Composition and method for potentiating musculoskeletal effect of one or more anabolic amino acids by using one or more autophagy-inducing amino acids

Abstract

To provide a method and a composition for potentiating effect to a musculoskeletal system of one or more anabolic amino acids in an individual which requires potentiating effect to the musculoskeletal system.SOLUTION: A method includes a step of administering a composition comprising one or more anabolic amino acids to an individual, and the composition further comprises one or more amino acids or precursors thereof, which induce autophagy, in a total amount effective to make the composition at least neutral regarding autophagy. One or more amino acids which induce autophagy are selected from a group consisting of glycine, cysteine, proline, glutamic acid, valine, tyrosine, or precursors thereof and a mixture thereof.SELECTED DRAWING: None

Description

Background Art

[0001]

[0001] The present disclosure generally relates to compositions and methods for enhancing the effects of one or more assimilable amino acids, such as leucine, isoleucine, arginine, glutamine, or citrulline, using one or more amino acids that induce autophagy, such as glycine, cysteine, proline, glutamic acid, valine, tyrosine, or precursors thereof. More specifically, the present disclosure relates to administering a composition comprising one or more assimilable amino acids, the composition further comprising, in an amount effective to render the composition at least neutral with respect to autophagy, preferably positive with respect to autophagy, one or more amino acids or precursors thereof that induce autophagy, even when the one or more assimilable amino acids have a negative effect on autophagy. The composition can simultaneously promote protein synthesis and the removal of damaged cellular material. Recipients of administration can be, for example, critically ill patients such as patients in an intensive care unit (ICU); elderly patients, such as aged individuals; patients with sarcopenia or frailty; or individuals with chronic kidney disease (e.g., amino acid loss due to dialysis) and / or individuals with acute kidney injury.

[0002]

[0002] Due to significant advances in intensive care, critically ill patients often survive acute diseases that were previously fatal. However, although they survive this initial phase, the mortality rate of patients entering the severe chronic phase remains high. Death is often due to refractory multiple organ failure, acute kidney injury and acute renal failure, severe myopathy, or low-grade muscle weakness. Therapies such as nutrition, growth hormone, or androgen have been introduced to improve muscle myopathy and muscle weakness, but these interventions have failed because they unexpectedly increase the risk of organ failure and death. Furthermore, nutritional supplementation for trauma and surgical patients can actually have harmful effects.

[0003]

[0003] There is still no effective means for providing appropriate treatment and adequate nutrition to critically ill patients.

[0004]

[0004] Furthermore, although the decline in muscle mass and muscle function associated with aging is inevitable in all individuals, its progression varies greatly depending on genetic factors and environmental factors such as physical activity and nutritional intake. Sarcopenia is defined as a state in which the decline in muscle mass and muscle function associated with aging has deteriorated to the point of affecting the quality of life. In contrast, frailty is another classification of the decline in physical function associated with aging, characterized by a decline in muscle strength and muscle function rather than muscle mass. Sarcopenia is clinically defined by a decline in muscle mass and muscle function using a cut-off that stratifies the elderly population for individuals in a pathological state of mobility. Future physical disability and death are predicted from sarcopenia, and a formal ICD-10 disease code was assigned to sarcopenia in 2016 (Anker et al., 2016).

Summary of the Invention

Problems to be Solved by the Invention

[0005]

[0005] The degradation of cytoplasmic proteins is mediated by a cellular process called macroautophagy (also simply called autophagy). The autophagy process is also involved in the inflammatory response and promotes the destruction of the immune system by bacteria. Autophagy constitutes a major lysosomal degradation pathway that recycles damaged and possibly harmful cellular materials such as damaged mitochondria. In particular, autophagy attenuates the effects of cell death and extends lifespan in various aging models.

[0006] As detailed in the experimental data described later in this specification, the inventors have found that several amino acids known to be involved in skeletal muscle anabolism via the mTOR pathway, such as arginine, glutamine, and leucine, and / or anabolic branched-chain amino acids, such as leucine and isoleucine, decrease the basal level of autophagy. However, the inventors have found that several amino acids, such as glycine, cysteine, proline, glutamic acid, valine, tyrosine, or their precursors, such as serine (as a precursor of glycine), N-acetylcysteine, and methionine (as a precursor of cysteine), can strongly induce autophagy and, thus, can counteract the negative effects of anabolic amino acids on autophagy, such as muscle and neuromuscular degeneration and decreases in muscle mass and muscle function.

Means for Solving the Problems

[0007]

[0007] Accordingly, in a general embodiment, the present disclosure provides a method for enhancing the action of one or more anabolic amino acids on the skeletal muscle system in an individual in need of enhancing the action on the skeletal muscle system. The method includes administering to the individual a composition comprising one or more anabolic amino acids, the composition further comprising one or more amino acids or their precursors that induce autophagy in a total amount effective to render the composition at least neutral with respect to autophagy, preferably positive with respect to autophagy.

[0008]

[0008] In one embodiment, the one or more anabolic amino acids are selected from the group consisting of leucine, isoleucine, arginine, glutamine, citrulline, and mixtures thereof. The one or more anabolic amino acids may comprise at least one of leucine, glutamine, or arginine in an amount effective to activate mTOR in the individual.

[0009]

[0009] In one embodiment, the one or more amino acids that induce autophagy are selected from the group consisting of glycine, cysteine, proline, glutamic acid, valine, tyrosine, or precursors thereof, and mixtures thereof.

[0010]

[0010] In one embodiment, the composition induces autophagy in skeletal muscle.

[0011]

[0011] In one embodiment, the individual is an elderly individual.

[0012]

[0012] In one embodiment, the individual has sarcopenia or frailty, or is at risk of developing sarcopenia or frailty.

[0013]

[0013] In one embodiment, the individual is severely ill.

[0014]

[0014] In one embodiment, the individual has severe myopathy or is at risk of developing severe myopathy.

[0015]

[0015] In one embodiment, the individual is in a severe condition accompanied by acute kidney injury or is at risk of developing acute kidney injury.

[0016]

[0016] In one embodiment, the individual has chronic kidney disease with or without associated reduction in muscle mass or muscle function.

[0017]

[0017] In one embodiment, the individual has cachexia or muscle wasting secondary to chronic diseases such as cancer, chronic obstructive pulmonary disease (COPD), chronic heart failure (CHF), acute kidney disease or chronic kidney disease (CKD).

[0018]

[0018] In one embodiment, the composition comprises at least a portion of one or more assimilable amino acids and / or a protein that provides at least a portion of one or more amino acids or precursors thereof that induce autophagy, and the protein is selected from the group consisting of (i) proteins derived from animal materials, (ii) proteins derived from plant materials, and (iii) mixtures thereof, and preferably is one or more of (a) milk protein, (b) whey protein, (c) casein salts, (d) casein micelles, (e) pea protein, (f) soy protein, and (g) mixtures thereof. In certain non-limiting examples, at least a portion of the protein is collagen, i.e., non-hydrolyzed collagen and / or hydrolyzed collagen.

[0019]

[0019] The protein can be selected from the group consisting of (i) free-form amino acids, (ii) non-hydrolyzed proteins, (iii) partially hydrolyzed proteins, (iv) extensively hydrolyzed proteins, and (v) mixtures thereof. The protein can include peptides having a length of 2 to 10 amino acids. Optionally, at least a portion of the protein is 5 to 95% hydrolyzed. Optionally, the protein has a formulation selected from the group consisting of (i) a formulation in which at least 50% of the protein has a molecular weight of 1 to 5 kDa, (ii) a formulation in which at least 50% of the protein has a molecular weight of 5 to 10 kDa, and (iii) a formulation in which at least 50% of the protein has a molecular weight of 10 to 20 kDa.

[0020]

[0020] In one embodiment, the composition includes a carbohydrate source and / or a fat source.

[0021]

[0021] In one embodiment, the step of administering uses at least one route selected from the group consisting of oral, enteral, parenteral, and intravenous injection.

[0022]

[0022] In one embodiment, the total amount of one or more assimilable amino acids is approximately equal to or greater than the total amount of one or more assimilable amino acids in the composition.

[0023]

[0023] In another embodiment, the present disclosure provides a composition comprising one or more assimilable amino acids, the composition further comprising one or more amino acids or precursors thereof that induce autophagy in an amount effective to render the composition at least neutral, preferably positive, with respect to autophagy. The composition may be selected from the group consisting of food compositions, dietary supplements, nutritional compositions, nutraceuticals, powdered nutritional formulations reconstituted with water or milk prior to ingestion, food additives, pharmaceuticals, drinks, and combinations thereof.

[0024]

[0024] In another embodiment, the present disclosure provides a method of making a therapeutic composition, the method comprising adding one or more amino acids or precursors thereof that induce autophagy to a base composition comprising one or more assimilable amino acids to form a therapeutic composition, the one or more amino acids or precursors thereof that induce autophagy being added to the base composition in an amount effective to render the therapeutic composition at least neutral, preferably positive, with respect to autophagy. The base composition and / or the therapeutic composition may be formulated for administration by at least one route selected from the group consisting of oral, enteral, parenteral, and intravenous injection. The base composition can be negative with respect to the induction of autophagy (i.e., the composition is overall negative), and / or the base composition can be neutral or positive with respect to the induction of autophagy, but contain an amount of one or more assimilable amino acids that is negative with respect to the induction of autophagy (i.e., the one or more assimilable amino acids form a portion that is negative with respect to the induction of autophagy).

[0025]

[0025] In one embodiment, the method includes quantifying the total amount of one or more assimilable amino acids in a base composition; and determining the total amount of one or more amino acids added to the base composition to induce autophagy using the total amount of the one or more assimilable amino acids in the base composition. The step of determining the total amount of one or more amino acids added to the base composition to induce autophagy using the total amount of the one or more assimilable amino acids in the base composition preferably includes determining the effect on autophagy expected from the total amount of the one or more assimilable amino acids. The step of determining the total amount of one or more amino acids added to the base composition to induce autophagy using the total amount of the one or more assimilable amino acids in the base composition further preferably includes determining the total amount of one or more amino acids added to the base composition to induce autophagy such that the effect on autophagy expected from the total amount of the one or more amino acids added to induce autophagy is approximately equal to or greater than the effect on autophagy expected from the total amount of the one or more assimilable amino acids.

[0026]

[0026] In another embodiment, the disclosure provides a method comprising administering to an individual in need thereof a composition that simultaneously promotes protein synthesis and removal of damaged cellular material, the composition comprising one or more assimilable amino acids, the composition further comprising one or more amino acids or precursors thereof that induce autophagy in a total amount effective for the composition to be at least neutral with respect to autophagy, preferably positive with respect to autophagy.

[0027]

[0027] In another embodiment, the present disclosure provides a method of overcoming one or more negative effects of one or more assimilable amino acids by preventing a degenerative process associated with a decrease in autophagy. The method includes administering to an individual a composition comprising one or more assimilable amino acids, the composition further comprising one or more amino acids or precursors thereof that induce autophagy, in an amount effective to render the composition at least neutral with respect to autophagy, preferably positive with respect to autophagy, for example in muscle.

[0028]

[0028] An advantage of one or more embodiments provided by the present disclosure is to improve the condition of a severely ill animal, a severely ill human, an elderly animal, or an elderly human.

[0029]

[0029] Another advantage of one or more embodiments provided by the present disclosure is to prevent or treat excessive catabolism, for example, in a severely ill patient or an elderly individual.

[0030]

[0030] Yet another advantage of one or more embodiments provided by the present disclosure is to reduce or prevent the risk of morbidity or death due to excessive catabolism, for example, in a severely ill patient or an elderly individual.

[0031]

[0031] An additional advantage of the present disclosure is to recover, treat, or cure a severely ill patient from multiple organ dysfunction syndrome.

[0032]

[0032] An additional advantage of one or more embodiments provided by the present disclosure is to protect an elderly individual from neurological diseases such as mild cognitive impairment, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, dementia, and related rare neurological diseases.

[0033]

[0033] Additional advantages of one or more embodiments provided by the present disclosure include protecting elderly individuals from muscle dysfunction such as sarcopenia, frailty, inclusion body myositis, drug-induced myopathy / rhabdomyolysis such as corticosteroids or statins, and muscle wasting induced by immobility or hospitalization.

[0034]

[0034] Additional advantages of one or more embodiments provided by the present disclosure include protecting patients suffering from genetic diseases, including but not limited to muscular dystrophies such as Duchenne muscular dystrophy or type VI collagen muscular dystrophy, mitochondrial encephalomyopathy, mitochondrial myopathy, glycogenosis, lysosomal storage diseases, and Pompe disease.

[0035]

[0035] Another advantage of one or more embodiments provided by the present disclosure is a composition that can be administered parenterally or enterally to critically ill patients, for example, as an aqueous liquid composition, to induce autophagy, for example, to treat multiple organ dysfunction or burns.

[0036]

[0036] Yet another advantage of one or more embodiments provided by the present disclosure is to shorten the period during which a critically ill patient is on a ventilator or to advance the period until the ventilator is removed.

[0037]

[0037] Another advantage of one or more embodiments provided by the present disclosure is to protect critically ill patients receiving parenteral nutrition from multiple organ failure or muscle weakness caused by, for example, parenteral nutrition delivery, particularly unbalanced nutrition or relative overnutrition.

[0038]

[0038] An additional advantage of one or more embodiments provided by the present disclosure is to protect elderly individuals from muscle weakness.

[0039]

[0039] Yet another advantage of one or more embodiments provided by the present disclosure is to improve the viability of critically ill patients or elderly individuals.

[0040]

[0040] An additional advantage of one or more embodiments provided by the present disclosure is to accelerate the recovery of mobility or shorten the period of immobility after discharge from the intensive care unit.

[0041]

[0041] Yet another advantage of one or more embodiments provided by the present disclosure is that the effect is beneficial even when the critically ill patient is already in a state where their life is seriously threatened.

[0042]

[0042] Additional features and advantages will be described in the following detailed description of the invention and the drawings, and will become apparent therefrom.

Brief Description of the Drawings

[0043]

[0043]

Figure 1

Figure 2

Figure 3

Figure 4

Modes for Carrying Out the Invention

[0044]

[0045] Definition

[0046] The following are some definitions. However, there may be definitions in the section "Embodiments" below, and the above heading "Definition" does not mean that such disclosure in the "Embodiments" section is not a definition.

[0045]

[0047] All percentages are by weight based on the total weight of the composition, unless otherwise specified. Similarly, all amounts and all ratios are by weight, unless otherwise specified. When a reference is made to pH, the value corresponds to the pH measured at 25 °C using standard equipment. As used herein, "about", "approximately", and "substantially" are understood to refer to numbers within the numerical range, for example, within -10% to +10% of the reference number, preferably within -5% to +5% of the reference number, more preferably within -1% to +1% of the reference number, and most preferably within -0.1% to +0.1% of the reference number.

[0046]

[0048] Furthermore, all numerical ranges in this specification are to be understood to include all integers, wholes, or fractions within that range. Furthermore, these numerical ranges are to be interpreted as supporting claims directed to any number or subset of numbers within this range. For example, the disclosure of 1 to 10 is to be interpreted as supporting ranges such as 1 to 8, 3 to 7, 1 to 9, 3.6 to 4.6, 3.5 to 9.9, etc.

[0047]

[0049] As used in this specification and the appended claims, unless the context clearly indicates otherwise, singular words include the plural. Thus, references to "one," "a," and "the" generally include the plural of each such term. For example, reference to "an amino acid" or "the amino acid" includes a plurality of such "amino acids." The term "and / or" as used in the context of "X and / or Y" should be construed to mean "X" or "Y" or "X and Y." Similarly, "at least one of X or Y" should be construed to mean "X" or "Y" or "both X and Y."

[0048]

[0050] Similarly, the terms "comprise," "comprises," and "comprising" should be construed as non-exclusive and may include other elements. Similarly, the terms "include," "including," and "or" are all to be construed as capable of including other elements unless such construction is clearly precluded by the context. However, the embodiments provided by the present disclosure may not include any element not specifically disclosed herein. Thus, the disclosure of embodiments defined using the term "comprising" is also a disclosure of embodiments "consisting essentially of" and "consisting of" the disclosed components.

[0049]

[0051] As used herein, the term "example" is merely illustrative and for the purpose of explanation and should not be considered exclusive or exhaustive, particularly when followed by a list of terms. All embodiments disclosed herein can be combined with any other embodiments disclosed herein, unless specifically indicated otherwise.

[0050]

[0052] Examples of "animals" include, but are not limited to, rodents, aquatic mammals, domestic animals such as dogs and cats, livestock such as sheep, pigs, cows and horses, and mammals including humans. When the terms "animal", "mammal", or their plurals are used, these terms also apply to any animal capable of autophagy, for example, an animal capable of autophagy, as indicated by the context of the article or for the effect intended to be shown. As used herein, the term "patient" is understood to include an animal, such as a mammal, preferably a human, that is receiving or scheduled to receive treatment as defined herein. As used herein, the terms "individual" and "patient" are often used to refer to humans, but the present disclosure is not limited to humans.

[0051]

[0053] Accordingly, the terms "individual" and "patient" refer to any animal, mammal or human to which the methods and compositions disclosed herein may be beneficial. In fact, animals other than humans experience long-term serious illnesses that closely resemble human conditions. These severely ill animals experience the same metabolic disorders, immune disorders, and endocrine gland disorders as those corresponding to humans, as well as the onset of organ failure and muscle wasting. Furthermore, animals also experience the effects of aging.

[0052]

[0054] The term "elderly" means, in relation to humans, an age of at least 55 years, preferably over 63 years, more preferably over 65 years, and most preferably over 70 years. The terms "older adult" or "ageing individual" in the context of humans mean an age of at least 45 years, preferably 50 years or older, more preferably 55 years or older, and include elderly individuals.

[0053]

[0055] For other animals, "senile adult" or "aged individual" refers to those that exceed 50% of the average lifespan of their respective species and / or genus within the species. An animal is considered "aged" when it exceeds 66% of its average life expectancy, preferably when it exceeds 75% of its average life expectancy, and more preferably when it exceeds 80% of its average life expectancy. An aged cat or dog is at least about 5 years old. An elderly cat or dog is at least about 7 years old.

[0054]

[0056] Sarcopenia is defined as a decrease in muscle mass and muscle function (including muscle strength and walking speed) associated with aging. Sarcopenia can be evaluated by one or more of muscle mass loss, muscle strength loss, and physical performance decline.

[0055]

[0057] Muscle mass loss can generally be based on a decrease in appendicular lean mass (ALM index) normalized to the square of height. Specifically, for men, an ALM index of less than 7.00 kg / m2 and for women, an ALM index of less than 5.40 kg / m2 can be used as a reference. The decline in physical performance can generally be based on walking speed, specifically a walking speed of less than 0.8 m / s. Muscle strength loss can generally be based on grip strength loss. Specifically, for men, a grip strength of less than 26 kg and for women, a grip strength of less than 18 kg can be used as a reference.

[0056]

[0058] Additionally or alternatively, sarcopenia can be diagnosed in a subject based on the definition of the European Working Group for Sarcopenia in Older People (EWGSOP), as described, for example, by Crutz-Jentoft et al. (2010). Muscle mass loss can generally be based on a decrease in appendicular lean mass (ALM index) normalized to the square of height, specifically an ALM index of less than 7.23 kg / m2 for men and less than 5.67 kg / m2 for women. Decrease in physical performance can generally be based on walking speed, specifically a walking speed of less than 0.8 m / sec. Muscle strength loss can generally be based on a decrease in grip strength, specifically a grip strength of less than 30 kg for men and less than 20 kg for women.

[0057]

[0059] Additionally or alternatively, sarcopenia can be diagnosed in a subject based on the definition of the Foundation for the National Institutes of Health (FNIH), as described, for example, by Studenski et al. (2014). Muscle mass loss can generally be based on a decrease in appendicular lean mass (ALM) normalized to body mass index (BMI; kg / m2), specifically an ALM to BMI of less than 0.789 for men and less than 0.512 for women. Decrease in physical performance can generally be based on walking speed, specifically a walking speed of less than 0.8 m / sec. Muscle strength loss can generally be based on a decrease in grip strength, specifically a grip strength of less than 26 kg for men and less than 16 kg for women. Muscle strength loss can also generally be based on a decrease in grip strength to body mass index, specifically a grip strength to body mass index of less than 1.00 for men and less than 0.56 for women.

[0058]

[0060] As used herein, "frailty" is defined as a clinically recognizable state in which, as a result of increased vulnerability due to a decline in reserve capacity and function across multiple physiological systems with aging, the ability to cope with daily or acute stressors is impaired. In the absence of established quantitative criteria, frailty is functionally defined by Fried et al. as meeting three of the following five phenotypic criteria indicating impaired energy characteristics: (1) reduced muscle strength (grip strength at baseline within the lowest 20% of the population, corrected for gender and body mass index), (2) low endurance and energy (self-reported fatigue related to maximal VO2), (3) slowness of movement (baseline based on 15-foot walking time within the lowest 20% of the population, corrected for gender and height), (4) low physical activity (weighted score of kilocalories consumed per week at baseline, lowest quintile of physical activity specified for each gender; e.g., less than 383 kcal / week for men and less than 270 kcal / week for women), and / or unintentional weight loss (10 pounds in the past year). Fried LP, Tangen CM, Walston J et al., "Frailty in older adults: evidence for a phenotype." J. Gerontol. A Biol. Sci. Med. Sci. 56(3):M146-M156 (2001). The pre-frail stage, in which one or two of these criteria are present, is identified as having a high risk of progression to frailty.

[0059]

[0061] "Cachexia" is a complex metabolic syndrome associated with underlying disease, characterized by muscle loss, with or without accompanying fat mass loss. The prominent clinical feature of cachexia is weight loss in adults (corrected for fluid retention) or growth failure in children (excluding endocrine disorders).

[0060]

[0062] Cachexia is often seen in patients with diseases such as cancer, chronic heart failure, kidney failure, chronic obstructive pulmonary disease, AIDS, autoimmune disorders, chronic inflammatory disorders, cirrhosis, anorexia nervosa, chronic pancreatitis, and / or metabolic acidosis and neurodegenerative diseases.

[0061]

[0063] In certain types of cancer, such as pancreatic cancer, esophageal cancer, gastric cancer, intestinal cancer, lung cancer, and / or liver cancer, cachexia is particularly commonly seen.

[0062]

[0064] Internationally recognized diagnostic criteria for cachexia are weight loss of more than 5% over a limited period, for example, 6 months, or weight loss of more than 2% in an individual who already shows depletion by current weight and height (body mass index [BMI] less than 20 kg / m 2 2) or skeletal muscle mass (measured by DXA, MRI, CT, or bioimpedance). Cachexia can progress gradually through various stages, that is, from pre-cachexia to cachexia and refractory cachexia. The severity can be classified in combination with ongoing weight loss according to the degree of depletion of energy stores and body proteins (BMI).

[0063]

[0065] In particular, cancer cachexia is defined as weight loss of more than 5% in the past 6 months (in the absence of simple starvation); or BMI less than 20 and weight loss of more than 2%; or appendicular lean mass that is not inconsistent with muscle mass reduction (less than 7.26 kg / m 2 in men and less than 5.45 kg / m 2 in women), and any degree of weight loss of more than 2% (Fearon et al., 2011).

[0064]

[0066] "Pre-cachexia" can be defined as weight loss of 5% or less in combination with anorexia nervosa and metabolic changes. Currently, there are no strong biomarkers to identify patients with pre-cachexia who are likely to progress further or the rate at which pre-cachexia progresses. Refractory cachexia is essentially defined based on the clinical characteristics and situation of the patient.

[0065]

[0067] The terms "treatment" and "treating" include any effect that brings about an improvement in a condition or disease (disorder), such as alleviating, reducing, controlling, or eliminating the condition or disease. This term does not necessarily mean that the subject is treated until complete cure. Non-limiting examples of "treating" a condition or disease include (1) inhibiting the condition or disease, i.e., stopping the onset of the condition or disease or its clinical symptoms, and (2) alleviating the condition or disease, i.e., causing a temporary or permanent remission of the condition or disease or its clinical symptoms. Treatment may be relevant to a patient or to a physician.

[0066]

[0068] The term "prevention" or "preventing" means not causing the clinical symptoms of the stated condition or disorder in an individual who may be exposed to or is prone to the condition or disorder but who has not yet exhibited or manifested the symptoms of the condition or disorder. The terms "condition" and "disease / disorder" mean any disease, condition, symptom, or sign.

[0067]

[0069] Relative terms such as "improved", "increased", "enhanced", etc. refer to the effect of a composition containing both one or more assimilable amino acids and one or more amino acids that induce autophagy, compared to a composition that is otherwise identical except for not containing one or more amino acids that induce autophagy or containing fewer than one or more amino acids that induce autophagy.

[0068]

[0070] The terms "food", "food product", and "food composition" mean a product or composition that is intended for ingestion by an individual such as a human and provides at least one nutrient to such an individual. The compositions of the disclosure, including many embodiments described herein, may include, consist of, or consist essentially of any additional or optional ingredients, components, or limitations described herein or useful in diet therapy, in addition to the essential elements and limitations described herein.

[0069]

[0071] As used herein, "complete nutrition" contains sufficient types and levels of macronutrients (protein, lipid, and carbohydrate) and micronutrients to be a sufficient sole source of nutrition for the animal to which the composition is administered. An individual can receive 100% of the nutrients the individual needs from such a complete nutrition composition.

[0070]

[0072] As used herein, the term "critically ill patient" is an individual who has developed acute life-threatening symptoms or who has been diagnosed as being at imminent risk of such development. Critically ill patients are medically unstable and have a high likelihood of death (e.g., >50% mortality rate) if not treated.

[0071]

[0073] Non-limiting examples of critically ill patients include patients who have, or are at risk of having, persistent life-threatening acute single or multiple organ system failure due to a disease or injury, patients who are undergoing surgery and have developed complications, and patients who have had surgery on a major organ or major surgery within the past week.

[0072]

[0074] More specific non-limiting examples of critically ill patients include patients in whom acute single or multiple organ system failure threatening life persists or has a risk of persisting due to a disease or injury, and patients who have undergone surgery and are suffering from complications. Further specific non-limiting examples of critically ill patients include patients who require one or more of cardiac surgery, brain surgery, thoracic surgery, abdominal surgery, vascular surgery, or transplantation, and patients suffering from one or more of neurological diseases, brain trauma, respiratory failure, peritonitis, multiple trauma, severe burns, or severe polyneuropathy.

[0073]

[0075] The term "intensive care unit (ICU)" refers to a part of a hospital that treats critically ill patients. The term "intensive care unit" also includes, if the treatment activities carried out there are the same as or similar to those of the ICU, nursing homes; clinics (e.g., private clinics), etc. "ICU patients" are included in the term "critically ill patients".

[0074]

[0076] The term "multiple organ dysfunction" refers to a condition resulting from infections, decreased blood flow, metabolic hyperactivity, or injuries such as accidents or surgeries. "Multiple organ failure", in which critically ill patients die, is considered a descriptive clinical syndrome defined as the dysfunction or failure of at least two major organ systems. The major organ systems that are uniformly and most specifically affected are the liver, kidneys, lungs, as well as the cardiovascular, nervous, and hematological systems. Non-limiting examples of multiple organ dysfunction include acute respiratory distress syndrome, heart failure, liver failure, kidney failure, respiratory failure, intensive care, shock, extensive burns, sepsis (e.g., systemic inflammatory response syndrome), and stroke.

[0075]

[0077] The term "enteral administration" includes oral administration (including oral forced nutrition) and rectal administration, with oral administration being preferred. The term "parenteral administration" refers to the delivery of substances administered by routes other than the gastrointestinal tract, including intravenous, intra-arterial, intramuscular, intraventricular, intraosseous, intradermal, subarachnoid, and also intraperitoneal administration, intravesical instillation, and intracorporal injection, etc.

[0076]

[0078] Preferred parenteral administration is intravenous administration. A specific form of parenteral administration is delivery by intravenous administration of nutrition. Parenteral nutrition is "total parenteral nutrition" when food is not provided by other routes. "Parenteral nutrition" preferably contains saccharides such as glucose and further contains one or more of lipids, amino acids, and vitamins, and is an isotonic aqueous solution or a hypertonic aqueous solution (or a solid composition to be dissolved, or a liquid concentrate diluted to obtain an isotonic solution or a hypertonic solution).

[0077]

[0079] Embodiment

[0080] One aspect of the present disclosure is a method for enhancing the action of one or more anabolic amino acids on the musculoskeletal system in an individual in need of enhanced action on the musculoskeletal system. The method includes the step of administering to the individual a composition containing one or more anabolic amino acids, the composition further containing one or more amino acids or their precursors that induce autophagy, for example in muscle, in an amount effective for the composition to be at least neutral with respect to autophagy, preferably positive with respect to autophagy. The composition can be administered parenterally, enterally, or intravenously. The one or more anabolic amino acids are different compounds from the one or more amino acids that induce autophagy.

[0078]

[0081] As used herein, "enhancing the action on the musculoskeletal system" means that (i) the positive (anabolic) effect of one or more anabolic amino acids is greater than that of a composition formulated identically except that one or more amino acids that induce autophagy are absent or present in a smaller amount, and / or (ii) the positive (anabolic) effect of one or more anabolic amino acids lasts longer than that of a composition formulated identically except that one or more amino acids that induce autophagy are absent or present in a smaller amount.

[0079]

[0082] Non-limiting examples of suitable anabolic amino acids include leucine, isoleucine, arginine, glutamine, citrulline, and mixtures thereof. The composition can contain one or more of leucine, isoleucine, or arginine in free form and / or in bound form as peptides and / or proteins (such as milk protein, animal protein, or plant protein). Preferably, any leucine or arginine is present in the composition in an amount effective to activate mTOR. The daily dose of the composition can be 0.175 - 142.85 mg / kg bw of leucine, preferably 0.35 - 71.425 mg / kg bw of leucine, 0.175 - 71.425 mg / kg bw of isoleucine; 20 - 300 mg / kg bw of arginine, preferably 50 - 200 mg / kg bw of arginine, and / or 20 - 300 mg / kg bw of citrulline, preferably 100 - 200 mg / kg bw of citrulline. The daily dose of one or more anabolic amino acids can be provided by ingesting the composition one or more times per day.

[0080]

[0083] Non-limiting examples of suitable amino acids for inducing autophagy include glycine, cysteine, proline, glutamic acid, valine, tyrosine, or their precursors, such as serine (as a precursor of glycine), N-acetylcysteine, methionine (as a precursor of cysteine), and mixtures thereof. The composition contains one or more amino acids or their precursors that induce autophagy in an amount effective to make the composition at least neutral with respect to autophagy, preferably positive with respect to autophagy, even if one or more anabolic amino acids have a negative effect on autophagy.

[0081]

[0084] Whey protein is rich in BCAA such as leucine and isoleucine. Therefore, some embodiments of the composition include whey protein that provides at least a portion of the assimilable amino acids in the composition. Further, hydrolyzed collagen is a rich source of glycine and proline, and thus some embodiments of the composition include amino acids that induce autophagy as providing at least a portion of the assimilable amino acids in the composition.

[0082]

[0085] The present composition can induce autophagy in muscles, such as skeletal muscle. Non-limiting examples of such muscles include one or more of the following: vastus lateralis, gastrocnemius, tibialis anterior, soleus, extensor digitorum longus (EDL), biceps femoris, semitendinosus, semimembranosus, gluteus maximus, extraocular muscles, facial muscles, or diaphragm.

[0083]

[0086] Individuals in need of autophagy induction can be elderly individuals such as elderly animals or elderly humans. In some embodiments, the individuals in need of autophagy induction are aged animals or aged humans.

[0084]

[0087] Individuals in need of autophagy induction can be critically ill patients. In various embodiments, the method can treat or prevent multiple organ dysfunction in critically ill patients, for example, when homeostasis fails or is impaired due to the patient receiving parenteral nutrition; protect critically ill patients from multiple organ dysfunction; treat or prevent the onset of lactic acidosis, such as lactic acidosis induced by parenteral nutrition; treat or prevent muscle weakness in critically ill patients; reduce or prevent morbidity or death due to deterioration of nutritional status by parenteral nutrition; and / or prevent the collapse of the body system.

[0085]

[0088] In some embodiments, a critically ill patient has at least one life-threatening condition selected from the group consisting of lactic acidosis, muscle weakness, hyperglycemia, multiple organ failure, failure of homeostasis, and disruption of homeostasis. In one embodiment, the critically ill patient has a non-infectious disease. In one embodiment, the critically ill patient has multiple organ dysfunction not caused by or related to sepsis. Multiple organ dysfunction and muscle weakness are common in the emergency rescue scene and can be caused or exacerbated by uncoordinated parenteral nutrition delivery or relative or absolute overnutrition delivered parenterally.

[0086]

[0089] In some embodiments, a critically ill patient has at least one disease selected from the group consisting of severe trauma, multiple trauma, high-risk surgery, extensive surgery, traumatic brain injury, cerebral hemorrhage, respiratory failure, peritonitis, acute kidney injury, acute liver injury, severe burns, severe polyneuropathy, severe myopathy, and ICU-acquired muscle weakness.

[0087]

[0090] In some embodiments, a critically ill patient is receiving enteral nutrition or parenteral nutrition. In some embodiments, the composition treats or prevents mitochondrial dysfunction, such as mitochondrial dysfunction induced by inadequate or uncoordinated parenteral nutrition in a critically ill patient.

[0088]

[0091] In another aspect of the present disclosure, the method overcomes one or more negative effects of one or more assimilated amino acids by preventing a degenerative process associated with a decrease in autophagy. The method includes administering to an individual a composition comprising one or more assimilated amino acids, the composition further comprising one or more amino acids or precursors thereof that induce autophagy, in an amount effective to render the composition at least neutral with respect to autophagy, preferably positive with respect to autophagy, for example in muscle.

[0089]

[0092] As used herein, the term "protein" includes free amino acids, molecules of 2 to 20 amino acids (referred to herein as "peptides"), and, similarly, longer amino acid chains. Small peptides, i.e., chains of 2 to 10 amino acids, are suitable for the present composition either alone or in combination with other proteins. The "free form" of an amino acid is the monomeric form of the amino acid. Suitable amino acids include both natural and non-natural amino acids. The present composition may comprise one or more proteins, e.g., a mixture of one or more (i) peptides, (ii) longer amino acid chains, or (iii) free amino acids; this mixture is preferably formulated to obtain a desired amino acid profile / content.

[0090]

[0093] The present composition can comprise a protein that provides at least a portion of one or more anabolic amino acids and / or at least a portion of one or more amino acids that induce autophagy, and at least a portion of the protein can be of animal or plant origin, e.g., dairy proteins such as, for example, milk protein concentrate or milk protein isolate; casein salts or casein, such as, for example, casein micelle concentrate or casein micelle isolate; or dairy product proteins such as one or more of whey protein, such as, for example, whey protein concentrate or whey protein isolate. Additionally or alternatively, at least a portion of the protein can be a plant protein such as one or more of soy protein or pea protein.

[0091]

[0094] Mixtures of these proteins, for example, mixtures in which casein is the majority but not all of the protein, mixtures in which whey protein is the majority but not all of the protein, mixtures in which pea protein is the majority but not all of the protein, and mixtures in which soy protein is the majority but not all of the protein are also suitable. In one embodiment, at least 10% by weight, preferably at least 20% by weight, more preferably at least 30% by weight of the protein is whey protein. In one embodiment, at least 10% by weight, preferably at least 20% by weight, more preferably at least 30% by weight of the protein is casein. In one embodiment, at least 10% by weight, preferably at least 20% by weight, more preferably at least 30% by weight of the protein is vegetable protein.

[0092]

[0095] Whey protein can be any whey protein selected from the group consisting of, for example, whey protein concentrate, whey protein isolate, whey protein micelle, whey protein hydrolyzate, acid whey, sweet whey, denatured sweet whey (sweet whey from which caseinoglycomacropeptide has been removed), fractions of whey protein, and any combination thereof.

[0093]

[0096] Casein can be obtained from any mammal, preferably from milk, and preferably obtained as casein micelles.

[0094]

[0097] The protein may not be hydrolyzed, may be partially hydrolyzed (i.e., peptides having a molecular weight of 3 kDa to 10 kDa and an average molecular weight of less than 5 kDa), or may be significantly hydrolyzed (i.e., 90% are peptides having a molecular weight of less than 3 kDa), for example, 5% to 95% may be hydrolyzed. In some embodiments, the peptide profile of the hydrolyzed protein can be within different molecular weight ranges. For example, the majority (>50 mol% or >50 wt%) of the peptides can have a molecular weight within 1 to 5 kDa or 5 to 10 kDa or 10 to 20 kDa.

[0095]

[0098] In one embodiment, the composition comprises a carbohydrate source. Any suitable carbohydrate may be used in the composition, including, but not limited to, starch (e.g., modified starch, amylose starch, tapioca starch, corn starch), sucrose, lactose, glucose, fructose, solid corn syrup, maltodextrin, xylitol, sorbitol, or combinations thereof.

[0096]

[0099] The carbohydrate source is preferably 50 energy % or less of the composition, more preferably 36 energy % or less of the composition, and most preferably 30 energy % or less of the composition.

[0097]

[0100] In one embodiment, the composition comprises a fat source. The fat source can include any suitable fat or fat mixture. Non-limiting examples of suitable fat sources include vegetable fats (e.g., olive oil, corn oil, sunflower oil, high oleic sunflower oil, rapeseed oil, canola oil, hazelnut oil, soybean oil, palm oil, coconut oil, croton tiglium seed oil, perilla oil, lecithin, etc.), animal fats (such as milk fat); or combinations thereof.

[0098]

[0101] The composition can be administered to an individual such as a human, e.g., an elderly individual or a critically ill individual, in a therapeutically effective dose. A therapeutically effective dose can be determined by one of ordinary skill in the art and can vary depending on several factors known to those of ordinary skill in the art, such as the severity of the condition and the weight and general condition of the individual.

[0099]

[0102] The composition is preferably administered to an individual at least twice a week, more preferably at least three times a week, and most preferably seven times a week; for at least one week, at least one month, at least two months, at least three months, at least six months, or a longer period. In some embodiments, the composition is administered to the individual continuously for several days, for example, until at least a therapeutic effect is achieved. In some embodiments, the composition can be administered to the individual daily for at least 30 days, 60 days, or 90 days continuously.

[0100]

[0103] The above dosage examples do not require continuous daily administration without interruption. Rather, there may be several short-term interruptions in administration, such as a 2- to 4-day interruption during the administration period. The ideal duration of administration of the composition can be determined by those skilled in the art.

[0101]

[0104] In a preferred embodiment, the composition is administered to the individual orally or enterally (e.g., by tube feeding). For example, the composition can be administered to the individual as a beverage, capsule, tablet, powder, or suspension.

[0102]

[0105] The composition can be any type of composition suitable for ingestion by humans and / or animals. For example, the composition can be selected from the group consisting of food compositions, dietary supplements, nutritional compositions, nutraceuticals, powdered nutritional preparations reconstituted with water or milk before ingestion, food additives, pharmaceuticals, beverages, and drinks. In one embodiment, the composition is an oral nutritional supplement (ONS), a complete nutritional formulation, a pharmaceutical, a drug, or a food product. In a preferred embodiment, the composition is administered to the individual as a beverage. The composition can be stored in sachets as a powder and then suspended in a liquid such as water when used.

[0103]

[0106] In some cases where oral or enteral administration is not possible or not recommended, the composition may also be administered parenterally.

[0104]

[0107] In some embodiments, the composition is administered to an individual in a single-dose formulation, i.e., all of the compounds are present in one formulation that is given to the individual with a meal. In other embodiments, the composition is co-administered in separate dosage forms, e.g., at least one of the components and one or more of the other components of the composition are co-administered separately.

[0105]

[0108] In another embodiment, the present disclosure provides a method of making a therapeutic composition, the method comprising adding one or more amino acids or precursors thereof that induce autophagy to a base composition comprising one or more assimilable amino acids to form a therapeutic composition, wherein the one or more amino acids or precursors thereof that induce autophagy are added to the base composition in an amount effective for the therapeutic composition to be at least neutral with respect to autophagy, preferably positive with respect to autophagy. The base composition and / or the therapeutic composition can be formulated for administration by at least one route selected from the group consisting of oral, enteral, parenteral, and intravenous injection. The base composition can be negative with respect to autophagy induction (i.e., the composition is negative overall), and / or the base composition can be neutral or positive with respect to autophagy induction, but can contain one or more assimilable amino acids in an amount that is negative with respect to autophagy induction (i.e., the one or more assimilable amino acids form a portion that is negative with respect to autophagy induction).

[0106]

[0109] In one embodiment, the method includes quantifying the total amount of one or more assimilable amino acids in a base composition; and determining, using the total amount of one or more assimilable amino acids in the base composition, the total amount of one or more amino acids to be added to the base composition to induce autophagy. The step of determining, using the total amount of one or more assimilable amino acids in the base composition, the total amount of one or more amino acids to be added to the base composition to induce autophagy preferably includes determining the effect on autophagy expected from the total amount of one or more assimilable amino acids. The step of determining, using the total amount of one or more assimilable amino acids in the base composition, the total amount of one or more amino acids to be added to the base composition to induce autophagy preferably further includes determining the total amount of one or more amino acids to be added to the base composition to induce autophagy such that the effect on autophagy expected from the total amount of one or more amino acids to be added to the base composition to induce autophagy is approximately equal to or greater than the effect on autophagy expected from the total amount of one or more assimilable amino acids.

Example

[0107]

[0110] Example

[0111] The following non-limiting examples present scientific data that develop and support the concept of administering a composition comprising one or more assimilable amino acids to induce autophagy in an individual in need thereof, the composition further comprising one or more amino acids that induce autophagy in an amount effective to render the composition at least neutral, preferably positive, with respect to autophagy, even when the one or more assimilable amino acids have a negative effect on autophagy.

[0108]

[0112] Example 1

[0113] Experimental protocol

[0114] The zebrafish autophagy reporter was generated by stable expression of an LC3 protein fused to ZsGreen under the control of a skeletal muscle-specific promoter. Larvae of outbred transgenic zebrafish were reared at 28 °C under standard laboratory conditions and treated at 48 hours post-fertilization with indicated amino acids at concentrations ranging from 0.25 to 10 mM in 96-well plates (n = 24). After 16 hours of treatment, the larvae were anesthetized with 0.016% tricaine and imaged at 20× magnification using an ImageXpress confocal system (Molecular Devices). Z-stack images of each larva were captured and maximum projection images were generated. The number of LC3 puncta was calculated using MetaXpress software (Molecular Devices) and normalized by the area of the fish.

[0115] Figures 1-3 show the experimental results.

[0109]

[0116] Example 2

[0117] Materials and Methods

[0118] Aged mice are a good model for evaluating the effects of nutritional therapy on aging-related decline. Using this model, a decline in muscle function with age can be observed, similar to that in humans. In this model, 20-month-old mice were fed either a normal diet or the same diet supplemented with a specific amino acid mixture (AA) for 3 months (see Table 1). The dose of the AA mixture was 1.65 mg / kg BW / day.

[0119]

[0110]

Table 1

[0111]

[0120] To evaluate the effects of aging, adult mice (6 months old) were also fed a normal diet for 3 months. The age-related decline in in vivo force-frequency response was measured with a 305C muscle lever system. Figure 4 shows the effect of a specific amino acid mixture (AA) on the force-frequency response in aged rats and a comparison with adult mice fed a normal diet. The above force-frequency response was significantly improved by AA supplementation, suggesting an improvement in muscle function.

[0112]

[0121] It should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the subject matter of the present invention and without sacrificing the intended advantages. Therefore, such changes and modifications are intended to be included within the scope of the appended claims.

Claims

**Claim 1** A method for enhancing the action of one or more anabolic amino acids on the musculoskeletal system in an individual in whom it is necessary to enhance the action on the musculoskeletal system, the method comprising the step of administering to the individual a composition comprising the one or more anabolic amino acids, wherein the composition further comprises one or more amino acids that induce autophagy or precursors thereof in a total amount effective for the composition to be at least neutral with respect to autophagy. **Claim 2** The method according to claim 1, wherein the one or more amino acids that induce autophagy are selected from the group consisting of glycine, cysteine, proline, glutamic acid, valine, tyrosine, or precursors thereof, and mixtures thereof. **Claim 3** The method according to claim 1, wherein the precursor is serine, N-acetylcysteine (NAC), or methionine. **Claim 4** The method according to claim 1, wherein the one or more anabolic amino acids are selected from the group consisting of leucine, isoleucine, arginine, glutamine, citrulline, and mixtures thereof. **Claim 5** The method according to claim 1, wherein the one or more anabolic amino acids comprise at least one of leucine, arginine, or glutamine in an amount effective to activate mTOR in the individual. **Claim 6** The method according to claim 1, wherein the composition induces autophagy in skeletal muscle. **Claim 7** The method according to claim 1, wherein the individual is an elderly individual. **Claim 8** The method according to claim 1, wherein the individual has sarcopenia or frailty, or is at risk of developing sarcopenia or frailty. **Claim 9** The method according to claim 1, wherein the individual has at least one condition selected from the group consisting of (i) severe, (ii) acute kidney injury, (iii) chronic kidney injury, (iv) muscle mass reduction due to chronic kidney disease, and (v) muscle function reduction due to chronic kidney disease. **Claim 10** The method according to claim 1, wherein the individual has severe myopathy or is at risk of developing severe myopathy. **Claim 11** The method according to claim 1, wherein the individual has cachexia or muscle wasting secondary to a chronic disease such as cancer, chronic obstructive pulmonary disease (COPD), chronic heart failure (CHF), acute kidney disease, or chronic kidney disease (CKD). **Claim 12** The method according to claim 1, wherein the composition contains at least a part of the one or more assimilable amino acids and / or a protein that provides at least a part of the one or more amino acids or precursors that induce autophagy, and at least a part of the protein is selected from the group consisting of (i) a protein derived from an animal material, (ii) a protein derived from a plant material, and (iii) a mixture thereof.

13. The method according to claim 12, wherein at least a part of the protein is selected from the group consisting of (i) milk protein, (ii) whey protein, (iii) casein salt, (iv) casein micelle, (v) pea protein, (vi) soy protein, and (vii) a mixture thereof.

14. The method according to claim 12, wherein at least a part of the protein is selected from the group consisting of (i) free-form amino acids, (ii) non-hydrolyzed proteins, (iii) partially hydrolyzed proteins, (iv) extensively hydrolyzed proteins, and (v) a mixture thereof.

15. The method according to claim 12, wherein at least a part of the protein is 5 to 95% hydrolyzed.

16. The method according to claim 12, wherein the protein contains a peptide having a length of 2 to 10 amino acids.

17. The method according to claim 12, wherein the protein has a formulation selected from the group consisting of (i) a formulation in which at least 50% of the protein has a molecular weight of 1 to 5 kDa, (ii) a formulation in which at least 50% of the protein has a molecular weight of 5 to 10 kDa, and (iii) a formulation in which at least 50% of the protein has a molecular weight of 10 to 20 kDa.

18. The method according to claim 1, wherein the composition contains a carbohydrate source and / or a fat source.

19. The method according to claim 1, wherein the step of administering uses at least one route selected from the group consisting of oral, enteral, parenteral, and intravenous injection.

20. The method according to claim 1, wherein the total amount of the one or more assimilable amino acids is approximately equal to or more than the total amount of the one or more assimilable amino acids in the composition.

21. The method according to claim 1, wherein the total amount of the one or more assimilable amino acids is at least twice more than the total amount of the one or more assimilable amino acids in the composition.

22. A composition comprising one or more assimilable amino acids, further comprising one or more amino acids or precursors thereof that induce autophagy in a total amount effective for the composition to be at least neutral with respect to autophagy.

23. The composition according to claim 22, wherein the composition is selected from the group consisting of a food composition, a dietary supplement, a nutritional composition, nutraceuticals, a powdered nutritional preparation reconstituted with water or milk before ingestion, a food additive, a pharmaceutical, a drink, and combinations thereof.

24. A method for preparing a therapeutic composition, comprising the step of adding one or more amino acids or precursors thereof that induce autophagy to a base composition comprising one or more assimilable amino acids to form the therapeutic composition, wherein the one or more amino acids or precursors that induce autophagy are added to the base composition in a total amount effective for the therapeutic composition to be at least neutral with respect to autophagy.

25. The method according to claim 24, wherein the base composition is formulated for administration by at least one route selected from the group consisting of oral, enteral, parenteral, and intravenous injection.

26. The method according to claim 24, wherein the base composition is negative with respect to the induction of autophagy.

27. The method according to claim 24, wherein the base composition contains the one or more assimilable amino acids in an amount that forms a part of the base composition that is negative with respect to the induction of autophagy.

28. The method according to claim 24, comprising the step of quantifying the total amount of the one or more assimilable amino acids in the base composition and the step of using the total amount of the one or more assimilable amino acids in the base composition to determine the total amount of the one or more amino acids added to the base composition that induce autophagy.

29. The method according to claim 28, wherein the step of using the total amount of the one or more assimilable amino acids in the base composition to determine the total amount of the one or more amino acids added to the base composition that induce autophagy comprises determining the effect on autophagy expected from the total amount of the one or more assimilable amino acids.

30. A method according to claim 28, further comprising determining the total amount of one or more amino acids that are added to the base composition and induce autophagy, using the total amount of the one or more assimilable amino acids in the base composition, such that the effect on autophagy expected from the total amount of the one or more amino acids that are added to the base composition and induce autophagy is approximately equal to or greater than the effect on autophagy expected from the total amount of the one or more assimilable amino acids.

31. A method comprising administering to an individual in need of said synthesis and removal a composition that simultaneously promotes protein synthesis and removal of damaged cellular material, said composition comprising one or more assimilable amino acids, said composition further comprising one or more amino acids or precursors thereof that induce autophagy in an amount effective for said composition to be at least neutral with respect to autophagy.

32. A method of overcoming one or more negative effects of one or more assimilable amino acids by preventing a degenerative process associated with a decrease in autophagy, said method comprising administering to an individual in need of said overcoming a composition comprising one or more assimilable amino acids, said composition further comprising one or more amino acids or their precursors that induce autophagy in an amount effective for said composition to be at least neutral with respect to autophagy.

Images