disclosed herein for the purpose of suppressing or preventing the occurrence of at least one symptom associated with the condition. Further, "prevention" includes a reduction in the risk, incidence, and / or severity of a condition or disorder.

[0025]

[0028] As used herein, an "effective amount" is an amount that treats or prevents a deficiency, treats or prevents a disease or medical condition, or more generally, reduces symptoms, manages disease progression, or provides nutritional, physiological, or medical benefits to an individual.

[0026]

[0029] Relative terms such as "improved", "increased / enhanced / augmented / elevated", "enhanced", etc. refer to the effect of a composition of an effective amount disclosed herein, i.e., a composition containing at least one fisetin or its derivative, compared to administration of the same composition over the same period of time of a composition lacking fisetin and fisetin derivatives.

[0027]

[0030] As used herein, "administering" includes providing an individual with the composition recited such that the individual can ingest the composition, and also includes simply the act of the individual itself ingesting the composition recited.

[0028]

[0031] "Animal" includes, but is not limited to, mammals such as rodents; aquatic mammals; domestic animals such as dogs, cats, and other pets; livestock such as sheep, pigs, cows, and horses; and humans. When the terms "animal", "mammal", or their plurals are used, these terms also apply to any animal to which the effect shown or intended, for example, by the animal's benefit from improved mitochondrial calcium transport, can be shown depending on the context of the situation. The term "individual" or "subject" is often used herein to refer to a human, but the present disclosure is not so limited. Thus, the term "individual" or "subject" refers to any animal, mammal, or human that can benefit from the methods and compositions disclosed herein.

[0029]

[0032] The term "pet" means any animal that can benefit from or tolerate the compositions provided by the present disclosure. For example, a pet may be an animal such as a bird, bovine, canine, equine, feline, goat, lupine, rodent, ovine, or swine, but a pet can be any suitable animal. The term "companion animal" means a dog or a cat.

[0030]

[0033] "Subject" or "individual" is a mammal, preferably a human. The term "elderly" in the context of humans means an age of at least 60 years, preferably over 63 years, more preferably over 65 years, and most preferably over 70 years. The term "older adult" in the context of humans means a postnatal age of 45 years or older, preferably over 50 years, more preferably over 55 years, and includes the elderly. The term "older adult" in the context of humans means a postnatal age of 45 years or older, preferably over 50 years, more preferably over 55 years, and includes the elderly.

[0031]

[0034] As used herein, "frail" is defined as a clinically distinguishable state in which, as a result of increased vulnerability due to a decline in reserve capacity and function across multiple biological systems with aging, the ability to cope with daily or acute stressors is impaired. A pre-frail stage in which one or two of these criteria are present is identified as having a high risk of progressing to frailty.

[0032]

[0035] As used herein, the terms "serving" or "unit dosage form" are interchangeable and refer to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined amount of a composition comprising at least one fisetin or a derivative thereof, preferably with a pharmaceutically acceptable diluent, carrier, or vehicle, in an amount sufficient to produce the desired effect. The specifications of the unit dosage form are determined by the specific compound used, the effect to be achieved, and the pharmacodynamics associated with each compound in the host body. In one embodiment, the unit dosage form can be a predetermined amount of liquid contained within a container such as a bottle.

[0033]

[0036] "Oral nutritional supplement" or "ONS" is a composition containing at least one macronutrient and / or at least one micronutrient, for example, in the form of a sterile liquid, semi-solid or powder, and is intended to supplement other nutritional intakes such as nutritional intake from food. Non-limiting examples of commercially available ONS products include MERITENE®, BOOST®, NUTREN®, and SUSTAGEN®. In some embodiments, the ONS can be ingested without further addition of liquid, for example, it can be a beverage in liquid form where the liquid volume is for one serving of the composition.

[0034]

[0037] As used herein, "incomplete nutrition" preferably refers to a nutritional product in which the macronutrients (protein, fat and carbohydrates) or micronutrients contained in the nutritional product are not at levels sufficient to be the sole source of nutrition for the animal to which the nutritional product is administered. The term "complete nutrition" refers to a product that can be the sole source of nutrition for the subject. An individual can obtain 100% of their nutritional requirements from a complete nutrient composition.

[0035]

[0038] "Kit" means that the components of the kit are physically associated in or with one or more containers and are regarded as one unit for manufacture, distribution, sale, or use. Containers include, but are not limited to, bags, boxes, cartons, bottles, packages of any type or design or material, overwraps, shrink wraps, attached components (such as stapled or glued ones), or combinations thereof.

[0036]

[0039] "Metabolic fatigue" means a decrease in mitochondrial function in one or more cells (such as one or more of the liver, kidney, brain, skeletal muscle) due to substrate deficiency in one or more cells and / or accumulation of metabolic products in muscle fibers, which inhibits either the release of calcium or the ability to stimulate mitochondrial function by calcium. Physiological states associated with metabolic fatigue may include muscle fatigue or muscle weakness, lack of energy, especially lack of physical energy, lack of vitality or muscle weakness.

[0037]

[0040] Embodiments

[0041] The present disclosure provides a composition comprising a combination of fisetin and / or its derivatives and quercetin and / or derivatives in a therapeutically effective amount for use in (i) improving physiological states associated with metabolic fatigue in one or more cells, (ii) increasing mitochondrial energy and mitochondrial calcium uptake in one or more cells, and (iii) enhancing antioxidant capacity, reducing oxidative stress and / or enhancing mitochondrial function, (iv) treating or preventing calcium deficiency / depletion disorders in an individual.

[0038]

[0042] Fisetin (7,3’,4’-flavon-3-ol) (see Figure 1) is a polyphenol found in many plants and functions as a yellow / ochre colorant. Fisetin is also found in many fruits and vegetables such as strawberries, apples, persimmons, grapes, onions, and cucumbers.

[0039]

[0043] In one embodiment, at least a portion of the fisetin is obtained by known means, for example, by extraction from plant / vegetable / fruit sources of fisetin. Additionally or alternatively, at least a portion of the fisetin and / or derivatives can be obtained by chemical synthesis.

[0040]

[0044] Non-limiting examples of suitable derivatives of fisetin include these glucuronic acid conjugated forms, these sulfate forms, these derivatives and mixtures thereof. In a preferred embodiment, the derivative is gerardol.

[0041]

[0045] Quercetin is the aglycone form of many other flavonoid glycosides such as rutin and quercitrin found in citrus fruits, buckwheat and onions. Quercetin forms the glycosides quercitrin and rutin with rhamnose and rutinose respectively.

[0042]

[0046] Similarly, guaijaverin is 3-O-arabinoside, hyperoside is 3-O-galactoside, isoquercetin is 3-O-glucoside, spireoside is 4'-O-glucoside. Miquelianin is quercetin 3-O-β-D-glucuronopyranoside.

[0043]

[0047] In a preferred embodiment, the derivative of quercetin can be selected from the group consisting of quercetin 3-O-galactoside, quercetin 3-O-glucoside (isoquercetin), quercetin 3-O-xyloside, quercetin 3-O-rhamnoside (quercitrin), quercetin 3-O-glucuronide, quercetin 7-O-glucoside, quercetin 3-O-diglucoside, quercetin 3,4'-diglucoside, quercetin 3-O-rhamnoside-7O-glucoside, quercetin 3-O-rutinoside (rutin), quercetin 3-O-6''-acetylglucoside, quercetin 3-methyl ether, quercetin 3,3'-dimethyl ether, isorhamnetin, and mixtures thereof.

[0044]

[0048] Quercetin may be derived from any suitable raw material and / or may be chemically synthesized.

[0045]

[0049] In a preferred embodiment, fisetin, quercetin and derivatives are obtained from plant-based raw materials. For example, fisetin can be obtained from strawberries, apples, persimmons, grapes, onions, and cucumbers, etc. Quercetin can be obtained from onions, green tea, apples, berries, Ginkgo biloba, St. John's wort, American ginseng, and buckwheat tea, etc.

[0046]

[0050] The composition may also contain one or more additional bioactive compounds, for example, one or more compounds selected from the group consisting of antioxidants, anti-inflammatory compounds, glycosaminoglycans, prebiotics, fiber, probiotics, fatty acids, enzymes, minerals, trace elements, and vitamins. A "bioactive compound" is any compound that contributes to an individual's health or has an effect on the human body beyond meeting basic nutritional requirements. One or more additional bioactive compounds may be derived from natural sources. That is, the compound may be obtained from extracts of plants, animals, fish, fungi, algae, or microbial fermentates. Minerals are considered to be derived from natural sources. In a preferred embodiment, the enzyme may be a protease such as trypsin or an enzyme extract such as bromelain.

[0047]

[0051] The respective effective amounts of fisetin and / or its derivatives and quercetin and / or its derivatives vary depending on the specific composition, the age and condition of the user, and the specific disorder or disease being treated. However, in general embodiments, 0.001 mg to 1.0 g per day, preferably 0.01 mg to 0.9 g per day, more preferably 0.1 mg to 750 mg per day, more preferably 0.5 mg to 500 mg per day, and most preferably 1.0 mg to 200 mg per day can be administered to an individual. Furthermore, the inventors have found that the active dosage of fisetin or its derivative in the combination can be reduced for equivalent effectiveness.

[0048]

[0052] In some embodiments, the combination of fisetin or its derivative and quercetin or its derivative is administered in a composition further comprising calcium. At least a portion of the calcium may be one or more calcium salts such as calcium acetate, calcium carbonate, calcium chloride, calcium citrate, calcium gluceptate, calcium gluconate, calcium lactate, or mixtures thereof. In general embodiments, 0.1 g to 1.0 g of calcium per day, preferably 125 mg to 950 g of calcium per day, more preferably 150 mg to 900 mg of calcium per day, more preferably 175 mg to 850 mg of calcium per day, and most preferably 200 mg to 800 mg of calcium per day are administered to an individual.

[0049]

[0053] In alternative embodiments, the combination of fisetin and quercetin can be administered continuously in a composition separate from calcium. The term "continuously" means that at a first time, at least one fisetin or its derivative is administered without calcium, and at a second time (before or after the first time), calcium is administered without the combination of fisetin and quercetin, such that calcium and at least one fisetin or its derivative are administered sequentially. The time between successive administrations may be, for example, 1 second or several seconds, several minutes, or several hours on the same day; 1 day or several days, or several weeks in the same month; or 1 month or several months in the same year.

[0050]

[0054] Fisetin or a derivative thereof and quercetin or a derivative thereof can be formulated in a specific ratio. In some embodiments, the formulation may contain these components in the following exemplary ratios: 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:20. Each of these ratios can be fisetin:quercetin in some embodiments and quercetin:fisetin in other embodiments. Preferably, the ratio is from 1:1 to 1:10.

[0051]

[0055] In some embodiments, fisetin or a derivative thereof and quercetin or a derivative thereof are the only polyphenols in the composition and / or the only polyphenols administered to the individual.

[0052]

[0056] The composition may contain an effective amount of at least one fisetin or a derivative thereof. For example, one dose or administration of the composition can contain an effective amount, and the package can contain more than one dose or administration amount. Optionally, the composition may further contain calcium.

[0053]

[0057] The composition can contain food additives selected from the group consisting of acidulants, thickeners, pH buffering or adjusting agents, chelating agents, colorants, emulsifiers, excipients, flavoring agents, minerals, penetration enhancers, pharmaceutically acceptable carriers, preservatives, stabilizers, sugars, sweeteners, texturizers, vitamins, minerals, and combinations thereof.

[0054]

[0058] The combination of fisetin or a derivative thereof and quercetin or a derivative thereof can be administered in any composition suitable for human and / or animal ingestion. In a preferred embodiment, such combination is administered to the individual orally or enterally (e.g., by tube feeding). For example, such combination can be administered to the individual as a beverage, food product, capsule, tablet, powder or suspension.

[0055]

[0059] Non-limiting examples of suitable compositions include food compositions, dietary supplements, dietary supplements (e.g., liquid ONS), complete nutritional compositions, beverages, pharmaceuticals, oral nutritional supplements, medical foods, nutraceuticals, foods for special medical purposes (FSMP), powdered nutritional products that are reconstituted with water or milk before ingestion, food additives, medicaments, drinks, pet foods, and combinations thereof.

[0056]

[0060] Food products according to the present invention include dairy products, such as fermented dairy products such as yogurt and buttermilk; ice cream; condensed milk; milk, dairy cream; flavored milk drinks; whey-based drinks; toppings; coffee creamers; chocolate; cheese-based products; soups; sauces; purees; dressings; puddings; custards; infant foods; nutritional formulations, such as complete nutritional formulations for infants, children, teenagers, adults, the elderly, or the critically ill; cereals and cereal bars, by way of example.

[0057]

[0061] Drinks include, for example, milk- or yogurt-based drinks, fermented milk, protein drinks, coffee, tea, energy drinks, soy drinks, fruit drinks and / or vegetable drinks, fruit juices and / or vegetable juices.

[0058]

[0062] A combination of fisetin or a derivative and quercetin or a derivative can be administered in a food product further comprising a component selected from the group consisting of protein, carbohydrate, fat, and mixtures thereof.

[0059]

[0063] In one embodiment, the protein source is preferably a purified protein (i.e., isolated from the natural food raw material 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.

[0060]

[0064] Non-limiting examples of proteins or their sources 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), animals (e.g., meat, fish), grains (e.g., rice, corn), or vegetables (e.g., soybeans, peas). A source or a combination of multiple proteins may be used. Non-limiting examples of proteins or their sources include raw pea protein, raw pea protein isolate, raw 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 fully skimmed milk, yogurt, soy protein isolate, and soy protein concentrate, and combinations thereof. A source or a combination 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.

[0061]

[0065] The protein source can be provided by each amino acid, a polypeptide containing an amino acid, or a mixture thereof. In many treatments for muscle growth, muscle maintenance, and / or muscle enhancement, certain beneficial amino acids 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 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 (or all) of each amino acid, for example, leucine, isoleucine, and L-arginine.

[0062]

[0066] In one embodiment, the composition further includes a medium-chain triglyceride, for example, one or more of caproic acid, caprylic acid, capric acid, and lauric acid. In one embodiment, the composition further includes a phospholipid, for example, phosphatidylcholine.

[0063]

[0067] The composition may also contain a carbohydrate source and / or a fat source. Non-limiting examples of suitable fats include canola oil, corn oil, and high-oleic sunflower oil. Non-limiting examples of suitable carbohydrates include sucrose, lactose, glucose, fructose, corn syrup solids, maltodextrin, and mixtures thereof. Additionally or alternatively, dietary fiber may be added. Dietary fiber passes through the small intestine without being digested by enzymes and functions as a natural bulking agent and laxative. The dietary fiber may be soluble or insoluble, and generally a blend of two types is preferred. Non-limiting examples of suitable dietary fibers include soybeans, peas, oats, pectin, guar gum, partially hydrolyzed guar gum, gum arabic, fructooligosaccharides, acidic oligosaccharides, galactooligosaccharides, sialyllactose, and oligosaccharides derived from animal milk. A preferred fiber blend is a mixture of inulin and relatively short-chain fructooligosaccharides. In one embodiment, the fiber content is 2 - 40 g / L of the composition, for example 4 - 10 g / L.

[0064]

[0068] In addition to any calcium, one or more other minerals can be used in the composition. Non-limiting examples of suitable minerals include boron, chromium, copper, iodine, iron, magnesium, manganese, molybdenum, nickel, phosphorus, potassium, selenium, silicon, tin, vanadium, zinc, or combinations thereof.

[0065]

[0069] One or more other vitamins can be used in the composition. Non-limiting examples of suitable vitamins include vitamin A, vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin or niacinamide), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine, pyridoxal, or pyridoxamine, or pyridoxine hydrochloride), vitamin B7 (biotin), vitamin B9 (folic acid), and vitamin B12 (various cobalamins; generally, cyanocobalamin in vitamin supplements), vitamin C, vitamin D, vitamin E, vitamin K, folic acid and biotin), and combinations thereof. "Vitamin" includes compounds such as provitamins, their derivatives, and their analogs that are obtained naturally from plant and animal foods or synthesized.

[0066]

[0070] One or more food emulsifiers, such as diacetyl tartaric acid esters of monoglycerides and diglycerides, lecithin, and / or monoglycerides and diglycerides, etc., may be incorporated into the composition. Suitable salts and stabilizers may also be included.

[0067]

[0071] Any of various formulations for therapeutic administration can be used for 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 achieved by various methods including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, and intratracheal administration. The active ingredient may be systemic after administration or may 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.

[0068]

[0072] In pharmaceutical dosage forms, the compounds may be administered as pharmaceutically acceptable salts. They may also be used in suitable association with other pharmacologically active compounds. The following methods and additives are merely illustrative and in no way limiting.

[0069]

[0073] In oral formulations, the compounds can be used alone or in combination with suitable additives for manufacturing tablets, powders, granules or capsules, for example, in combination with conventional additives such as lactose, mannitol, corn starch or potato starch, in combination with binders such as crystalline cellulose, cellulose functional derivatives, gum arabic, corn starch or gelatin, in combination with disintegrants such as corn starch, potato starch or sodium carboxymethyl cellulose, in combination with lubricants such as talc or magnesium stearate; and, if desired, in combination with diluents, buffers, wetting agents, preservatives and flavoring agents, they can be used.

[0070]

[0074] The composition may be administered at least once a week, preferably at least twice a week, more preferably at least three or four days a week (e.g., every other day), most preferably at least five days a week, six days a week, or seven days 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 receive more than one administration per day. In some embodiments, the administration is continued throughout the remaining life of the individual. In other embodiments, the administration is carried out until no detectable symptoms of the medical condition remain. In a specific embodiment, the administration is carried out until a detectable improvement occurs for at least one symptom and, in further cases, is continued to maintain remission.

[0071] Treatment method

[0075] The compositions disclosed herein may be effective for: (i) improving a physiological state associated with metabolic fatigue in one or more cells, (ii) increasing mitochondrial energy and mitochondrial calcium uptake in one or more cells, and (iii) enhancing antioxidant capacity, reducing oxidative stress and / or enhancing mitochondrial function, (iv) treating or preventing calcium deficiency / exhaustion disorders in an individual.

[0072]

[0076] 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, and skeletal muscle.

[0073]

[0077] In another embodiment, metabolic fatigue includes lack of energy, particularly physical energy, lack of vitality or decreased muscle strength.

[0074]

[0078] In one embodiment, the invention relates to a method for preventing (e.g., reducing the incidence, frequency, and / or severity) or treating exercise-induced muscle fatigue, particularly reducing muscle fatigue, in an individual participating in exercise that includes at least one of 1) resistance exercise, 2) anaerobic exercise or repeated sprint-type exercise, or 3) endurance exercise, the method comprising orally administering to the individual an effective amount of a combination of fisetin and at least one quercetin or a metabolite thereof. In some embodiments, the method includes identifying the individual as having or being at risk of having the condition prior to administration.

[0075]

[0079] In one embodiment, the composition is administered in at least one dose during at least one period selected from the group consisting of (i) the pre-exercise period between 1 hour before the start of exercise and 1 second before the start of exercise, e.g., between 30 minutes before the start of exercise and 1 minute before the start of exercise, (ii) the exercise period from the start of exercise to the end of exercise, and (iii) the post-exercise period between 1 second after the end of exercise and 1 hour after the end of exercise, e.g., between 1 minute after the end of exercise and 30 minutes after the end of exercise.

[0076]

[0080] In another embodiment, the present disclosure provides a combination of fisetin and / or its derivatives and quercetin and / or its derivatives for treating or preventing (e.g., reducing the incidence and / or severity of) mitochondrial-related diseases or conditions associated with altered mitochondrial function in an individual in need of treatment or prophylaxis or at risk. The method comprises orally administering to an individual in need or at risk an effective amount of at least one fisetin or its derivative.

[0077]

[0081] Without being bound by theory, it is believed that various types of stress cause mitochondrial stress damage, reducing the ability of mitochondria to perform many of their essential roles in overall cellular 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.

[0078]

[0082] Mitochondrial diseases result from either inherited or spontaneous mutations in mitochondrial DNA or nuclear DNA, which cause changes in the function of proteins or RNA molecules normally present within the mitochondria. However, problems with mitochondrial function can affect only certain 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 clinically observed mitochondrial disease syndromes.

[0079]

[0083] Mitochondrial diseases are caused by damage to mitochondria, which are specialized compartments present in all cells of the body except red blood cells. Mitochondria are involved in the production of more than 90% of the energy required by the body to support life maintenance and growth. When mitochondria cease to function, the energy produced in cells decreases. Cells become 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.

[0080]

[0084] Mitochondrial diseases seem to cause the most damage to cells in the brain, heart, liver, skeletal muscle, kidneys, and cells of the endocrine and respiratory systems.

[0081]

[0085] Many symptoms in mitochondrial abnormalities are non-specific. 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 abnormalities, 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 high energy requirements of the brain such that patients are unable to produce sufficient ATP, psychological stressors often trigger symptoms.

[0082]

[0086] Depending on which cells are affected, symptoms may include loss of motor control, muscle weakness and pain, gastrointestinal disorders and swallowing difficulties, inadequate growth, heart disease, liver disease, diabetes, respiratory complications, seizures, visual / auditory problems, lactic acidosis, developmental delay, and increased susceptibility to infections.

[0083]

[0087] Mitochondrial diseases include, but are not limited to, Alpers syndrome, 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.

[0084]

[0088] Accordingly, one aspect of the present disclosure is a unit dosage form composition comprising fisetin and / or its derivatives and quercetin and / or derivatives in an effective amount for the treatment or prevention of at least one symptom selected from the group consisting of stress (e.g., childhood stress and / or its effects), obesity, decreased metabolic rate, metabolic syndrome, type 2 diabetes, hyperlipidemia, neurodegenerative diseases, cognitive impairment, stress-induced or stress-related cognitive dysfunction, mood disorders (e.g., stress-induced or stress-related mood disorders), anxiety disorders (e.g., stress-induced or stress-related anxiety disorders), and age-related neuronal death or dysfunction (e.g., age-related neuronal death or dysfunction not caused by specific neurodegenerative diseases), trauma, infections (e.g., ICU), or cancer.

[0085]

[0089] Another aspect of the present disclosure is a method of treating at least one symptom selected from the group consisting of stress, obesity, decreased metabolic rate, metabolic syndrome, type 2 diabetes, cardiovascular disease, hyperlipidemia, neurodegenerative diseases, cognitive impairment, stress-induced or stress-related cognitive impairment, mood disorders (e.g., stress-induced or stress-related mood disorders), anxiety disorders (e.g., stress-induced or stress-related anxiety disorders), and age-related neuronal death or dysfunction (e.g., age-related neuronal death or dysfunction not caused by specific neurodegenerative diseases), trauma, infections (e.g., ICU), or cancer in an individual having at least one symptom.

[0086]

[0090] 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.

[0087]

[0091] 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 impact on cognitive abilities, including psychological parameters such as the incidence or increased susceptibility to depression, anxiety, and abnormal risk-taking behavior. In individuals who have experienced childhood stress, a high incidence of attention deficit / hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), and major depression has been reported.

[0088]

[0092] Another aspect of the present disclosure is a method for delaying the onset of metabolic decline, maintaining muscle mass, reducing oxidative stress, maintaining immune function, and / or maintaining cognitive function in healthy adults or middle-aged and elderly individuals.

[0089]

[0093] 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 reduced sperm motility, macular degeneration, and other age-related and hereditary eye disorders and hearing loss (e.g., age-related hearing loss).

[0090]

[0094] Yet another aspect of the present disclosure is a unit dosage form comprising a combination of fisetin and / or its derivatives and quercetin and / or derivatives in an effective amount for at least one of (i) the treatment, reduction in incidence, or reduction in severity of mitochondrial-related diseases or conditions associated with altered mitochondrial function, (ii) the improvement of physiological states associated with metabolic fatigue in one or more cells, (iii) the increase in mitochondrial energy and mitochondrial calcium uptake in one or more cells, and (iv) the treatment or prevention of calcium deficiency / depletion disorders, (v) the increase in metabolic rate, (vi) the improvement or maintenance of cognitive function, (vii) the improvement or maintenance of mitochondrial function.

[0091]

[0095] In one embodiment, physiological states related to metabolic fatigue include muscle fatigue or muscle strength decline, lack of energy, lack of physical energy, lack of vitality or decline in vitality.

[0092]

[0096] In a further embodiment, the unit dosage form consists essentially of a combination of fisetin and / or its derivatives and quercetin and / or its derivatives. In some embodiments, one or more of these compounds may be isolated compounds.

[0093]

[0097] The present disclosure also provides a kit comprising, in one or more containers, a combination of a combination of fisetin and / or its derivatives and quercetin and / or its derivatives. In one embodiment of the kit, the one or more containers include at least one first container that houses fisetin and / or its derivatives separately from quercetin and / or its derivatives housed in at least one second container, and the kit further includes instructions for mixing fisetin with quercetin in a unit dosage form.

[0094]

[0098] In one embodiment of the kit, the combination may be provided together as one or more pre-packaged unit dosage forms, for example, provided as separate containers each containing a dry powder such that each container contains one pre-packaged unit dosage form.

[0095]

[0099] In another embodiment, the kit can include a plurality of compositions for mixing 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 that are related to each other, and each of these separate powders contains a portion of the final unit dosage form. As a non-limiting example of such an embodiment, the kit can include one or more first containers that house fisetin, and can also include one or more second containers that house quercetin. The contents of one of the first containers can be admixed with one of the second containers to form at least a portion of a unit dosage form of the composition.

[0096]

[0100] The above administration examples do not require continuous daily administration without interruption. Rather, there may be several short-term interruptions in administration, such as a 2- to 4-day interruption during the administration period. The ideal duration of continuous administration of the composition of the present invention can be determined by those skilled in the art.

Examples

[0097]

[0102] The following non-limiting examples show experimental data that support the compositions and methods disclosed herein.

[0098]

[0103] Example 1

[0104] To test the effects of fisetin, quercetin, and combinations thereof in living cells, the inventors measured mitochondrial calcium elevation in HeLa cells. HeLa cells were purchased from ATCC. HeLa cells were seeded at a density of 50,000 cells / well in 96-well plates in minimum essential medium (DMEM, Gibco), high glucose, +10% fetal bovine serum. Mitochondrial calcium measurements were performed using HeLa cells (from Sirion biotech) infected with an adenovirus expressing mitochondrial-targeted aequorin, a calcium sensor for mitochondria (Montero et al., 2004). For aequorin reconstitution, 1 μM of wild-type coelenterazine was added to the standard medium (145 mM NaCl, 5 mM KCl, 1 mM MgCl 2 , 1 mM CaCl 2, in 10 mM glucose and 10 mM Hepes, pH 7.4), the cells were incubated at room temperature (22 ± °C) for 2 hours. For the treatment, the compound was directly added to the cell culture or myotube culture 2 hours before the measurement. Luminescence was measured with FLIPR Tetra Aequorin (Molecular Devices). Calcium elevation in mitochondria was obtained by stimulating the cells with 100 μM histamine. Using the algorithm as described above, the conversion (Calibration) of luminescence data to calcium concentration was performed (Alvarez & Montero, 2002). For quantification, custom module analysis based on Excel (Microsoft) and GhaphPad Prism 7.02 (GrhaphPad) software was used.

[0099]

[0105] As shown in Figure 2, the effect of the combination of phycetin and quercetin is greater than the effect of phycetin or quercetin alone on the activation of mitochondria by the elevation of mitochondrial Ca2+ in HeLa cells. As shown in Figure 3, phycetin synergizes with quercetin to activate mitochondria by the elevation of mitochondrial Ca2+ in HeLa cells.

[0100]

[0106] 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 and without sacrificing the intended advantages. Accordingly, such changes and modifications are intended to be encompassed by the appended claims.

Claims

1. A composition comprising a combination of fisetin and / or its derivatives and quercetin and / or its derivatives in a therapeutically effective amount for use in the treatment or prevention of calcium deficiency / depletion disorders in an organism, comprising: (i) improvement of physiological conditions associated with metabolic fatigue in one or more cells; (ii) increased mitochondrial energy and mitochondrial calcium uptake in one or more cells; and (iii) increased antioxidant capacity, reduced oxidative stress and / or enhanced mitochondrial function; and (iv) a combination of fisetin and / or its derivatives and quercetin and / or its derivatives.

2. The composition for use according to claim 1, wherein 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, and skeletal muscle.

3. The composition for use according to claim 1, wherein the physiological state related to metabolic fatigue includes muscle fatigue or weakness, lack of energy, lack of physical energy, lack of vitality, or muscle weakness.

4. A composition for use according to claim 1, for preventing or treating muscle fatigue caused by exercise.

5. The composition for use according to claim 1, comprising administering the combination of the effective amount of fisetin and / or its derivative and quercetin and / or its derivative orally on a daily basis for at least one week.

6. The composition for use according to claim 1, wherein the derivative of fisetin is selected from the group consisting of these glucuronidated forms, these sulfate forms, these derivatives and mixtures, and is preferably geraldol.

7. The composition for use according to claim 1, wherein the quercetin derivative is selected from the group consisting of quercetin 3-O-galactoside, quercetin 3-O-glucoside (isoquercetin), quercetin 3-O-xyloside, quercetin 3-O-rhamnoside (quercitrin), quercetin 3-O-glucuronide, quercetin 7-O-glucoside, quercetin 3-O-diglucoside, quercetin 3,4'-diglucoside, quercetin 3-O-rhamnoside-7O-glucoside, quercetin 3-O-rutinoside (rutin), quercetin 3-O-6''-acetylglucoside, quercetin 3-methyl ether, quercetin 3,3'-dimethyl ether, isorhamnetin, and mixtures thereof.

8. The composition for use according to claim 1, further comprising at least one compound selected from the group consisting of antioxidants, anti-inflammatory compounds, glycosaminoglycans, prebiotics, fibers, probiotics, fatty acids, enzymes, minerals, trace elements and / or vitamins.

9. A composition for use according to claim 1, selected from the group consisting of food compositions, nutritional supplements, nutritional compositions, oral nutritional supplements, medical foods, nutraceuticals, beverages, powdered nutritional products that are reconstituted with water or milk before ingestion, food additives, foods for special medical purposes (FSMPs), pharmaceuticals, drinks, pet food, and combinations thereof.

10. A composition for use according to claim 1, which is in the form of a solid powder, powder stick, capsule, or solution.

11. The composition for use according to claim 1, wherein the combination of the effective amount of fisetin and / or its derivative and quercetin and / or its derivative is administered in a food product further comprising a component selected from the group consisting of proteins, carbohydrates, fats, and mixtures thereof.

12. A composition comprising a therapeutically effective dose of fisetin and / or its derivatives and quercetin and / or its derivatives for treating, reducing the incidence, and / or reducing the severity of mitochondrial-related diseases or conditions associated with altered mitochondrial function in individuals who require or are at risk of such conditions.

13. The composition for use according to claim 12, wherein the aforementioned mitochondrial-related disease or condition associated with altered mitochondrial function is selected from the group consisting of stress, physiological aging, obesity, decreased metabolic rate, metabolic syndrome, diabetes mellitus, complications of diabetes, hyperlipidemia, neurodegenerative disease, cognitive impairment, stress-induced or stress-related cognitive impairment, mood disorders, anxiety disorders, age-related neuronal cell death or dysfunction, musculoskeletal disorders, frailty, pre-frailty, chronic kidney disease, renal failure, trauma, infection, cancer, hearing loss, macular degeneration, myopathy and dystrophy, and combinations thereof.

14. A composition comprising a therapeutically effective amount of a combination of fisetin and / or its derivatives and quercetin and / or its derivatives for the purpose of delaying the onset of metabolic decline, maintaining muscle mass and / or muscle function, reducing oxidative stress, maintaining immune function, and / or maintaining cognitive function in healthy adults or middle-aged and elderly individuals.

15. A composition comprising a combination of fisetin and / or its derivatives and quercetin and / or its derivatives in a therapeutically effective amount for enhancing at least one of mental or muscular performance in an individual.

16. A composition comprising a combination of fisetin and / or its derivatives and quercetin and / or its derivatives in a therapeutically effective amount for improving or maintaining cognitive function in an individual.

17. The composition for use according to claim 15, 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.

18. A composition for use according to any one of claims 1 to 17, wherein the combination of the effective amount of fisetin and / or its derivative and quercetin and / or its derivative is administered with a composition further comprising calcium.

19. The composition for use according to any one of claims 1 to 17, wherein the individual is an adult, a middle-aged or elderly person, an elderly person, or an ICU patient.

20. A unit dosage form comprising, in an effective amount, a combination of fisetin and / or its derivatives and quercetin and / or its derivatives for at least one of the following: i) treatment of mitochondrial-related diseases or conditions associated with altered mitochondrial function, reduction of their incidence, or reduction of their severity; (ii) improvement of physiological conditions associated with metabolic fatigue in one or more cells; (iii) increase of mitochondrial energy and mitochondrial calcium uptake in one or more cells; and (iv) treatment or prevention of calcium deficiency / depletion disorders; (v) increase of metabolic rate; (vi) improvement or maintenance of cognitive function; or (vii) improvement or maintenance of mitochondrial function.

21. The unit dosage form according to claim 20, wherein the physiological state related to metabolic fatigue includes muscle fatigue or weakness, lack of energy, lack of physical energy, lack of vitality or decreased vitality.

22. The unit dosage form according to claim 20 or 21, which essentially consists of a combination of fisetin and / or its derivatives and quercetin and / or its derivatives.

23. A kit comprising one or more containers containing a combination of fisetin and / or its derivatives and quercetin and / or its derivatives.

24. The kit according to claim 23, wherein the one or more containers include at least one first container which contains the fisetin and / or derivative thereof separately from the quercetin and / or derivative thereof contained in at least one second container, and the kit further includes instructions for mixing the fisetin with the quercetin into unit dosage forms.

25. The kit according to claim 23 or 24, wherein each of the one or more containers contains a unit dosage form of a combination of fisetin and / or a derivative thereof and quercetin and / or a derivative thereof.

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