Compositions and methods for increasing beneficial tryptophan metabolites

Abstract

The invention provides compositions, combinations, supplement formulations and methods of use for increasing tryptophan metabolism to generate beneficial metabolites. These include Indole-3-propionic acid (IPA) and indole-3-propionamide (IPAM). The invention provides increased plasma tryptophan and tryptophan metabolites that include IPA and IPAM.

Description

COMPOSITIONS AND METHODS FOR INCREASING BENEFICIAL TRYPTOPHAN METABOLITESCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 550,216 filed on February 6, 2024, incorporated by reference herein in its entirety.FIELD OF THE INVENTION

[0002] The present disclosure relates to compositions, combinations, and methods comprising the generation and use of tryptophan metabolite precursors, supporting antioxidants, and specific excipients to improve cognition and health.BACKGROUND OF THE INVENTION

[0003] Tryptophan is a rate-limiting essential amino acid that is the precursor to molecules such as melatonin, serotonin, and other neurotransmitters that improves health, quality of life and wellbeing. Certain try ptophan metabolites have health benefits because they act as potent protective antioxidant agents. The same tryptophan metabolites have an anti-inflammatoiy properties and have regenerative influences in the body. Indolic acids represent one class of beneficial tryptophan metabolism products. Other tryptophan metabolites are potentially toxic. Examples include indoxy l and indoxy l sulfate which can be potentially prooxidant and toxic.

[0004] Gut metabolites are increasingly recognized as key mediators of many bodily systems. They, and the bacteria which produce them, influence and are influenced by processes implicated in aging and disease. Tryptophan metabolites, particularly Indole -3 -propionic acid (IP A), are a common predictive factor in the pathology of most age, diet, and immune-related diseases. They could even play a role in female reproductive longevity.

[0005] Several try ptophan metabolites that have potential health benefits are exclusively produced by gut microbiota. Indole-3 -propionic acid (IP A) and indole-3 -propionamide (IP AM) are produced by gut microbiota and are absorbed through the intestine and can be found in the serum. IPA and IP AM cross the blood brain barrier and prevent neurodegeneration by neutralizing free radicals. Additionally, IPA is an important intestinal barrier protector. It is anti-inflammatory for the intestine and has beneficial effects on glucose and energy metabolism.

[0006] IPA’s beneficial effects on the mucosal barrier and its pro -re generative effects are mediated through IPA’s action on the pregnane X receptor (PXR) and the aryl hydrocarbon receptor (AhR). Activation of the PXR promotes gut barrier function while activation of AhR inside local intestinal immune cells by IPA modulates intestinal immune responses by promoting interleukin- 22 (IL-22). AhR is also present in the liver where it regulates detoxification, in immune cellsthroughout the body, and in epithelial cells that make up the skin barrier. Hence. IPA is a crucial regulator}' molecule for the aging process.

[0007] IPA and IP AM levels depend on dietary tryptophan as well as the balance betw een host and gut microbiota metabolism of tryptophan. These levels vary greatly among individuals. A tryptophan-enriched diet is a component of the dietary management of neurode generative diseases of elderly individuals. It improves cognition and health because it increases the levels of antiinflammatory, regenerative, nootropic, neurotrophic and neuroprotective antioxidant indole agents IPA and IP AM.

[0008] Enhanced protection and regeneration determine longevity and healthspan. The ratio of tryptophan to kynurenine is a key parameter reflecting endogenous adaptation to stress determining inflammation and degeneration (Tsuji et al., IntJ Mol Sei. 2023 Mar 17;24(6):5742. doi: 10.3390 / ijms24065742; Poeggeler, B. et al., FHM Bielefeld 2023, 15, 65-74, incorporated by reference herein in its entirety.) Tryptophan metabolites such as IPA and IP AM act as potent catalytic antioxidant and bioenergetic agents that facilitate regeneration and protection against oxidative stress and premature aging.SUMMARY OF THE INVENTION

[0009] Despite the beneficial actions of indolic acids, the increased levels of toxic tryptophan metabolites has detrimental effects on health. The invention provides compositions and interventions that selectively improve tryptophan metabolism by diverting metabolism to the gut microbiota in order to enhance production of beneficial tryptophan metabolites. This improves lifespan and healthspan as well as reduces the formation of toxic compounds. The present invention thus provides selective improvements of tryptophan metabolism that produce beneficial gut microbiota derived metabolites that increases lifespan and healthspan.

[0010] The invention provides a composition, comprising: a pea protein isolate; an L-tryptophan isolate; an L-arginine isolate; a sea buckthorn extract; and an acerola extract. In some aspects, the pea protein isolate is about 80% w / w pea protein. In other aspects, the pea protein isolate is about 66% w / w of the composition. In other aspects, the L-tryptophan isolate is about 6.7% w / w of the composition. In other aspects, the L-arginine isolate is about 6.7% w / w of the composition. In other aspects, the buckthorn extract is about 6.7% w / w of the composition. In other aspects, the acerola extract is about 6.7% w / w of the composition.

[0011] In some aspects of the invention, the composition further comprises a buckwheat extract. In some aspects, the buckwheat extract is about 3.3% w / w of the composition. In other aspects, the composition further comprises a sweetener. In some aspects, the sweetener is xylitol. In preferred aspects, the xylitol is about 3.3% w / w of the composition.

[0012] In some aspects of the invention, the composition further comprises an excipient. In someaspects, the excipient is selected from the group consisting of fibersol-2, malic acid, citric acid, tricalciumphosphate and magnesium stearate.

[0013] In some aspects of the invention, the composition comprises a ratio of pea protein isolate to L-tryptophan isolate to L-arginine isolate of 10: 1 : 1.

[0014] The invention provides a supplemental formulation comprising the compositions of the invention disclosed herein, wherein the supplemental formulation is a liquid, powder, gel, paste, solid, concentrate, suspension, ready -to-use enteral formula, or an oral formula. In other aspects, the supplemental formulation is in a food product, food additive, beverage, beverage additive, capsule, tablet, aqueous suspension, or solution. In preferred aspects, the beverage is water, fruit juice, animal milk, or a plant-based milk.

[0015] The invention provides a method of increasing serum IPA or IP AM in a subject, the method comprising administering to the subject the compositions of the invention as disclosed herein. In some aspects, the method does not increase serum idoxyl sulfate in the subject. In other aspects, the method does not increase serum idoxyl sulfate by more than 10% above the levels observed prior to administering the compositions of the invention to the subject. In other aspects, the method does not increase serum idoxyl sulfate by more than 20% above the levels observ ed prior to administering the compositions of the invention to the subject. In other aspects, the method does not increase serum idoxyl sulfate by more than 30% above the levels observed prior to administering the compositions of the invention to die subject. In other aspects, the method decreases C-Reactive Protein (CRP) in die subject. In other aspects, the mediod decreases a kynurenine to tryptophan ratio in the subject.

[0016] In some aspects of the invention, the composition is administered daily. In other aspects, the administration continues for at least about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8. about 9. about 10, about 11, about 12 months, or more.

[0017] In some aspects of the invention, the method decreases a biological age of the subject. In other aspects, the method increases a cerebral blood flow of the subject. In other aspects, the method increases a duration of slow wave sleep of the subject. In other aspects, the method increases a cognitive health (CogHealth) of the subject.BRIEF DESCRIPTION OF THE DRAWINGS

[0018] FIG. 1A is a comparison of arginine serum levels in 30 young volunteers (mean age 27.9 years old) and 30 elderly volunteers (mean age 66.7 years old). FIG. IB is a comparison of try ptophan serum levels in 30 young volunteers and 30 elderly volunteers. FIG. 1C is a comparison of indole-3 -propionic acid serum levels in 30 young and 30 elderly volunteers. FIG. ID is a comparison of indole -3 -priopionamide serum levels in 30 young and 30 elderly volunteers. FIG. IE is a comparison of peroxynitrite serum levels in 30 young and 30 elderlyvolunteers. FIG. IF is a comparison of nitrotyrosine semm levels in 30 young and 30 elderly volunteers.

[0019]

[0012] FIG. 2A is a comparison of arginine serum levels in the placebo group and in the venim group. FIG. 2B is a comparison of tryptophan serum levels in the placebo group and in the verum group. FIG. 2C is a comparison of indole-3-priopionic acid serum levels in the placebo group and in the verum group. FIG. 2D is a comparison of indole-3- priopionamide serum levels in the placebo group and in the verum group. FIG. 2E is a comparison of peroxynitrite serum levels in the placebo group and in the verum group. FIG 2F is a comparison of nitrotyrosine serum levels of in the placebo group and in the verum group.

[0020]

[0013] FIG. 3 A is a comparison of biological age in the placebo group and in the verum group. FIG. 3B is a comparison of cerebral blood flow in the placebo group and in the verum group. FIG. 3C is a comparison of slow wave sleep duration in the placebo group and in the verum group. FIG. 3D is a comparison of cognitive health in the placebo group and in the verum group.DETAILED DESCRIPTION OF THE INVENTION

[0021] Reference now will be made in detail to the embodiments of the present invention, one or more examples of which are set forth herein. Each example is provided by way of explanation of the compositions and methods of the present invention and is not a limitation. In fact, it will be apparent to those skilled in the art that various modifications and variations can be made to the teachings of the present invention without departing from the scope of the disclosure. For instance, features illustrated or described as part of one embodiment can be used with another embodiment to yield a still further embodiment.

[0022] It is intended that the present invention covers such modifications and variations as come within the scope of the appended claims and their equivalents. Other objects, features, and aspects of the present invention are disclosed herein or are within the skill of the art from the following detailed description. Thus, it is to be understood by one of ordinary skill in the art that the present discussion is a description of exemplary’ embodiments only and is not intended as limiting the broader aspects of the present disclosure.

[0023] The present invention relates to compositions and supplement formulations that are tailored to improve health by increasing the metabolism of tryptophan into beneficial metabolites including IPA and IPAM. Further, the supplement formulations of the presentinvention also increase serum try ptophan and try ptophan metabolites including IPA and IPAM. Additionally, the compositions and supplement formulations improve health by decreasing certain metabolites such as peroxynitrite, nitrotyrosine, idoxyl sulfate, and kynurenine.

[0024] The compositions disclosed herein direct try ptophan metabolism from the diet towards the gut microbiota in order to produce beneficial indole metabolites. The pea protein base of the blend acts as a carrier, forming vesicles that encapsulate amino acids, including added arginine and tryptophan, to facilitate their sustained release. Arginine increases NO. In turn, NO, coupled to the blend’s vitamin C and bioflavonoid mixture (derived from sea buckthorn and acerola), scavenge superoxide anion radicals that are cosubstrates for tryptophan catabolism enzymes. Such enzymes include indole 2,3 dioxygenase (IDO) and tryptophan 2,3 -dioxygenase (TDO). Reducing IDO activity' along the intestinal mucosa decreases metabolic breakdow n of try ptophan and increases the availability of try ptophan for the gut microbiota. B vitamins in the blend (in part, for example, from buckwheat extract) further prevent tryptophan degradation by IDO. In addition, the rich anti-oxidant protection from blend ingredients also increases tryptophan and its indole product bioavailability' directly within the intestinal tract as it prevents their oxidative breakdown. The net result is a blend with components that act in synergy' to boost levels of tryptophan and indole metabolites in the intestinal tract. These include, for example, indole-3-propionic acid.

[0025] Wherein, given that the technology' diverts tryptophan away from the IDO pathway that degrades tryptophan and from the TDO pathway that produces kynurenine, the invention decreases the kynurenine / tryptophan ratio in humans or non-human mammals. The kynurenine / tryptophan ratio in serum and cerebrospinal fluid increases in a number of neuroinflammatory, neuropysciatric (e.g. depression, schizophrenia) and systemic inflammatory related illnesses, such as infection (e.g. neurological infections, SARS- CoV2, and Tuberculosis), traumatic brain injury, toxic metabolite exposure, neurodegenerative diseases and autoimmunity. Thus, the invention reverses increased kynurenine / tryptophan ratios contributing to such inflammation. This is measured by transcriptome and metabolome profiling as is known in the art.

[0026] Dietary' tryptophan metabolism is altered w'ith age. This results in reduced levels of these metabolites and increased levels of undesirable metabolites associated with cell damage. IPA and IPAM serum levels may be boosted by eating soluble fiber alone as well as by consuming probiotics. Prebiotics in some instances, however, can subsume theeffect of probiotics. Except in the most extreme cases of bacterial extinction, even highly diminished populations of beneficial bacteria can rapidly expand if given the right prebiotic molecules. The compositions of the invention disclosed herein feed and sustain the growth of its own efficacy.

[0027] Thus, the invention surprisingly discloses, for the first time, that the compositions disclosed herein are a highly-effective way to boost serum levels of beneficial tryptophan metabolites such as IPA and IP AM. This nutritional technology unlocks synergistic properties of non-toxic, well -tolerated ingredients to access the benefits of the beneficial tryptophan metabolites disclosed herein and is a scalable approach to increasing human healthspan by ten or more years.

[0028] The invention may improve parameters of health in mammals that are measured with blood tests. Where the invention decreases C-Reactive Protein (CRP) in humans or animals by > 10% after being consumed for a period of 1 month, a period of 1-3 months, a period of 3-6. months, or for more than 6 months, compared to levels of CRP when usage of the supplement invention first begins. CRP is a protein produced by the liver that acts as a marker for inflammation in the body. Its levels rise significantly when there is an infection or tissue damage present, allowing doctors to assess the severity of inflammation through a blood test. High CRP levels can indicate conditions like infections, rheumatoid arthritis, or increased risk of cardiovascular disease. Its levels may rise with age. of which chronic inflammation is a hallmark.

[0029] The invention may also improve a person’s performance on a variety of functional health tests that are known in the art to determine physical and mental fitness. One such test is the 6-minute w alk test (6MWT). The (6MWT) is a medical assessment where a patient walks as far as they can in a designated area for six minutes, allowing healthcare providers to evaluate their functional exercise capacity, particularly for conditions affecting the lungs or heart, by measuring the distance covered during that time. Distance covered in a 6MWT tends to decrease with age. Another test is the grip-strength test, a relevant indicator of health in adult and elderly individuals. Often, participants are asked to squeeze a hand dynamometer as hard as they can. one hand at a time, though other methods can be used to assess grip strength. A third test is the VO2 max test, which measures maximal oxygen consumption during intense exercise. VO2 max is a key indicator of cardiorespiratory fitness and overall endurance capacity, reflecting the body's efficiency in oxygen utilization. This test is typically conducted on a treadmill or stationary bike, where an individual exercises at increasing intensity while their oxygenintake and carbon dioxide output are monitored. VO2 max tends to decline with age and is correlated with metabolic health, cardiovascular function, and longevity’. Improvements in VO2 max indicate enhanced aerobic capacity that is associated with reduced risk of chronic diseases and improved physical performance. Regarding cognitive performance tests, the invention may particularly improve short-term memory’ performance, which can be measured using a variety of clinical batteries.

[0030] The invention may also reduce biological age. which can be measured using “biological age clocks.” A biological age clock is a computational or biochemical system known in the art that estimates an individual's biological age. This may differ from their chronological age based on molecular, cellular, or physiological markers. The clock utilizes biological data — such as DNA methylation patterns, transcriptomic profiles, proteomic markers, metabolomic signatures, or functional physiological metrics — to generate an age estimate that correlates w ith health status, disease risk, and longevity7potential. Some examples of these “clocks” include, but are not limited to, the Horvath Clock, wherein site-specific CpG dinucleotide methylation levels serve as biomarkers of aging, or the Aging. Al clock made by Insilico Medicine which is a metabolomic clock. It applies deep neural netw orks (DNNs) to a dataset of thousands of blood biochemical markers, including amino acids, lipids, and oxidative stress indicators, to predict biological age. It has been integrated with gut microbiome data by linking microbial- derived metabolites (such as short-chain fatty acids and polyamines) with systemic aging processes. This establishes a relative biological age for an individual compared to the metabolomic profiles of individuals of various chronological ages.

[0031] The invention may also increase the consumer’s duration of slow wave sleep in each 24 hour period where the invention is consumed. Slow-wave sleep, characterized by high- amplitude, low-frequency delta waves (0.5-4 Hz) in the electroencephalogram (EEG), is the deepest stage of non-rapid eye movement (NREM) sleep and plays a crucial role in memory’ consolidation, metabolic regulation, and neuroprotection. Empirical data indicate that SWS duration and intensity decline with advancing age. Thsi phenomenon is linked to neurological degeneration, metabolic dysregulation, and systemic aging processes. Slow w ave sleep can be measured w ith a variety7of techniques and devices. The invention may increase duration of slow7wave sleep in a clinical setting where polysomnography is employed. This is a multimodal assessment that combines brain activity7, eye movement, facial-muscular movement, respiratory monitoring, and heart-rate variability. Consumer wearable devices can also be used to track an individual’s sleep-profile. This includes theamount of slow wave sleep they get on any given night. The consumer may have an Apple Watch®, Oura Ring®, Fitbit®, or comparable device that connects with a smartdevice to provide information on the quality of their sleep.

[0032] The invention is designed to increase levels of IPA and IPAM which can be measured in serum, cerebrospinal fluid, and fecal matter. IPA levels have been causally linked with mortality while altered tryptophan metabolism has been causally linked with poor outcomes in the aging process. Hence, reduced IPA levels can be considered an independent biomarker of biological age.

[0033] The invention may improve the consumer’s health in some or all of these areas in a statistically significant fashion, where a p value of p>0.05 is used to determine statistical significance.

[0034] In describing and claiming one or more embodiments of the present invention, the following terminology will be used in accordance with the definitions described below.

[0035] As used herein, the articles “a” and “an’’ refer to one or more than one (i.e. , at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0036] The term “absorption” is the movement of a beneficial supplement, active ingredient, molecule, or combination of these into the bloodstream. An active ingredient needs to be introduced via some route of administration (e.g. oral, topical or dermal, subcutaneous, intramuscular, or intravenous) or in a specific dosage form such as a tablet, patch, capsule or liquid.

[0037] “Administration” is broader than “enteral administration” and includes parenteral administration or any other route of administration by which a substance is taken into a subject’s body.

[0038] The term “bioavailability” refers to the fraction of an administered dose of unchanged ingredients that reaches the systemic circulation, one of the principal pharmacokinetic properties of ingredients. When an active ingredient is administered intravenously, its bioavailability is 100%. When an active ingredient is administered via other routes (such as orally), its bioavailability generally decreases (due to incomplete absorption and first- pass metabolism) or may vary from patient to patient. Bioavailability is an important parameter in pharmacokinetics that is considered when calculating dosages for non- intravenous routes of administration.

[0039] An "effective amount" refers to an amount of an active ingredient or combination of active ingredients that is effective, at dosages and for periods of time necessary, toachieve the desired result. An "effective amount" of a beneficial supplement may vary according to factors such as the disease state, age, sex, and weight of the individual. An effective amount may be measured, for example, by lowered biological age or other acceptable biomarkers or surrogate markers such as tryptophan, arginine, IPA, or IPAM. An effective amount is also one in which any toxic or detrimental effects of the beneficial supplement are outweighed by the beneficial effects. A "prophylactically effective amount" refers to an amount of beneficial supplement that is effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, but not necessarily, since a prophylactic dose is used in subjects prior to or at an earlier stage of aging, the prophylactically effective amount may be less than that required for a subject at a more advanced age.

[0040] As used herein, “enteral” means deliverable through or within the gastrointestinal or digestive tract. “Enteral administration” includes oral feeding, intragastric feeding transpyloric administration or any other administration into the digestive tract.

[0041] An "individual." "subject" or "patient" is a vertebrate. In certain embodiments, the vertebrate is a mammal. Mammals include, but are not limited to. primates (including human and non-human primates) and rodents (e g., mice, hamsters, guinea pigs, and rats). In certain embodiments, a mammal is a human. A "control subject" refers to a healthy subject who has not been diagnosed as having a disease, dysfunction, or condition that has been identified in an individual, subject, or patient. A control subject does not suffer from any sign or symptom associated with the disease, dysfunction, or condition.

[0042] As used herein, “IPA” refers to indole-3-propionic acid . The invention contemplates, however, other beneficial compounds such as indole-3-pyruvic acid, indole-3-lactic acid, indole-3-acrylic acid, indole-3-aldehyde, indole, and melatonin which may also be important to the present invention.

[0043] As used herein “IPAM” refers to indole propionamide including indole-3- propionamide.

[0044] A "response" can be assessed using any endpoint indicating a benefit to the patient, including, without limitation, (1) arrest, or to some extent, inhibition, of age progression, including stabilization, slowing down and complete arrest; (2) reduction in the number of age-related symptoms; (3) favorable change in the expression of a biomarker; or (4) relief, to some extent, of one or more symptoms associated with aging.

[0045] As used herein, an " acceptable carrier" or " effective carrier" is aqueous or nonaqueous (solid), for example alcoholic or oleaginous, or a mixture thereof, and cancontain a surfactant, emollient, lubricant, stabilizer, dye, perfume, preservative, acid or base for adjustment of pH, a solvent, emulsifier, gelling agent, moisturizer, stabilizer, wetting agent, time release agent, humectant, or other component commonly included in a particular form of pharmaceutical composition. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, and oils such as olive oil or injectable organic esters. An acceptable earner can contain physiologically acceptable compounds that act, for example, to stabilize or to increase the absorption of specific supplements. Examples include carbohydrates such as glucose, sucrose or dextrans, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins, or other stabilizers or excipients.

[0046] A "supplement" is an active ingredient or formulation of active ingredients that has been manufactured to benefit the health of its consumer.

[0047] “Supplement formulation” means a substance or formulation that is suitable for use in the present invention. For example, a supplement formulation of the present invention may refer to liquids, powders, gels, pastes, solids, concentrates, suspensions or ready-to- use enteral formulas, and oral formulas.

[0048] As used herein, "treatment" refers to clinical intervention in an attempt to improve health through the use of beneficial supplements. Desirable effects of treatment include preventing the occurrence or recurrence of a disease or a condition or symptom thereof, alleviating a condition or symptom of the disease, diminishing any direct or indirect pathological consequences of the disease, decreasing the rate of disease progression, ameliorating or palliating the disease state, and achieving remission or improved prognosis. In some embodiments, methods and compositions of the invention are useful in attempts to delay development of a disease or disorder. In some embodiments, the disease or disorder is associated with aging.

[0049] A “vitamin” is a recognized term in the art and is defined as a fat-soluble or w ater- soluble organic substance essential in minute amounts for normal growth and activity of the body and is obtained naturally from plant and animal foods or supplements.

[0050] The invention provides effective routes for beneficial supplement administration of the compositions disclosed herein to a subject. The invention provides alternative routes of beneficial supplement administration that are more cost-effective or favorable to the patients when compared to the drugs without the inventions described herein.

[0051] The invention further provides effective routes of beneficial supplement administration via transdermal, oral, parenteral, subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrastemal, intrathecal, intralesional, intracranial injection, infusion, inhalation, ocular, topical, rectal, nasal, buccal, sublingual, vaginal, or implanted reservoir modes.

[0052] Exemplary formulations of the invention include aqueous solutions, organic solutions, powder formulations, solid formulations and mixed phase formulations.

[0053] Some embodiments of the supplement formulation of the present invention can be comprised within a liquid as a suspension for oral or enteral administration. In a nonlimiting example, water can be the base / liquid of supplement formulation. It is also understood that all components in the supplement formulation, including excipients, are ty pically of food or pharmaceutical grade and suitable for, e.g., oral or enteral administration in humans or non-human animals.

[0054] Some embodiments of the supplement formulation of the present invention include L- arginine and L-tryptophan. They help support optimal tryptophan metabolism have beneficial effects on neurological and brain health. Other embodiments of the invention include food-based ingredients or other protein sources rich in L-arginine and L- tryptophan. Exemplary' protein sources include, but are not limited to, pea protein isolate, lupin protein, and buckwheat protein / extract. These protein sources increase serum levels of L-arginine, L-tryptophan, indole-3 -propionic acid, and indole-3 -propionamide.

[0055] Other embodiments of the supplement formulation of the present invention also include components that are B vitamin donors and / or antioxidants. Some components may naturally include all 8 B vitamins. These components can be used as part of the formulation of the present invention without additional added B vitamins. Other embodiments include B vitamins (thiamin, riboflavin, niacin, pantothenic acid, pyridoxine, biotin, folate / folic acid, and cobalamin). One of skill in the art would be able to determine the levels of B vitamins in the B vitamin donor. Based on this understanding, B vitamins or B vitamin donor levels are tailored to the formulations of the invention. In other embodiments, the formulations contain two or more B vitamins or B vitamin donors.

[0056] Without limitation, B vitamin donors and / or antioxidants suitable for the present invention include buckwheat extract, B vitamins, vitamin C, vitamin E, carotenoids (e.g., beta-carotene, astaxanthin, zeaxanthin, lycopene, and lutein), minerals (e.g., selenium and manganese), glutathione (e.g., N-acetyl cysteine), coenzymes (e.g, Q10), lipoic acid.flavonoids (including resveratrol, apigenin, luteolin, quercetin), rutin, flavonols, phenols, polyphenols, pro-anthocyanins, catechins, phytoestrogens, and coumaric acids.

[0057] In other embodiments, suitable components of the invention include "superfoods". Examples of superfoods include, but are not limited to, acerola extract, sea buckthorn extract, pomegranate extract, blueberry', acai, green legume extract (e.g. , kidney beans), goji berries, pecans, artichokes, elderberry, blackberry, cranberry, cilantro, squash, and super spices (e.g, cloves, cinnamon, oregano, cumin, basil, ginger, thyme, turmeric, and parsley) and taurine.

[0058] In other embodiments, the ratios of formulation components are optimized. In one preferred embodiment, the ratio of L-tryptophan and L-arginine is 1 : 1 (w / w). Another preferred ratio of pea protein isolate to L-tryptophan to L-arginine is 10: L 1. These ratios support a targeted sustained release of tryptophan and enhance IPA and IPAM formation in the gastrointestinal tract after administration.

[0059] One exemplary embodiment of the present invention is a liquid supplement formulation comprising the components in ratios that are exemplified in Table 1 below:Table 1

[0060] In some embodiments, the supplement formulations powders, liquids, liquid concentrates, suspensions, suspension concentrates, or solid / powder mixtures. In other embodiments, the concentrates, solids, and powders preserve the correct ratio of components prior to dilution, mixing, or hydrating to the final volume prior to administration.

[0061] Embodiments of the present invention can be administered daily for certain periods of time. One preferred method is daily oral administration either as a powder or as a liquid for at least 1 month, two months, three months, four months, five months, six months, ormore. In some embodiments, the compositions of the invention may be diluted in water, fruit juice, animal milk, or plant-based milks such as sweetened or unsweetened almond, pea, soy, cashew, and oat milk for at least 1 month. Another preferred method is daily oral administration either as a powder or as a liquid (e.g. diluted in water or fruit juice) for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, or more. In some embodiments, because the formulation of the present invention is derived from natural food sources and is safe and highly tolerated, the present invention may be administered for a long period of time and for as long as the desired effects of increased cognitive function and increase healthspan are wanted. In other embodiments, the ingredients are generally recognized as safe (GRAS).

[0062] Parameters such as increased serum arginine, tryptophan, indole-3-propionic acid and indole-3-propionamide are present in younger populations compared to elderly population. These increased levels of serum arginine, try ptophan, indole-3-propionic acid and indole-3 -propionamide (either each alone or together) facilitate regeneration and protection against oxidative stress and premature aging, as well as other factors for better cognitive health. Additionally, these increased levels decrease biological age. Methods for determining biological age are known in the art. Such methods include consideration of immune function parameters. These immune function parameters include neutrophil chemotaxis and phagocytosis, lymphocyte chemotaxis, natural killer cell activity and lymphoproliferation in response to mitogen stimulus (Diaz-Del Cerro et al.. Environmental Health (2020) 19: 118 (https: / / doi.org / 10.1186 / sl2940-20-00674-y, ) and Martinez de Toda, I., et al.. Aging (2016) 8(11); 3110-9). The foregoing are incorporated by reference herein in their entirety.

[0063] Other parameters such as lower levels of serum peroxynitrite and nitrotyrosine are present in younger populations compared to elderly populations. Two reactive nitrogen species (RNS), peroxynitrite and nitrotyrosine, are two exemplar}' indicators of cellular damage. Lower serum levels of these RNS species correlate with decreased cellular damage and anti-aging (e.g. decreased biological age).

[0064] Embodiments of the present invention allow' for a targeted, sustained release of tryptophan in the gastrointestinal tract that naturally boost IPA and IPAM formation. This results in increased levels of both IPA and IPAM levels in the brain. This in turn results in better cognitive health and / or increased healthspan.

[0065] Nutraceutical or pharmaceutical compositions of this invention comprise any of the compounds of the present invention, and pharmaceutically acceptable salts thereof, with any pharmaceutically acceptable carrier, adjuvant or vehicle. Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0066] Pharmaceutically acceptable salts retain the desired biological activity of the beneficial supplement without toxic side effects. Examples of such salts are (a) acid addition salts formed with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like / and salts formed with organic acids such as, for example, acetic acid, trifluoroacetic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tanic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalene disulfonic acid, polygalacturonic acid and the like; (b) base addition salts or complexes formed with polyvalent metal cations such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, and the like; or with an organic cation formed from N,N' -dibenzylethylenediamine or ethlenediamine; or (c) combinations of (a) and (b), e.g. a zinc tannate salt and the like.

[0067] The nutraceutical or pharmaceutical of this invention may be administered by subcutaneous, transdermal, oral, parenteral, inhalation, ocular, topical, rectal, nasal, buccal (including sublingual), vaginal, or implanted reservoir modes. The pharmaceutical compositions of this invention may contain any conventional, non-toxic, pharmaceutically-acceptable carriers, adjuvants or vehicles. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrastemal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0068] Also contemplated, in some embodiments, are nutraceutical or beneficial supplement compositions comprising as an active ingredient or an acceptable salt thereof, in a mixturewith an acceptable, non-toxic component. As mentioned above, such compositions may be prepared for parenteral administration, particularly in the form of liquid solutions or suspensions; for oral or buccal administration, particularly in the form of tablets or capsules; for intranasal administration, particularly in the form of powders, nasal drops, evaporating solutions or aerosols; for inhalation, particularly in the form of liquid solutions or dry powders with excipients, defined broadly; for transdermal administration, particularly in the form of a skin patch or microneedle patch; and for rectal or vaginal administration, particularly in the form of a suppository.

[0069] The formulations of the invention may be nutraceutical, beneficial supplement, or nutritional technology compositions. These terms may be used interchangeably herein. The compositions may conveniently be administered in unit dosage form and may be prepared by any of the methods well-known in the pharmaceutical art, for example, as described in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Co., Easton, PA (1985), incorporated herein by reference in its entirety. Formulations for parenteral administration may contain as excipients sterile water or saline alkylene glycols such as propylene glycol, polyalkylene glycols such as polyethylene glycol, saccharides, oils of vegetable origin, hydrogenated napthalenes, serum albumin or other nanoparticles (as used in Abraxane™, American Pharmaceutical Partners, Inc. Schaumburg, IL), and the like. For oral administration, the formulation can be enhanced by the addition of bile salts or acylcamitines. Formulations for nasal administration may be solid or solutions in evaporating solvents such as hydrofluorocarbons, and may contain excipients for stabilization, for example, saccharides, surfactants, submicron anhydrous alpha-lactose or dextran, or may be aqueous or oily solutions for use in the form of nasal drops or metered spray. For buccal administration, typical excipients include sugars, calcium stearate, magnesium stearate, pregel atinated starch, and the like.

[0070] Delivery of modified nutraceutical or pharmaceutical compositions described herein to a subj ect over prolonged periods of time, for example, for periods of one w eek to one year, may be accomplished by a single administration of a controlled release system containing sufficient active ingredient for the desired release period. Various controlled release systems, such as monolithic or reservoir-type microcapsules, depot implants, polymeric hydrogels, osmotic pumps, vesicles, micelles, liposomes, transdermal patches, iontophoretic devices and alternative injectable dosage forms may be utilized for this purpose. Localization at the site to which delivery of the active ingredient is desired is anadditional feature of some controlled release devices, which may prove beneficial in the treatment of certain disorders.

[0071] One form of controlled-release formulation contains the beneficial supplement or salts thereof dispersed or encapsulated in a slowly degrading, non-toxic, non-antigenic polymer such as copoly(lactic / gly colic) acid, as described in Kent et al., US Patent No. 4,675,189, incorporated by reference herein. The supplements, or their salts, may also be formulated in cholesterol, other lipid matrix pellets, or silastomer matrix implants. Additional slow release, depot implant, or injectable formulations will be apparent to the skilled artisan. See, e.g., Sustained and Controlled Release Drug Delivery' Systems, JR Robinson ed., Marcel Dekker Inc., New York, 1978; and Controlled Release of Biologically Active Agents, RW Baker, John Wiley & Sons. New York. 1987. The foregoing are incorporated by reference in their entirety.

[0072] An additional form of controlled-release formulation comprises a solution of biodegradable polymer, such as copoly(lactic / glycolic acid) or block copolymers of lactic acid and PEG, is a bioacceptable solvent, which is injected subcutaneously or intramuscularly to achieve a depot formulation. Mixing of the beneficial supplements described herein with such a polymeric formulation is suitable to achieve very long duration of action formulations.

[0073] When formulated for nasal administration, the absorption across the nasal mucous membrane may be further enhanced by surfactants, such as. for example, glycocholic acid, cholic acid, taurocholic acid, ethocholic acid, deoxycholic acid, chenodeoxy cholic acid, dehdryocholic acid, glycodeoxy cholic acid, cycledextrins and the like in an amount in the range of between about 0. 1 and 15 weight percent, between about 0.5 and 4 weight percent, or about 2 weight percent. An additional class of absorption enhancers reported to exhibit greater efficacy with decreased irritation is the class of alkyl maltosides, such as tetradecylmaltoside (Arnold, JJ et al., 2004, J Pharm Sci 93: 2205-13; Ahsan, F et al., 2001, Pharm Res 18:1742-46) and references therein, all of which are hereby incorporated by reference.

[0074] The nutraceutical or beneficial supplement compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, powders, food additives, prepared food products, capsules, tablets, and aqueous suspensions and solutions. In the case of tablets for oral use, carriers that are commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents includelactose and dried com starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents may be added.

[0075] The formulations of the invention may comprise an emulsifier or surfactant. In some embodiments, the concentration of the emulsifier is about 1.0% to 10% v / v. In preferred embodiments, the concentration may be about 1.0% to 2.0%, 2.0% to 3.0%, 3.0% to 4.0%, 4.0% to 5.0%. 5.0% to 6.0%, 6.0% to 7.0%, 7.0% to 8.0%. 8.0% to 9.0%, or 9.0% to 10.0% v / v, or increments therebetween. In a more preferred embodiment, the concentration is about 3.0%.

[0076] Emulsifiers for pharmaceutical, nutraceutical, and other human consumption are well- known in the art. Exemplary’ emulsifiers for use in the formulations of the invention include food emulsifiers such as egg yolk (lecitihin), mustard (mucilage), soy lecithin, pickering stabilization, sodium stearoyl lactylate, and DATEM (Diacetyl Tartaric Acid Ester of Monoglyceride) and anise. Other emulsifiers include emulsifying wax, cetearyl alcohol, polysorbate 20, and ceteareth 20.

[0077] The formulations of the invention might comprise additional active ingredients or flavor enhancers. Examples include compounds, extracts or essential oils from one or more of the following sources: ascorbic acid, vitamin E, omega 3, salt water, menthol, agar essential oil, agar extract, ajwain, aloe vera, amyris, angelica root, anise, balsam, basil, bay rum. bergamot, black pepper, buchu, butterbur, cajeput, cannabis flower, caraway, cardamom seed, carrot seed, cedarwood, Cedarleaf, chamomile, cinnamon, cistus, citrus vulgaris, citronella, clary sage, clove leaf, coriander, costmary, cranberry’ seed, cumin / black seed, cypress, davana, dill, eucalyptus, fennel seed, fenugreek, frankincense, galbanum, geranium, ginger, grapefruit, grape seed (e.g. Vitis vinifera), henna, jasmine, juniper berry', lavender, lemon, lemongrass, lime, litsea cubeba, lobelia / neem, melissa (Lemon balm), mentha arvensis / Mint, mugwort, mustard, myrrh, neroli, nutmeg, orange, oregano, orris, parsley, patchouli, perilla, pennyroyal, peppermint, pine, rose, rosehip, rosemary, rosewood, sage, sandalwood, sassafras, savory, schisandra, spearmint, star anise, tarragon, tea tree, thyme, vetiver, yarrow ylang-ylang, and other herbs, natural flavorings, or artificial flavorings known in the art.

[0078] As the skilled artisan wi 11 appreciate, lower or higher doses than those recited otherwise recited herein may be beneficial. Specific dosage and treatment regimens for any particular subject will depend upon a variety of factors, including the activity of the specific beneficial supplement employed, the age, body weight, general health status.gender, diet, time of administration, rate of excretion, drug combination, the severity and course of an infection, the patient's disposition to the infection and the judgment of the treating physician.

[0079] Other embodiments of the present invention is a supplement formulation comprising 30 grams, 25 grams, 20 grams, 19 grams, 18 grams, 17 grams, 16 grams, 15 grams, 14 grams, 13 grams. 12 grams, 11 grams, 10 grams, 5 grams of pea protein isolate 80%. Alternatively, pea protein isolate (80%) of this supplement formulation may be administered in 300 ml volume of liquid.

[0080] In other embodiments, the present invention is a supplement formulation comprising 3.0 grams, 2.8 grams, 2.5 grams, 2.3 grams, 2.0 grams, 1.9 grams, 1.8 grams, 1.7 grams, 1.6 grams, 1.5 grams, 1.4 grams. 1.3 grams, 1.2 grams. 1.1 grams, 1.0 grams. 0.75 grams, 0.5 grams of L- tryptophan. Alternatively, tryptophan in this supplement formulation may be administered in 300 ml volume of liquid.

[0081] In other embodiments, the present invention is a supplement formulation comprising 3.0 grams, 2.8 grams, 2.5 grams. 2.3 grams, 2.0 grams, 1.9 grams, 1.8 grams. 1.7 grams, 1.6 grams, 1.5 grams, 1.4 grams. 1.3 grams. 1.2 grams. 1.1 grams, 1.0 grams. 0.75 grams, 0.5 grams of L- arginine (min. 98% purity)- Alternatively, L-arginine in this supplement formulation may be administered in 300 ml volume of liquid.

[0082] In other embodiments, the present invention is a supplement formulation comprising 3.0 grams, 2.5 grams, 2.4 grams. 2.3 grams, 2.2 grams, 2. 1 grams, 2.0 grams. 1.9 grams, 1 .8 grams, 1.7 grams, 1 .6 grams, 1 .5 grams, 1 .0 grams of sea buckthorn extract.Alternatively, sea buckthorn extract of this supplement formulation may be administered in 300 ml volume of liquid.

[0083] In other embodiments, the present invention is a supplement formulation comprising 3.0 grams, 2.5 grams, 2.4 grams, 2.3 grams, 2.2 grams, 2. 1 grams, 2.0 grams, 1.9 grams, 1.8 grams, 1.7 grams, 1.6 grams, 1.5 grams, 1.0 grams of acerola extract (powder). Alternatively, acerola extract (powder) of this supplement formulation may be administered in 300 ml volume of liquid.

[0084] In other embodiments, the present invention is a supplement formulation comprising 1.5 grams, 1.4 grams, 1.3 grams, 1.2 grams, 1.1 grams, 1.0 grams, 0.9 grams, 0.8 grams, 0.75 grams, 0.7 grams, 0.6 grams, 0.5 grams of buckwheat extract. Alternatively, buckwheat extract of this supplement formulation may be administered in 300 ml volume of liquid.

[0085] In some embodiments, the present invention is a supplement formulation further comprises a sweeter. Non-limiting examples of sweeteners include sugar, stevia, xylitol, aspartame, saccharine, sucralose, neotame, monkfruit extract, mogrosides and derivatives, and acesulfame-K.

[0086] In other embodiments, the present invention is a supplement formulation further comprising a suitable excipient. Some of these excipients may also impart anti-aging biological effects. In a non-limiting example, suitable excipients include fibersol-2, malic acid, citric acid, tricalciumphosphate, magnesium stearate. Additional food grade preservants may also be used in the supplement formulation of the present invention.Further excipients may include substances that increase the viscosity of the suspension for administration. These agents may increase the viscosity and improve the mouthfeel when administering orally or enterally. Other agents may also be included such as natural flavorings to improve taste of the supplement formulation for oral or enteral administration.

[0087] In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.EXAMPLESExample 1 : Composition optimized for tryptophan metabolism

[0088]

[0043] A formulation for a composition that is optimized for tryptophan metabolism to produce higher levels of endogenous L-arginine, L-tryptophan, indole-3-propionic acid and indole-3-propionamide was produced as follows: 20 grams 80% pea protein isolate (Erbotin® PF, Gustav Parmetier GmbH, Frankfurt, Germany), 2 grams L-arginine, 2 grams L-tryptophan, 2 grams sea buckthorn on maltodextrin (Bio Sanddom Pulver, 50%, Lienig Wildfruchtverarbeitung GmbH, Dabendorf, Germany), 2 grams of acerola on acacia fiber (Nexira Health, Rouen, France, Cat. No. PF1500491), 1 gram buckwheat extract with 100% NRV of all eight B vitamins and 1 gram xylitol. The formulation provided a total of 360 mg ascorbate, 3600 mg L-arginine and 2400 mg L-tryptophan.

[0089] The pea protein acted as a carrier for the amino acids that allowed for their targeted and sustained release to the symbionts in the gastrointestinal tract that, upon arginine and tryptophan supply, increased the formation of the antioxidant indole agents IPA andIP AM. Pea protein formed vesicles having a 90 pm diameter that encapsulated the arginine and tryptophan allowing for their safe transport and efficient delivery in the gastrointestinal tract. The Advanced Carrier Technologies (ACT) allow for the implementation of the Amino Acid and Ascorbate Retention Technologies (ART) which increased bioaccessibility, bioavailability, and bioactivity of the nutrients by the targeted sustained release of the amino acids in the gastrointestinal tract (TSR) supplied by the supplementation. Poeggeler, B. et al., FHM Bielefeld 2023, 15, 65-74; Overduin, J. et al.. Food Nutr Res 2012, 59, 25622. The foregoing are incorporated by reference herein in their entirety.Example 2: Beneficial Nutrient and Metabolite Levels in Human Plasma

[0090] Plasma levels for the beneficial nutrients disclosed in Example 1 were measured in 30 young volunteers (mean age 27.9 years old) and 30 elderly volunteers (mean age 66.7 years old). Both male and female non-smoking participants were enrolled. They had no pre-existing liver, kidney, or heart disease. Breast or testicular cancer patients were not excluded. The formulations of Example 1 were compared to placebo (30g milk powder, maltodextrin and cocoa).

[0091] Plasma levels in the volunteers were measured for the following: arginine, tryptophan, indole-3 -propionic acid, and indole-3- propionamide. L-arginine was measured by Ultra Performance Liquid Chromatography (UPLC) using standard methods. (Do you have a reference?) L-tryptophan, indole-3-propionic acid and indole-3 -proprionamide were measured using High Pressure Liquid Chromatography (HPLC) using standard methods. Poeggeler, B. et al., novel endogenous indole protects rodent mitochondria and extends rotifer lifespan, PLoS ONE 2010, 5, el 0206.

[0092] As seen in FIGS. 1A-1D, levels of plasma arginine, tryptophan, indole-3 -propionic acid and indole-3 -propionamide were all significantly higher in the young volunteer group compared to the elderly volunteer group. As seen in FIGS. IE and IF, levels of plasma peroxynitrite and nitrotyrosine were all significantly higher in the elderly volunteer group compared to the young volunteer group. FIG. 1A shows levels of plasma arginine to be almost two-fold higher in the young volunteers group compared to the elderly volunteer group. Adults under 30 years had about 79pM plasma arginine where adults over 60 years had about 44pM plasma arginine. Similarly, FIG. IB shows levels of plasma tryptophan to be at least two-fold or more higher in the young volunteer groupcompared to the elderly volunteer group. Adults under 30 years had about 68pM plasma tryptophan where adults over 60 years had about 27 pM plasma tryptophan. FIG. 1C shows almost a two-fold higher level of plasma IPA levels in the young volunteers group compared to the elderly volunteer group. Adults under 30 years had about 1.5pM plasma IPA where adults over 60 years had about 0.9pM plasma tryptophan. FIG. ID shows levels of plasma IP AM to be at more than two-fold higher in the young volunteers group compared to the elderly volunteer group. Adults under 30 years had about 7.8pM plasma tryptophan where adults over 60 years had about 3.5pM plasma tryptophan. FIG. IE shows levels of plasma peroxy nitrite to be about 1.5-fold higher in elderly volunteers group compared to the young volunteers group. Adults under 30 years had about 4.6 pmol / mg protein of plasma peroxynitrite where adults over 60 years had about 6.8 pmol / mg protein of plasma peroxynitrite. Similarly, FIG. IF shows levels of plasma nitrotyrosine to be 2.4-fold higher in elderly volunteers group compared to the young volunteers group. Adults under 30 years had about 1.6 pmol / mg protein of plasma nitrosine where adults over 60 years had about 3.8 pmol / mg protein of plasma nitrosine.Example 3: Decreased Biological Age from Beneficial Nutrient Supplements

[0093] The beneficial nutrients of the invention decrease the biological age recipient subjects. A randomized, double-blind and placebo-controlled clinical study investigated the effects of a composition that is optimized for try ptophan metabolism in 60 volunteers with an average age of 69 years old. The volunteers were randomized and divided into two groups: one group receiving a placebo composition (milk powder, maltodextrin and cocoa) and the other group receiving the composition in Example 1 above (verum group). Both groups took the compositions daily for one year. The compositions were taken either as a 30g powder formulation or as a shake (in liquid form) with the 30g powder formulation mixed with 300 ml water or juice. Three volunteers from the placebo composition group stopped the study prior to completion (not study related) and the final results were based on 27 volunteers receiving the placebo composition and 30 volunteers in the verum group.

[0094] After 1 year, the volunteers were measured for circulating plasma levels of arginine, try ptophan, indole-3-propionic acid, and indole-3-propionamide. As seen in FIGS. 2A- 2D, plasma levels of arginine, tryptophan, indole-3 -propionic acid and indole-3- propionamide were all significantly increased in the group of volunteers in the verum group compared to the group receiving the placebo composition. As seen in FIG. 2E and2F, plasma levels of peroxynitrite and nitrotyrosine were significantly decreased in the group of volunteers in the verum group compared to the group receiving the placebo composition. FIG. 2A shows levels of plasma arginine to be about two-fold higher in the verum group compared to the placebo group. The placebo group had 48pM plasma arginine where the verum group had about 89pM plasma arginine. FIG. 2B shows plasma tryptophan levels to be at least about three-fold higher in the verum group compared to the placebo group. The placebo group had 25 pM plasma arginine where the verum group had about 78pM plasma arginine. FIG. 2C shows plasma levels of IPA to be at least about two-fold higher in the verum group compared to the placebo group. The placebo group had 1 pM plasma IPA where the verum group had about 2pM plasma IPA. FIG. 2D shows plasma levels of IP AM to be at least about two-fold higher in the verum group compared to the placebo group. The placebo group had 3.4nM plasma IPAM where the verum group had about 7.9nM plasma IPAM. FIG. 2E shows plasma levels of peroxynitrite to be almost about 1.5-fold lower in the verum group compared to the placebo group. The placebo group had 6.9 pmol / mg protein plasma peroxynitrite where the verum group had about 4.5 pmol / mg protein plasma peroxynitrite. FIG. 2F shows plasma levels of nitrotyrosine to be about a 2.3 -fold lower in the verum group compared to the placebo group. The placebo group had 3.9 pmol / mg protein plasma nitrotyrosine where the verum group had about 1.7 pmol / mg protein plasma nitrotyrosine.

[0095] Secondary7endpoints were also measured in the volunteers, specifically cerebral brain flow, duration of restorative deep slow wave sleep, cognitive performance and biological age. Cerebral brain flow was determined by Two-dimensional phase-contrast magnetic resonance imaging (2D PC-MRI) and was normalized to brain volume and brain flow. The duration of restorative deep slow wave sleep was recorded by polysomnography. Cognitive performance was analyzed by the CogHealth procedure. Biological age was calculated using a mathematical model that considers five immune function parameters. These include neutrophil chemotaxis and phagocytosis, lymphocyte chemotaxis, natural killer (NK) cell activity, and lymphoproliferation in response to mitogen stimulus. These were constructed throughout multiple linear regression.

[0096] Volunteers in the verum group had longer duration of slow wave sleep compared to that of the placebo group. Fig. 3 A shows at least about a 15% decrease in biological age in the verum group compared to the placebo group. The placebo group had a biological age of about 68 years where the verum group had about a biological age of about 57 years. Fig. 3B shows that cerebral blood flow was also increased in the verum groupcompared to that of the placebo group. The placebo group had a had a cerebral blood flow of about 68 ml / lOOg / min where the verum group had a cerebral blood flow of about 79 ml / lOOg / min. Fig. 3C shows an increased in the duration of slow wave sleep in the verum group compared to the placebo group. The placebo group had about 107 minutes of slow wave sleep where the verum group had about 146 minutes of slow wave sleep. Fig. 3D shows a significant increase in cognitive performance in the verum group compared to the placebo group as demonstrated in the faster reaction time. The placebo group showed about a 789ms working memory reading where the verum group showed a 669ms working memory reading. A lower reaction time shows better cognition.

[0097] Overall, there was a decrease in biological age and an increase in cognition in the verum group compared to the biological age of the placebo group. This was attributed to the tryptophan supplements of the invention.

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[0099] All publications and patent documents disclosed or referred to herein are incorporated by reference in their entirety. The foregoing description has been presented only for purposes of illustration and description. This description is not intended to limit the invention to the precise form disclosed. It is intended that the scope of the invention be defined by the claims appended hereto.

Claims

What is claimed:

1. A composition, comprising: a. pea protein isolate; b. L-tryptophan isolate; c. L-arginine isolate; d. sea buckthorn extract; and e. acerola extract.

2. The composition of claim 1, wherein said pea protein isolate is about 80% w / w pea protein.

3. The composition of either one of claims 1 or 2, wherein said pea protein isolate is about 66% w / w of said composition.

4. The composition of any one of claims 1-3, wherein said L-tryptophan isolate is about 6.7% w / w of said composition.

5. The composition of any one of claims 1-4, wherein said L-arginine isolate is about 6.7% w / w of said composition.

6. The composition of any one of claims 1-5, wherein said buckthorn extract is about 6.7% w / w of said composition.

7. The composition of any one of claims 1-6, wherein said acerola extract is about 6.7% w / w of said composition.

8. The composition of any one of claims 1 -7, further comprising a buckwheat extract.

9. The composition of claim 8, wherein said buckwheat extract is about 3.3% w / w of said composition.

10. The composition of any one of claims 1-9, further comprising a sweetener.

11. The composition of claim 10, wherein said sweetener is xylitol.

12. The composition of claim 11, wherein said xylitol is about 3.3% w / w of said composition.

13. The composition of any one of claims 1-12, wherein composition further comprises an excipient.

14. The composition of claim 13, wherein the excipient is selected from the group consisting of fibersol-2, malic acid, citric acid, tricalciumphosphate and magnesium stearate.

15. The composition of any one of claims 1-14, wherein said composition comprises aratio of pea protein isolate to L-tryptophan isolate to L-arginine isolate of 10: 1 : 1 .

16. A supplemental formulation, comprising the composition of any one of claims 1-15, wherein said supplemental formulation is a liquid, powder, gel, paste, solid, concentrate, suspension, ready-to-use enteral formula, or an oral formula.

17. The supplemental formulation of claim 16, wherein said supplemental formulation is in a food product, food additive, beverage, beverage additive, capsule, tablet, aqueous suspensions, or solution.

18. The supplemental formulation of claim 17, wherein said beverage is water, fruit juice, animal milk, or a plant-based milk.

19. A method of increasing serum IPA or IP AM in a subject, the method comprising administering to the subject the composition of any one of claims 1-15.

20. The method of claim 19, wherein said method docs not increase scrum idoxyl sulfate in said subject.

21. The method of claim 19. wherein said method does not increase serum idoxyl sulfate by more than 10% above the levels observed prior to administering the composition to said subject.

22. The method of claim 19, wherein said method does not increase serum idoxyl sulfate by more than 20% above the levels observed prior to administering the composition to said subject.

23. The method of claim 19. wherein said method does not increase serum idoxyl sulfate by more than 30% above the levels observed prior to administering the composition to said subject.

24. The method of any one of claims 19-23. wherein said method decreases a C-Reactive Protein (CRP) in said subject.

25. The method of any one of claims 19-24, wherein said method decreases a kynurenine to tryptophan ratio in said subject.

26. The method of any one of claims 19-25, wherein said composition is administered daily.

27. The method of any one of claims 19-26, wherein said administration continues for at least about 1. about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10. about 11, or about 12 months.

28. The method of any one of claims 19-27, wherein said method decreases a biological age of said subject.

29. The method of any one of claims 19-28, wherein said method increases a cerebral blood flow of said subject.

30. The method of any one of claims 19-29. wherein said method increases a duration of slow wave sleep of said subject.

31. The method of any one of claims 19-30, wherein said method increases a cognitive health (CogHealth) of said subject.

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