Compositions and methods using a combination of oleuropein and taurine

Abstract

A composition is provided that includes a combination of oleuropein or a metabolite thereof and taurine or a functional derivative thereof. The composition may be an oral nutritional composition, such as a dietary supplement, an oral nutritional supplement, a food product, or a food for special medical purposes (FSMP). The composition can be administered to an individual in need thereof for (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) improving antioxidant capacity, reducing oxidative stress, and / or enhancing mitochondrial function, or (iv) treating or preventing calcium deficiency / depletion disorders in the individual. Additionally or alternatively, the method can be used to treat or prevent a mitochondrial-related disease or condition associated with altered mitochondrial function in an individual in need of or at risk for such disease or condition.

Description

[Background technology]

[0001]

[0001] The present disclosure generally relates to compositions and methods for managing energy at the cellular level using a combination of oleuropein or a metabolite thereof and taurine or a metabolite thereof, in some embodiments, the compositions and methods can enhance mitochondrial function in middle-aged or elderly individuals, increasing bioenergetics through activation of the mitochondrial calcium uniporter, and thus promoting cellular activity.

[0002]

[0002] Population aging is a significant demographic phenomenon. As the growth of the elderly population exceeds the growth of the total population due to longer lifespans, the proportion of the elderly population to the rest of the population has increased significantly, partly due to declining birth rates. For example, in the 1950s, one in twelve people was aged 60 or older; by the end of the 2000s, this figure had fallen to one in ten. It is predicted that by the end of the 2050s, one in five people worldwide will be aged 60 or older.

[0003]

[0003] Middle-aged and elderly individuals often experience some degree of cognitive impairment, including progressive age-related decline in physical function and / or cognitive function, and age-related changes in brain morphology and cerebrovascular function are commonly observed. Cognitive decline has consistently 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, with the fronto-striatal system being the most severely damaged with age. This loss of cortical volume may be due to many deleterious cellular processes associated with normal aging, such as the long-term accumulation of free radical damage leading to oxidative damage, chronic low-grade inflammation, the accumulation of homocysteine ​​(which, if increased, is a risk factor for cognitive impairment and dementia), and declining 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] Mitochondria are the primary source of aerobic energy production in mammalian cells and maintain a large Ca2+ gradient across the inner membrane, providing signaling potential for these molecules. Furthermore, mitochondrial Ca2+ may play a role in regulating ATP production in mitochondria and contribute to orchestrating cellular metabolic homeostasis. (Glancy and Balaban, Biochemistry, 2012 Apr 10;51(14):2959-73). "Role of mitochondrial Ca2+ in the regulation of cellular energetics." Biochemistry 51(14):2959-2973. Alterations in mitochondrial Ca2+ homeostasis have been associated with various pathological conditions and are important in the pathogenesis of several human diseases. (Arduino et al. Journal Physiol. 2018 Jul;596(14):2717-2733).

[0005]

[0005] In recent years, nutrition, education, physical activity, and cognitive exercise have been demonstrated as potential interventions to prevent age-related physical and cognitive decline. Abundant 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 yielded mixed results (Schmitt et al., Nutrition Reviews 68:S2-S5 (2010)). Furthermore, while efforts have been made to harness the mitochondrial Ca2+ transport mechanism for therapeutic intervention, there are currently no pharmacological compounds that induce and selectively modulate mitochondrial Ca2+ homeostasis. Summary of the Invention

[0006]

[0006] In view of the experimental data disclosed later in this specification, the present inventors believe that the combination of oleuropein and taurine improves the efficiency of mitochondrial energy production.

[0007]

[0007] Thus, in a general embodiment, the present disclosure provides a composition comprising a therapeutically effective amount of a combination of oleuropein and / or metabolites and taurine and / or functional derivatives for use in improving a physiological condition associated with metabolic fatigue in one or more cells, (ii) increasing mitochondrial energy and mitochondrial calcium uptake in one or more cells, and (iii) improving antioxidant capacity, reducing oxidative stress and / or enhancing mitochondrial function, and (iv) treating or preventing calcium deficiency / depletion disorders in an individual.

[0008]

[0008] In another embodiment, the present disclosure provides a composition comprising a therapeutically effective amount of a combination of oleuropein and / or its metabolites with taurine and / or functional derivatives 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 middle-aged and older individuals.

[0009] In a further embodiment, the present disclosure also provides a method for manufacturing a semiconductor device comprising: i) enhancing at least one of mental or muscular performance in an individual; or ii) Improving or maintaining cognitive function in an individual The present invention provides a composition for the treatment of atopic dermatitis, the composition comprising a therapeutically effective amount of a combination of oleuropein and / or a metabolite thereof and taurine and / or a functional derivative thereof.

[0010]

[0010] In another embodiment, the present invention provides a unit dosage form comprising an effective amount of a combination of oleuropein and / or its metabolites in combination with taurine and / or functional derivatives for at least one of: (i) treating, reducing the incidence, or reducing the severity of a mitochondrial-related disease or a condition associated with altered mitochondrial function; (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 calcium deficiency / depletion disorders; (v) increasing metabolic rate; (vi) improving or maintaining cognitive function; and (vii) enhancing or maintaining mitochondrial function.

[0011]

[0011] In another embodiment, the present invention provides a kit comprising, in one or more containers, a combination of oleuropein and / or its metabolites in combination with taurine and / or functional derivatives.

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

[0013] [Figure 1] Graph showing that taurine supplementation enhances mitochondrial Ca2+ elevation in C2C12-derived myotubes. Statistical evaluation of the effect of taurine on the cumulative mitochondrial calcium elevation evoked by 5 mM caffeine. Taurine was used at the indicated concentrations (μM). Graph shows the average of 28 experiments. Results are expressed as mean ± SEM. * indicates statistically significant difference from control (white) with P<0.05 (one-way ANOVA test). [Figure 2]Co-supplementation of oleuropein (aglycone form) with taurine results in greater mitochondrial activation (measured as mitochondrial calcium elevation) than the effect of each compound alone. The effects of oleuropein aglycone (3 μM, black), taurine (200 μM, black), and the combination of 3 μM oleuropein aglycone and 200 μM taurine on mitochondrial activation, measured as cumulative mitochondrial calcium elevation, are shown in myotubes differentiated from C2C12 cells. Results are presented as mean ± SEM of n=28 experiments. * indicates statistical significance with P<0.05 (Student's t-test). [Figure 3] This graph shows that oleuropein (3 μM) synergizes with taurine (200 μM) to promote mitochondrial calcium elevation in C2C12 cell-derived myotubes. The graph, derived from the data shown in FIG. 2, compares the theoretical additive effect of taurine supplementation plus oleuropein (aglycone) supplementation with the measured effect of simultaneous supplementation of the taurine + oleuropein (aglycone) combination on mitochondrial calcium elevation. The theoretical effect is compared to the measured effect to estimate synergy. Data are the average of 28 experiments. Results are expressed as mean ± SEM. * indicates statistical significance at P<0.05 (Student's t-test) for the difference between measured and theoretical mitochondrial calcium. DETAILED DESCRIPTION OF THE INVENTION

[0014]

[0016] definition

[0017] Below are some definitions. 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.

[0015]

[0018] All percentages set forth herein are by weight of the total composition unless otherwise specified. As used herein, "about," "approximately," and "substantially" are understood to refer to numbers within a range of numerical values, e.g., within -10% to +10% of the referenced number, preferably within -5% to +5% of the referenced number, 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 that range. Furthermore, these numerical ranges should be interpreted as supporting claims directed to any number or subset of numbers within that range. For example, a disclosure of 1 to 10 should be interpreted as corresponding to ranges of 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 dictates otherwise. Thus, for example, reference to "a metabolite" or "the metabolite" includes one metabolite, but also includes two or more metabolites.

[0017]

[0020] The terms "comprise," "comprises," and "comprising" should be interpreted as inclusive rather than exclusive. Similarly, the terms "include," "including," and "or" should all be interpreted as inclusive unless such interpretation is clearly prohibited by context. However, the compositions disclosed herein may not include elements not specifically disclosed herein. Thus, disclosure of embodiments using the term "comprising" includes disclosure of embodiments "consisting essentially of" the specified components, as well as embodiments "consisting of" the specified components.

[0018]

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

[0019]

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

[0020]

[0023] As used herein, the terms "example" and "such as," particularly when followed by a list of terms, are merely exemplary and illustrative and should not be considered 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 the other specified condition.

[0021]

[0024] The terms "food," "food product," and "food composition" refer to a product or composition intended for consumption by an individual, such as a human, and which provides at least one nutrient to such an individual. The compositions of the present disclosure, including the many embodiments described herein, may comprise, consist of, or essentially consist of the elements disclosed herein, as well as any additional or optional ingredients, components, or elements described or not described herein that are useful in a diet.

[0022]

[0025] As used herein, the terms "treatment" and "treating" refer to administering a composition disclosed herein to a subject having a condition with the intent of attenuating, reducing, or ameliorating at least one symptom associated with the condition and / or slowing, reducing, or preventing the progression of the condition. The terms "treatment" and "treating" include both preventative or prophylactic treatments (treatments that prevent and / or slow the onset or progression of the targeted pathological condition or disorder) and curative, therapeutic, or disease-modifying treatments, including, for example, therapeutic measures to cure, delay, alleviate symptoms, and / or halt the progression of a diagnosed pathological condition or disorder, as well as treatment of patients at risk of or suspected of having the condition, and patients who are unwell or diagnosed with a disease or medical condition. The terms "treatment" and "treating" do not necessarily imply treating the subject until full recovery. The terms "treatment" and "treating" also refer to maintaining and / or promoting the health of an individual who is not afflicted with a disease but who may be susceptible to an ill-health condition. The terms "treatment" and "treating" are also intended to include the synergism or otherwise potentiation of one or more primary preventative or therapeutic measures. By way of non-limiting example, treatment can be performed by the patient, a caregiver, a doctor, a nurse, or another medical professional.

[0023]

[0026] Both human and animal treatments are within the scope of this disclosure. Preferably, at least one oleuropein or metabolite thereof is administered in a serving or unit dosage form that provides a therapeutically or prophylactically effective amount.

[0024]

[0027] The terms "prevent" and "prevention" refer to administering a composition disclosed herein to a subject not exhibiting any symptoms of the condition to reduce or prevent the onset of at least one symptom associated with the condition. Furthermore, "prevention" includes reducing 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 in an individual, or more generally, reduces symptoms, manages the progression of a disease, or provides a nutritional, physiological, or medical benefit to the individual.

[0026]

[0029] As used herein, "administering" includes another individual providing the referenced composition to an individual so that the individual can ingest the composition, and also simply includes the individual's own act of ingesting the referenced composition.

[0027]

[0030] "Animal" includes mammals, including, but not limited to, rodents; aquatic mammals; domestic animals, such as dogs, cats, and other pets; livestock, such as sheep, pigs, cattle, and horses; and humans. When "animal," "mammal," or their plural forms are used, these terms also apply, depending on the context, to any animal in which the effect exhibited or intended by the animal can be exhibited, for example, by the animal benefiting from improved mitochondrial calcium transport. The term "individual" or "subject" is often used herein to refer to a human, although 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.

[0028]

[0031] The term "pet" refers to any animal that can benefit from or enjoy the compositions provided by the present disclosure. For example, a pet may be an animal such as a bird, bovine, canine, equine, feline, caprine, wolf, murine, ovine, or porcine, although a pet may be any suitable animal. The term "companion animal" refers to a dog or cat.

[0029]

[0032] A "subject" or "individual" is a mammal, preferably a human. The term "older" in the human context means an age of at least 60 years, preferably greater than 63 years, more preferably greater than 65 years, and most preferably greater than 70 years. The term "older adult" in the human context means a postnatal age of 45 years or greater, preferably greater than 50 years, and more preferably greater than 55 years, and includes elderly people. The term "older adult" in the human context means a postnatal age of 45 years or greater, preferably greater than 50 years, and more preferably greater than 55 years, and includes elderly people.

[0030]

[0033] As used herein, "frailty" is defined as a clinically identifiable state in which increased vulnerability results from age-related declines in reserve and function across multiple biological systems, resulting in an impaired ability to cope with everyday 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.

[0031]

[0034] As used herein, the terms "serving" and "unit dosage form" are interchangeable and refer to physically discrete units suitable as single doses for human and animal subjects, each unit containing a predetermined amount of a composition comprising at least one oleuropein or metabolite thereof as disclosed herein, preferably with a pharmaceutically acceptable diluent, carrier, or vehicle, in an amount sufficient to produce a desired effect. The specifications for the unit dosage form depend on the particular compound used, the effect to be achieved, and the pharmacodynamics associated with each compound in the host. In one embodiment, the unit dosage form may be a predetermined amount of liquid contained in a container such as a bottle.

[0032]

[0035] An "oral nutritional supplement" or "ONS" is a composition containing at least one macronutrient and / or at least one micronutrient, e.g., in a sterile liquid, semisolid, or powder form, intended to supplement other nutritional intakes, such as those from food. Non-limiting examples of commercially available ONS products include MERITENE®, BOOST®, NUTREN®, and SUSTAGEN®. In some embodiments, an ONS can be a liquid beverage that can be consumed without the addition of additional liquid, e.g., the liquid volume is one serving of the composition.

[0033]

[0036] As used herein, "incomplete nutrition" preferably refers to a nutritional product that does not contain sufficient levels of macronutrients (protein, fat, and carbohydrates) or micronutrients to be the sole source of nutrition for the animal to which it is administered. The term "complete nutrition" refers to a product that can be the sole source of nutrition for a subject. An individual can obtain 100% of their nutritional needs from a complete nutritional composition.

[0034]

[0037] "Kit" means that the components of the kit are physically associated in or with one or more containers and are considered a single unit for manufacture, distribution, sale, or use. Containers include, but are not limited to, bags, boxes, cartons, bottles, packaging of any type or design or material, overwrap, shrink wrap, attached components (e.g., stapled or glued), or combinations thereof.

[0035]

[0038] "Metabolic fatigue" refers to a decline in mitochondrial function in one or more cells (e.g., one or more of the liver, kidney, brain, and skeletal muscle) due to a lack of substrates within one or more cells and / or accumulation of metabolic products within muscle fibers, which inhibits either calcium release or the ability of calcium to stimulate mitochondrial function. Physiological conditions associated with metabolic fatigue can include muscle fatigue or weakness, lack of energy, particularly lack of physical energy, lack of vitality, or weakness.

[0036]

[0039] Embodiment

[0040] The present disclosure provides compositions comprising a therapeutically effective amount of oleuropein and / or its metabolites in combination with taurine and / or functional derivatives for use in (i) improving physiological conditions associated with metabolic fatigue in one or more cells, (ii) increasing mitochondrial energy and mitochondrial calcium uptake in one or more cells, and (iii) improving antioxidant capacity, reducing oxidative stress and / or enhancing mitochondrial function, and (iv) treating or preventing calcium deficiency / depletion disorders in an individual.

[0037]

[0041] Oleuropein is a polyphenol found in the fruit, roots, stems, and more particularly the leaves of plants belonging to the Oleaceae family, in particular the olive (Olea europaea).

[0038]

[0042] In one embodiment, at least a portion of the oleuropein is obtained by extraction, for example, from a plant, such as one or more of the stems, leaves, fruits, or pits of a plant belonging to the Oleaceae family, preferably a plant belonging to the Oleaceae family, such as the olive (olive tree), plants of the genus Ligustrum, plants of the genus Syringa, plants of the genus Fraximus, plants of the genus Jasminum, and plants of the genus Osmanthus. Additionally or alternatively, at least a portion of the oleuropein and / or its metabolites can be obtained by chemical synthesis.

[0039]

[0043] Non-limiting examples of suitable metabolites of oleuropein include oleuropein aglycone, hydroxytyrosol, elenolic acid, homovanillyl alcohol, isohomovanillyl alcohol, glucuronidated forms thereof, sulfated forms thereof, derivatives thereof, and mixtures thereof.

[0040]

[0044] Taurine, also known as 2-aminoethanesulfonic acid, is an organic acid that occurs naturally in foods, particularly shellfish (e.g., scallops, mussels, clams), as well as dark meat from turkey and chicken, and other meats and eggs.

[0041]

[0045] Non-limiting examples of suitable functional derivatives of taurine include structural analogs of taurine, its metabolites, or acceptable salts thereof. Such compounds include, for example, taurolidine, taurultam, taurinamide, 1,4,5-oxathiazinane-4,4-dioxide, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, N-acyltaurine, acetylhomotaurine, N,N-diacetylsalicyloxyethyltaurine, acylmethyltaurine, homotaurine, or salts thereof, as described in "Taurine analogues; a new class of therapeutics: retrospect and prospects," Gupta et al., S. Curr. Med. Chem. 2005;12(17):2021-39.

[0042]

[0046] An example of a taurine metabolite is hypotaurine.

[0043]

[0047] The term "acceptable salt" means a salt selected because it is completely harmless insofar as the composition according to the invention is intended to be administered to an individual. Alkali metal or alkaline earth metal salts, in particular magnesium salts, manganese salts, iron(II) salts or zinc salts, are particularly suitable for the present invention in this respect.

[0044]

[0048] The taurine derivative may also be a natural extract rich in taurine (2-aminoethanesulfonic acid) or its derivatives. According to the present invention, it is preferred to use taurine or an acceptable salt thereof.

[0045]

[0049] According to a preferred embodiment, taurine and / or hypotaurine are used.

[0046]

[0050] The effective amount of each of oleuropein and / or its metabolites and taurine and / or its functional derivatives will vary depending on the specific composition, the age and condition of the recipient, and the specific disorder or disease being treated.

[0047]

[0051] However, in a typical embodiment, an individual can be administered 0.001 mg to 1.0 g / day, preferably 0.01 mg to 0.9 g / day, more preferably 0.1 mg to 750 mg / day, more preferably 0.5 mg to 500 mg / day, and most preferably 1.0 mg to 200 mg / day of oleuropein. Furthermore, the inventors have discovered that the active dose of oleuropein or a derivative in a combination can be reduced for comparable efficacy. In a typical embodiment, taurine, its functional derivatives, and / or acceptable salts thereof are used in a daily dose ranging from 1 to 3,000 mg / day, advantageously from 5 to 2,000 mg / day, and preferably from 10 to 300 mg / day. According to a preferred embodiment, the daily dose is about 50 to 150 mg / day. Doses indicated herein for taurine derivatives or salts thereof are doses in terms of taurine equivalents.

[0048]

[0052] In some embodiments, the combination of oleuropein or a metabolite and taurine or a functional 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 glubionate, calcium gluconate, calcium lactate, or mixtures thereof. In general embodiments, an individual is administered 0.1 g to 1.0 g of calcium per day, preferably 125 mg to 950 mg 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.

[0049]

[0053] In some embodiments, the combination of oleuropein or a metabolite and taurine or a functional 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 glubionate, calcium gluconate, calcium lactate, or mixtures thereof. In general embodiments, an individual is administered 0.1 g to 1.0 g of calcium per day, preferably 125 mg to 950 mg 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.

[0050]

[0054] In an alternative embodiment, the combination of oleuropein and taurine can be administered continuously with calcium in separate compositions. The term "continuously" refers to sequential administration of calcium and oleuropein or at least one of its metabolites, such that at a first time, oleuropein or at least one of its metabolites is administered without calcium, and at a second time (before or after the first time), calcium is administered without the combination of oleuropein and taurine. The time between consecutive administrations can be, for example, one or several seconds, minutes, or hours on the same day; one or several days, or several weeks on the same month; or one or several months on the same year.

[0051]

[0055] In some embodiments, oleuropein or a metabolite thereof and taurine or a functional derivative thereof are the only polyphenols in the composition and / or the only polyphenols administered to the individual.

[0052]

[0056] The composition may comprise an effective amount of oleuropein or at least one of its metabolites. For example, a single serving or dose of the composition may contain an effective amount, and a package may contain one or more servings or doses. Optionally, the composition may further comprise calcium.

[0053]

[0057] The composition can include a food additive selected from the group consisting of an acidulant, a thickener, a buffer or pH adjuster, a chelating agent, a colorant, an emulsifier, an excipient, a flavoring agent, a mineral, an osmotic agent, a pharmaceutically acceptable carrier, a preservative, a stabilizer, a sugar, a sweetener, a tonic, a vitamin, a mineral, and combinations thereof.

[0054]

[0058] The combination of oleuropein or a metabolite and taurine or a functional derivative can be administered in any composition suitable for human and / or animal consumption. In a preferred embodiment, the combination is administered to an individual orally or enterally (e.g., by tube feeding). For example, the combination can be administered to an 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 to be reconstituted with water or milk before ingestion, food additives, medicaments, drinks, pet foods, and combinations thereof.

[0056]

[0060] Examples of food products according to the present invention include dairy products, such as fermented dairy products, e.g., yogurt, buttermilk, etc.; 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 formulas, e.g., complete nutritional formulas for infants, children, teenagers, adults, the elderly, or the seriously ill; cereals and cereal bars.

[0057]

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

[0058]

[0062] The combination of oleuropein or a metabolite and taurine or a functional derivative may be administered in a food product further comprising an ingredient selected from the group consisting of proteins, carbohydrates, fats, and mixtures thereof.

[0059]

[0063] In one embodiment, the protein source is preferably a purified protein (i.e., isolated from the natural food source in which the protein is produced). The protein content of the composition is preferably 20-99% by weight of the composition, such as 20-90% by weight of the composition, for example, 30-80% by weight of the composition, for example, 40-80% by weight of the composition, such as 50-80% by weight, for example, 40-70% by weight of the composition.

[0060]

[0064] Non-limiting examples of proteins or sources thereof suitable for use in the compositions 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., soy, pea). Combinations of sources or proteins may also be used. Non-limiting examples of proteins or sources thereof 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, as well as combinations thereof. Combinations of sources or proteins may also be used. Preferred proteins include pea protein, whey protein, soy protein, and casein, which may include, for example, sodium caseinate and calcium caseinate.

[0061]

[0065] The protein source can be provided by individual amino acids, polypeptides containing amino acids, or mixtures thereof. In many muscle growth, muscle maintenance, and / or muscle building treatments, 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 can be provided as protein sources or can be added to the main source of protein. Thus, the protein source in the composition can 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 contains 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.

[0062]

[0066] 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 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 enzymatically digested and functions as a natural bulking and laxative. Dietary fiber may be soluble or insoluble, with blends of the two generally being preferred. Non-limiting examples of suitable dietary fiber include soybean, pea, oat, pectin, guar gum, partially hydrolyzed guar gum, gum arabic, fructooligosaccharides, acid 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 from 2 to 40 g / L of the composition, for example from 4 to 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, pyridoxamine, or pyridoxine hydrochloride), vitamin B7 (biotin), vitamin B9 (folic acid), and vitamin B12 (various cobalamins; commonly cyanocobalamin in vitamin supplements), vitamin C, vitamin D, vitamin E, vitamin K, folic acid, and biotin), and combinations thereof. "Vitamins" includes compounds such as provitamins, their derivatives, and their analogs, which are naturally obtained from plant and animal foods or synthesized.

[0066]

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

[0067]

[0071] The compositions disclosed herein can be administered in any of a variety of formulations for therapeutic purposes. More specifically, pharmaceutical compositions can contain suitable pharmaceutically acceptable carriers or diluents and can be formulated as solid, semi-solid, liquid, or gaseous preparations, such as tablets, capsules, powders, granules, ointments, liquids, suppositories, injections, inhalants, gels, microspheres, and aerosols. Thus, administration of the compositions can be achieved in a variety of ways, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, and intratracheal administration. The active ingredient 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.

[0068]

[0072] In pharmaceutical dosage forms, the compounds may be administered as pharmaceutically acceptable salts. They may also be used in appropriate 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 producing 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, functional cellulose derivatives, gum arabic, corn starch, or gelatin; in combination with disintegrants such as corn starch, potato starch, or sodium carboxymethylcellulose; in combination with lubricants such as talc or magnesium stearate; and, if desired, in combination with diluents, buffers, wetting agents, preservatives, and flavorings.

[0070]

[0074] 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 receive one or more administrations per day. In some embodiments, administration continues for the remainder of the individual's lifespan. In other embodiments, administration is administered until there are no detectable symptoms of the medical condition. In specific embodiments, administration is administered until there is a detectable improvement in at least one symptom, and in further cases, is continued to maintain remission.

[0071] Treatment method

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

[0072]

[0076] In one embodiment, at least a portion of the one or more cells are part of at least one body part selected from the group consisting of liver, kidney, brain, and skeletal muscle.

[0073]

[0077] In another embodiment, metabolic fatigue includes a lack of energy, particularly physical energy, lack of vitality or weakness.

[0074]

[0078] In some embodiments, the methods include identifying the individual as having or at risk for the condition prior to administration.

[0075]

[0079] In another embodiment, the present disclosure provides a combination of oleuropein and / or its metabolites with taurine and / or functional derivatives for treating or preventing (e.g., reducing the incidence and / or severity of) a mitochondrial-associated disease or a condition associated with altered mitochondrial function in an individual in need of or at risk for such treatment or prevention. The method comprises orally administering an effective amount of at least one oleuropein or metabolite thereof to the individual in need of or at risk for such treatment.

[0076]

[0080] Without being bound by theory, it is believed that various types of stress lead to mitochondrial stress damage, thereby reducing the ability of mitochondria to perform the many roles essential to overall cellular function. The methods disclosed herein can be useful for treating conditions involving stress damage to mitochondria. This damage can be manifested in any of a number of ways, including, but not limited to, mitochondrial diseases.

[0077]

[0081] Mitochondrial diseases are the result of either inherited or spontaneous mutations in mitochondrial or nuclear DNA, which alter the function of proteins or RNA molecules normally present in mitochondria. However, problems with mitochondrial function may only affect specific 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 system involvement seen in clinical mitochondrial disease syndromes.

[0078]

[0082] Mitochondrial diseases result from damage to mitochondria, specialized compartments present in all cells of the body except red blood cells. Mitochondria are responsible for generating over 90% of the energy the body needs to sustain life and support development. When mitochondria stop functioning, less energy is produced in cells, leading to cell damage and even cell death. When this process repeats throughout the body, the entire system begins to break down, and this breakdown can severely threaten the individual's life. Mitochondrial diseases primarily affect children, but adult onset is also becoming more prevalent.

[0079]

[0083] Mitochondrial diseases are most likely to cause damage to cells of the brain, heart, liver, skeletal muscle, kidneys, and the endocrine and respiratory systems.

[0080]

[0084] Many symptoms of mitochondrial disorders are nonspecific. Symptoms may also show a temporary course with periodic worsening. In mitochondrial medicine review articles, among the various manifestations of mitochondrial diseases, transient migraine headaches, as well as muscle pain, gastrointestinal symptoms, tinnitus, depression, chronic fatigue, and diabetes are mentioned. In patients with mitochondrial disorders, 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 cause symptoms, possibly due to the brain's high energy demands, which prevent the patient from producing sufficient ATP.

[0081]

[0085] Depending on which cells are affected, symptoms can include loss of motor control, muscle weakness and pain, gastrointestinal problems and difficulty swallowing, poor growth, heart disease, liver disease, diabetes, respiratory complications, seizures, visual / hearing problems, lactic acidosis, developmental delays, and increased susceptibility to infections.

[0082]

[0086] Mitochondrial disorders include, but are not limited to, Alpers syndrome; Barth syndrome; beta-oxidation defects; 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's hereditary optic neuropathy; Leigh syndrome; lethal infantile cardiomyopathy. 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 recessive ataxia syndrome; muscular dystrophy, myoclonic epilepsy, and ragged-red fiber disease, myoneurogenic gastrointestinal encephalopathy; neuropathy, ataxia, retinitis pigmentosa, and ptosis; Pearson syndrome; POLG mutations; pyruvate carboxylase deficiency; pyruvate dehydrogenase deficiency; SCHAD (short-chain acyl-CoA dehydrogenase deficiency); and very long-chain acyl-CoA dehydrogenase deficiency.

[0083]

[0087] Accordingly, one aspect of the present disclosure is a composition in unit dosage form comprising an effective amount of a combination of oleuropein and / or its metabolites and taurine and / or a functional derivative thereof for the treatment or prevention of a condition selected from the group consisting of at least 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 stress-related cognitive dysfunction, mood disorder (e.g., stress-induced or stress-related mood disorder), anxiety disorder (e.g., stress-induced or stress-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.

[0084]

[0088] Another aspect of the present disclosure is a method of treating at least one symptom 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 stress-related cognitive dysfunction, mood disorder (e.g., stress-induced or stress-related mood disorder), anxiety disorder (e.g., stress-induced or stress-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 symptom.

[0085]

[0089] 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 increased free fatty acids. In one embodiment of these methods, the age-related neuronal death or dysfunction treated or prevented is by administration of a composition to a middle-aged or elderly subject, e.g., an elderly subject.

[0086]

[0090] The stress to be treated or prevented can be early life stress, i.e., stress experienced during the first five years of life. Early life stress has been reported to have significant adverse effects on psychological parameters, such as cognitive ability, including increased incidence or susceptibility to depression, anxiety, and abnormal risk-taking behavior. Individuals who have experienced early life stress have been reported to have higher incidences of attention deficit / hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), and major depression.

[0087]

[0091] 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 and older adults.

[0088]

[0092] 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 improved mitochondrial function produces 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 genetic eye disorders and hearing loss (e.g., age-related hearing loss).

[0089]

[0093] Yet another aspect of the present disclosure is a unit dosage form comprising an effective amount of a combination of oleuropein and / or its metabolites and taurine and / or functional derivatives for at least one of: i) treating, reducing the incidence of, or reducing the severity of a mitochondrial-related disease or a condition associated with altered mitochondrial function; (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 calcium deficiency / depletion disorders; (v) increasing metabolic rate; (vi) improving or maintaining cognitive function; and (vii) enhancing or maintaining mitochondrial function.

[0090]

[0094] In one embodiment, physiological conditions associated with metabolic fatigue include muscle fatigue or weakness, lack of energy, lack of physical energy, lack of vitality or weakness.

[0091]

[0095] In one embodiment, the present 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 comprising at least one of 1) resistance exercise, 2) anaerobic exercise or repeated sprint-type exercise, or 3) endurance exercise, comprising orally administering to the individual an effective amount of a combination of taurine or a functional derivative and at least one oleuropein or metabolite thereof. In some embodiments, the method comprises identifying the individual as having or at risk for a condition prior to administration.

[0092]

[0096] In one embodiment, the composition is administered in at least one dose during at least one time period selected from the group consisting of: (i) a pre-exercise time between 1 hour and 1 second before exercise begins, e.g., between 30 minutes and 1 minute before exercise begins; (ii) an exercise time from exercise begins to exercise end; and (i) a post-exercise time between 1 second and 1 hour after exercise ends, e.g., between 1 minute and 30 minutes after exercise ends.

[0093]

[0097] In further embodiments, the unit dosage form consists essentially of oleuropein and / or its metabolites in combination with taurine and / or functional derivatives, in some embodiments, one or more of these compounds may be isolated compounds.

[0094]

[0098] The present disclosure also provides a kit comprising a combination of oleuropein and / or its metabolites in combination with taurine and / or functional derivatives in one or more containers. In one embodiment of the kit, the one or more containers include at least one first container that contains oleuropein and / or metabolites separately from taurine and / or functional derivatives contained in at least one second container, and the kit further comprises instructions for combining the oleuropein with taurine to form a unit dosage form.

[0095]

[0099] In one embodiment of the kit, the combination may be provided together as one or more prepackaged unit dosage forms, for example, as separate containers each containing a dry powder, with each container containing one prepackaged unit dosage form.

[0096]

[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 related to each other, each containing 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 containing oleuropein and one or more second containers containing taurine. The contents of one of the first containers can be mixed with one of the second containers to form at least a portion of the unit dosage form of the composition.

[0097]

[0101] The above dosing examples do not require uninterrupted daily administration. Rather, administration may be interrupted by several short periods, such as a 2-4 day break during the administration period. The ideal duration of administration of the compositions of the present invention can be determined by one of skill in the art.

[0102] [Example]

[0098]

[0103] The following non-limiting examples provide experimental data supporting the compositions and methods disclosed herein.

[0099]

[0104] To test the effects of oleuropein (or oleuropein aglycone), taurine, and their combination in living cells, we measured mitochondrial calcium elevation in myotubes differentiated from C2C12 cells. C2C12 cells were purchased from ATCC. C2C12 cells were seeded in 96-well plates at a density of 8000 cells / well in DMEM high glucose (Gibco) plus 10% fetal bovine serum. Myotubes were differentiated by growing C2C12 cells in DMEM containing 2% horse serum for 4 days. Mitochondrial calcium measurements were performed using myotubes infected with an adenovirus (Sirion Biotech) expressing the mitochondrially targeted calcium sensor, mitochondrially localized modified aequorin (Montero et al., 2002 Biochem J. 2002 Jul 15;365(Pt 2):451-9). For aequorin reconstitution, 24 h after infection, myotubes were incubated for 2 h at room temperature (22°C) in standard medium (145 mM NaCl, 5 mM KCl, 1 mM MgCl2, 1 mM CaCl2, 10 mM glucose, and 10 mM Hepes, pH 7.4) supplemented with 1 μM wild-type coelenterazine. For treatment, compounds were added directly to cell or myotube cultures 2 h before measurement. Luminescence was measured using a FLIPR Tetra Aequorin (Molecular Devices). Conversion of luminescence data to calcium concentrations (calibration) was performed using an algorithm as previously described (Montero et al., 2002, Biochem J. 2002 Jul 15;365(Pt 2):451-9). Quantification was performed using a custom module analysis based on Excel (Microsoft) and GraphPad Prism 7.02 (GraphPad) software.

[0100]

[0105] As shown in Figure 1, taurine increased mitochondrial Ca in C2C12 myotubes.2+ Figure 2 also shows that co-supplementation of oleuropein (aglycone) with taurine results in greater mitochondrial activation (measured as mitochondrial calcium elevation) than the effect of each compound alone. As shown in Figure 3, oleuropein (aglycone) synergizes with taurine to promote mitochondrial calcium elevation during stimulation.

[0101]

[0106] It should be understood that various changes and modifications to the 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 present subject matter and without diminishing its intended advantages. Accordingly, such changes and modifications are intended to be covered by the appended claims.

Claims

1. A composition comprising a therapeutically effective amount of oleuropein and / or its metabolites in combination with taurine and / or functional derivatives for use in (i) improving physiological conditions 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) treating or preventing calcium deficiency / depletion disorders in an individual.

2. 2. The composition for use of 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 liver, kidney, brain, and skeletal muscle.

3. 3. The composition for use according to claim 1 or 2, wherein the physiological conditions associated with metabolic fatigue include muscle fatigue or weakness, lack of energy, lack of physical energy, lack of vitality or weakness.

4. A composition for use according to any one of claims 1 to 3 for preventing or treating exercise-induced muscle fatigue.

5. 5. The composition for use according to any one of claims 1 to 4, wherein the effective amount of a combination of oleuropein and / or its metabolites and taurine and / or functional derivatives is orally administered daily for at least one week.

6. 6. The composition for use according to any one of claims 1 to 5, wherein the metabolite of oleuropein is selected from the group consisting of oleuropein aglycone, hydroxytyrosol, elenolic acid, homovanillyl alcohol, isohomovanillyl alcohol, glucuronidated forms thereof, sulfated forms thereof, derivatives thereof, and mixtures thereof.

7. 7. The composition for use according to any one of claims 1 to 6, wherein the functional derivative of taurine is selected from the group consisting of taurolidine, taurultam, taurinamide, and 1,4,5-oxathiazinane-4,4-dioxide, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, N-acyltaurine, acetylhomotaurine, N,N-diacetylsalicyloxyethyltaurine, acylmethyltaurine, homotaurine, and hypotaurine.

8. 8. The composition for use according to any of claims 1 to 7, 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. 9. The composition for use according to any of claims 1 to 8, selected from the group consisting of food compositions, dietary supplements, nutritional compositions, oral nutritional supplements, medical foods, nutraceuticals, beverages, powdered nutritional formulations to be reconstituted with water or milk before ingestion, food additives, foods for special medical purposes (FSMP) medicinal products, drinks, pet foods, and combinations thereof.

10. The composition for use according to any one of claims 1 to 9, which is in the form of a solid powder, a powder stick, a capsule or a solution.

11. 11. The composition for use according to any of claims 1 to 10, wherein the effective amount of a combination of oleuropein and / or its metabolites and taurine and / or functional derivatives is administered in a food product further comprising an ingredient selected from the group consisting of proteins, carbohydrates, fats, and mixtures thereof.

12. 1. A composition for treating, reducing the incidence and / or reducing the severity of a mitochondrial-associated disease or a condition associated with altered mitochondrial function in an individual in need thereof or at risk thereof, comprising a therapeutically effective amount of a combination of oleuropein and / or its metabolites and taurine and / or functional derivatives thereof, said composition comprising a therapeutically effective amount of oleuropein and / or its metabolites and taurine and / or functional derivatives thereof in combination ... therapeutically effective amount of oleuropein and / or its metabolites and taurine and / or functional derivatives thereof in combination,

13. 13. The composition for use of claim 12, wherein the mitochondrial-related disease or condition is selected from the group consisting of stress, physiological aging, obesity, decreased metabolic rate, metabolic syndrome, diabetes mellitus, diabetic complications, hyperlipidemia, neurodegenerative diseases, cognitive impairment, stress-induced or stress-related cognitive dysfunction, 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 dystrophies, and combinations thereof.

14. A composition comprising a therapeutically effective amount of a combination of oleuropein and / or its metabolites with taurine and / or functional derivatives 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 middle-aged and older adults.

15. A composition comprising a therapeutically effective amount of a combination of oleuropein and / or its metabolites and taurine and / or functional derivatives thereof for enhancing at least one of mental performance or muscular performance in an individual.

16. A composition comprising a therapeutically effective amount of a combination of oleuropein and / or its metabolites and taurine and / or functional derivatives thereof for improving or maintaining cognitive function in an individual.

17. 17. The composition for use according to claim 16, 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. 18. The composition for use according to any one of claims 1 to 17, wherein the effective amount of a combination of oleuropein and / or its metabolites and taurine and / or functional derivatives is administered in a composition further comprising calcium.

19. The composition for use according to any one of claims 1 to 18, wherein the individual is a middle-aged or elderly person, an elderly person, or an ICU patient.

20. A unit dosage form comprising an effective amount of a combination of oleuropein and / or its metabolites in combination with taurine and / or functional derivatives for at least one of: (i) treating, reducing the incidence of, or reducing the severity of a mitochondrial-related disease or a condition associated with altered mitochondrial function; (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 calcium deficiency / depletion disorders; (v) increasing metabolic rate; (vi) improving or maintaining cognitive function; and (vii) improving or maintaining mitochondrial function.

21. 21. The unit dosage form of claim 20, wherein the physiological conditions associated with metabolic fatigue include muscle fatigue or weakness, lack of energy, lack of physical energy, lack of vitality, or weakness.

22. 22. A unit dosage form according to claim 20 or 21, consisting essentially of a combination of oleuropein and / or its metabolites and taurine and / or functional derivatives.

23. A kit comprising, in one or more containers, a combination of oleuropein and / or its metabolites and taurine and / or functional derivatives.

24. 24. The kit of claim 23, wherein the one or more containers include at least one first container that contains the oleuropein and / or metabolites separately from the taurine and / or functional derivatives contained in at least one second container, the kit further comprising instructions for combining the oleuropein with the taurine to form a unit dosage form.

25. 25. The kit of claim 23 or 24, wherein each of the one or more containers contains a unit dosage form of the combination of oleuropein and / or its metabolites and taurine and / or functional derivatives.

Images