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WO2016044167A1 - Methods for increasing muscle strength and mobility in subjects experiencing significant physical inactivity using gamma linolenic acid - Google Patents

Methods for increasing muscle strength and mobility in subjects experiencing significant physical inactivity using gamma linolenic acid Download PDF

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Publication number
WO2016044167A1
WO2016044167A1 PCT/US2015/049990 US2015049990W WO2016044167A1 WO 2016044167 A1 WO2016044167 A1 WO 2016044167A1 US 2015049990 W US2015049990 W US 2015049990W WO 2016044167 A1 WO2016044167 A1 WO 2016044167A1
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WO
WIPO (PCT)
Prior art keywords
oil
subject
protein
mobility
linolenic acid
Prior art date
Application number
PCT/US2015/049990
Other languages
French (fr)
Inventor
Suzette Pereira
Neile Edens
Stephen Demichele
Original Assignee
Abbott Laboratories
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Publication of WO2016044167A1 publication Critical patent/WO2016044167A1/en

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A23L33/12—Fatty acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present disclosure relates to methods for increasing muscle strength and mobility in a subject experiencing significant physical inactivity by administering nutritional compositions containing gamma linolenic acid to the subject.
  • the methods include
  • a nutritional composition comprising at least one of protein and carbohydrate in addition to the fat.
  • Administration of the nutritional composition to the subject increases muscle strength and mobility of the subject by increasing levels of peroxisome proliferator- activated receptor ⁇ coactivator- ⁇ (PGC-l ) in muscle of the subject.
  • the disclosure provides a method of increasing muscle strength and mobility in an elderly individual.
  • the method includes administering 500 mg to 5 gm of gamma linolenic acid to the elderly individual per day as part of a nutritional composition comprising at least one of protein and carbohydrate in addition to fat.
  • the methods of the present disclosure involve administering
  • compositions containing gamma linolenic acid to an inactive individual to improve muscle strength and mobility in the individual.
  • the "nutritional composition” is suitable for enteral administration to a subject.
  • inactivity refers to infrequent movement of the limbs or body. “Inactivity” can result from hospitalization, restriction of movement by others, self-imposed restriction, mental or physical disease, or other condition. "Significant” inactivity as used herein, unless otherwise specified, refers to a period of inactivity of two or more days.
  • subject and “individual” as used herein, unless otherwise specified, refers to a mammal, including, but not limited to, a human (e.g., a toddler, child, or an adult), a domesticated farm animal (e.g., a cow, horse, or pig), or a pet (e.g., a dog or cat).
  • a human e.g., a toddler, child, or an adult
  • a domesticated farm animal e.g., a cow, horse, or pig
  • a pet e.g., a dog or cat
  • yielderly refers to a subject or individual at or above an age that is associated with frequent inactivity.
  • the various embodiments of the nutritional compositions used in the methods of the present disclosure may also be substantially free of any optional or selected essential ingredient or feature described herein, provided that the remaining composition still contains all of the required ingredients or features as described herein.
  • the term "substantially free” means that the selected product contains less than a functional amount of the optional ingredient, typically less than about 1%, including less than about 0.5%, including less than about 0.1%, and also including zero percent, by weight of such optional or selected essential ingredient.
  • the nutritional compositions and methods may comprise, consist of, or consist essentially of the essential elements of the products as described herein, as well as any additional or optional element described herein or otherwise useful in nutritional composition applications.
  • the nutritional compositions including gamma linolenic acid which are useful in the methods of the present disclosure, may be formulated in any known or otherwise suitable product form for enteral administration, including oral administration.
  • Oral product forms are generally preferred and include any solid, liquid, or powder formulation suitable for use herein, provided that such a formulation allows for safe and effective oral delivery of the essential and other selected ingredients from the selected product form.
  • Non-limiting examples of solid nutritional composition forms suitable for use in the methods herein include snack and meal replacement products, including those formulated as bars; sticks; cookies, breads, cakes, or other baked goods; frozen liquids; candy; breakfast cereals; powders, granulated solids, or other particulates; snack chips or bites; frozen or retorted entrees; and so forth.
  • liquid product forms suitable for use herein include snack and meal replacement products, hot or cold beverages, carbonated or non carbonated beverages, juices or other acidified beverages, milk or soy-based beverages, shakes, coffees, teas, enteral feeding compositions, and so forth.
  • compositions are most typically formulated as suspensions or emulsions, but can also be formulated in any other suitable forms such as clear liquids, substantially clear liquids, solutions, liquid gels, and so forth.
  • suitable oral product forms include semi-solid or semi-liquid compositions (e.g., puddings, gels), as well as more
  • the quantity of the nutritional composition for providing an effective amount of gamma linolenic acid to the targeted user may be contained in one or a plurality of individual dosage forms that may be administered in single or multiple dosages per day, per week, per month, or over another periodic basis determined to be appropriate for the individual.
  • the nutritional compositions may be administered as a sole (4-6 servings or 1-1.5 liters per day), primary, or supplemental (1-2 servings per day) source of nutrition.
  • the nutritional compositions include a protein source.
  • the protein source can be any protein source known in the art that can be used in a nutritional composition as disclosed herein.
  • Exemplary, non-limiting protein sources include whey protein concentrates, whey protein isolates, whey protein hydrolysates, acid caseins, sodium casemates, calcium casemates, potassium casemates, casein
  • milk protein concentrates milk protein isolates, milk protein hydrolysates, nonfat dry milk, condensed skim milk, soy protein concentrates, soy protein isolates, soy protein hydrolysates, pea protein concentrates, pea protein isolates, pea protein hydrolysates, collagen proteins, potato proteins, rice proteins, fungal proteins, insect proteins, algal proteins, and proteins expressed by microorganisms.
  • the nutritional compositions include one or more essential amino acids (i.e., isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine) provided as free amino acids.
  • essential amino acids i.e., isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine
  • freeform essential amino acids which may be included in the nutritional compositions include L-leucine, L-valine, L-isoleucine, and L-tryptophan.
  • the nutritional compositions include a carbohydrate.
  • the carbohydrate can include any carbohydrate known in the art that can be used in a nutritional composition as disclosed herein.
  • Exemplary, non-limiting carbohydrates include maltodextrin, hydrolyzed or modified starch or cornstarch, glucose polymers, corn syrup, corn syrup solids, rice-derived carbohydrates, high fructose corn syrup, honey, sugar alcohols, maltitol, erythritol, sorbitol, glycerine, sucrose, glucose, fructose, lactose, isomaltulose, sucromalt, pullulan, potato starch, and other slowly- digested carbohydrates, oligosaccharides including fructo-oligosaccharides, oat fiber, soy fiber, gum arabic, sodium carboxymethylcellulose, methylcellulose, guar gum, gellan gum, locust bean gum, konjac flour, hydroxypropyl methylcellulose, tragacanth gum, karaya gum, gum acacia, chitosan, arabinoglactins, glucomannan, xanthan gum, alginate, pectin, low
  • the nutritional compositions include a fat.
  • the fat can include any fat known in the art that can be used in a nutritional composition as disclosed herein.
  • Exemplary, non-limiting fats include borage oil, coconut oil, fractionated coconut oil, soy oil, corn oil, olive oil, safflower oil, high oleic safflower oil, medium chain triglyceride oil, high gamma linolenic acid safflower oil, sunflower oil, high oleic sunflower oil, palm oil, palm kernel oil, palm olein, canola oil, marine oils, algal oils, cottonseed oils, evening primrose oil, interesterified oils, and transesterified oils.
  • the fat includes an oil which is enriched in gamma linolenic acid.
  • Oils enriched in gamma linolenic acid include those oils with at least 20%, including at least 30%, and including at least 40% gamma linolenic acid, by weight of the oil.
  • Exemplary, non-limiting oils enriched in gamma linolenic acid suitable for use in the nutritional compositions disclosed herein include borage oil, and high gamma linolenic acid safflower oil.
  • Gamma linolenic acid for use as described herein can also be obtained from plants or cells genetically engineered to produce oils enriched in gamma linolenic acid.
  • the nutritional compositions containing gamma linolenic acid and macronutrients may also contain other optional ingredients that may modify the physical, nutritional, chemical, hedonic, or processing characteristics of the products or serve as pharmaceutical or additional nutritional components when used in a targeted population.
  • optional ingredients are known or otherwise suitable for use in nutritional compositions and may be used in the nutritional compositions described herein, provided that such optional ingredients are safe and effective for oral administration and are compatible with the essential and other ingredients in the selected product form.
  • preservatives antioxidants, emulsifying agents, buffers, fructooligosaccharides, pharmaceutical actives, additional nutrients as described herein, colorants, flavors, thickening agents and stabilizers, and so forth.
  • the nutritional compositions may further comprise vitamins or related nutrients, non-limiting examples of which include vitamin A, vitamin D, vitamin E, vitamin K, thiamine, riboflavin, pyridoxine, vitamin B12, carotenoids, niacin, folic acid, pantothenic acid, biotin, vitamin C, choline, inositol, salts, and derivatives thereof, and combinations thereof.
  • vitamins or related nutrients include vitamin A, vitamin D, vitamin E, vitamin K, thiamine, riboflavin, pyridoxine, vitamin B12, carotenoids, niacin, folic acid, pantothenic acid, biotin, vitamin C, choline, inositol, salts, and derivatives thereof, and combinations thereof.
  • the nutritional compositions may further comprise additional minerals, non-limiting examples of which include phosphorus, magnesium, calcium, sodium, potassium, molybdenum, chromium, selenium, chloride, and combinations thereof.
  • the nutritional compositions may also include one or more other compounds which contribute to muscle health.
  • the nutritional compositions include one or more of beta-hydroxy-beta-methylbutyrate (HMB), metabolites of leucine (alpha-ketoisocaproic acid, HICA), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), green tea polyphenols, curcumin, and polyphenols from cocoa and fruit extracts.
  • HMB beta-hydroxy-beta-methylbutyrate
  • HICA metabolites of leucine
  • DHA docosahexaenoic acid
  • EPA eicosapentaenoic acid
  • green tea polyphenols curcumin
  • curcumin polyphenols from cocoa and fruit extracts.
  • the nutritional compositions may be manufactured by any known or otherwise suitable method for making nutritional compositions, including nutritional liquids such as emulsions.
  • a nutritional liquid is prepared using at least three separate slurries, including a protein-in-fat (PIF) slurry, a
  • the PIF slurry is formed by heating and mixing the selected oils (e.g. , canola oil, corn oil, and fish oil) and then adding an emulsifier (e.g., lecithin), fat soluble vitamins, and a portion of the total protein (e.g. , milk protein concentrate) with continued heat and agitation.
  • oils e.g. , canola oil, corn oil, and fish oil
  • an emulsifier e.g., lecithin
  • fat soluble vitamins e.g., lecithin
  • a portion of the total protein e.g., milk protein concentrate
  • the CHO-MIN slurry is formed by adding, with heated agitation, to water: minerals (e.g., potassium citrate, dipotassium phosphate, and sodium citrate), trace and ultra trace minerals (TM/UTM premix), and thickening or suspending agents (e.g., Avicel, gellan, and carrageenan).
  • minerals e.g., potassium citrate, dipotassium phosphate, and sodium citrate
  • trace and ultra trace minerals TM/UTM premix
  • thickening or suspending agents e.g., Avicel, gellan, and carrageenan
  • the PIW slurry is then formed by mixing remaining protein (e.g., sodium caseinate and soy protein concentrate) with heat and agitation into water.
  • remaining protein e.g., sodium caseinate and soy protein concentrate
  • the resulting slurries are then blended together with heated agitation and the pH adjusted to the desired range, typically from 6.6-7.0, after which the composition is subjected to high-temperature short-time (HTST) processing during which the composition is heat treated, emulsified and homogenized, and then allowed to cool.
  • HTST high-temperature short-time
  • Water soluble vitamins and ascorbic acid are added, the pH is again adjusted to the desired range if necessary, flavors are added, and water is added to achieve the desired total solid level.
  • the composition is then aseptically packaged to form an aseptically packaged nutritional emulsion, or the composition is added to retort stable containers and then subjected to retort sterilization to form retort sterilized nutritional emulsions.
  • the nutritional solid such as a spray dried nutritional powder or dry- mixed nutritional powder, may be prepared by any collection of known or otherwise effective techniques, suitable for making and formulating a nutritional powder.
  • the spray drying step may likewise include any spray drying technique that is known for or otherwise suitable for use in the production of nutritional powders. Many different spray drying methods and techniques are known for use in the nutrition field, all of which are suitable for use in the manufacture of the spray dried nutritional powders herein.
  • One method of preparing the spray dried nutritional powder comprises forming and homogenizing an aqueous slurry or liquid comprising fat containing gamma linolenic acid, protein, and carbohydrate, and then spray drying the slurry or liquid to produce a spray dried nutritional powder.
  • the method may further comprise the step of spray drying, dry mixing, or otherwise adding additional nutritional ingredients, including any one or more of the ingredients described herein, to the spray dried nutritional powder.
  • the nutritional compositions including gamma linolenic acid are administered orally to an individual as needed to improve muscle strength and mobility.
  • the compositions can be administered to any individual who could benefit from improved muscle strength and mobility.
  • Such individuals include any individual undergoing a significant period of inactivity.
  • the individuals can be healthy or already suffer from one or more diseases or conditions such as sarcopenia, diabetes, insulin resistance, and obesity.
  • Other individuals who can benefit from the use of the compositions and methods disclosed herein include, without limitation, individuals who have experienced or are currently experiencing sickness, injury, bed rest and/or immobilization, surgery, recovery and/or rehabilitation, stress induced muscle wasting, catabolic conditions such as cancer, chronic obstructive pulmonary disease (COPD), and end-stage renal disease (ESRD).
  • COPD chronic obstructive pulmonary disease
  • ESRD end-stage renal disease
  • the individuals can be of any age group, in some embodiments, the methods are used with elderly individuals and other groups of individuals who may be at an increased risk of developing disease from inactivity.
  • Such increased risk may arise not only due to age, but also, e.g., due to genetic or environmental predispositions that lead to greater susceptibility to disease from inactivity.
  • individuals with increased risk due to a genetic predisposition will include individuals with genetic mutations in genes associated with muscle health, including PGC-l and MafBx, as disclosed herein, and/or with mutations in genes which regulate the expression of genes associated with muscle health.
  • individuals to be benefited from the methods disclosed herein are those who are specifically "in need of increased muscle strength, mobility, or both. Such individuals will include those individuals with elevated risks of a disease or condition from inactivity as well as those individuals currently manifesting a disease or condition resulting from inactivity.
  • compositions containing gamma linolenic acid modulates the expression of genes whose expression is associated with muscle health. Specifically, supplementation of the diet with gamma linolenic acid increases the expression of PGC-l , and decreases the expression of MafBx. As PGC-l expression is correlated with improved muscle strength and mobility, and MafBx expression is correlated with increased muscle breakdown (proteolysis), consumption of gamma linolenic acid is expected to increase muscle strength and mobility by increasing the level of PGC-la , decreasing the level of MafBx, or both. Furthermore, low levels of PGC-la expression are correlated with insulin resistance and the development of diabetes. Thus, in some embodiments, by increasing the level of PGC-la, improved insulin sensitivity is also expected.
  • the above-described benefits can be obtained by administering about 100 mg to about 5 gm of gamma linolenic acid to a subject per day. Dosing ranges at the higher or lower ends of the spectrum can be used, based on the age and size of the subject. For example, for human adults and elderly humans a dose of about 500 mg to about 5 gm of gamma linolenic acid per day is preferred. Other exemplary doses include 100 mg to 500 mg per day, 500 mg to 1 gm per day, and 2 gm to 5 gm per day.
  • the desired dosing can be achieved by orally administering a nutritional composition containing any amount of gamma linolenic acid that results in the recipient receiving a dose within the desired range.
  • a desired dosage of gamma linolenic acid in an individual can be achieved by varying the quantity of the administered nutritional composition and the frequency at which the nutritional composition is administered to the individual.
  • the administration regimen to achieve a desired dosage of gamma linolenic acid for a particular individual is determined by identifying an administration regimen which is sufficient to keep the level of PGC-la in a biological sample taken from the individual after extended ⁇ e.g., 2, 3, 4, 5, 6, 7, or more days) inactivity at or above the level of PGC-la in a biological sample taken from the individual prior to beginning inactivity.
  • the level of PGC- ⁇ in the individual prior to and after inactivity can be determined by methods known in the art, e.g., by measuring gene or protein expression levels.
  • the administration regimen to achieve a desired dosage of gamma linolenic acid for a particular individual can be determined by identifying an administration regimen which is sufficient to keep the level of MafBx in a biological sample taken from the individual after extended ⁇ e.g., 2, 3, 4, 5, 6, 7, or more days) inactivity at or below the level of MafBx in a biological sample taken from the individual prior to beginning inactivity.
  • the level of MafBx in the individual prior to and after inactivity can be determined by methods known in the art, e.g., by measuring gene or protein expression levels.
  • Biological samples used can include any biological samples from which PGC- ⁇ and/or MafBx expression can be measured, including bodily fluids and tissues. In some embodiments, the biological samples are samples of muscle tissue.
  • An administration regimen can be continued for any period of time necessary to overcome or lessen the effects of inactivity on the individual's muscle strength and mobility. This can include administration for a period of days, weeks, months, or years and may depend on the extent and period of inactivity as well as other factors including the individual's susceptibility to muscle weakness or immobility as a result of the inactivity.
  • the administration regimen can be continued for any amount of time during and after the period of inactivity occurs. In some embodiments, e.g., where the individual is an elderly individual, administration may begin in anticipation of an ensuing period of inactivity.
  • Example 1 Gamma linolenic acid (GLA) supplementation regulates the expression of PGC-la and MafBx in rats.
  • GLA Gamma linolenic acid
  • a chronic feeding study (8 week) was carried out in aged (20 month) Sprague Dawley rats. Rats (n 10/group) were fed a control diet (modified AIN-93M containing 10% fat from soybean oil; Composition: 12.4% protein, 62.4% carbohydrate, and 10% fat) or a test diet (a modified AIN93M diet which was the same as the control diet except that the source of fat was from a GLA oil blend where the GLA oil blend contained 47% GLA-safflower oil, 27% soybean oil, and 26% safflower oil). The final dose of GLA delivered to the animals was equivalent to 1 gm GLA/kg of bodyweight/day.
  • PGC-l Peroxisome proliferator-activated receptor ⁇ coactivator- ⁇
  • RT-PCR reverse-transcriptase polymerase chain reaction
  • Mafbx protein expression was determined by western blot analysis of protein from the muscle tissue. Rats on the test diet exhibited about a 30% decrease in Mafbx protein expression (expressed 0.7 times the amount of Mafbx protein) relative to rats on the control diet (p-value of 0.10).
  • GLA-supplementation of diet both increases the expression of genes whose expression is beneficial to muscle health and decreases the expression of genes whose expression negatively affects muscle health.
  • genes like PGC- ⁇
  • administration of nutritional compositions containing GLA to an individual is expected to lead to preventing progression of muscle atrophy during aging, maintaining neuromuscular junction (NMJ) integrity, and preventing development of diabetes with age in the individual.
  • NMJ neuromuscular junction
  • administration of nutritional compositions containing GLA to an individual is expected to lead to downregulation of muscle protein degradation that increases during catabolic conditions (e.g., during inactivity) and which can cause muscle atrophy in the individual.

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Abstract

Methods of increasing muscle strength and mobility in a subject experiencing significant physical inactivity include administering gamma linolenic acid to the subject as part of a nutritional composition containing fat and at least one of protein and carbohydrate. Administration of the nutritional composition to the subject increases muscle strength and mobility of the subject by increasing levels of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) in muscle of the subject.

Description

METHODS FOR INCREASING MUSCLE STRENGTH AND MOBILITY IN
SUBJECTS EXPERIENCING SIGNIFICANT PHYSICAL INACTIVITY USING
GAMMA LINOLENIC ACID
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to and any benefit of U.S. Provisional Application No. 62/050,346, filed September 15, 2014, the content of which is incorporated herein by reference in its entirety.
FIELD OF THE DISCLOSURE
[0002] The present disclosure relates to methods for increasing muscle strength and mobility in a subject experiencing significant physical inactivity by administering nutritional compositions containing gamma linolenic acid to the subject.
BACKGROUND OF THE DISCLOSURE
[0003] Individuals may become inactive for any number of reasons. As a result of the inactivity, individuals may suffer a loss of muscle strength, decreased future mobility, or both. Methods for increasing or maintaining muscle strength and mobility during periods of inactivity may improve an individual's ability to return to an active state after a period of inactivity.
SUMMARY OF THE DISCLOSURE
[0004] Disclosed herein are methods of increasing muscle strength and mobility in a subject experiencing significant physical inactivity. The methods include
administering 100 mg to 5 gm of gamma linolenic acid to the subject per day as part of a nutritional composition comprising at least one of protein and carbohydrate in addition to the fat. Administration of the nutritional composition to the subject increases muscle strength and mobility of the subject by increasing levels of peroxisome proliferator- activated receptor γ coactivator-ΐ (PGC-l ) in muscle of the subject.
[0005] In another embodiment, the disclosure provides a method of increasing muscle strength and mobility in an elderly individual. The method includes administering 500 mg to 5 gm of gamma linolenic acid to the elderly individual per day as part of a nutritional composition comprising at least one of protein and carbohydrate in addition to fat.
DETAILED DESCRIPTION OF THE DISCLOSURE
[0006] The methods of the present disclosure involve administering
compositions containing gamma linolenic acid to an inactive individual to improve muscle strength and mobility in the individual. The essential features of the methods, as well as some of the many optional variations and additions, are described in detail hereafter.
[0007] The term "nutritional composition" as used herein, unless otherwise specified, refers to nutritional liquids, gels, semi-liquids and semi-solids and solids, including nutritional powders. Solid and semi-solid forms may be reconstituted to form a nutritional liquid. The "nutritional composition" is suitable for enteral administration to a subject.
[0008] The term "inactivity" as used herein, unless otherwise specified, refers to infrequent movement of the limbs or body. "Inactivity" can result from hospitalization, restriction of movement by others, self-imposed restriction, mental or physical disease, or other condition. "Significant" inactivity as used herein, unless otherwise specified, refers to a period of inactivity of two or more days.
[0009] The terms "subject" and "individual" as used herein, unless otherwise specified, refers to a mammal, including, but not limited to, a human (e.g., a toddler, child, or an adult), a domesticated farm animal (e.g., a cow, horse, or pig), or a pet (e.g., a dog or cat).
[0010] The term "healthy" as used herein, unless otherwise specified, refers to a subject or individual with no medically-recognized disease at the time administration of a nutritional composition disclosed herein is started.
[001 1] The term "elderly" as used herein, unless otherwise specified, refers to a subject or individual at or above an age that is associated with frequent inactivity.
[0012] All percentages, parts and ratios as used herein, are by weight of the total product, unless otherwise specified. All such weights as they pertain to listed ingredients are based on the active level and, therefore, do not include solvents or by-products that may be included in commercially available materials, unless otherwise specified.
[0013] All references to singular characteristics or limitations of the present disclosure shall include the corresponding plural characteristic or limitation, and vice versa, unless otherwise specified or clearly implied to the contrary by the context in which the reference is made.
[0014] All combinations of method or process steps as used herein can be performed in any order, unless otherwise specified or clearly implied to the contrary by the context in which the referenced combination is made.
[0015] The various embodiments of the nutritional compositions used in the methods of the present disclosure may also be substantially free of any optional or selected essential ingredient or feature described herein, provided that the remaining composition still contains all of the required ingredients or features as described herein. In this context, and unless otherwise specified, the term "substantially free" means that the selected product contains less than a functional amount of the optional ingredient, typically less than about 1%, including less than about 0.5%, including less than about 0.1%, and also including zero percent, by weight of such optional or selected essential ingredient.
[0016] The nutritional compositions and methods may comprise, consist of, or consist essentially of the essential elements of the products as described herein, as well as any additional or optional element described herein or otherwise useful in nutritional composition applications.
Product Form
[0017] The nutritional compositions including gamma linolenic acid, which are useful in the methods of the present disclosure, may be formulated in any known or otherwise suitable product form for enteral administration, including oral administration. Oral product forms are generally preferred and include any solid, liquid, or powder formulation suitable for use herein, provided that such a formulation allows for safe and effective oral delivery of the essential and other selected ingredients from the selected product form.
[0018] Non-limiting examples of solid nutritional composition forms suitable for use in the methods herein include snack and meal replacement products, including those formulated as bars; sticks; cookies, breads, cakes, or other baked goods; frozen liquids; candy; breakfast cereals; powders, granulated solids, or other particulates; snack chips or bites; frozen or retorted entrees; and so forth.
[0019] Non-limiting examples of liquid product forms suitable for use herein include snack and meal replacement products, hot or cold beverages, carbonated or non carbonated beverages, juices or other acidified beverages, milk or soy-based beverages, shakes, coffees, teas, enteral feeding compositions, and so forth. These liquid
compositions are most typically formulated as suspensions or emulsions, but can also be formulated in any other suitable forms such as clear liquids, substantially clear liquids, solutions, liquid gels, and so forth. [0020] Other non-limiting examples of suitable oral product forms include semi-solid or semi-liquid compositions (e.g., puddings, gels), as well as more
conventional product forms such as capsules, tablets, caplets, pills, and so forth.
[0021] The quantity of the nutritional composition for providing an effective amount of gamma linolenic acid to the targeted user may be contained in one or a plurality of individual dosage forms that may be administered in single or multiple dosages per day, per week, per month, or over another periodic basis determined to be appropriate for the individual. The nutritional compositions may be administered as a sole (4-6 servings or 1-1.5 liters per day), primary, or supplemental (1-2 servings per day) source of nutrition.
Macronutrients
[0022] In some embodiments, the nutritional compositions include a protein source. The protein source can be any protein source known in the art that can be used in a nutritional composition as disclosed herein. Exemplary, non-limiting protein sources include whey protein concentrates, whey protein isolates, whey protein hydrolysates, acid caseins, sodium casemates, calcium casemates, potassium casemates, casein
hydrolysates, milk protein concentrates, milk protein isolates, milk protein hydrolysates, nonfat dry milk, condensed skim milk, soy protein concentrates, soy protein isolates, soy protein hydrolysates, pea protein concentrates, pea protein isolates, pea protein hydrolysates, collagen proteins, potato proteins, rice proteins, fungal proteins, insect proteins, algal proteins, and proteins expressed by microorganisms.
[0023] In some embodiments, the nutritional compositions include one or more essential amino acids (i.e., isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine) provided as free amino acids. Examples of such freeform essential amino acids which may be included in the nutritional compositions include L-leucine, L-valine, L-isoleucine, and L-tryptophan. [0024] In some embodiments, the nutritional compositions include a carbohydrate. The carbohydrate can include any carbohydrate known in the art that can be used in a nutritional composition as disclosed herein. Exemplary, non-limiting carbohydrates include maltodextrin, hydrolyzed or modified starch or cornstarch, glucose polymers, corn syrup, corn syrup solids, rice-derived carbohydrates, high fructose corn syrup, honey, sugar alcohols, maltitol, erythritol, sorbitol, glycerine, sucrose, glucose, fructose, lactose, isomaltulose, sucromalt, pullulan, potato starch, and other slowly- digested carbohydrates, oligosaccharides including fructo-oligosaccharides, oat fiber, soy fiber, gum arabic, sodium carboxymethylcellulose, methylcellulose, guar gum, gellan gum, locust bean gum, konjac flour, hydroxypropyl methylcellulose, tragacanth gum, karaya gum, gum acacia, chitosan, arabinoglactins, glucomannan, xanthan gum, alginate, pectin, low and high methoxy pectin, cereal beta-glucans, carrageenan and psyllium, digestion resistant maltodextrins, resistant modified food starches, other resistant starches, and soluble and insoluble fibers derived from fruits or vegetables.
[0025] The nutritional compositions include a fat. The fat can include any fat known in the art that can be used in a nutritional composition as disclosed herein.
Exemplary, non-limiting fats include borage oil, coconut oil, fractionated coconut oil, soy oil, corn oil, olive oil, safflower oil, high oleic safflower oil, medium chain triglyceride oil, high gamma linolenic acid safflower oil, sunflower oil, high oleic sunflower oil, palm oil, palm kernel oil, palm olein, canola oil, marine oils, algal oils, cottonseed oils, evening primrose oil, interesterified oils, and transesterified oils.
[0026] In some embodiments, the fat includes an oil which is enriched in gamma linolenic acid. Oils enriched in gamma linolenic acid include those oils with at least 20%, including at least 30%, and including at least 40% gamma linolenic acid, by weight of the oil. Exemplary, non-limiting oils enriched in gamma linolenic acid suitable for use in the nutritional compositions disclosed herein include borage oil, and high gamma linolenic acid safflower oil. Gamma linolenic acid for use as described herein can also be obtained from plants or cells genetically engineered to produce oils enriched in gamma linolenic acid.
Optional Ingredients
[0027] The nutritional compositions containing gamma linolenic acid and macronutrients may also contain other optional ingredients that may modify the physical, nutritional, chemical, hedonic, or processing characteristics of the products or serve as pharmaceutical or additional nutritional components when used in a targeted population. Many such optional ingredients are known or otherwise suitable for use in nutritional compositions and may be used in the nutritional compositions described herein, provided that such optional ingredients are safe and effective for oral administration and are compatible with the essential and other ingredients in the selected product form.
[0028] Non-limiting examples of such optional ingredients include
preservatives, antioxidants, emulsifying agents, buffers, fructooligosaccharides, pharmaceutical actives, additional nutrients as described herein, colorants, flavors, thickening agents and stabilizers, and so forth.
[0029] The nutritional compositions may further comprise vitamins or related nutrients, non-limiting examples of which include vitamin A, vitamin D, vitamin E, vitamin K, thiamine, riboflavin, pyridoxine, vitamin B12, carotenoids, niacin, folic acid, pantothenic acid, biotin, vitamin C, choline, inositol, salts, and derivatives thereof, and combinations thereof.
[0030] The nutritional compositions may further comprise additional minerals, non-limiting examples of which include phosphorus, magnesium, calcium, sodium, potassium, molybdenum, chromium, selenium, chloride, and combinations thereof.
[0031] The nutritional compositions may also include one or more other compounds which contribute to muscle health. For example, in some embodiments, the nutritional compositions include one or more of beta-hydroxy-beta-methylbutyrate (HMB), metabolites of leucine (alpha-ketoisocaproic acid, HICA), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), green tea polyphenols, curcumin, and polyphenols from cocoa and fruit extracts. The combination of gamma linolenic acid with one or more of these compounds may provide a synergistic improvement in muscle health to the individual.
Methods of Manufacture
[0032] The nutritional compositions may be manufactured by any known or otherwise suitable method for making nutritional compositions, including nutritional liquids such as emulsions.
[0033] In one suitable manufacturing process, a nutritional liquid is prepared using at least three separate slurries, including a protein-in-fat (PIF) slurry, a
carbohydrate-mineral (CHO-MIN) slurry, and a protein-in-water (PIW) slurry. The PIF slurry is formed by heating and mixing the selected oils (e.g. , canola oil, corn oil, and fish oil) and then adding an emulsifier (e.g., lecithin), fat soluble vitamins, and a portion of the total protein (e.g. , milk protein concentrate) with continued heat and agitation. The CHO-MIN slurry is formed by adding, with heated agitation, to water: minerals (e.g., potassium citrate, dipotassium phosphate, and sodium citrate), trace and ultra trace minerals (TM/UTM premix), and thickening or suspending agents (e.g., Avicel, gellan, and carrageenan). The resulting CHO-MIN slurry is held for 10 minutes with continued heat and agitation before adding additional minerals (e.g., potassium chloride, magnesium carbonate, and potassium iodide) and carbohydrates (e.g. ,
fructooligosaccharide, sucrose, and corn syrup). The PIW slurry is then formed by mixing remaining protein (e.g., sodium caseinate and soy protein concentrate) with heat and agitation into water.
[0034] The resulting slurries are then blended together with heated agitation and the pH adjusted to the desired range, typically from 6.6-7.0, after which the composition is subjected to high-temperature short-time (HTST) processing during which the composition is heat treated, emulsified and homogenized, and then allowed to cool. Water soluble vitamins and ascorbic acid are added, the pH is again adjusted to the desired range if necessary, flavors are added, and water is added to achieve the desired total solid level. The composition is then aseptically packaged to form an aseptically packaged nutritional emulsion, or the composition is added to retort stable containers and then subjected to retort sterilization to form retort sterilized nutritional emulsions.
[0035] The manufacturing processes for the nutritional powders may be carried out in ways other than those set forth herein without departing from the spirit and scope of the present disclosure. The present embodiments are, therefore, to be considered in all respects illustrative and not restrictive. All changes and equivalents, as would be known to one of skill in the art, will also come within the description of the present disclosure.
[0036] The nutritional solid, such as a spray dried nutritional powder or dry- mixed nutritional powder, may be prepared by any collection of known or otherwise effective techniques, suitable for making and formulating a nutritional powder.
[0037] For example, when the nutritional powder is a spray dried nutritional powder, the spray drying step may likewise include any spray drying technique that is known for or otherwise suitable for use in the production of nutritional powders. Many different spray drying methods and techniques are known for use in the nutrition field, all of which are suitable for use in the manufacture of the spray dried nutritional powders herein.
[0038] One method of preparing the spray dried nutritional powder comprises forming and homogenizing an aqueous slurry or liquid comprising fat containing gamma linolenic acid, protein, and carbohydrate, and then spray drying the slurry or liquid to produce a spray dried nutritional powder. The method may further comprise the step of spray drying, dry mixing, or otherwise adding additional nutritional ingredients, including any one or more of the ingredients described herein, to the spray dried nutritional powder. Methods of Use
[0039] The nutritional compositions including gamma linolenic acid are administered orally to an individual as needed to improve muscle strength and mobility. The compositions can be administered to any individual who could benefit from improved muscle strength and mobility.
[0040] Such individuals include any individual undergoing a significant period of inactivity. The individuals can be healthy or already suffer from one or more diseases or conditions such as sarcopenia, diabetes, insulin resistance, and obesity. Other individuals who can benefit from the use of the compositions and methods disclosed herein include, without limitation, individuals who have experienced or are currently experiencing sickness, injury, bed rest and/or immobilization, surgery, recovery and/or rehabilitation, stress induced muscle wasting, catabolic conditions such as cancer, chronic obstructive pulmonary disease (COPD), and end-stage renal disease (ESRD). While the individuals can be of any age group, in some embodiments, the methods are used with elderly individuals and other groups of individuals who may be at an increased risk of developing disease from inactivity. Such increased risk may arise not only due to age, but also, e.g., due to genetic or environmental predispositions that lead to greater susceptibility to disease from inactivity. For example, individuals with increased risk due to a genetic predisposition will include individuals with genetic mutations in genes associated with muscle health, including PGC-l and MafBx, as disclosed herein, and/or with mutations in genes which regulate the expression of genes associated with muscle health. In some embodiments, individuals to be benefited from the methods disclosed herein are those who are specifically "in need of increased muscle strength, mobility, or both. Such individuals will include those individuals with elevated risks of a disease or condition from inactivity as well as those individuals currently manifesting a disease or condition resulting from inactivity.
[0041] As shown in Example 1, administration of compositions containing gamma linolenic acid modulates the expression of genes whose expression is associated with muscle health. Specifically, supplementation of the diet with gamma linolenic acid increases the expression of PGC-l , and decreases the expression of MafBx. As PGC-l expression is correlated with improved muscle strength and mobility, and MafBx expression is correlated with increased muscle breakdown (proteolysis), consumption of gamma linolenic acid is expected to increase muscle strength and mobility by increasing the level of PGC-la , decreasing the level of MafBx, or both. Furthermore, low levels of PGC-la expression are correlated with insulin resistance and the development of diabetes. Thus, in some embodiments, by increasing the level of PGC-la, improved insulin sensitivity is also expected.
[0042] The above-described benefits can be obtained by administering about 100 mg to about 5 gm of gamma linolenic acid to a subject per day. Dosing ranges at the higher or lower ends of the spectrum can be used, based on the age and size of the subject. For example, for human adults and elderly humans a dose of about 500 mg to about 5 gm of gamma linolenic acid per day is preferred. Other exemplary doses include 100 mg to 500 mg per day, 500 mg to 1 gm per day, and 2 gm to 5 gm per day. The desired dosing can be achieved by orally administering a nutritional composition containing any amount of gamma linolenic acid that results in the recipient receiving a dose within the desired range. For any given amount of gamma linolenic acid within a nutritional composition, a desired dosage of gamma linolenic acid in an individual can be achieved by varying the quantity of the administered nutritional composition and the frequency at which the nutritional composition is administered to the individual.
[0043] Individualized administration regimens {i.e., amount, manner, and time of administration) can be determined by one of skill in the art. In an exemplary embodiment, the administration regimen to achieve a desired dosage of gamma linolenic acid for a particular individual is determined by identifying an administration regimen which is sufficient to keep the level of PGC-la in a biological sample taken from the individual after extended {e.g., 2, 3, 4, 5, 6, 7, or more days) inactivity at or above the level of PGC-la in a biological sample taken from the individual prior to beginning inactivity. The level of PGC-Ι in the individual prior to and after inactivity can be determined by methods known in the art, e.g., by measuring gene or protein expression levels. Alternatively or additionally, the administration regimen to achieve a desired dosage of gamma linolenic acid for a particular individual can be determined by identifying an administration regimen which is sufficient to keep the level of MafBx in a biological sample taken from the individual after extended {e.g., 2, 3, 4, 5, 6, 7, or more days) inactivity at or below the level of MafBx in a biological sample taken from the individual prior to beginning inactivity. The level of MafBx in the individual prior to and after inactivity can be determined by methods known in the art, e.g., by measuring gene or protein expression levels. Biological samples used can include any biological samples from which PGC-Ι and/or MafBx expression can be measured, including bodily fluids and tissues. In some embodiments, the biological samples are samples of muscle tissue.
[0044] An administration regimen can be continued for any period of time necessary to overcome or lessen the effects of inactivity on the individual's muscle strength and mobility. This can include administration for a period of days, weeks, months, or years and may depend on the extent and period of inactivity as well as other factors including the individual's susceptibility to muscle weakness or immobility as a result of the inactivity. The administration regimen can be continued for any amount of time during and after the period of inactivity occurs. In some embodiments, e.g., where the individual is an elderly individual, administration may begin in anticipation of an ensuing period of inactivity.
EXAMPLES
[0045] The following example illustrates specific embodiments and/or features of the present disclosure. The example is given solely for the purpose of illustration and is not to be construed as limiting on the present disclosure, as many variations thereof are possible without departing from the spirit and scope of the disclosure. All exemplified amounts are weight percentages based upon the total weight of the nutritional product, unless otherwise specified. [0046] The exemplified methods make use of gamma linolenic acid-containing nutritional compositions prepared in accordance with manufacturing methods well known in the nutrition industry for preparing nutritional emulsions and powders and suitable for use in the methods of the present disclosure.
Example 1: Gamma linolenic acid (GLA) supplementation regulates the expression of PGC-la and MafBx in rats.
[0047] A chronic feeding study (8 week) was carried out in aged (20 month) Sprague Dawley rats. Rats (n=10/group) were fed a control diet (modified AIN-93M containing 10% fat from soybean oil; Composition: 12.4% protein, 62.4% carbohydrate, and 10% fat) or a test diet (a modified AIN93M diet which was the same as the control diet except that the source of fat was from a GLA oil blend where the GLA oil blend contained 47% GLA-safflower oil, 27% soybean oil, and 26% safflower oil). The final dose of GLA delivered to the animals was equivalent to 1 gm GLA/kg of bodyweight/day. After 8 weeks of feeding, animals on the control and test diets were sacrificed and gastrocnemius muscles were analyzed. Peroxisome proliferator-activated receptor γ coactivator-ΐ (PGC-l ) expression was determined by reverse-transcriptase polymerase chain reaction (RT-PCR) analysis of RNA from the muscles from rats on the control and test diets. Rats on the test diet exhibited a 5.967-fold increase in PGC-la gene expression compared to rats on the control diet; a significant change in PGC-la gene expression relative to the animals on the control diet (p-value of 0.00003).
[0048] Mafbx protein expression was determined by western blot analysis of protein from the muscle tissue. Rats on the test diet exhibited about a 30% decrease in Mafbx protein expression (expressed 0.7 times the amount of Mafbx protein) relative to rats on the control diet (p-value of 0.10).
[0049] The data suggest that GLA-supplementation of diet both increases the expression of genes whose expression is beneficial to muscle health and decreases the expression of genes whose expression negatively affects muscle health. By increasing the expression of genes, like PGC-Ι , administration of nutritional compositions containing GLA to an individual is expected to lead to preventing progression of muscle atrophy during aging, maintaining neuromuscular junction (NMJ) integrity, and preventing development of diabetes with age in the individual. By decreasing the expression of proteins, like Mafbx, administration of nutritional compositions containing GLA to an individual is expected to lead to downregulation of muscle protein degradation that increases during catabolic conditions (e.g., during inactivity) and which can cause muscle atrophy in the individual.
[0050] Unless otherwise indicated herein, all sub-embodiments and optional embodiments are respective sub-embodiments and optional embodiments to all embodiments described herein. While the present application has been illustrated by the description of embodiments thereof, and while the embodiments have been described in considerable detail, it is not the intention of the applicants to restrict or in any way limit the scope of the appended claims to such detail. Additional advantages and modifications will readily appear to those skilled in the art. Therefore, the application, in its broader aspects, is not limited to the specific details, the representative compositions or formulations, and illustrative examples shown and described. Accordingly, departures may be made from such details without departing from the spirit or scope of the applicant's general disclosure herein.

Claims

WHAT IS CLAIMED IS:
1. A method of increasing muscle strength and mobility in a subject experiencing significant physical inactivity, the method comprising: administering 100 mg to 5 gm of gamma linolenic acid per day to an inactive subject as part of a nutritional composition comprising fat and at least one of protein and carbohydrate; wherein the nutritional composition increases muscle strength and mobility of the subject by increasing levels of peroxisome proliferator-activated receptor γ coactivator-l (PGC-la) in muscle of the subject.
2. The method of claim 1, wherein the subject is a healthy individual.
3. The method of claim 1, wherein the subject is in need of increased muscle strength, mobility, or both.
4. The method of any one of claims 1-3, wherein the subject is an elderly individual.
5. The method of any one of claims 3-4, wherein the subject suffers from at least one of sarcopenia, diabetes, insulin resistance, and obesity.
6. The method of any one of claims 1-5, wherein the nutritional composition further promotes insulin sensitivity in the subject.
7. The method of any one of claims 1-6, wherein the nutritional composition is administered in an amount, manner, and for a time sufficient to keep the level of PGC-la in a biological sample taken from the subject following 3 or more days of physical inactivity at or above a baseline level of PGC-la in a biological sample taken from the subject at the beginning of or prior to the physical inactivity.
8. The method of any one of claims 1-7, wherein the nutritional composition further increases muscle strength and mobility in the subject by decreasing muscle proteolysis in the subject.
9. The method of any one of claims 1-3, wherein the subject is a toddler or a child.
10. The method of any one of claims 1-9, wherein the protein is selected from the group consisting of whey protein concentrates, whey protein isolates, whey protein
hydrolysates, acid caseins, sodium casemates, calcium casemates, potassium casemates, casein hydrolysates, milk protein concentrates, milk protein isolates, milk protein hydrolysates, nonfat dry milk, condensed skim milk, soy protein concentrates, soy protein isolates, soy protein hydrolysates, pea protein concentrates, pea protein isolates, pea protein hydrolysates, collagen proteins, potato proteins, rice proteins, fungal proteins, proteins expressed by microorganisms, and combinations thereof.
11. The method of any one of claims 1-10, wherein the carbohydrate is selected from the group consisting of maltodextrin, hydrolyzed or modified starch or cornstarch, glucose polymers, corn syrup, corn syrup solids, rice-derived carbohydrates, high fructose corn syrup, honey, sugar alcohols, maltitol, erythritol, sorbitol, glycerine, sucrose, glucose, fructose, lactose, isomaltulose, sucromalt, pullulan, potato starch, and other slowly- digested carbohydrates, oligosaccharides including fructo-oligosaccharides, oat fiber, soy fiber, gum arabic, sodium carboxymethylcellulose, methylcellulose, guar gum, gellan gum, locust bean gum, konjac flour, hydroxypropyl methylcellulose, tragacanth gum, karaya gum, gum acacia, chitosan, arabinoglactins, glucomannan, xanthan gum, alginate, pectin, low and high methoxy pectin, cereal beta-glucans, carrageenan and psyllium, digestion resistant maltodextrins, resistant modified food starches, other resistant starches, soluble and insoluble fibers derived from fruits or vegetables, and combinations thereof.
12. The method of any one of claims 1-11, wherein the fat is selected from the group consisting of borage oil, evening primrose oil, coconut oil, fractionated coconut oil, soy oil, corn oil, olive oil, safflower oil, high oleic safflower oil, medium chain triglyceride oil, high gamma linolenic safflower oil, sunflower oil, high oleic sunflower oil, palm oil, palm kernel oil, palm olein, canola oil, marine oils, algal oils, cottonseed oils, interesterified oils, transesterified oils, and combinations thereof.
13. The method of claim 12, wherein the fat comprises an oil having at least 20 weight % of gamma linolenic acid by weight of the oil.
14. The method of claim 13, wherein the oil is one of the borage oil and the high gamma linolenic acid-safflower oil.
15. The method of any one of claims 1-14, wherein the composition further comprises one or more essential amino acids as free amino acids.
16. The method of any one of claims 1-15, wherein the composition further comprises one or more other compounds which contribute to muscle health selected from the group consisting of beta-hydroxy-beta-methylbutyrate (HMB), metabolites of leucine (alpha- ketoisocaproic acid, HICA), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), green tea polyphenols, curcumin, and polyphenols from cocoa and fruit extracts.
17. A method of increasing muscle strength and mobility in an elderly individual, the method comprising: administering 500 mg to 5 gm of gamma linolenic acid to the elderly individual per day as part of a nutritional composition comprising fat and at least one of protein and carbohydrate.
18. The method of any one of claims 1-17, wherein the nutritional composition is administered as a sole, primary, or supplemental source of nutrition.
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