Composition comprising trigonelline and urolithin

Abstract

Disclosed are compositions comprising urolithin, or a pharmaceutically acceptable salt thereof, and trigonelline, or a pharmaceutically acceptable salt thereof, and methods for increasing or maintaining mitochondrial function.

Description

Related applications

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 469,244, filed May 26, 2023. Background Technology

[0002] Urolithin has been shown to be effective in improving many health conditions, and it has been demonstrated to possess high bioactivity both in vitro and in vivo. Urolithin has been proposed as a treatment for various disorders, including those related to insufficient mitochondrial activity, such as obesity, memory decline, decreased metabolic rate, metabolic syndrome, diabetes, cardiovascular disease, hyperlipidemia, neurodegenerative diseases, cognitive impairment, mood disorders, stress, anxiety disorders, fatty liver disease, and for improving liver function and weight management. In particular, urolithin has been shown to have beneficial effects in enhancing muscle function.

[0003] Trigonelline is an alkaloid formed by the methylation of the nitrogen atom of nicotinic acid (vitamin B3). It is a product of nicotinic acid metabolism and is excreted in the urine of mammals. Trigonelline is a precursor to NAD+. + Important NAD in the pathway + Precursor. NAD + Trigonelline is an essential enzyme cofactor for the function of several enzymes involved in reduction-oxidation reactions and energy metabolism. It has been shown that trigonelline helps increase NAD+ levels in skeletal muscle cells and rodent tissues. + Horizontal. Its extension has also been shown. Elegant Concealed Pole nematodes The lifespan of the model (US 2022 / 0241259 A1). Furthermore, it has been shown to induce muscle mass in rodents (US9241938 B2; US 2011 / 0142974 A1). Summary of the Invention

[0004] One aspect of the invention is a composition comprising urolithin or a pharmaceutically acceptable salt thereof and trigonelline or a pharmaceutically acceptable salt thereof.

[0005] This article also provides methods for increasing or maintaining mitochondrial function, or for enhancing or maintaining muscle performance, the methods comprising administering an effective amount of the composition to a subject in need. Attached Figure Description

[0006] Figure 1 The diagram shows the induction of mitochondrial respiration with 50 μM urolithin A alone, 50 μM trigonelline alone, or a combination of both (basic, top); and the induction of mitochondrial respiration with 50 μM urolithin A alone, 50 μM trigonelline alone, or a combination of both (maximum, bottom).

[0007] Figure 2 The figures show basal (top) and maximal (bottom) mitochondrial respiration, expressed as oxygen consumption rate (OCR, pmol / min), normalized relative to cellular DNA content and expressed as fold changes relative to the basal respiration experimental conditions and the DMSO control. Cells were treated with urolithin A (UA) 6.25 uM and trigonelline (Trig) 500 uM, alone or in combination, as indicated. DMSO 0.1% was used as a control. Data are presented as mean + / - SD. One-way ANOVA, * p < 0.05. Detailed Implementation

[0008] definition For convenience, certain terms used in this specification, embodiments, and appended claims are collected herein before further description of the invention. These definitions should be read in light of the remainder of this disclosure and should be understood as those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0009] To facilitate understanding of the invention, certain terms and phrases are defined below and throughout the specification.

[0010] As used in this article, "urolithin" refers to compounds of formula I: (I) in R 1 R 2 R 3 R 4 R 5 R 6 R 7 and R 8 Independently select groups composed of H and OR; and R is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted monosaccharide, or substituted or unsubstituted oligosaccharide each time it appears.

[0011] In one implementation, "urolithin" refers to any one or a combination of urolithin A, urolithin B, urolithin C, and urolithin D.

[0012] In another implementation, "urolithin" refers to any one or a combination of urolithin A.

[0013] Compounds of Formula I can be prepared according to the procedures described in WO / 2015 / 100213 A2 or WO / 2019 / 168972 A1.

[0014] Trigonelline has the structure of formula II: (II).

[0015] Trigonelline salts refer to any salt form of trigonelline that can be used to formulate trigonelline into a nutritionally acceptable form. Examples of suitable trigonelline salts include sulfates, bisulfates, chlorides, phosphates, and citrates. The monohydrate form of trigonelline can also be used in the compositions of this invention.

[0016] In some embodiments, the trigonelline in the composition is a component of or derived from coffee bean extract.

[0017] In some embodiments, the trigonelline in the composition is a component of fenugreek or is derived from fenugreek.

[0018] In some embodiments, the trigonelline in the composition is a component of oats or is derived from oats.

[0019] In some embodiments, the composition comprises coffee bean extract.

[0020] In some embodiments, the composition comprises oat extract.

[0021] As used in this article, the article “a / an” refers to the grammatical object of one / a kind or more / a kind (i.e., at least one / a kind). For example, “a / a kind of element” refers to one / a kind of element or more / a kind of element.

[0022] As used herein in the specification and claims, the phrase “and / or” should be understood to mean “any one or both” of the elements so combined (i.e., elements that coexist in some cases and exist separately in others). Multiple elements listed with “and / or” should be understood in the same way, i.e., “one or more” of the elements so combined. In addition to the elements explicitly identified by the “and / or” clause, other elements may optionally be present, whether related to or unrelated to those explicitly identified. Thus, as a non-limiting example, when used in conjunction with open-ended language such as “comprising”, a reference to “A and / or B” may refer to only A (optionally including elements other than B) in one embodiment; only B (optionally including elements other than A) in another embodiment; both A and B (optionally including other elements) in yet another embodiment; and so on.

[0023] As used herein in the specification and claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” should be interpreted as inclusive, that is, including multiple elements or at least one element in a list of elements, but also including more than one element, as well as optional other items not listed. Only terms that clearly indicate the opposite meaning, such as “only one” or “exactly one”, or when used in the claims, “consisting of…”, will refer to multiple elements or exactly one element in a list of elements. In general, the term “or” as used herein, when followed by an exclusive term (such as “any,” “one of,” “only one of,” or “exact one of”), should be interpreted only to indicate an exclusive alternative (i.e., “one or the other but not both”). “Substantially consisting of…”, when used in the claims, should have the usual meaning as used in the field of patent law.

[0024] As used herein in the specification and claims, the phrase “at least one” when referring to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but does not necessarily include at least one of every element specifically listed in the list of elements, nor exclude any combination of elements in the list of elements. This definition also allows for the optional presence of elements other than those expressly identified in the list of elements referred to by the phrase “at least one”, whether related to or unrelated to the expressly identified elements. Thus, as a non-limiting example, “at least one of A and B” (or equivalently, “at least one of A or B”, or equivalently, “at least one of A and / or B”) may refer to at least one A in one embodiment, optionally including more than one A, but without B (and optionally including elements other than B); in another embodiment, refer to at least one B, optionally including more than one B, but without A (and optionally including elements other than A); in yet another embodiment, refer to at least one A, optionally including more than one A, and at least one B, optionally including more than one B (and optionally including other elements); and so on.

[0025] It should also be understood that, unless the context otherwise requires, in any method claimed herein that includes more than one step or action, the order of the steps or actions of the method is not necessarily limited to the order in which the steps or actions of the method are listed herein.

[0026] In the claims and the aforementioned description, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” and “consisting of” should be understood as open-ended, meaning including but not limited to. As explained in Section 2111.03 of the U.S. Patent Examination Procedure Manual, only the transitional phrases “consisting of” and “substantially consisting of” are closed or semi-closed transitional phrases, respectively.

[0027] As used herein, the term "prodrug" encompasses compounds that are converted into therapeutically active agents under physiological conditions. A common method for preparing prodrugs involves hydrolysis under physiological conditions to reveal selected moieties of the desired molecule. In other embodiments, the prodrug is converted via the enzymatic activity of the host animal.

[0028] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that participates in the transport or transfer of the subject chemical from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of compatibility with other components of the formulation, harmless to the patient, and substantially pyrogen-free. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered astragalus gum; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution. (19) ethanol; (20) phosphate buffer solution; and (21) other non-toxic and compatible substances used in the pharmaceutical composition. In some embodiments, the pharmaceutical composition of the present invention is pyrogen-free, i.e., it does not cause a significant increase in body temperature when administered to a patient.

[0029] The term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic or organic acid addition salt of a compound. These salts can be prepared in situ during the final separation and purification of the compound, or by reacting the purified free base form of the compound with a suitable organic or inorganic acid and then separating the resulting salt. Representative salts include hydrobromide, hydrochloride, sulfate, hydrogen sulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, methanesulfonate, glucono-p-ethyl, lacturonate, and laurylsulfonate, etc. (See, for example, Berge et al. (1977) "Pharmaceutical Salts") J. Pharm. Sci 66:1-19. In other cases, compounds used in the methods of this invention may contain one or more acidic functional groups and are therefore capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these cases, the term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic and organic base addition salt of one or more compounds. These salts can also be prepared in situ during the final separation and purification of one or more of the said compounds, or by reacting one or more purified compounds in their free acid form with a suitable base (such as a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation), with ammonia, or with a pharmaceutically acceptable primary, secondary, or tertiary organic amine. Representative alkali metal or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, etc. Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. (see, for example, Berge et al., ibid.).

[0030] The "therapeutic effective amount" (or "effective amount") of a compound used in treatment refers to the amount of a compound in a formulation which, when administered as part of a desired dosing regimen (to mammals, preferably humans), is of clinically acceptable standard or cosmetic purpose, such as to relieve symptoms, improve the condition, or slow the onset of a disease, based on a reasonable benefit / risk ratio suitable for any drug treatment.

[0031] The terms "preventive" or "therapeutic" treatment are recognized in the art and include the administration of one or more subject compositions to a host. Treatment is preventive (i.e., it protects the host from developing the unwanted disease) if it is administered before the clinical manifestation of an unwanted condition (e.g., a disease or other unwanted state in the host animal), and therapeutic (i.e., it is intended to alleviate, improve, or stabilize an existing unwanted condition or its side effects) if it is administered after the manifestation of the unwanted condition.

[0032] The terms "patient" or "subject" refer to a mammal in need of specific treatment. In some embodiments, the patient is a primate, canine, feline, or equine. In some embodiments, the patient is a human.

[0033] "Effective amount" is an amount sufficient to achieve a beneficial or desired result. For example, a therapeutic amount is an amount that achieves a desired therapeutic effect. This amount may be the same as or different from a preventive effective amount, which is the amount necessary to prevent the onset of disease or disease symptoms. An effective amount may be administered, applied, or dosed once or multiple times. The therapeutically effective amount of a composition depends on the composition chosen. The composition may be administered once or multiple times daily to once or multiple times weekly; including every other day. Those skilled in the art will understand that certain factors can affect the dosage and duration required for effective treatment of a subject, including but not limited to, the severity of the disease or condition, prior treatment, the subject's general health and / or age, and any other pre-existing conditions. Furthermore, treatment of a subject with a therapeutically effective amount of the composition described herein may include a single treatment or a series of treatments.

[0034] The terms “decrease,” “reduce,” “reduced,” “reduction,” “decrease,” or “inhibit” are generally used herein to mean a statistically significant reduction relative to a reference level. However, to avoid ambiguity, “reduce,” “reduction,” “decrease,” or “inhibit” generally mean a reduction of at least 10% compared to a reference level and may include, for example, a reduction of at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99% compared to a given entity or parameter, up to and including, for example, the complete absence of the given entity or parameter, or a reduction between 10% and 99% compared to the absence of a given treatment.

[0035] The terms “increased,” “increase,” “enhance,” or “activate” are generally used throughout this document to mean an increase in a statistically significant amount; to avoid any doubt, the terms “increased,” “increase,” “enhance,” or “activate” mean an increase of at least 10% compared to a reference level, such as at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at most and including 100% increase, or any increase between 10% and 100%, or at least about 2 times, or at least about 3 times, or at least about 4 times, or at least about 5 times, or at least about 10 times, or any increase between 2 times and 10 times or more compared to a reference level.

[0036] As used in this article, the term “regulation” includes both upregulation and downregulation, such as enhancing or inhibiting a response.

[0037] "Optional" or "optionally" means that the event or condition described below may or may not occur, and the description includes both the case where said event or condition occurs and the case where it does not occur. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.

[0038] As used herein, the term “treatment” in conjunction with a subject’s disease, symptom, or ailment means reducing at least one clinical or objective manifestation of a subject’s disease, symptom, or ailment to a detectable level. In one implementation, the term “treatment” in conjunction with a subject’s disease, symptom, or ailment means curing the subject’s disease, symptom, or ailment.

[0039] As used herein, “food product” means a product made from natural foods. Non-limiting examples of food products include fruit juices, wines, concentrated juices, jams, jellies, preserves, sauces, and extracts.

[0040] As used in this article, “nutritional supplement” refers to a product that is suitable for consumption or other application primarily because of its health-promoting properties rather than its calorie content.

[0041] As used herein, the term "alkyl" refers to a straight-chain or branched, acyclic or cyclic, unsaturated or saturated aliphatic hydrocarbon group containing a carbon atom. Representative saturated straight-chain alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, etc.; while saturated branched alkyl groups include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, etc. Representative saturated cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.; while unsaturated cyclic alkyl groups include cyclopentenyl and cyclohexenyl, etc. Unsaturated alkyl groups contain at least one double or triple bond between adjacent carbon atoms (referred to as "alkenyl" or "alkynyl," respectively). Representative straight-chain and branched alkenyl groups include vinyl, propenyl, 1-butenyl, 2-butenyl, isobutenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, etc.; while representative straight-chain and branched alkyne groups include ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, etc.

[0042] As used herein, the term "aryl" refers to a hydrocarbon ring system group comprising hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring. For the purposes of this invention, aryl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused or bridged ring systems. Aryl groups include, but are not limited to, aryl groups derived from anthracene, acenaphthene, phenanthrene, anthracene, azulene, benzene, arsenic, fluoranthene, fluorene, asymmetric indole, symmetric indole, indene, indene, naphthalene, phenanthracene, pleiadene, pyrene, and triphenylene. Unless otherwise specifically stated in the specification, the term "aryl" or the prefix "ar-" (as in "aralkyl") means including optionally substituted aryl groups.

[0043] As used herein, the term "monosaccharide" refers to a monosaccharide of the formula (CH₂O)n. Monosaccharides can be linear or cyclic systems and may contain sucrose units of the formula —CH(OH)—C(═O)—. Examples of monosaccharides include erythulose, threose, ribose, arabinose, xylose, lythulose, allose, adroose, glucose, mannose, gulose, idole, galactose, tarose, erythulose, ribulose, xyulose, allulose, fructose, sorbose, tagatose, erythpentulose, threpentulose, glycerotetrulose, pyranose, and furanose. In some embodiments, the monosaccharide refers to pyranose.

[0044] As used herein, the term “oligosaccharide” refers to a sugar consisting of at least two and at most 10 monosaccharide units linked by glycosides, preferably 2 to 8 monosaccharide units, more preferably 2 to 7 monosaccharide units, and even more preferably 2 to 6 or 2 to 5 monosaccharide units.

[0045] As used herein, the term "substituted" (e.g., in the context of substituted alkyl or substituted aryl) means that at least one hydrogen atom is substituted by a substituent. In the context of this invention, "substituent" includes halogen, hydroxyl, oxo, cyano, nitro, imino, thio, amino, alkylamino, dialkylamino, alkyl, alkoxy, alkylthio, haloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic and heterocyclic alkyl, and -NR. a R b -NR a C(=O)R b -NRaC(=O)NRaNRb, -NR a C(=O)OR b -NR a SO2R b -C(=O)R a -C(=O)OR a -C(=O)NR a R b -OC(=O)NR a R b -OR a -SR a -SOR a -S(=O)2R a -OS(=O)2R a -S(=O)2OR a =NSO2R a and -SO2NR a R b In the foregoing, R a and R b In this context, the substituents may be the same or different, and independently can be hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, or heterocyclic. Furthermore, the above substituents may be further substituted by one or more of the above substituents.

[0046] The composition of the present invention This article provides a composition comprising urolithin or a pharmaceutically acceptable salt thereof; and trigonelline or a pharmaceutically acceptable salt thereof.

[0047] This article also provides a composition comprising urolithin or a pharmaceutically acceptable salt thereof; and nicotinic acid or a pharmaceutically acceptable salt thereof.

[0048] This article also provides a composition comprising urolithin or a pharmaceutically acceptable salt thereof; trigonelline or a pharmaceutically acceptable salt thereof; and nicotinic acid or a pharmaceutically acceptable salt thereof.

[0049] In some implementations, urolithin is urolithin A.

[0050] In some implementations, urolithin is urolithin B.

[0051] In some implementations, urolithin is urolithin C.

[0052] In some implementations, urolithin is urolithin D.

[0053] In some implementations, urolithin is selected from the group consisting of: urolithin A, urolithin B, urolithin C, urolithin D, and any combination thereof.

[0054] In some implementations, urolithin is selected from the group consisting of urolithin A, urolithin B, and combinations of urolithin A and urolithin B.

[0055] In some implementations, trigonelline is trigonelline monohydrate.

[0056] In some implementations, trigonelline is trigonelline hydrochloride.

[0057] In some embodiments, the composition also includes a pharmaceutically acceptable carrier.

[0058] In some embodiments, the composition comprises 50 mg–500 mg of trigonelline or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, the composition comprises 70 mg–1050 mg of urolithin or a pharmaceutically acceptable salt thereof.

[0060] In some embodiments, the composition comprises about 500 mg or about 1000 mg of urolithin or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, the composition comprises about 140 mg to about 630 mg of urolithin or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, the composition comprises about 210 mg to about 560 mg of urolithin or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, the composition comprises about 140 mg to about 525 mg of urolithin or a pharmaceutically acceptable salt thereof.

[0064] In some embodiments, the composition comprises about 280 mg to about 490 mg of urolithin or a pharmaceutically acceptable salt thereof.

[0065] In some embodiments, the composition contains about 250 mg of urolithin or a pharmaceutically acceptable salt thereof.

[0066] In some embodiments, the composition comprises about 500 mg of urolithin or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments, the composition comprises about 1000 mg of urolithin or a pharmaceutically acceptable salt thereof.

[0068] In some embodiments, the composition comprises about 500 mg to about 2000 mg of nicotinic acid or a pharmaceutically acceptable salt thereof.

[0069] In some embodiments, the composition comprises about 500 mg, about 1000 mg, or about 2000 mg of nicotinic acid or a pharmaceutically acceptable salt thereof.

[0070] The method of the present invention This article provides a method for increasing or maintaining mitochondrial function, the method comprising administering an effective amount of the composition of the present invention to a subject in need, thereby increasing or maintaining mitochondrial function.

[0071] In some implementations, mitochondrial function is selected from mitochondrial respiration, mitochondrial activity, and / or mitochondrial biogenesis.

[0072] In some implementations, mitochondrial function is increased, mitochondrial activity is increased, and / or mitochondrial biogenesis is increased.

[0073] In some implementations, ATP levels are increased in the subject's tissues (e.g., muscle tissue).

[0074] In some implementations, autophagy (e.g., mitophagy) is increased in subjects.

[0075] In some implementations, nicotinamide adenine dinucleotide (NAD) + The production of this substance increased in the subjects.

[0076] This article provides a method to increase NAD + A method of generating NAD+, the method comprising administering an effective amount of the composition of the invention to a subject in need, thereby increasing NAD+. + produce.

[0077] The present invention provides a method for treating, preventing or controlling mitochondrial-related diseases or disorders associated with altered mitochondrial function or reduced mitochondrial density, the method comprising administering a therapeutically effective amount of the composition of the present invention to a subject in need, thereby treating, preventing or controlling the diseases or disorders associated with altered mitochondrial function or reduced mitochondrial density.

[0078] In some implementations, mitochondrial-related diseases or disorders are selected from obesity, decreased metabolic rate, metabolic syndrome, diabetes, cardiovascular disease, hyperlipidemia, neurodegenerative diseases, cognitive impairment, mood disorders, and stress and anxiety disorders.

[0079] In some implementations, mitochondrial-related diseases or disorders are declines in muscle or mental performance, age-related declines in mitochondrial function, or genetic diseases.

[0080] This article provides a method for increasing muscle mass or reducing the amount of muscle mass lost during periods of less muscle activity in combination with exercise, the method comprising administering an effective amount of the composition of the invention to a subject in need, thereby increasing muscle mass.

[0081] In some implementations, the application is performed during resistance training, bodybuilding, or weight training.

[0082] This article provides a method for enhancing or maintaining muscle performance, the method comprising administering an effective amount of the composition of the present invention to a subject in need, thereby enhancing muscle performance.

[0083] In some implementations, muscle performance is selected from strength, speed, and endurance.

[0084] In some implementations, the enhancement is improved muscle function.

[0085] In some implementations, the enhancement is improved muscle mass.

[0086] In some implementations, the method maintains muscle function.

[0087] In some implementations, the method maintains muscle mass.

[0088] In some implementations, the subjects suffer from cachexia or muscle atrophy.

[0089] In some implementations, the subjects do not have a viral infection.

[0090] This article provides a method for improving or increasing autophagy, the method comprising administering an effective amount of the composition of the present invention to a subject in need, thereby improving or increasing autophagy.

[0091] In some implementations, autophagy is mitochondrial autophagy.

[0092] In some implementations, the subjects are elderly subjects.

[0093] In some implementations, the subjects are healthy subjects, such as those who do not have cancer or are prone to developing cancer.

[0094] This article provides a method for treating, preventing, or controlling diseases selected from the group consisting of: muscle degenerative diseases, sarcopenia, muscular dystrophy, cardiomyopathy, Ulrich myopathy, obesity, cardiovascular diseases, atherosclerosis, and mitochondrial-related diseases associated with altered mitochondrial function or decreased mitochondrial density; or diseases related to metabolic function; the method comprising administering an effective amount of the composition of the invention to a vertebrate in need.

[0095] This article provides a method for preventing, treating, or controlling diseases selected from the group consisting of weakness, muscle atrophy, disuse atrophy, age-related skeletal muscle atrophy or impaired muscle strength and skeletal muscle injury; mitochondrial-related disorders associated with altered mitochondrial function or decreased mitochondrial density; disorders related to metabolic function; protecting against muscle injury or damage; protecting or maintaining the myocardium; improving muscle function, muscle strength, muscle mass, muscle endurance, post-exercise muscle recovery; improving balance or coordination; improving mitochondrial function; or weight management; said method comprising administering an effective amount of the composition of the invention to a vertebrate in need.

[0096] This article provides a method for treating diseases or disorders selected from the group consisting of sarcopenia, age-related sarcopenia, osteoarthritis, muscle atrophy, disuse atrophy of muscles, skeletal muscle atrophy, cardiac degeneration, age-related cardiac degeneration, and negative effects related to aging; improving activity during the aging process, reducing age-related cataracts, improving balance or coordination, and frailty, said method comprising administering a therapeutically effective amount of the composition of the invention to a subject in need.

[0097] In some embodiments, the composition is administered orally.

[0098] In some embodiments, the composition is applied topically.

[0099] In some implementations, the subjects are humans.

[0100] In some implementations, the person is an elderly person.

[0101] In some implementations, the person is an elderly person.

[0102] In some implementations, urolithiasis is administered in tablet or capsule form.

[0103] In some implementations, urolithiasis is administered over a period of at least about one month (e.g., at least about two months, at least about three months, at least about four months, at least about five months, at least about six months).

[0104] In some implementations, the person is at least about 40 years old (e.g., at least about 50 years old, at least about 60 years old, at least about 70 years old, at least about 80 years old, at least about 90 years old).

[0105] In some embodiments, the composition is applied at least weekly. In other embodiments, the composition is applied at least daily.

[0106] In some embodiments, the composition is administered in the form of a drug.

[0107] In some embodiments, the composition is administered in the form of a medical food.

[0108] In some embodiments, the composition is administered in the form of a functional food.

[0109] In some embodiments, the composition is applied in the form of a food additive.

[0110] In some embodiments, the composition is administered in the form of a dietary supplement.

[0111] In some embodiments, the composition is applied in the form of a food product.

[0112] Formulation and clinical use The composition can be administered to subjects (e.g., mammals) in a variety of ways. For example, the composition can be administered orally or parenterally. Parenterally administration includes, but is not limited to, intravenous, intramuscular, intraperitoneal, subcutaneous, intra-articular, intrasynovial, intraocular, intrathecal, topical, or inhalation. Therefore, urolithin dosage forms can be diverse, including natural foods, processed foods, natural fruit juices, concentrates and extracts, injectable solutions, microcapsules, nanocapsules, liposomes, ointments, inhalation forms, nasal sprays, nasal drops, eye drops, sublingual tablets, and sustained-release formulations.

[0113] The compounds of the present invention can be provided in an isolated form. As used herein, the term "isolated" means substantially removed from other compounds or components that might otherwise be present with the target compound, for example, as is found in nature. In one embodiment, the compound is isolated when it is substantially completely removed from other compounds or components that might otherwise be present with the target compound. In one embodiment, the compound is isolated when it is pure.

[0114] The compounds of the present invention can be incorporated into a variety of formulations for therapeutic administration. More specifically, the compounds of the present invention can be formulated into pharmaceutical compositions by combination with suitable pharmaceutically acceptable carriers or diluents, and can be formulated into formulations in solid, semi-solid, liquid, or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalers, gels, microspheres, and aerosols. Therefore, the administration of the compounds can be achieved in a variety of ways, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, percutaneous, and intratracheal administration. The active agent can be systemic after administration or localized by application to the site of use, internal administration, or by use of an implant that maintains an active dose at the implantation site.

[0115] The compounds of this invention can also be formulated into food additives, food ingredients, functional foods, dietary supplements, medical foods, nutritional health products, or food supplements.

[0116] In pharmaceutical dosage forms, compounds may be administered in the form of their pharmaceutically acceptable salts. They may also be used in appropriate combinations with other pharmaceutically active compounds. The methods and excipients described below are merely exemplary and in no way limiting.

[0117] For oral formulations, compounds may be used alone or in combination with appropriate additives to form tablets, powders, granules, or capsules, for example with conventional additives such as lactose, mannitol, corn starch, or potato starch; with binders such as crystalline cellulose, cellulose derivatives, gum arabic, corn starch, or gelatin; with disintegrants such as corn starch, potato starch, or sodium carboxymethyl cellulose; with lubricants such as talc or magnesium stearate; and (if necessary) with diluents, buffers, wetting agents, preservatives, and flavoring agents.

[0118] The compound can be formulated into an injectable formulation by dissolving, suspending or emulsifying it in an aqueous or non-aqueous solvent, such as vegetable oil or other similar oil, synthetic aliphatic acid glycerides, esters of higher fatty acids or propylene glycol; and, where necessary, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers and preservatives.

[0119] The compounds can be used in aerosol formulations for administration via inhalation. The compounds of the present invention can be formulated into pressurized, acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, etc.

[0120] Furthermore, the compounds can be formulated into suppositories by mixing with various matrices such as emulsion matrices or water-soluble matrices. The compounds of the present invention can be administered rectally via suppositories. Suppositories may include media such as cocoa butter, carbon wax, and polyethylene glycol, which melt at body temperature and solidify at room temperature.

[0121] Unit dosage forms (such as syrups, elixirs, and suspensions) for oral or rectal administration are available, wherein various dosage units (e.g., a teaspoon, a tablespoon, a tablet, or a suppository) contain a predetermined amount of a composition containing one or more compounds of the present invention. Similarly, unit dosage forms for injection or intravenous administration may comprise compounds of the present invention as a solution in sterile water, physiological saline, or another pharmaceutically acceptable carrier, wherein each dosage unit (e.g., mL or L) contains a predetermined amount of a composition containing one or more compounds of the present invention.

[0122] Implants for sustained-release formulations are well known in the art. Implants are formulated with biodegradable or non-biodegradable polymers into microspheres, sheets, etc. For example, polymers of lactic acid and / or glycolic acid form erosive polymers that are well tolerated by the host. Implants containing inhibitory compounds can be placed near the target site, resulting in an increased local concentration of the active agent relative to the rest of the body.

[0123] As used herein, the term "unit dosage form" refers to a physically discrete unit suitable for a single dose in human and animal subjects, each unit containing a predetermined amount of the compound of the invention associated with a pharmaceutically acceptable diluent, carrier, or medium, said predetermined amount being sufficient to produce the desired effect. The specifications of the novel unit dosage forms of the invention depend on the specific compound used and the effect to be achieved, as well as the pharmacodynamics associated with each compound in the host.

[0124] Pharmaceutically acceptable excipients, such as mediators, adjuvants, carriers, or diluents, are readily available to the public. Furthermore, pharmaceutically acceptable auxiliary substances, such as pH adjusters and buffers, tension modifiers, stabilizers, and wetting agents, are readily available to the public.

[0125] For clinical use, the composition is administered in a therapeutically effective amount.

[0126] The compounds of the present invention can also be formulated as food additives, food ingredients, functional foods, dietary supplements, medical foods, nutritional supplements, or food supplements. In some embodiments, the compounds of the present invention can be contained in nutritional beverages of varying volumes to allow for convenient administration of daily doses. As a non-limiting example, the beverage can deliver the effective dose in a final volume ranging from 5 mL to 1,000 mL, as a single or multiple dose delivery. In some embodiments, the compositions and methods of the present invention are used in non-human animals. Therefore, the compounds and compositions of the present invention can be formulated as veterinary products. The compounds and compositions can also be formulated as functional foods for administration to animals (e.g., dogs, cats, horses, etc.).

[0127] Dosing will typically be administered once daily to once weekly. In one implementation, dosing will be administered at least once weekly. For example, a subject may receive a dose once a week, twice a week, three times a week, or every other day. In another implementation, dosing will be administered at least once daily. For example, a subject may receive one or more doses daily.

[0128] It is believed that dosing for maximum efficacy in humans involves prolonged daily administration. Extended use is expected to include use for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or even longer.

[0129] For clinical use, urolithin is typically administered at a dose equal to or equivalent to 0.2–2000 mg urolithin / kg body weight / day. In one embodiment, urolithin is administered at a dose equal to or equivalent to 2–2000 mg urolithin / kg body weight / day. In one embodiment, urolithin is administered at a dose equal to or equivalent to 20–2000 mg urolithin / kg body weight / day. In one embodiment, urolithin is administered at a dose equal to or equivalent to 50–2000 mg urolithin / kg body weight / day. In one embodiment, urolithin is administered at a dose equal to or equivalent to 100–2000 mg urolithin / kg body weight / day. In one embodiment, urolithin is administered at a dose equal to or equivalent to 200–2000 mg urolithin / kg body weight / day.

[0130] Urolithiasis preparations can be administered to human subjects at therapeutically effective doses. Typical dose ranges are from approximately 0.01 micrograms / kg to approximately 2 mg / kg body weight / day. The dosage of the drug to be administered may depend on variables such as the type and severity of the condition, the overall health status of the specific subject, the specific compound administered, the excipients used to formulate the compound, and its route of administration. Routine experiments can be used to optimize the dosage and dosing frequency of any particular compound.

[0131] In one embodiment, urolithiasis is administered at concentrations ranging from about 0.001 micrograms / kg to greater than about 500 mg / kg. For example, the concentration can be 0.001 μg / kg, 0.01 μg / kg, 0.05 μg / kg, 0.1 μg / kg, 0.5 μg / kg, 1.0 μg / kg, 10.0 μg / kg, 50.0 μg / kg, 100.0 μg / kg, 500 μg / kg, 1.0 mg / kg, 5.0 mg / kg, 10.0 mg / kg, 15.0 mg / kg, 20.0 mg / kg, 25.0 mg / kg, 30.0 mg / kg, 35.0 mg / kg, 40.0 mg / kg, 45.0 mg / kg, 50.0 mg / kg, 60.0 mg / kg, 70.0 mg / kg, 80.0 mg / kg, 90.0 mg / kg, 100.0 mg / kg, 150.0 mg / kg, 200.0 mg / kg, 250.0 mg / kg. mg / kg, 300.0 mg / kg, 350.0 mg / kg, 400.0 mg / kg, 450.0 mg / kg up to greater than about 500.0 mg / kg or any increment thereof. It should be understood that the present invention is intended to cover all values ​​and ranges between these values ​​and ranges.

[0132] In one implementation, urolithiasis is administered at a dose ranging from about 0.2 mg / kg / day to more than about 100 mg / kg / day. For example, the dosage can be 0.2 mg / kg / day to 100 mg / kg / day, 0.2 mg / kg / day to 50 mg / kg / day, 0.2 mg / kg / day to 25 mg / kg / day, 0.2 mg / kg / day to 10 mg / kg / day, 0.2 mg / kg / day to 7.5 mg / kg / day, 0.2 mg / kg / day to 5 mg / kg / day, 0.25 mg / kg / day to 100 mg / kg / day, 0.25 mg / kg / day to 50 mg / kg / day, 0.25 mg / kg / day to 25 mg / kg / day, 0.25 mg / kg / day to 10 mg / kg / day, 0.25 mg / kg / day to 7.5 mg / kg / day, 0.25 mg / kg / day to 5 mg / kg / day, 0.5 mg / kg / day to 50 mg / kg / day, 0.5 mg / kg / day to 25 mg / kg / day. mg / kg / day, 0.5 mg / kg / day to 20 mg / kg / day, 0.5 mg / kg / day to 15 mg / kg / day, 0.5 mg / kg / day to 10 mg / kg / day, 0.5 mg / kg / day to 7.5 mg / kg / day, 0.5 mg / kg / day to 5 mg / kg / day, 0.75 mg / kg / day to 50 mg / kg / day, 0.75 mg / kg / day to 25 mg / kg / day, 0.75 mg / kg / day to 20 mg / kg / day, 0.75 mg / kg / day to 15 mg / kg / day, 0.75 mg / kg / day to 10 mg / kg / day, 0.75 mg / kg / day to 7.5 mg / kg / day, 0.75 mg / kg / day to 5 mg / kg / day, 1.0 mg / kg / day to 50 mg / kg / day, 1.0 mg / kg / day to 25 mg / kg / day mg / kg / day, 1.0 mg / kg / day to 20 mg / kg / day, 1.0 mg / kg / day to 15 mg / kg / day, 1.0 mg / kg / day to 10 mg / kg / day, 1.0 mg / kg / day to 7.5 mg / kg / day, 1.0 mg / kg / day to 5 mg / kg / day, 2 mg / kg / day to 50 mg / kg / day, 2 mg / kg / day to 25 mg / kg / day, 2 mg / kg / day to 20 mg / kg / day, 2 mg / kg / day to 15 mg / kg / day, 2 mg / kg / day to 10 mg / kg / day, 2 mg / kg / day to 7.5 mg / kg / day, or 2 mg / kg / day to 5 mg / kg / day.

[0133] In one embodiment, urolithiasis is administered at a dose ranging from about 0.25 mg / kg / day to about 25 mg / kg / day. For example, the dosage could be 0.25 mg / kg / day, 0.5 mg / kg / day, 0.75 mg / kg / day, 1.0 mg / kg / day, 1.25 mg / kg / day, 1.5 mg / kg / day, 1.75 mg / kg / day, 2.0 mg / kg / day, 2.25 mg / kg / day, 2.5 mg / kg / day, 2.75 mg / kg / day, 3.0 mg / kg / day, 3.25 mg / kg / day, 3.5 mg / kg / day, 3.75 mg / kg / day, 4.0 mg / kg / day, 4.25 mg / kg / day, 4.5 mg / kg / day, 4.75 mg / kg / day, 5 mg / kg / day, 5.5 mg / kg / day, 6.0 mg / kg / day, 6.5 mg / kg / day, 7.0 mg / kg / day, 7.5 mg / kg / day, 8.0 mg / kg / day, etc. mg / kg / day, 8.5 mg / kg / day, 9.0 mg / kg / day, 9.5 mg / kg / day, 10 mg / kg / day, 11 mg / kg / day, 12 mg / kg / day, 13 mg / kg / day, 14 mg / kg / day, 15 mg / kg / day, 16 mg / kg / day, 17 mg / kg / day, 18 mg / kg / day, 19 mg / kg / day, 20 mg / kg / day, 21 mg / kg / day, 22 mg / kg / day, 23 mg / kg / day, 24 mg / kg / day, 25 mg / kg / day, 26 mg / kg / day, 27 mg / kg / day, 28 mg / kg / day, 29 mg / kg / day, 30 mg / kg / day, 31 mg / kg / day, 32 mg / kg / day, 33 mg / kg / day, 34 mg / kg / day, 35 mg / kg / day, 36 ... mg / kg / day, 37 mg / kg / day, 38 mg / kg / day, 39 mg / kg / day, 40 mg / kg / day, 41 mg / kg / day, 42 mg / kg / day, 43 mg / kg / day, 44 mg / kg / day, 45 mg / kg / day, 46 mg / kg / day, 47 mg / kg / day, 48 mg / kg / day, 49 mg / kg / day, or 50 mg / kg / day.

[0134] In another embodiment, urolithin is administered at concentrations ranging from 0.01 μmol to greater than or equal to 500 μmol. For example, the dosage may be 0.01 μmol, 0.02 μmol, 0.05 μmol, 0.1 μmol, 0.15 μmol, 0.2 μmol, 0.5 μmol, 0.7 μmol, 1.0 μmol, 3.0 μmol, 5.0 μmol, 7.0 μmol, 10.0 μmol, 15.0 μmol, 20.0 μmol, 25.0 μmol, 30.0 μmol, 35.0 μmol, 4... 0.0 μmol, 45.0 μmol, 50.0 μmol, 60.0 μmol, 70.0 μmol, 80.0 μmol, 90.0 μmol, 100.0 μmol, 150.0 μmol, 200.0 μmol, 250.0 μmol, 300.0 μmol, 350.0 μmol, 400.0 μmol, 450.0 μmol to greater than about 500.0 μmol or any increment thereof. It should be understood that this invention is intended to cover all values ​​and ranges between these values ​​and ranges.

[0135] In yet another implementation, urolithiasis is administered at concentrations ranging from 0.10 μg / mL to 500.0 μg / mL. For example, the concentration can be 0.10 μg / mL, 0.50 μg / mL, 1 μg / mL, 2.0 μg / mL, 5.0 μg / mL, 10.0 μg / mL, 20 μg / mL, 25 μg / mL, 30 μg / mL, 35 μg / mL, 40 μg / mL, 45 μg / mL, 50 μg / mL, 60.0 μg / mL, 70.0 μg / mL, 80.0 μg / mL, 90.0 μg / mL, 100.0 μg / mL, 150.0 μg / mL, 200.0 μg / mL, 250.0 μg / mL, 300.0 μg / mL, 350.0 μg / mL, 400.0 μg / mL, 450.0 μg / mL to greater than about 500.0 μg / mL or any increment thereof. It should be understood that this invention is intended to cover all values ​​and ranges between these values ​​and ranges.

[0136] Further non-limiting illustrative examples of usable urolithiasis doses are provided in Table 1.

[0137] Table 1. Urolithiasis administration in mice and humans

[0138] Further non-limiting illustrative examples of the range of urolithiasis doses that can be used are provided in Table 2.

[0139] Table 2. Administration of urolithiasis in humans

[0140] Any dose can be given as a single dose or as multiple doses.

[0141] In one embodiment, urolithin is administered at a dose sufficient to achieve a peak serum level of at least 0.001 micromoles (μM) of urolithin and its known metabolites (glucuronic acid, sulfonates, etc.). In one embodiment, urolithin is administered at a dose sufficient to achieve a peak serum level of at least 0.01 μM of urolithin. In one embodiment, urolithin is administered at a dose sufficient to achieve a peak serum level of at least 0.1 μM of urolithin. In one embodiment, urolithin is administered at a dose sufficient to achieve a peak serum level of at least 1 μM of urolithin. In various embodiments, urolithin is administered at a dose sufficient to achieve a peak serum level of at least 10 μM, at least 20 μM, at least 30 μM, at least 40 μM, at least 50 μM, at least 60 μM, at least 70 μM, at least 80 μM, at least 90 μM, at least 100 μM, or at least 200 μM of urolithin.

[0142] In one embodiment, urolithin is administered at a dose sufficient to achieve a sustained serum level of at least 0.001 micromoles (μM). In one embodiment, urolithin is administered at a dose sufficient to achieve a sustained serum level of at least 0.01 μM. In one embodiment, urolithin is administered at a dose sufficient to achieve a sustained serum level of at least 0.1 μM. In one embodiment, urolithin is administered at a dose sufficient to achieve a sustained serum level of at least 1 μM. In one embodiment, urolithin is administered at a dose sufficient to achieve a sustained serum level of at least 10 μM, and urolithin is administered at a dose sufficient to achieve a sustained serum level of at least 50 μM. The sustained serum level can be measured using any suitable method, such as high-performance liquid chromatography (HPLC) or HPLC-MS.

[0143] In one embodiment, trigonelline is administered at a dose of 5 to 5,000 mg / day. In other embodiments, trigonelline is administered at a dose of 10 to 3,000 mg / day. In still other embodiments, trigonelline is administered at a dose of 50 to 500 mg / day.

[0144] In some implementations, trigonelline is administered at doses of 50-100 mg / day, 75-125 mg / day, 100-150 mg / day, 125-175 mg / day, 200-225 mg / day, or 250-300 mg / day.

[0145] Example The invention has now been generally described, and the invention will be more readily understood with reference to the following embodiments, which are for illustrative purposes only and are not intended to limit the invention.

[0146] Example 1: Synergistic effect of urolithin A and trigonelline on mitochondrial respiration Urolithin A and trigonelline were combined to treat rodent skeletal muscle cells, and mitochondrial respiration was measured.

[0147] method Fatty acid oxidation assays for C2C12 myotubes were performed using a Seahorse XF96 extracellular flux analyzer. C2C12 cells were seeded at 8,000 cells / well in XF96 cell culture microplates. Once cells reached confluence, they were differentiated for 5 days in DMEM (Gibco, 31966047) supplemented with 2% horse serum, 1% PenStrep, and 1% Hepes. Cells were treated for 24 hours in substrate-limiting medium (Gibco, A1443001) supplemented with 50 μM UA and 50 μM trigonelline (Sigma, T5509), which was supplemented with 0.5 mM glucose, 1 mM glutamine, 1% oleic acid, and 0.5 mM L-carnitine. Maximal respiration was monitored by injecting 3 µM FCCP into the chamber. Before the assay, cells were incubated for 20 minutes in fatty acid oxidation medium (111 mM NaCl, 4.7 mM KCl, 1.25 mM CaCl2, 2 mM MgSO4, 1.2 mM NaH2PO4, 5 mM L-carnitine, 5 mM hpes, 2.5 mM glucose), and the solution was adjusted to pH 7.4 at 37°C.

[0148] result Mouse muscle C2C12 myotubes were treated for 24 hours with urolithin A alone, trigonelline alone, or a combination of both compounds. Urolithin A alone induced mitochondrial respiration. Figure 1 As previously shown (Ryu, D. et al. Nature Medicine 2016, 22, 879). Use of trigonelline alone also increased mitochondrial respiration (…). Figure 1 This was unexpected because this dose of trigonelline did not show a significant biological effect on NAD production in human cells (see US 2022 / 0241259 A1). Figure 1 ).

[0149] Surprisingly, the combination of urolithin A (UA) and trigonelline (TRIG) showed a synergistic effect on basal levels of mitochondrial respiration. Figure 1 (See the image above), and also shows a maximum increase in level when combined ( Figure 1 (See the image below).

[0150] Example 2: Synergistic effect of urolithin A and trigonelline on mitochondrial respiration (human primary skeletal muscle myoblasts) Human primary skeletal muscle cells were treated with a combination of urolithin A and trigonelline, and mitochondrial respiration was measured.

[0151] method Mitochondrial respiration was measured as oxygen consumption on an HSMM (LZ-CC-2580, Lonza) using a Seahorse XF96 extracellular flux analyzer, specifically human primary skeletal muscle myoblasts. HSMM cells were seeded at 3,500 cells / well in XF96 cell culture microplates and cultured in SKM-M growth medium (AMSbio) at 37°C under humidified conditions of 5% CO2. The day after seeding, cells were treated for 24 hours in SKM-M growth medium with 6.25 μM UA and 500 μM trigonelline (Sigma, T5509). Oxygen consumption was measured in Krebs circulating medium (135 mM NaCl, 3.6 mM KCl, 0.5 mM NaH2PO4, 0.5 mM MgSO4, 10 mM HEPES, 5 mM NaHCO3) supplemented with 10 mM glucose, 10 mM pyruvate, and 2 mM glutamine. Maximum respiration was monitored by injecting 6 µM FCCP into the kit. To normalize for differences in cell number between wells, cellular DNA content was measured in the same microplate using the CyQuant NF kit (Thermofisher, C35006) according to the manufacturer's instructions. Normalized mitochondrial respiration was then calculated as the ratio between oxygen consumption rate and DNA content, expressed as a fold change relative to DMSO at baseline.

[0152] result Human HSMM cells were treated with urolithin A alone, trigonelline alone, or a combination of both compounds for 24 hours. Oxygen consumption values ​​were normalized relative to cellular DNA content. As previously shown in the C2C12 myocyte line, urolithin A alone induced mitochondrial respiration (Ryu, D. et al., Nature Medicine 2016, 22, 879). Trigonelline alone also increased mitochondrial respiration. This was unexpected, as trigonelline did indeed show an improvement in mitochondrial respiration in HSMM myocytes, only at higher doses of 1000 uM, after longer treatment (72 hours), and only by simultaneously blocking the NAD+ rescue pathway with FK866 (Membrez, M. et al., Nat Metab. 6, 433-447).

[0153] Surprisingly, the combination of urolithin A (UA) and trigonelline (TRIG) showed a significant synergistic effect on basal levels of mitochondrial respiration (p<0.05). Figure 2 (See the image above), and also shows a maximum increase in level when combined ( Figure 2 (See the image below).

[0154] By incorporating via reference All patents and published patent applications mentioned in the above description are incorporated herein by reference in their entirety.

[0155] Equivalent solution For clarity, the invention has now been described in detail by way of illustration and examples. It will be apparent to those skilled in the art that the invention can be practiced by modifying or altering the formulations and other parameters within a broad and equivalent range of conditions without affecting the scope of the invention or any particular embodiment thereof, and such modifications or alterations are intended to be included within the scope of the appended claims.

Claims

1. A composition comprising urolithin or a pharmaceutically acceptable salt thereof; and trigonelline or a pharmaceutically acceptable salt thereof.

2. The composition of claim 2, wherein the urolithin is urolithin A.

3. The composition according to claim 1 or 2, wherein the trigonelline is trigonelline monohydrate.

4. The composition according to any one of claims 1-3, wherein the composition further comprises a pharmaceutically acceptable carrier.

5. A method for increasing or maintaining mitochondrial function, the method comprising administering an effective amount of the composition of any one of claims 1-4 to a subject in need, thereby increasing or maintaining mitochondrial function.

6. The method of claim 5, wherein the mitochondrial function is selected from mitochondrial respiration, mitochondrial activity, and / or mitochondrial biogenesis.

7. A method for treating, preventing, or controlling mitochondrial-related diseases or disorders associated with altered mitochondrial function or reduced mitochondrial density, the method comprising administering to a subject in need a therapeutically effective amount of the composition of any one of claims 1-4, thereby treating, preventing, or controlling the diseases or disorders associated with altered mitochondrial function or reduced mitochondrial density.

8. The method of claim 7, wherein the mitochondrial-related disease or disorder is selected from obesity, decreased metabolic rate, metabolic syndrome, diabetes, cardiovascular disease, hyperlipidemia, neurodegenerative disease, cognitive impairment, mood disorder, stress and anxiety disorder.

9. A method for increasing muscle mass or reducing the amount of muscle mass lost during periods of less muscle activity in combination with exercise, the method comprising administering an effective amount of the composition of any one of claims 1-4 to a subject in need, thereby increasing muscle mass.

10. A method for enhancing or maintaining muscle performance, the method comprising administering an effective amount of the composition of any one of claims 1-4 to a subject in need, thereby enhancing muscle performance.

11. The method of claim 10, wherein the muscle properties are selected from strength, speed, and endurance.

12. The method of claim 10, wherein the enhancement is improved muscle function.

13. The method of claim 10, wherein the enhancement is improved muscle mass.

14. The method of any one of claims 9-13, wherein the subject suffers from cachexia or muscle atrophy.

15. A method for improving or increasing autophagy (e.g., mitophagy), the method comprising administering an effective amount of the composition of any one of claims 1-4 to a vertebrate in need.

16. The method of claim 16, wherein the autophagy is mitochondrial autophagy.

17. A method for treating, preventing, or controlling a disease selected from the group consisting of: muscle degenerative diseases, sarcopenia, muscular dystrophy, cardiomyopathy, Ulrich's myopathy, obesity, cardiovascular diseases, atherosclerosis, and mitochondrial-related diseases associated with altered mitochondrial function or decreased mitochondrial density; or diseases related to metabolic function; said method comprising administering to a vertebrate in need an effective amount of the composition of any one of claims 1-4.

18. A method for the prevention, treatment, or control of a disease selected from the group consisting of weakness, muscle atrophy, disuse atrophy of muscles, age-related skeletal muscle atrophy or impaired muscle strength and skeletal muscle injury; mitochondrial-related disorders associated with altered mitochondrial function or decreased mitochondrial density; and disorders related to metabolic function. Protects against muscle injury or damage; protects or maintains the heart muscle; improves muscle function, muscle strength, muscle mass, muscle endurance, and post-exercise muscle recovery; A method for improving balance or coordination; improving mitochondrial function; or weight management; said method comprising administering an effective amount of the composition of any one of claims 1-4 to a vertebrate in need.

19. A method for treating a disease or disorder selected from the group consisting of sarcopenia, age-related sarcopenia, osteoarthritis, muscle atrophy, disuse atrophy of muscles, skeletal muscle atrophy, cardiac degeneration, age-related cardiac degeneration, and negative effects related to aging; improving activity during the aging process, reducing age-related cataracts, improving balance or coordination, and frailty, said method comprising administering to a subject in need a therapeutically effective amount of the composition of any one of claims 1-4.

20. The method of any one of claims 1-19, wherein the composition comprises 50 mg to 500 mg of trigonelline or a pharmaceutically acceptable salt thereof.

21. The method of any one of claims 1-20, wherein the composition comprises 70 mg to 1050 mg of the urolithin or a pharmaceutically acceptable salt thereof.

22. The method of claim 21, wherein the composition comprises about 500 mg or about 1000 mg of the urolithin or a pharmaceutically acceptable salt thereof.

23. The method of any one of claims 1-22, wherein the composition is administered orally.

24. The method of any one of claims 1-22, wherein the composition is applied topically.

25. The method of any one of claims 1-24, wherein the subject is a human being.

26. The method of any one of claims 1-24, wherein the subject is an elderly person.

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