Composition and method for nutritional supplement

Abstract

To provide improved compositions with beneficial / synergistic combination of polyphenols.SOLUTION: The present invention provides compositions for inhibiting one or more enzymes involved in pathways associated with health and healthy aging, the enzymes being selected from a group consisting of BACE1, CD38, CD73, CDK5, JAK1, JAK2, and JAK3, the composition comprising chemically distinct polyphenols, the polyphenols including organic acids, phenols, flavonols, flavanols, anthocyanins, chlorogenic acids, and betacyanins, the polyphenols being derived from plant material having a red, green, orange-yellow, and purple-blue color, and the polyphenols being in a synergistic combination with respect to inhibition of at least one biochemical marker selected from a group consisting of BACE1, CD38, CD73, CDK5, JAK1, JAK2, and JAK3.SELECTED DRAWING: Figure 32

Description

Related Applications

[0001] This application claims the benefit of our co-pending U.S. Provisional Patent Application No. 62 / 970,615, filed February 5, 2020, U.S. Provisional Patent Application No. 63 / 010,183, filed April 15, 2020, and U.S. Provisional Patent Application No. 63 / 086,207, filed October 1, 2020, which are incorporated by reference in their entireties. [Technical field]

[0002] The field of the invention is dietary supplement compositions and methods, and in particular their use in conditions, disorders, and diseases associated with polyphenols and polyphenol mixtures commonly associated with diets rich in fruits and vegetables, and various enzymes inhibited by such polyphenol mixtures. [Background technology]

[0003] The Background Description contains information that is helpful to understanding the present disclosure. There is no admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.

[0004] All publications and patent applications mentioned herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. If a definition or use of a term in an incorporated reference contradicts or is contrary to a definition of the term provided herein, the definition of that term provided herein shall apply and the definition of that term in the reference shall not apply.

[0005] There are a significant variety of vitamins and other isolated nutritional compounds, and the purported benefits of such compounds include immune support, anti-inflammatory effects, anti-aging effects, cardiac support, and digestive support, among many other effects. Unfortunately, there is fairly little evidence to substantiate some aspects of these purported benefits when these vitamins and other isolated nutritional compounds are ingested. Similarly, when dietary supplements are in the form of extracts or powders of plant parts, various benefits are advertised, but the actual benefits are largely unproven, or not at all. Furthermore, like individual plant extracts and concentrates, isolated nutritional compounds generally do not reflect a healthy diet.

[0006] In particular, there are certain geographical and ethnographic dietary types that are associated with overall health, longevity, and / or physical resilience, and such beneficial effects are well documented and demonstrated in practice. For example, the Mediterranean diet is typically associated with lower cardiovascular risk factors (see, e.g., Nutrients 2018,10,379,doi:10.3390 / nu10030379), lower inflammatory and metabolic biomarkers, lower risk of Alzheimer's disease (see, e.g., J Alzheimers Dis. 2010,22(2),pp. 483-492), and reduced certain inflammatory markers (see, e.g., Nutrients 2018,10,62,doi:10.3390 / nu10010062). One common class of components included in such diets are polyphenols, and various studies have been published on the specific benefits of individual dietary polyphenols (see, e.g., Inhibitory Properties of Phenolic Compounds Against Enzymes Linked with Human Diseases, URL: dx.doi.org / 10.5772 / 66844) and selected colored polyphenols (see, e.g., Annu. Rev. Food Sci. Technol. 2020.11:10.1-10.38). However, due to the large number of complex and chemically distinct polyphenols, many studies have focused only on a single polyphenol and the specific biochemical effects of such compounds, or have provided general epidemiological information without a more detailed molecular characterization of the diet.

[0007] Various supplements are known to supplement the diet with multiple polyphenols. For example, Vital Reds (Gundry MD) provides a commercially available concentrated polyphenol powder mixture from many red plant materials to increase energy and improve digestion. Such mixtures advantageously contain a variety of chemically distinct polyphenols. However, the selection of plant materials used as a source of polyphenols does not reflect the general dietary intake. Similarly, Fytexia's Oxxynea, a commercially available mixture of grape, olive, pomegranate, green tea, grapefruit, bilberry, and orange extracts, is offered as an antioxidant preparation to protect cells against oxidative stress (see, for example, Fytexia's Oxxynea). Although beneficial in reducing oxidative stress, the source ingredients of such antioxidant preparations do not reflect the general dietary intake. Surprisingly, despite the presence of many beneficial ingredients in various dietary supplements, no supplement is expected to provide the various benefits of the Mediterranean diet, particularly the benefits of the colored polyphenol components of the Mediterranean diet.

[0008] Thus, although various dietary supplements are known in the art, all or almost all of them suffer from various shortcomings.Therefore, there is a need to provide improved compositions and methods of dietary supplements, especially beneficial / synergistic combinations of polyphenols known to be associated with healthy diets, such as the Mediterranean diet. Summary of the Invention

[0009] The inventors have discovered various compositions and methods for specific combinations of polyphenols and / or polyphenol-rich materials (e.g., extracts and powders) that, when combined, provide many of the benefits associated with the benefits of the Mediterranean diet. Indeed, the compositions and methods disclosed herein have provided substantial, and in some cases significant, synergistic effects on various molecular biomarkers associated with the benefits of the Mediterranean diet, such as markers of aging, senescence, inflammation, immune function, NAD / energy metabolism, and gut microbiota.

[0010] In one aspect of the subject matter of the present invention, the inventors contemplate a nutritional composition comprising a nutritionally acceptable carrier in combination with a plurality of chemically distinct polyphenols from plant materials having red, green, orange-yellow, and purple-blue colors.Preferably, the chemically distinct polyphenols from the plant materials are present in a synergistic combination with respect to the inhibition of at least one biochemical marker selected from the group consisting of BACE1, CD38, CD73, CDK5, JAK1, JAK2, and JAK3.

[0011] For example, in some embodiments, the red plant material includes at least one (or two, or three, or all) of apple extract, pomegranate extract, tomato powder, and beet root powder; the green plant material includes at least one (or two, or three, or all) of olive extract, rosemary extract, green coffee bean extract, and kale powder; the orange-yellow plant material includes at least one (or two, or three, or all) of onion extract, ginger extract, grapefruit extract, and carrot powder; and the purple-blue plant material includes at least one (or two, or three, or all) of grape extract, blueberry extract, currant powder, and elderberry powder.

[0012] In further aspects of the present subject matter, the chemically distinct polyphenols further inhibit at least one additional biochemical marker selected from the group consisting of ARG-1, ARG-2, SIRT-1, CD39, IDO1, IDO2, NAMPT, PCSK9, CD47. Additionally, contemplated compositions may further inhibit Keap / Nrf2 binding and / or ACE2 / Spike binding.

[0013] Although not required, most typically, the compositions are formulated in single dosage units for oral administration (e.g., each containing 50-1,000 mg of the composition), which may be formulated as capsules, gummies, or powders. Optionally, the compositions may also further include vitamins, dietary trace elements or minerals, nicotinamide riboside, probiotics, and / or prebiotics.

[0014] Therefore, in another aspect of the subject matter of the present invention, the inventor contemplates a nutritional composition comprising a nutritionally acceptable carrier in combination with a plurality of chemically different polyphenol-containing plant materials having red, green, orange-yellow, and purple-blue colors.Most preferably, the red plant materials comprise apple extract, pomegranate extract, tomato powder, and beetroot powder, the green plant materials comprise olive extract, rosemary extract, green coffee bean extract, and kale powder, the orange-yellow plant materials comprise onion extract, ginger extract, grapefruit extract, and carrot powder, and the purple-blue plant materials comprise grape extract, blueberry extract, currant powder, and elderberry powder.For example, apple extract, pomegranate extract, olive extract, rosemary extract, green coffee bean extract, onion extract, ginger extract, grapefruit extract, grape extract, and blueberry extract can be ethanol extract or ethanol / water extract.

[0015] In such compositions, the combination of plant materials is a synergistic combination with respect to inhibition of at least one biochemical marker selected from the group consisting of BACE1, CD38, CD73, CDK5, JAK1, JAK2 and JAK3, and in particular with respect to inhibition of BACE1, CD38 and CD73. More preferred compositions further inhibit at least one additional biochemical marker selected from the group consisting of ARG-1, ARG-2, SIRT-1, CD39, IDO1, IDO2, NAMPT, PCSK9, CD47 and Cathepsin S, and may also inhibit Keap / Nrf2 binding and / or ACE2 / Spike binding.

[0016] As mentioned above, it is preferred (but not required) that the composition be formulated in a single dosage unit for oral administration. Typically, the dosage unit contains between 50-1,000 mg of the composition and is formulated as a capsule, gummy, or powder. Optionally, contemplated compositions may further include vitamins, dietary trace elements or minerals, nicotinamide riboside, probiotics, and / or prebiotics.

[0017] Among other uses, contemplated compositions are effective in treating and / or alleviating the symptoms of inflammatory conditions, cardiovascular conditions, neurological conditions, metabolic conditions, and cancer.

[0018] Therefore, the present inventor also contemplates a method for supporting the health of an individual, comprising administering the composition provided herein.For example, the composition may be administered to provide immune support, metabolic support, longevity support, central nervous system (CNS) function support, reduce inflammatory response, reduce the impact of cardiovascular disease, and reduce the rate of amyloid beta plaque formation.

[0019] In further examples of such methods, the composition is orally administered, typically at a daily dose of between 50-1,000 mg, for at least 30 days. As previously mentioned, contemplated compositions may further include co-administering vitamins, dietary trace elements or minerals, nicotinamide riboside, probiotics, and / or prebiotics (which may be performed in the same dosage unit or separately).

[0020] In another aspect of the inventive subject matter, the inventors also contemplate a method of reducing NAD+ loss (e.g., age-related NAD+ loss) in an individual comprising administering to the individual a synergistic combination of polyphenols derived from red, green, orange-yellow, and purple-blue plant material, which combination synergistically inhibits CD38. In some embodiments, the polyphenols are provided from plant material.

[0021] Preferably, the red plant material is selected from the group consisting of apple extract, pomegranate extract, tomato powder, and beet root powder, the green plant material is selected from the group consisting of olive extract, rosemary extract, green coffee bean extract, and kale powder, the orange-yellow plant material is selected from the group consisting of onion extract, ginger extract, grapefruit extract, and carrot powder, and the purple-blue plant material is selected from the group consisting of grape extract, blueberry extract, gooseberry powder, and elderberry powder.

[0022] In a further aspect of the present subject matter, the inventors contemplate a method of supporting longevity in an individual comprising administering to the individual a synergistic combination of polyphenols derived from plant material having a red, green, orange-yellow, or purple-blue color, the combination synergistically inhibiting CD73. In some embodiments, the polyphenols are provided from the plant material.

[0023] Preferably, the red plant material is selected from the group consisting of apple extract, pomegranate extract, tomato powder, and beet root powder, the green plant material is selected from the group consisting of olive extract, rosemary extract, green coffee bean extract, and kale powder, the orange-yellow plant material is selected from the group consisting of onion extract, ginger extract, grapefruit extract, and carrot powder, and the purple-blue plant material is selected from the group consisting of grape extract, blueberry extract, gooseberry powder, and elderberry powder.

[0024] In yet another aspect of the present subject matter, the inventors contemplate a method of supporting cognitive function in an individual comprising administering a synergistic combination of polyphenols derived from plant material having a red, green, orange-yellow, or purple-blue color, which combination synergistically inhibits BACE1. In some embodiments, the polyphenols are provided from plant material, and administration increases immune function, thereby preserving longevity and / or reducing the rate of amyloid-β plaque formation.

[0025] Preferably, the red plant material is selected from the group consisting of apple extract, pomegranate extract, tomato powder, and beet root powder, the green plant material is selected from the group consisting of olive extract, rosemary extract, green coffee bean extract, and kale powder, the orange-yellow plant material is selected from the group consisting of onion extract, ginger extract, grapefruit extract, and carrot powder, and the purple-blue plant material is selected from the group consisting of grape extract, blueberry extract, gooseberry powder, and elderberry powder.

[0026] In yet another aspect of the present subject matter, the inventors contemplate a method of supporting central nervous system (CNS) function in an individual comprising administering a synergistic combination of polyphenols derived from plant material having red, green, orange-yellow, or purple-blue colors, which combination synergistically inhibits CDK5. In some embodiments, the polyphenols are provided from plant material, and the administration reduces age-related cognitive decline.

[0027] Preferably, the red plant material is selected from the group consisting of apple extract, pomegranate extract, tomato powder, and beet root powder, the green plant material is selected from the group consisting of olive extract, rosemary extract, green coffee bean extract, and kale powder, the orange-yellow plant material is selected from the group consisting of onion extract, ginger extract, grapefruit extract, and carrot powder, and the purple-blue plant material is selected from the group consisting of grape extract, blueberry extract, gooseberry powder, and elderberry powder.

[0028] In a further aspect of the inventive subject matter, the inventors contemplate a method of supporting immune function in an individual comprising administering a synergistic combination of polyphenols derived from plant material having a red, green, orange-yellow, or purple-blue color, which combination synergistically inhibits at least one of JAK1, JAK2, and JAK3. In some embodiments, the polyphenols are provided from plant material, and the administration reduces symptoms of rheumatoid arthritis, psoriasis, or inflammatory bowel disease.

[0029] Preferably, the red plant material is selected from the group consisting of apple extract, pomegranate extract, tomato powder, and beet root powder, the green plant material is selected from the group consisting of olive extract, rosemary extract, green coffee bean extract, and kale powder, the orange-yellow plant material is selected from the group consisting of onion extract, ginger extract, grapefruit extract, and carrot powder, and the purple-blue plant material is selected from the group consisting of grape extract, blueberry extract, gooseberry powder, and elderberry powder.

[0030] Additionally, the inventors also contemplate a method of inhibiting at least one of BACE1, CD38, CD73, CDK5, JAK1, JAK2, and JAK3 comprising contacting at least one of BACE1, CD38, CD73, CDK5, JAK1, JAK2, and JAK3 with a plurality of chemically distinct polyphenols derived from plant material having a red, green, orange-yellow, or purple-blue color, wherein the chemically distinct polyphenols derived from the plant material are in a synergistic combination with respect to inhibition of at least one biochemical marker selected from the group consisting of BACE1, CD38, CD73, CDK5, JAK1, JAK2, and JAK3. In some embodiments, the polyphenols are provided from the plant material.

[0031] For example, the red plant material is selected from the group consisting of apple extract, pomegranate extract, tomato powder, and beet root powder, the green plant material is selected from the group consisting of olive extract, rosemary extract, green coffee bean extract, and kale powder, the orange-yellow plant material is selected from the group consisting of onion extract, ginger extract, grapefruit extract, and carrot powder, and the purple-blue plant material is selected from the group consisting of grape extract, blueberry extract, gooseberry powder, and elderberry powder.

[0032] Advantageously, the contacting step is performed in vivo (e.g., oral administration to a mammal), and administration of the multiple chemically distinct polyphenols provides immune support, metabolic support, longevity support, supports central nervous system (CNS) function, reduces inflammatory responses, reduces the effects of cardiovascular disease, and / or reduces the rate of amyloid beta plaque formation.

[0033] In another aspect, the inventors also contemplate methods of treating a condition associated with activity of at least one of BACE1, CD38, CD73, CDK5, JAK1, JAK2, JAK3, ARG-1, ARG-2, SIRT-1, CD39, IDO1, IDO2, NAMPT, PCSK9, CD47, and cathepsin S in a mammal. Such methods typically include administering to the mammal a plurality of chemically distinct polyphenols in an amount effective to inhibit at least one of BACE1, CD38, CD73, CDK5, JAK1, JAK2, JAK3, ARG-1, ARG-2, SIRT-1, CD39, IDO1, IDO2, NAMPT, PCSK9, CD47, and cathepsin S. In preferred embodiments, the chemically distinct polyphenols synergistically inhibit BACE1, CD38, CD73, CDK5, JAK1, JAK2, and / or JAK3.

[0034] For example, the condition may be an inflammatory condition, a cardiovascular condition, a neurological condition, a metabolic condition, and / or cancer.Optionally, the multiple chemically distinct polyphenols are derived from plant materials having red, green, orange-yellow, and purple-blue colors.For example, the red plant material is selected from the group consisting of apple extract, pomegranate extract, tomato powder, and beet root powder, the green plant material is selected from the group consisting of olive extract, rosemary extract, green coffee bean extract, and kale powder, the orange-yellow plant material is selected from the group consisting of onion extract, ginger extract, grapefruit extract, and carrot powder, and the purple-blue plant material is selected from the group consisting of grape extract, blueberry extract, currant powder, and elderberry powder.It should also be understood that polyphenols may be provided from plant materials.

[0035] It is further contemplated that the multiple chemically distinct polyphenols may be orally administered to the mammal, typically at a daily dose of between 50-1,000 mg. Optionally, such methods may further include co-administering to the mammal vitamins, dietary trace elements or minerals, nicotinamide riboside, probiotics, and / or prebiotics.

[0036] In further contemplated embodiments, the chemically distinct polyphenols are administered in an amount effective to inhibit at least three (or at least five, at least ten, or all) of BACE1, CD38, CD73, CDK5, JAK1, JAK2, JAK3, ARG-1, ARG-2, SIRT-1, CD39, IDO1, IDO2, NAMPT, PCSK9, CD47, and cathepsin S.

[0037] Therefore, in another aspect, the present inventor also contemplates using multiple chemically distinct polyphenols to support healthy aging.Furthermore, it is contemplated that the multiple chemically distinct polyphenols in such use further inhibit SIRT-1, IDO1, IDO2, NAMPT, PCSK9, CD47, Keap / Nrf2 binding, and / or ACE2 / Spike binding, and / or that the chemically distinct polyphenols synergistically inhibit BACE1, CD38, CD73, CDK5, JAK1, JAK2, and / or JAK3.

[0038] As previously mentioned, it is preferred that the red plant material is selected from the group consisting of apple extract, pomegranate extract, tomato powder, and beet root powder, the green plant material is selected from the group consisting of olive extract, rosemary extract, green coffee bean extract, and kale powder, the orange-yellow plant material is selected from the group consisting of onion extract, ginger extract, grapefruit extract, and carrot powder, and the purple-blue plant material is selected from the group consisting of grape extract, blueberry extract, gooseberry powder, and elderberry powder.

[0039] Various objects, features, aspects and advantages of the present subject matter will become more apparent from the following detailed description of preferred embodiments, taken in conjunction with the accompanying drawings in which like numerals represent like elements. [Brief description of the drawings]

[0040] [Figure 1] FIG. 1 is a graph showing exemplary results of ARG-1 inhibition using compositions according to the present subject matter.

[0041] [Diagram 2] FIG. 2 is a graph showing exemplary results of ARG-2 inhibition using compositions according to the present subject matter.

[0042] [Diagram 3] FIG. 3 is a graph showing exemplary results of SIRT1 inhibition using compositions according to the present subject matter.

[0043] [Figure 4] FIG. 4 is a graph showing exemplary results of Keap1-Nrf2 binding inhibition using compositions according to the present subject matter.

[0044] [Diagram 5] FIG. 5 is a graph showing exemplary results of ACE2-Spike S1 binding inhibition using compositions according to the present subject matter.

[0045] [Figure 6] FIG. 6 is a graph showing exemplary results of ACE2-Spike S1 binding inhibition using a multivitamin composition.

[0046] [Figure 7] FIG. 7 is a graph showing exemplary results of ACE2-Spike S1 binding inhibition using various additional compositions according to the present subject matter.

[0047] [Figure 8]FIG. 8 is a graph showing exemplary results of BACE1 inhibition using compositions according to the present subject matter.

[0048] [Figure 9] FIG. 9 is a graph showing exemplary results of BACE1 inhibition using various additional compositions and multivitamin compositions in accordance with the present subject matter.

[0049] [Figure 10] FIG. 10 is a graph showing exemplary results of Cathepsin S inhibition using compositions according to the present inventive subject matter.

[0050] [Figure 11] FIG. 11 is a graph showing exemplary results of Cathepsin S inhibition using various additional compositions according to the present subject matter.

[0051] [Figure 12] FIG. 12 is a graph showing exemplary results of Cathepsin S inhibition using compositions according to the present subject matter and multivitamin compositions.

[0052] [Figure 13] FIG. 13 is a graph showing exemplary results of CDK5 / p25 binding inhibition using compositions according to the present subject matter.

[0053] [Figure 14] FIG. 14 is a graph showing exemplary results of CDK5 / p25 binding inhibition using various additional compositions and multivitamin compositions in accordance with the present subject matter.

[0054] [Figure 15] FIG. 15 is a graph showing exemplary results of IDO1 inhibition using compositions according to the present subject matter.

[0055] [Figure 16]FIG. 16 is a graph showing exemplary results of IDO2 inhibition using compositions according to the present subject matter.

[0056] [Figure 17] FIG. 17 is a graph showing exemplary results of NAMPT inhibition using compositions according to the present subject matter.

[0057] [Figure 18] FIG. 18 is a graph showing exemplary results of PCSK9:LDLR binding inhibition using compositions according to the present subject matter.

[0058] [Figure 19] FIG. 19 is a graph showing exemplary results of CD47 inhibition using compositions according to the present subject matter.

[0059] [Figure 20] FIG. 20 is a graph showing exemplary results of CD38 inhibition using compositions according to the present subject matter.

[0060] [Figure 21] FIG. 21 is a graph showing exemplary results of CD38 inhibition using additional compositions according to the present subject matter.

[0061] [Figure 22] FIG. 22 is a graph showing exemplary results of CD38 inhibition using known compositions containing nicotinamide riboside.

[0062] [Diagram 23] FIG. 23 is a graph showing exemplary results of CD38 inhibition using compositions according to the present inventive subject matter and known multivitamin compositions.

[0063] [Figure 24] FIG. 24 is a graph showing exemplary results of JAK1 inhibition using compositions according to the present subject matter.

[0064] [Diagram 25] FIG. 25 is a graph showing exemplary results of JAK2 inhibition using compositions according to the present subject matter.

[0065] [Figure 26] FIG. 26 is a graph showing exemplary results of JAK3 inhibition using compositions according to the present subject matter.

[0066] [Figure 27] FIG. 27 is a graph showing exemplary results of CD39 inhibition using compositions according to the present subject matter.

[0067] [Figure 28] FIG. 28 is a graph showing exemplary results of CD39 inhibition using low concentration compositions in accordance with the present subject matter.

[0068] [Figure 29] FIG. 29 is a graph showing exemplary results of CD39 inhibition using additional compositions according to the present subject matter.

[0069] [Diagram 30] FIG. 30 is a graph showing exemplary results of CD39 inhibition using selected compositions according to the present subject matter.

[0070] [Diagram 31] FIG. 31 is a graph showing exemplary results of CD39 inhibition using compositions according to the present subject matter and known multivitamin compositions.

[0071] [Diagram 32] FIG. 32 is a graph showing exemplary results of CD73 inhibition using compositions according to the present subject matter.

[0072] [Diagram 33] FIG. 33 is a graph showing exemplary results of CD73 inhibition using low concentration compositions in accordance with the present subject matter.

[0073] [Diagram 34] FIG. 34 is a graph showing exemplary results of CD73 inhibition using additional compositions according to the present subject matter.

[0074] [Diagram 35] FIG. 35 is a graph showing exemplary results of CD73 inhibition using compositions according to the present subject matter and known multivitamin compositions. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0075] The inventors have discovered that certain combinations of polyphenol-containing materials (and the polyphenols found therein) strongly modulate a number of biomarkers associated with the beneficial effects of the Mediterranean diet. Thus, in light of these findings, the inventors contemplate use in a variety of compositions, compositions, and medicinal foods for dietary supplements and other nutritional products, as well as medical uses.

[0076] Most notably, the compositions presented herein have substantial and synergistic effects on many biomarkers associated with proper immune and CNS function, effective cellular metabolism, and longevity, and further demonstrated significant effects on additional biomarkers associated with inflammatory responses, adverse cardiovascular disease outcomes, and / or amyloid beta plaque formation. For example, the compositions and methods presented herein have been demonstrated to have significant and beneficial effects on multiple enzymatic targets involved in various aspects of health and healthy aging, such as ARG-1, ARG-2, SIRT1, BACE1, cathepsin S, CDK5, IDO1, IDO2, NAMPT, PCSK9, CD47, CD38, JAK1, JAK2, JAK3, CD39, CD73, and Keap / Nrf2. From a different perspective, it should be understood that the compositions presented herein are useful for beneficially affecting multiple pathways associated with health and healthy aging through the inhibition of key signaling components and / or enzymes in these pathways. Surprisingly, the modulation of these biomarkers observed using the compositions presented herein paralleled the biomarker profile in individuals who adhered to a Mediterranean diet and who had significant longevity.

[0077] For example, arginase 1 (ARG1) and arginase 2 (ARG2) are key enzymes in the urea cycle, which cleave L-arginine to form urea and L-ornithine. While the urea cycle protects against excess ammonia, L-ornithine is necessary for cell proliferation, collagen formation, and other important physiological functions. In particular, increased arginase activity in mammals has been linked to dysfunction and pathologies of the cardiovascular system, kidney, and central nervous system, as well as immune system dysfunction and the development of cancer. Two important aspects of arginase overactivity may be involved in disease. First, overactive arginase may reduce the supply of L-arginine required for the production of nitric oxide (NO) by NO synthase. Second, excessive amounts of L-ornithine may cause structural problems in the vasculature, toxicity in neuronal cells, and abnormal proliferation of tumor cells (see, e.g., Physiol Rev 98:641-665,2018). Furthermore, studies have demonstrated that increased formation of reactive oxygen species and key inflammatory mediators promote pathological elevation of arginase activity. Therefore, inhibition of ARG1 and ARG2 is believed to beneficially counteract the adverse effects of arginase overactivity. As shown in more detail below, the contemplated composition was effective in inhibiting ARG1 and ARG2 activity even at relatively low concentrations.

[0078] In another example, Sirtuin 1 (SIRT1) is a nuclear enzyme that deacetylates transcription factors that contribute to cell regulation, particularly in response to stressors. For example, SIRT1 deacetylates members of the PGC1-α / ERR-α complex, an important metabolic regulatory transcription factor, and deacetylates / deactivates p53 protein, an important factor in many neoplastic diseases. SIRT1 has also been shown to play a role in activating T helper 17 cells, which contribute to autoimmune diseases. As shown in more detail below, the contemplated compositions were effective in mildly inhibiting SIRT1 activity at relatively moderate concentrations.

[0079] In yet another example, beta-secretase 1 (BACE1) has been shown to be essential for the generation of beta-amyloid in Alzheimer's disease and has been reported to be associated with cognitive decline and reduced central nervous system (CNS) function (see, e.g., Molecules. October 13, 2017, 22(10), p. 1723). Indeed, beta-amyloid accumulation is a hallmark of aging, and such inhibitory compounds are believed to beneficially slow or halt beta-amyloid accumulation and preserve or maintain cognitive and CNS function. As described in more detail below, contemplated compositions have demonstrated significant, potent, and even synergistic effects with respect to BACE1 inhibition.

[0080] In yet another example, it has been reported that higher levels of cathepsin S are associated with a higher risk of death, and some studies have reported that it is also associated with a higher risk of cardiovascular death (e.g., JAMA, September 14, 2011, Vol. 306, No. 10, p. 1113). Other experimental studies have suggested that cathepsin S activity is involved in the development of cardiovascular disease through the promotion of atherosclerotic plaques and the destabilization of advanced plaques. Furthermore, it has been reported that cathepsin S activity is also involved in the development of cancer through the stimulation of cancer cell migration and tumor angiogenesis, and higher levels of cathepsin S activity are correlated with brain aging. Therefore, it is believed that a reduction in cathepsin S activity levels beneficially counteracts these risks. In particular, the contemplated composition has shown a remarkable and strong inhibitory effect on BACE1 inhibition.

[0081] Similarly, cyclin-dependent kinase 5 (CDK5) has been found to be essential for proper CNS function, and its role in peripheral tissues and diseases is increasing. For example, acute CDK5 inhibition has high potential therapeutic value to prevent neuronal damage in cases of stroke or brain injury, or during high-risk operations such as neurovascular or cardiovascular surgery, or during potentially prolonged and complicated births. Pharmacological inhibition of CDK5 has been shown to protect neurons under various stressful conditions and aging (see, e.g., Curr Pharm Des. 2016, 22(5), pp. 527-534). Again, the contemplated compositions showed significant, potent, and synergistic inhibitory effects with respect to CDK5 inhibition.

[0082] In yet another example, Janus kinases 1, 2 and 3 (JAK1, JAK2, JAK3) are involved in regulating the cell cycle and cancer, possibly through NF-kB activation (see, for example, Cells 2020, 9, p. 1451). Furthermore, small molecule drugs that inhibit Janus kinases (JAK1-3), which are important signaling mediators downstream of many proinflammatory cytokines, have attracted attention as a safe and effective option for immune-mediated diseases. Not surprisingly, inhibition of JAKs has emerged as a major treatment for inflammation-driven pathologies such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, and cardiovascular disease. In particular, the contemplated composition showed a remarkable and potent synergistic inhibitory effect (especially at high concentrations) with respect to JAK1, JAK2, and JAK3 inhibition.

[0083] In yet another example, inhibition of indoleamine 2,3-dioxygenase-1 (IDO1) has emerged as a new therapeutic strategy for immune support, especially in the reversal of tumor-mediated immune suppression (see, e.g., Cancer Res. 2017 Dec. 15, 77(24), pp. 6795-6811). Similarly, indoleamine 2,3-dioxygenase-2 (IDO2) has recently been implicated in cancer, inflammation, and immune regulation, and considerable resources have been devoted to identifying IDO2-specific inhibitors. Increases in IDO1 and IDO2 activity have also been observed as a function of aging (e.g., Immunity & Aging, 2011, 8:9), with age-related increases in inflammation, autoimmune diseases, and malignancies. Surprisingly, as shown in more detail below, the compositions of the present invention have shown strong inhibitory effects with respect to IDO1 and IDO2 inhibition.

[0084] With regard to energy metabolism, NAMPT and CD38 are known to regulate intracellular NAD+ and are believed to be essential for maintaining and supporting cellular energy and proper metabolic function. In fact, it has been reported that CD38 hyperactivity increases with aging (see, for example, Biochem Biophys Res Commun. May 28, 2019, 513(2), 486-493), cancer and aging diseases (see, for example, Trends Pharmacol Sci. April 2018, 39(4), 424-436), immunoregulatory and metabolic diseases (see, for example, FIMMU, May 2019, Vol. 10, 1187). In this context, it is believed that inhibition of CD38 reduces or even prevents diseases associated with CD38 hyperactivity. On the other hand, nicotinamide phosphoribosyltransferase (NAMPT) mediates the rate-limiting step of the NAD salvage pathway, which maintains cellular bioenergetics and provides substrates necessary for essential functions in cells, especially in rapidly proliferating cancer cells. Again, the contemplated compositions exhibited potent and synergistic inhibitory effects on CD38 inhibition and potent inhibition of NAMPT activity.

[0085] Moreover, it has been reported that overactivity of CD39 and CD73 contributes to immune suppression, suppression of checkpoint inhibition in tumors, and other aspects of immune regulation (see, for example, FIMMU, June 2017, Vol. 8, p. 727; Immunol Rev. March 2017, 276(1), p. 121-144). Furthermore, centenarians showed significantly lower expression of CD39 and CD73 compared to younger individuals (here, octogenarians), suggesting that CD39 and CD73 mRNA levels may be characteristic of the outcome of human aging. From another perspective, aging is associated with a decline in immune function, which leads to increased susceptibility to infections and a higher incidence of malignant diseases. Thus, it is believed that a decline in CD39 activity is directly related to healthy aging and longevity. Surprisingly, the contemplated composition had a significant and synergistic effect in inhibiting CD73 and had a remarkable inhibitory effect on the activity of CD39, as shown in more detail below. Similarly, CD47 inhibition has been shown to lead to stimulation of phagocytosis of cancer cells, and CD47 blockade has been linked not only to enhancing the function of innate immune cells but also to adaptive immune responses (see, e.g., Cell Reports 31, 107494, April 14, 2020). Notably, as shown in further detail below, contemplated compositions had a significant inhibitory effect in inhibiting CD47.

[0086] In yet another example, proprotein convertase subtilisin / kexin type 9 (PCSK9) has been reported as a contributor to plasma cholesterol levels, and inhibitors targeting PCSK9 have lowered plasma cholesterol in humans. Again, as shown in more detail below, contemplated compositions had significant synergistic effects in inhibiting PCSK9.

[0087] Furthermore, the Keap1-Nrf2 pathway is a major regulator of cytoprotective responses to endogenous and exogenous stress caused by reactive oxygen species (ROS), and Nrf2 activates the expression of various genes encoding stress response proteins. Therefore, inhibitors of Keap1-Nrf2 binding are believed to increase the expression of stress response-related proteins. Surprisingly, as shown in more detail below, the contemplated composition had a significant effect in inhibiting Keap1-Nrf2 binding (thus increasing the availability of Nrf2).

[0088] Finally, the present inventors have also found that the contemplated composition has an inhibitory effect on ACE2-Spike protein binding, which is involved in the viral proliferation of coronaviruses, particularly Sars-CoV2. Therefore, as can be easily understood, the contemplated composition may provide at least some protective effect against coronaviruses, particularly Sars-CoV2.

[0089] Based on extensive research, the inventors have found that it is possible to prepare a specific blend of selected plant materials common in the Mediterranean diet that mimics the benefits of the Mediterranean diet as evidenced by the modulation of biomarkers.Preferably, such blends are combinations of colored plant materials that belong to a number of (e.g., at least two, at least three, or at least four) different color groups, particularly plant materials with red, green, orange-yellow, and / or purple-blue colors.For example, in one embodiment of the contemplated composition, the polyphenol-containing product / extract is obtained from red raw materials including apple extract, pomegranate extract, tomato powder, and beet root, green raw materials including olive extract, rosemary extract, green coffee bean extract, and kale, orange-yellow raw materials including onion extract, ginger extract, grapefruit extract, and carrot, and purple-blue raw materials including grape extract, blueberry extract, currant, and elderberry, with the specific ingredients and proportions described in more detail below. Thus, viewed from different perspectives, contemplated compositions include multiple polyphenols up to at least two, or at least three, or at least four different polyphenol classes, including organic acids, phenolics, flavonols, flavanols, anthocyanins, chlorogenic acids, betacyanins, etc. As will be readily appreciated, the particular selection of plant material will depend on the desired (polyphenol) components in the plant material and their effects on particular biological systems and / or signaling pathways.

[0090] Of course, it should also be understood that the plant material may be provided in a variety of forms, including whole plant material or parts thereof (e.g., roots, fruits, leaves, etc.) in fresh or dried form, juices or macerations from plant material or parts thereof in fresh or dried form, and aqueous or aqueous / alcoholic extracts and chromatographic fractions of the aforementioned plant material. Furthermore, it should be noted that one or more polyphenols of the plant material may be provided as purified (naturally isolated or synthetic) chemicals, typically having a chemical purity of at least 90%, or at least 95%, or at least 98%, or at least 99%. However, it should be recognized that in most embodiments, the plant material is a complex mixture, providing a combination of desired biological effects on a number of different molecular entities (e.g., enzymes, receptors, ion channels), with at least some of the biological effects (e.g., at least one, or at least two, or at least three, etc.) being synergistic. Furthermore, it is believed that the biological effects on certain molecular entities are also complementary in biological function. Thus, based on the tests and desired goals described in more detail below, it should be understood that the compositions of the present subject matter may be formulated to meet specific needs. However, in particularly preferred embodiments, contemplated compositions inhibit multiple targets (e.g., at least two, at least three, at least four, etc.) in multiple distinct (e.g., at least two, at least three, at least four, etc.) signaling pathways.

[0091] Thus, from another perspective, the mechanism of action of the contemplated compositions is not limited to a single specific function (e.g., antioxidants) or a specific chemical category (e.g., vitamins), but actually provides multiple biological activities across different metabolic and signaling pathways in a complementary and synergistic manner. Thus, the contemplated compositions and methods target various biological systems, including energy metabolism, immune function, neurological and CNS function, cardiac function, inflammation, and the like. In particular, as described in more detail below, the compositions contemplated herein also influenced many biomarkers associated with longevity (e.g., in blue zone regions such as the Mediterranean coastal region, Okinawa region, etc.). In addition, it is believed that the plant material also provides various micronutrients to assist or complement the function of the polyphenols and other color pigments present in the composition.

[0092] It is therefore understood that the compositions contemplated herein can be advantageously used as stand-alone products to support various aspects of health and healthy aging, such as supporting proper immune function, reducing inflammation, supporting normal NAD+ levels, and supporting heart health. In this context, it is noted that the term "support" when used in connection with a physiological function or condition is intended to mean preventing a decline in one or more components or activity of components associated with the physiological function or condition, at least partially reversing a decline in one or more components or activity of components associated with the physiological function or condition, maintaining normal function or activity of one or more components associated with the physiological function or condition, preventing abnormal overactivity (or overexpression) of one or more components associated with the physiological function or condition, and / or at least partially reversing abnormal overactivity (or overexpression) of one or more components associated with the physiological function or condition. Alternatively, the compositions contemplated herein can be combined with other dietary supplements and / or vitamins to provide beneficial effects not otherwise available from such supplements or vitamins. In this regard, it should be appreciated that, as will be shown in more detail below, most, if not all, of the biomarkers tested herein were not substantially modulated by the multivitamin compositions. It should therefore be appreciated that the compositions presented herein provide a new and distinct class of health support with a variety of beneficial effects beyond the benefits of multivitamin formulations.

[0093] In further contemplated aspects of the subject matter of the present invention, it should be understood that the compositions presented herein may be formulated in various forms, with particularly preferred formulations including those combined with nutritionally or pharma- ceutically acceptable carriers, most preferably for oral administration (although parenteral administration is also expressly contemplated). Thus, contemplated compositions can be formulated as solid or liquid products. For example, when contemplated compositions are formulated as solid products, suitable product forms include single-dose unit formulations such as capsules, tablets, and powders, and other solid formulations include snack bars, gummies, or other edible products coated with the composition (e.g., on cereals), or mixed or layered with the composition (e.g., in chewing gum). In another example, when contemplated compositions are formulated as liquid products, suitable product forms include flavored and / or carbonated beverages (e.g., tea, juice), functional beverages (e.g., sports or energy drinks) or infusions, or liquid dairy products (e.g., yogurt, kefir).

[0094] Thus, contemplated compositions may be provided in bulk as part of an edible or drinkable product and / or in single dosage units for consumption. Most typically, the daily dosage of contemplated compositions (excluding carrier) is preferably at least 10 mg, or at least 100 mg, or at least 200 mg, or at least 300 mg, or at least 400 mg, or at least 500 mg, or at least 750 mg, or at least 1,000 mg, or at least 1,500 mg. For example, suitable dosages are between 10-100 mg, or between 100-200 mg, or between 200-400 mg, or between 300-600 mg, or between 400-800 mg, or between 600-1,000 mg, or between 1,000-2,000 mg.

[0095] As will be readily appreciated, contemplated compositions can be combined with one or more additional ingredients to further impart desirable functionality; suitable additional ingredients include vitamins (e.g., a single vitamin or a vitamin blend, such as a multivitamin blend), dietary trace elements or minerals (e.g., individual elements or minerals or mixtures of multiple elements or minerals in various forms), various specialty compounds and mixtures (e.g., compositions including nicotinamide riboside, prebiotics, human milk oligosaccharides), and / or one or more probiotic microorganisms (e.g., Lactobacillus species, Bifidobacterium species, Leuconostoc species, Saccharomyces boulardii, etc.).

[0096] Of course, it should be appreciated that the compositions according to the subject matter of the present invention can be administered to humans as well as other non-human mammals, particularly livestock and companion animals (e.g., dogs, cats, horses). Administration is typically performed once to three times a day (and sometimes more) for a period of at least 2 days, 3 days, 5 days, 1 week, 2-4 weeks, 1-3 months, or even longer. Most typically, administration is performed for a period sufficient to provide at least symptomatic relief of the condition (e.g., pain and swelling associated with inflammation, low energy levels, frequent infections, etc.) or to be prophylactic and avoid or reduce the severity of the health condition. Working Example Typical composition:

[0097] Unless otherwise stated, all tests were performed using a defined mixture of selected polyphenol-containing products / extracts common to the Mediterranean diet. The polyphenol-containing products / extracts were obtained from raw materials characterized by their color as follows: red group: apple extract, pomegranate extract, tomato powder, and beet root; green group: olive extract, rosemary extract, green coffee bean extract, and kale; orange-yellow group: onion extract, ginger extract, grapefruit extract, and carrot; purple-blue group: grape extract, blueberry extract, currant, and elderberry. Corn starch, silica, and sunflower lecithin were used as processing aids. The relative proportions are shown in Table 1 below. JPEG2025004025000002.jpg128166

[0098] Phytochemical HPLC / MS / MS Analysis: HPLC / MS compositional analysis of the above exemplary compositions revealed the following components and ratios, where each column in Tables 2-8 shows the analyte ID (col. 1), chemical (col. 2), MH (col. 3), RT (col. 4), peak intensity (col. 5), and MS / MS fragment (col. 6). JPEG2025004025000003.jpg89166JPEG2025004025000004.jpg216166JPEG2025004025000005.jpg113166JPEG202 5004025000006.jpg215166JPEG2025004025000007.jpg215166JPEG2025004025000008.jpg26166JPEG2025004025 000009.jpg216166JPEG2025004025000010.jpg53166JPEG2025004025000011.jpg216166JPEG2025004025000012. jpg220166JPEG2025004025000013.jpg73166JPEG2025004025000014.jpg33166JPEG2025004025000015.jpg62166

[0099] The biological activity of the compositions was tested for inhibition of various target entities central to various pathways related to health and healthy aging, and exemplary activity results are shown below. More specifically, the inventors tested the compositions for inhibition of human ARG-1, ARG-2, SIRT1, BACE1, Cathepsin S, CDK5, IDO1, IDO2, NAMPT, PCSK9, CD47, CD38, JAK1, JAK2, JAK3, CD39, and CD73, as well as Keap / Nrf2 binding inhibition and ACE2-Spike binding inhibition. ARG1 and ARG2:

[0100] In the following experiments, the inventors sought to determine whether representative compositions affect ARG1 and ARG2. The reagents used are shown in Tables 9-10 below and were tested as indicated unless otherwise noted (nor-NOHA is the reference compound). JPEG2025004025000016.jpg31166JPEG2025004025000017.jpg33166

[0101] Assay conditions: The assay was performed using human recombinant ARG1 or ARG2 as the enzyme and thioarginine as the substrate. UV absorbance at 412 nm correlated with the amount of ARG1 / ARG2 reaction product. Test samples (HP Color Blend) were dissolved to 1% (w / v) in 70% (w / v) ethanol (EtOH) and 0.22 μm filtered. Nor-NOHA was also dissolved to 10 mM in 100% (w / v) DMSO. 5 μl of 20X sample solution was added to 90 μl of substrate, and the reaction was started by adding 5 μl of 20X ARG1 / ARG2 solution. For the negative control (blank), 5 μl of assay buffer was added instead of ARG1 / ARG2. The resulting 100 μl reaction mixture contained the indicated amount of sample, 225 μM thioarginine, detection reagent, and 30 nM ARG1 or 5 nM ARG2 in 1X ARG assay buffer. All reactions were performed at room temperature and incubated for 30 min, ensuring that all wells containing either sample or control contained a final concentration of 0.7% (v / v) ethanol to eliminate solvent effects. UV absorbance was read at 0 and 30 min to obtain net values. Absorbance was measured using a Tecan Infinite M1000 microplate reader.

[0102] Data analysis: Experiments were performed twice at each concentration. Data were analyzed using the software GraphPad Prism. In the absence of compound, the net absorbance (At) of each data set was defined as 100% activity. In the absence of ARG1 / ARG2, the net absorbance (Ab) of each data set was defined as 0% activity. The percent activity in the presence of each compound was calculated according to the following formula: % activity = [(AA b ) / (A t -A b )]×100, where A is the absorbance in the presence of compound. Percent inhibition was calculated according to the following formula: % inhibition=100−% activity.

[0103] Results: Notably, significant inhibitory activity was found for both ARG-1 and ARG-2 across all tested concentrations, as shown in Tables 11-12 below. As can be readily seen from the results, the inhibition compared to the reference inhibitor was significant and was not specific for one or the other of ARG-1 and ARG-2, as can be seen from Table 13. The results for ARG-1 and ARG-2 are also shown in Figures 1 and 2, respectively. JPEG2025004025000018.jpg61166JPEG2025004025000019.jpg61166JPEG2025004025000020.jpg51166 SIRT1:

[0104] In the following experiments, the inventors sought to determine whether representative compositions affect SIRT1. The reagents used are shown in Tables 14-15 below and were tested as described unless otherwise stated (suramin was used as the reference compound). JPEG2025004025000021.jpg51166JPEG2025004025000022.jpg28166

[0105] Assay conditions: Samples were dissolved in 70% ethanol. Serial dilutions of compounds were made in 70% ethanol initially, with the highest concentration being 1%. Each intermediate compound dilution (in 70% ethanol) was then diluted 10-fold directly into assay buffer for intermediate dilutions of 7% ethanol in HDAC assay buffer, and 5 μl of dilution was added to a 50 μl reaction, resulting in a final concentration of ethanol of 0.7% in all reactions.

[0106] The enzymatic reaction of SIRT1 enzyme was carried out in duplicate in 50 μl of a mixture containing SIRT assay buffer, 5 μg BSA, HDAC substrate (see 2.3.1), SIRT enzyme, and test compound at 37°C for 30 min. After the enzymatic reaction, 50 μl of 2x SIRT Developer was added to each well for SIRT enzyme, and the plate was incubated at room temperature for an additional 15 min. Fluorescence intensity was measured at 360 nm excitation and 460 nm emission using a Tecan Infinite M1000 microplate reader.

[0107] Data analysis: SIRT activity assays were performed in duplicate at each concentration. Fluorescence intensity data were analyzed using computer software Graphpad Prism. In the absence of compound, the fluorescence intensity (F t ) was defined as 100% activity. In the absence of SIRT, the fluorescence intensity (F b ) was defined as 0% activity. The percent activity in the presence of each compound was calculated according to the following formula: % activity = (FF b ) / (F t -F b ), where F is the fluorescence intensity in the presence of the compound.

[0108] Results: The inhibition results are shown in the table below. The percent inhibition of the compounds against SIRT1 is summarized. The reference compound and the test composition and HP Color Blend precipitated at the 0.01% intermediate dilution step. Figure 3 presents the results in graphical form, and Table 16 provides the results in numerical form. As can be easily seen, the tested compositions had significant SIRT1 inhibitory activity. JPEG2025004025000023.jpg80166 Keap / Nrf2:

[0109] In a further series of experiments, the inventors investigated whether test compositions could disrupt Keap1-Nrf2 binding, and exemplary results are provided below. The reagents used are shown in Table 17 below and were tested as described unless otherwise stated (reference compound was LDEETGEFL-OH). JPEG2025004025000024.jpg48166

[0110] Assay conditions: Test compounds were diluted in 7% ethanol and 5 μl of the dilution was added to a 50 μl reaction to give a final concentration of ethanol of 0.7%. Reference compounds were diluted in 10% DMSO and 5 μl of the dilution was added to a 50 μl reaction to give a final concentration of DMSO of 1%. Binding reactions were carried out at room temperature for 30 min in a 50 μl mixture containing 10 mM HEPES, pH 7.4, 50 mM EDTA, 150 mM NaCl, 0.05% Tween20, 0.01% BSA, 100 nM Keap1, 5 nM fluorescent probe and test compound. Fluorescence intensity was measured at 475 nm excitation and 520 nm emission using a Tecan Infinite M1000 microplate reader.

[0111] Data analysis: All binding assays were performed in duplicate in 96-well plates. TecanMagellan6 software was used to convert fluorescence intensity to fluorescence anisotropy. Fluorescence anisotropy data were analyzed using computer software, Graphpad Prism. Fluorescence anisotropy (F At ) was defined as 100% activity. The fluorescence anisotropy (F Ab ) was defined as 0% activity. The percent binding availability in the presence of competing compounds was calculated according to the following formula: JPEG2025004025000025.jpg16113

[0112] where FA represents the fluorescence anisotropy in the presence of compound. The % bound values ​​were then plotted in a bar graph as shown in Figure 4, and the numerical results are shown in Table 18 below. JPEG2025004025000026.jpg48166

[0113] As can be easily seen from the results in the above table and FIG. 4, the tested compositions had significant inhibitory activity against Keap1-Nfr2 binding. ACE2-Spike:

[0114] In this series of experiments, the inventors investigated whether possible compositions and fractions thereof could reduce the binding of the SARS-CoV2 spike protein to ACE2 and whether vitamins also had any effect.

[0115] The reagents used are shown in Tables 19-21 below and were tested as described unless otherwise stated (* indicates reference compound). In this series of experiments, the representative compositions above were compared to individual colors as shown below and to a multivitamin formulation as also shown below. Table 19 shows the representative compositions and Table 20 shows color subfractions of the representative compositions, DC-5=yellow blend, DC-9=purple blend, DC-21=green blend, DC-13=red blend, where the red blend contained apple extract, pomegranate extract, tomato powder, and beet, the green blend contained olive extract, rosemary extract, green coffee bean extract, and kale, the orange-yellow blend contained onion extract, ginger extract, grapefruit extract, and carrot, and the purple-blue blend contained grape extract, blueberry extract, currant, and elderberry, as described above. Table 21 shows the multivitamin blends and Table 22 shows the ACE2 / Spike reagents used. JPEG2025004025000027.jpg41166JPEG2025004025000028.jpg55166JPEG2025004025000029.jpg36166JPEG2025004025000030.jpg25166

[0116] Assay conditions: Nickel plates were coated with 50 μl of 1 μg / ml ACE2-His for 1 h at room temperature, washed, and blocked before initiating the reaction. 10 μl of compound solution was incubated with 20 μl of 1X immunological buffer in the ACE2-His coated assay wells for 30 min, after which 20 μl of 5 μg / ml spiked S1-spike was added to initiate the reaction. A control with the same concentration as the solvent (ethanol) was included in the study. The reaction was allowed to proceed for 1 h at room temperature. Then, the wells were washed 3 times with 1X immunological buffer and blocked for 10 min with blocking buffer 2. 100 μl of streptavidin-HRP was added to all wells and incubated for 1 h. Finally, the plate was emptied, washed 3 times, and blocked before adding 100 μl of freshly prepared HRP chemiluminescent substrate to all wells. The luminescence of the samples was measured immediately thereafter on a BioTek Synergy 2 microplate reader.

[0117] Data Analysis: Luminescence data were analyzed and compared. In the absence of compound, the intensity of each data set (C e ) was defined as 100% activity. In the absence of enzyme, the intensity (C0) of each data set was defined as 0% activity. The percent activity in the presence of each compound was calculated according to the following formula: % activity = (C-C0) / (C e -C0), where C is the emission in the presence of the compound.

[0118] The results for the representative compositions are shown in Table 23 and Figure 5, and the results for the multivitamin formulation are shown in Table 24 and Figure 6. The results for the colored blends are shown in Table 25 and Figure 7. As can be readily seen from the data in Tables 23-25 ​​and Figures 5-7, the representative compositions exhibited synergistic inhibition of ACE2-spike S1 binding, especially at low concentrations, whereas the multivitamin formulation did not exhibit significant inhibitory effects. Additionally, selected DC-13 and DC9 also had some inhibitory effects by themselves. JPEG2025004025000031.jpg92166JPEG2025004025000032.jpg75166JPEG2025004025000033.jpg133166 BACE1:

[0119] In a further set of experiments, the inventors sought to determine whether the representative composition and its fractions, as well as the multivitamin mixture, affected the activity of recombinant human BACE1 using an in vitro fluorescent assay.

[0120] The reagents used are shown in Tables 26-28 below and were tested as described unless otherwise stated (*verubecestat was used as the reference compound). Table 26 shows the representative composition and Table 27 shows the color fraction and multivitamin mix, where DC-5=yellow blend, DC-9=purple blend, DC-21=green blend, DC-13=red blend DCH-TIV 1.0 (Centrum Vitamins for Adults), where the red blend contained apple extract, pomegranate extract, tomato powder, and beet, the green blend contained olive extract, rosemary extract, green coffee bean extract, and kale, the orange-yellow blend contained onion extract, ginger extract, grapefruit extract, and carrot, and the purple-blue blend contained grape extract, blueberry extract, currant, and elderberry, as described above. JPEG2025004025000034.jpg33166JPEG2025004025000035.jpg57166JPEG2025004025000036.jpg28166

[0121] Assay conditions: 80 μl of BACE1 was incubated with 10 μl of sample and reference compounds for 10 min. The reaction was then initiated by adding 10 μl of BACE1 FRET peptide substrate and product kinetics were measured for 1 h on an Infinite M1000 microplate reader (Tecan). Blank control wells received 80 μl of assay buffer instead of enzyme. All wells contained a final assay concentration of 0.7% (v / v) ethanol.

[0122] Data analysis: All conditions were run in duplicate at each concentration. Fluorescence intensity data were analyzed using Prism (GraphPad). In the absence of compound (no compound control), the fluorescence intensity (Ft) of each data set was defined as 100% activity. In the absence of enzyme (blank control), the fluorescence intensity (Fb) of each data set was defined as 0% activity. Percent activity in the presence of each compound was calculated according to the following formula: % activity = (F-Fb) / (Ft-Fb), where F is the fluorescence intensity in the presence of compound. Initial fluorescence was subtracted to obtain the net signal, measured in relative fluorescence units (RLU).

[0123] As can be seen from the data in Table 29 and Figure 8, the representative compositions had substantial inhibitory activity against the BACE1 tested. Surprisingly, the colored fraction also provided significant inhibition of BACE1, as can be seen from the data in Table 30 and Figure 9. Furthermore, it was apparent from these data that the BACE1 inhibition was synergistic, while the multivitamins tested had substantially no inhibitory effect. JPEG2025004025000037.jpg59166JPEG2025004025000038.jpg109166 Cathepsin S:

[0124] In yet another series of experiments, the inventors sought to determine whether the representative composition and fractions thereof, as well as the multivitamin mixture, affected the activity of recombinant human cathepsin S using in vitro enzyme assays.

[0125] The reagents used are shown in Tables 31-33 below and were tested as indicated unless otherwise stated (*E-64 was used as the reference compound), where the names and components of D5, D9, D13, and D21 are as above. JPEG2025004025000039.jpg36166JPEG2025004025000040.jpg49166JPEG2025004025000041.jpg38166

[0126] Assay conditions: Cathepsin S was activated by diluting concentrated stocks in acidic assay buffer for 30 min at room temperature. Then, 5 μl of sample or reference inhibitor was added to 20 μl of enzyme solution and pre-incubated for 30 min. The enzyme reaction was started by adding 25 μl of fluorogenic substrate, resulting in a total reaction volume of 50 μl. The reaction time was 60 min, after which the fluorescence intensity at 360 nm excitation and 460 nm emission was read using a Tecan Infinite M1000 microplate reader.

[0127] Data Analysis: Enzyme activity assays were performed in duplicate at each concentration. Fluorescence intensity data were analyzed and compared. In the absence of compound, the intensity of each data set was defined as 100% (Ce) activity. In the absence of enzyme, the intensity of each data set was defined as 0% (C0) activity. Percent activity in the presence of each compound was calculated according to the following formula: % activity = (C-C0) / (Ce-C0), where C is the intensity in the presence of compound (all percent activities less than zero are shown as zero in the table). Compound fluorescence was removed by subtracting the fluorescence at reaction time = 0.

[0128] The results of the above tests are shown in Tables 34-36, where Table 34 and Figure 10 show the results for the representative composition, Table 35 and Figure 11 show the results for the various colored fractions, and Table 36 and Figure 12 show the results for the multivitamin mix (DCH-TIC-0.5 is the representative composition and DCH-TIC-1.0 is the Centrum multivitamin mix). As can be readily seen from the results, the representative composition and colored blends D9 and D13 significantly inhibited cathepsin S, while the multivitamin mix had no substantial effect. JPEG2025004025000042.jpg67166JPEG2025004025000043.jpg105166JPEG2025004025000044.jpg69166 CDK5:

[0129] In a further series of experiments, the inventors sought to determine whether the representative composition and fractions thereof, as well as the multivitamin mixture, affected the enzymatic activity of recombinant human CDK5 / p25 using in vitro enzyme assays.

[0130] The reagents used are shown below in Tables 37-39 and were tested as described unless otherwise stated (Dinaciclib was used as the reference compound), where the names and components of D5, D9, D13, and D21 are as above. JPEG2025004025000045.jpg38166JPEG2025004025000046.jpg96166JPEG2025004025000047.jpg31166

[0131] Assay conditions: Analysis was performed using Kinase-Glo Plus Luminescent Kinase Assay Kit (Promega). Kinase activity is measured by quantifying the amount of ATP remaining in solution after the kinase reaction. The luminescent signal from the assay correlates with the amount of ATP present and inversely correlates with the amount of kinase activity. Reference compounds were diluted in 10% DMSO and 5 μl of dilution was added to 50 μl reactions such that the final concentration of DMSO was 1% in all reactions. Test compounds were diluted in water and 5 μl of dilution was added to 50 μl reactions. All enzymatic reactions were performed for 45 min at 30°C. The 50 μl reaction mixture contained 40 mM Tris, pH 7.4, 10 mM MgCl2, 0.1 mg / ml BSA, 1 mM DTT, 10 μM ATP, kinase substrate, and enzyme. After the enzymatic reaction, 50 μl of Kinase-Glo Plus Luminescent Kinase Assay Solution (Promega) was added to each reaction and incubated on the plate at room temperature for 15 min. Luminescent signals were measured using a BioTek Synergy 2 microplate reader.

[0132] Data analysis: Kinase activity assays were performed in duplicate at each concentration. Luminescence data were analyzed using computer software Graphpad Prism. The difference in luminescence intensity in the absence of kinase (Lut) and the presence of kinase (Luc) was defined as 100% activity (Lut-Luc). Using the luminescence signal in the presence of compound (Lu), % activity was calculated as follows: % activity = {(Lut-Lu) / (Lut-Luc)} x 100%, where Lu is the luminescence intensity in the presence of compound (all percent activities less than zero are shown as zero in the table).

[0133] The results of the above tests are shown in Tables 40-42, with Table 40 and Figure 13 showing the results for the representative composition, and Table 41 and Figure 14 showing the results for the various colored fractions and multivitamin mix (herein designated DCH-TIV 1.0). As can be easily seen from the presented data, the representative composition and its fractions showed significant inhibitory effects on CDK5, while the multivitamin mix showed substantially no apparent inhibitory effects compared to the representative composition. Furthermore, at least at medium and low concentrations, CDK5 inhibition showed at least a moderate synergistic effect in the representative composition. JPEG2025004025000048.jpg63166JPEG2025004025000049.jpg121166 IDO1 / IDO2:

[0134] In a further set of experiments, the inventors sought to determine whether the representative compositions affected the enzymatic activity of recombinant human IDO1 and / or IDO2 using a UV absorbance assay.

[0135] The reagents used are shown below in Tables 42-43 and were tested as indicated unless otherwise indicated. JPEG2025004025000050.jpg41166JPEG2025004025000051.jpg26166

[0136] Assay conditions: The assay was performed by measuring UV absorbance using recombinant IDO and L-tryptophan as substrates. UV absorbance at 321 nm correlates with the amount of N-formylkynurenine, the reaction product of IDO. Compounds (see 2.2) were diluted in 20% DMSO and 10 μl of the dilution was added to 200 μl reactions such that the final concentration of DMSO was 1% in all reactions. All reactions were performed at room temperature. 200 μl reaction mixtures in IDO assay buffer contained 400 nM IDO1 or IDO2, the indicated amounts of inhibitor, tryptophan, and coupled reaction components. Incubated reaction mixtures were for 180 min before reading UV absorbance. Negative controls (blanks) received 10 μl of assay buffer instead of IDO enzyme. Absorbance was measured using a Tecan Infinite M1000 plate reader.

[0137] Data analysis: Experiments were performed twice at each concentration. Data were analyzed using computer software GraphPad Prism. In the absence of compound, the absorbance signal (At) of each data set was defined as 100% activity. In the absence of IDO, the absorbance signal (Ab) of each data set was defined as 0% activity. Percent activity in the presence of each compound was calculated according to the following formula: % activity = [(A-Ab) / (At-Ab)] x 100, where A is the absorbance signal in the presence of compound. Percent inhibition was calculated according to the following formula: % inhibition = 100-% activity.

[0138] The results of the above tests are shown in Tables 44-45, where Table 44 and Figure 15 show the results of the representative compositions with respect to the inhibition of IDO1, and Table 45 and Figure 16 show the results of the representative compositions with respect to the inhibition of IDO2. As can be easily understood from the presented data, the representative compositions showed an inhibitory effect on IDO1 at high concentrations, and showed a significant inhibitory effect on IDO2 at high and medium concentrations. JPEG2025004025000052.jpg65166JPEG2025004025000053.jpg61166 NAMPT:

[0139] In yet another series of experiments, the inventors sought to determine whether the representative compositions affected the enzymatic activity of recombinant human NAMPT using an in vitro enzyme assay.

[0140] The reagents used are shown below in Tables 46-47 and were tested as indicated unless otherwise stated. JPEG2025004025000054.jpg43166JPEG2025004025000055.jpg30166

[0141] Assay conditions: Control compounds are dissolved in DMSO. Compound dilutions were initially made in 100% DMSO with the highest concentration being 0.01 mM. Each intermediate compound dilution (in 100% DMSO) was then directly diluted 10-fold in assay buffer to make intermediate dilutions of 10% DMSO in assay buffer with final concentrations of control compounds and NAMPT only reactions with a final concentration of 1% DMSO. For NAMPT, compounds (see 2.2) were pre-incubated with NAMPT enzyme (see 2.3.1) for 30 min. All enzymatic reactions were carried out in duplicate for 120 min at 30 °C by adding the substrate mixture in a 50 μl mixture containing 50 mM Tris-HCl, pH 8.0, 12.5 mM MgCl2, 20 μM nicotinamide, 40 μM PRPP, 20 μM ATP, 30 μg / mL alcohol dehydrogenase, 10 μg / mL NMNAT, 1.5% alcohol, 1 mM DTT, 0.02% BSA, 0.01% Tween. The final concentration of DMSO in all reactions was 1%. Fluorescence intensity was measured at 340 nm excitation and 460 nm emission using a Tecan Infinite M1000 microplate reader.

[0142] Data Analysis: NAMPT activity assays were performed in duplicate at each concentration. Fluorescence intensity data were analyzed using computer software, GraphPad Prism. In the absence of compound, the fluorescence intensity (Ft) of each data set was defined as 100% activity. In the absence of NAMPT, the fluorescence intensity (Fb) of each data set was defined as 0% activity. Percent activity in the presence of each compound was calculated according to the following formula: % activity = (F-Fb) / (Ft-Fb), where F is the fluorescence intensity in the presence of compound. Percent activity values ​​were plotted in a bar graph.

[0143] The results of the above experiments are shown in Table 48 and Figure 17. As can be easily seen, the representative compositions had an inhibitory effect on NAMPT. JPEG2025004025000056.jpg67166 PCSK9:

[0144] In further experiments, the inventors sought to determine whether representative compositions affected the binding of recombinant human PCSK9 and LDLR using in vitro ELISA.

[0145] The reagents used are shown in Tables 49-50 below and were tested as indicated unless otherwise noted (anti-PCSK9 was used as the reference compound). JPEG2025004025000057.jpg38166JPEG2025004025000058.jpg26166

[0146] Assay conditions: 5 μl of sample or reference inhibitor was pre-incubated in assay wells with 25 μl of 1X PCSK9 assay buffer before initiating the reaction by adding 20 μl of 2.5 ng / μl PCSK9-biotin. The reaction was then allowed to proceed for 2 h at room temperature. Wells were then washed 3 times with 1X PCSK9 assay buffer and blocked for 10 min with blocking buffer. 100 μl of streptavidin-HRP was added to all wells and incubated for 1 h. Finally, the plate was emptied, washed 3 times, and blocked before adding 100 μl of freshly prepared HRP chemiluminescent substrate to all wells. Sample luminescence was then measured immediately on a BioTek Synergy 2 microplate reader.

[0147] Data analysis: Binding activity assays were performed in duplicate at each concentration. Luminescence signals were analyzed and compared. In the absence of compound, the signal for each data set was defined as 100% (Ce) activity. In the absence of ligand (no LDLR), the signal for each data set was defined as 0% (C0) activity. Percent activity in the presence of each compound was calculated according to the following formula: % activity = (C-C0) / (Ce-C0), where C is the intensity in the presence of compound (all percent activities less than zero are shown as zero in the table). Compound fluorescence was removed by subtracting the fluorescence at reaction time = 0.

[0148] The results of the PCSK9 binding inhibition assay are shown in Table 51 and Figure 18. As can be seen from the data, the representative compositions exhibited significant inhibitory activity against the binding of recombinant human PCSK9 to LDLR. JPEG2025004025000059.jpg65166 CD47:

[0149] In further experiments, the inventors further sought to determine whether the representative compositions affected the binding activity of recombinant human CD47 (hCD47) with human SIRP-α (hSIRP-α) using an in vitro binding assay.

[0150] The reagents used are shown in Tables 52-53 below and were tested as indicated unless otherwise noted (anti-PCSK9 was used as the reference compound). JPEG2025004025000060.jpg37166JPEG2025004025000061.jpg40166

[0151] Assay conditions: CD47 was coated overnight at 4° C. using 50 μL at 2 ng / μL. After washing and blocking steps, test compounds were added to the CD47-coated plates, followed by the addition of SIRP-α-biotin. The reaction was incubated for 2 hours at room temperature. Binding was detected using HRP-conjugated streptavidin.

[0152] Data analysis: Binding assays were performed in duplicate at each concentration. Luminescence data was analyzed using computer software GraphPad Prism. Percent inhibition was determined by normalizing data to the signal from negative control wells (uncoated wells treated with biotinylated ligand, set as 100% inhibition) and positive control wells (coated wells treated with biotinylated ligand in the absence of inhibitor, set as 0% inhibition).

[0153] The results of the above experiments are listed in Table 54 and Figure 19. Again, it can be seen that the representative compositions had a significant inhibitory effect on the binding activity of recombinant human CD47 (hCD47) to human SIRP-α. JPEG2025004025000062.jpg85166 CD38:

[0154] In another series of experiments, the inventors sought to determine whether the representative composition and fractions thereof, as well as multivitamin mixtures and other compounds known to affect NAD+ levels, would affect the hydrolase activity of recombinant human CD38 using an in vitro enzyme assay.

[0155] The reagents used are shown in Tables 55-59 below and were tested as described unless otherwise stated (*apigenin was used as the reference compound). Table 55 shows a representative composition and Table 56 shows the color fraction and multivitamin mixture, where DC-5=yellow blend, DC-9=purple blend, DC-21=green blend, DC-13=red blend DCH-TIV 1.0 (Centrum Multivitamin for Adults), where, as above, the red blend contained apple extract, pomegranate extract, tomato powder, and beet, the green blend contained olive extract, rosemary extract, green coffee bean extract, and kale, the orange-yellow blend contained onion extract, ginger extract, grapefruit extract, and carrot, and the purple-blue blend contained grape extract, blueberry extract, currant, and elderberry. Table 57 shows two compounds known to affect NAD+ levels. Both commercially available "Elysium Health NAD" and "TrueNiagen" contain nicotinamide riboside, and Table 58 shows a representative composition (DCH-TIV-0.5) and a multivitamin composition (DCH-TIV-1.0 (Centrum Multivitamin for Adults)). Table 59 shows the enzymes and substrates used in this series of experiments. JPEG2025004025000063.jpg36166JPEG2025004025000064.jpg43166JPEG2025004025 000065.jpg49166JPEG2025004025000066.jpg42166JPEG2025004025000067.jpg27166

[0156] Assay conditions: 10 μl of sample or reference inhibitor was added to 20 μl of enzyme solution and pre-incubated for 30 min. The enzyme reaction was started by adding 20 μl of substrate ε-NAD+, the total reaction volume was 50 μl. The reaction time was 10 min, after which the fluorescence intensity was read at 300 nm excitation and 410 nm emission using a Tecan Infinite M1000 microplate reader.

[0157] Data Analysis: Enzyme activity assays were performed in duplicate at each concentration. Fluorescence intensity data were analyzed and compared. In the absence of compound, the intensity of each data set was defined as 100% (Ce) activity. In the absence of enzyme, the intensity of each data set was defined as 0% (C0) activity. Percent activity in the presence of each compound was calculated according to the following formula: % activity = (C-C0) / (Ce-C0), where C is the intensity in the presence of compound (all percent activities less than zero are shown as zero in the table). Compound fluorescence was removed by subtracting the fluorescence at reaction time = 0.

[0158] The results for the above substrates are shown in Tables 60-63 and Figures 20-23. More specifically, Table 60 and Figure 20 show the results when the representative compositions were used for inhibition of CD38. As can be easily seen from the data, the representative compositions showed significantly stronger inhibition. Table 61 and Figure 21 show the results when the colored fractions of the representative compositions were used for inhibition of CD38. Notably, strong inhibition was also observed here. Furthermore, it should be noted that the colored fractions in the representative compositions produced a strong synergistic effect with respect to CD38 inhibition.

[0159] Table 62 and Figure 22 show the results of corresponding experiments in which "Elysium Health NAD" and "TrueNiagen" (both containing nicotinamide riboside) were used for inhibition of CD38. Here, both formulations showed inhibition of CD38, but not to the same extent as the representative composition. In contrast, Table 63 and Figure 23 show the results of corresponding experiments in which a multivitamin composition was used to inhibit CD38. Here, a direct comparison is shown between the representative composition (DCH-TIV-0.5) and the multivitamin composition (DCH-TIV-1.0 in Table 63, DCH-TIG-1.0 in Figure 23). JPEG2025004025000068.jpg64166JPEG2025004025000069.jpg111166JPEG2025004025000070.jpg81166JPEG2025004025000071.jpg81166 JAK1 / JAK2 / JAK3:

[0160] In further experiments, the inventors sought to determine whether the representative compositions and fractions thereof affected the enzymatic activity of recombinant human kinases JAK1, JAK2, and JAK3 using in vitro enzyme assays.

[0161] The reagents used are shown in Tables 64-66 below and were tested as described unless otherwise stated (*apigenin was used as the reference compound). Table 64 shows the representative composition and Table 65 shows the colored fractions, where DC-5=yellow blend, DC-9=purple blend, DC-21=green blend, DC-13=red blend DCH-TIV 1.0 (Centrum Multivitamin for Adults), where the red blend contained apple extract, pomegranate extract, tomato powder, and beet, the green blend contained olive extract, rosemary extract, green coffee bean extract, and kale, the orange-yellow blend contained onion extract, ginger extract, grapefruit extract, and carrot, and the purple-blue blend contained grape extract, blueberry extract, currant, and elderberry, as described above. Staurosporine was also used as the reference compound. Table 66 shows the enzymes and substrates used in the assay. JPEG2025004025000072.jpg47166JPEG2025004025000073.jpg83166JPEG2025004025000074.jpg50166

[0162] Assay conditions: Analysis was performed using the Kinase-Glo Plus Luminescent Kinase Assay Kit (Promega). Kinase activity is measured by quantifying the amount of ATP remaining in solution after the kinase reaction. The luminescent signal from the assay correlates with the amount of ATP present and inversely correlates with the amount of kinase activity. Reference compounds were diluted as described. Compounds were diluted in water and 5 μl of dilution was added to 50 μl reactions. All enzymatic reactions were performed for 45 min at 30°C. The 50 μl reaction mixture contained 40 mM Tris, pH 7.4, 10 mM MgCl2, 0.1 mg / ml BSA, 1 mM DTT, 10 μM ATP, kinase substrate, and the respective enzyme. After the enzymatic reaction, 50 μl of Kinase-Glo Plus Luminescent Kinase Assay Solution (Promega) was added to each reaction and the plate was incubated at room temperature for 15 min. Luminescent signal was measured using a BioTek Synergy 2 microplate reader.

[0163] Data analysis: Kinase activity assays were performed in duplicate at each concentration. Luminescence data were analyzed using computer software GraphPad Prism. The difference in luminescence intensity in the absence of kinase (Lut) and the presence of kinase (Luc) was defined as 100% activity (Lut-Luc). Using the luminescence signal in the presence of compound (Lu), % activity was calculated as follows: % activity = {(Lut-Lu) / (Lut-Luc)} x 100%, where Lu is the luminescence intensity in the presence of compound (all percent activities less than zero are shown as zero in the table).

[0164] Inhibition results using representative compositions are shown in Tables 67-69 and Figures 24-26. Table 67 and Figure 24 show the results of JAK1 inhibition using representative compositions. Table 68 and Figure 25 show the results of JAK2 inhibition using representative compositions. Table 69 and Figure 26 show the results of JAK3 inhibition using representative compositions. As can be readily seen from these results, inhibition of all three JAK kinases tested was significant and substantial, matching or exceeding the inhibition provided by the reference compounds. JPEG2025004025000075.jpg67166JPEG2025004025000076.jpg65166JPEG2025004025000077.jpg67166

[0165] Tables 70-72 and Figures 27-29 show the corresponding results of the pigmented fractions. Here, Table 70 shows the results of JAK1 inhibition using the pigmented fractions of the representative compositions. Table 71 shows the results of JAK2 inhibition using the pigmented fractions of the representative compositions, and Table 72 shows the results of JAK3 inhibition using the pigmented fractions of the representative compositions. Table 73 is a table summarizing the results of Tables 70-72. Notably, a synergistic effect on inhibition against all three JAK kinases was observed at the higher concentrations where all the pigmented fractions were used together in the representative compositions compared to the individual pigmented fractions. Furthermore, it should be noted once again that the compositions presented herein had similar inhibitory properties compared to the reference compounds. JPEG2025004025000078.jpg113166JPEG2025004025000079.jpg114166JPEG2025004025000080.jpg113166JPEG2025004025000081.jpg102166 CD39:

[0166] In further experiments, the inventors sought to determine whether the representative compositions affected the enzymatic activity of recombinant human CD39 using an in vitro enzyme assay.

[0167] The reagents used are shown in Tables 74-77 below and were tested as described unless otherwise stated (*POM-1 was used as the reference compound). Table 74 shows a representative composition at standard concentration, and Table 75 shows a representative composition at low concentration. Table 76 shows the color fractions of the representative compositions at standard concentration, where D5 is the yellow blend, D9 is the purple blend, D21 is the green blend, D13 is the red blend, and D31 is CBD, respectively. Here, as above, the red blend included apple extract, pomegranate extract, tomato powder, and beet, the green blend included olive extract, rosemary extract, green coffee bean extract, and kale, the orange-yellow blend included onion extract, ginger extract, grapefruit extract, and carrot, and the purple-blue blend included grape extract, blueberry extract, currant, and elderberry. Table 77 shows CD39. JPEG2025004025000082.jpg35166JPEG2025004025000083.jpg39166JPEG2025004025000084.jpg51166JPEG2025004025000085.jpg25166

[0168] Assay conditions: In general, all assay points were performed according to the CD39 and CD73 inhibitor screening assay kit protocols (BPS Bioscience, #79278 and 72055, respectively). CD39 enzyme reactions were performed in duplicate for 30 min at room temperature in a 50 μl mixture containing assay buffer, ATP, CD39 enzyme, and test compound. Test compounds were pre-incubated with the enzyme for 30 min. The reaction was initiated by the addition of substrate. 50 μl reactions were performed in 96-well clear plates. After the enzyme reaction, 100 μl of colorimetric detection reagent was added to the reaction mixture. After 15 min incubation, absorbance was measured at 630 nm using a Tecan plate reader.

[0169] Data Analysis: Enzyme activity assays were performed in duplicate at each concentration. Absorbance data were analyzed and compared. In the absence of compound, the intensity of each data set was defined as 100% (Ce) activity. In the absence of enzyme, the intensity of each data set was defined as 0% (C0) activity. Percent activity in the presence of each compound was calculated according to the following formula: % activity = (C-C0) / (Ce-C0), where C is the intensity in the presence of compound (all percent activities less than zero are denoted as zero in the table).

[0170] As shown in Tables 77-78 below, remarkably high and significant inhibitory activity was observed for CD39 across all tested concentrations, with Table 78 and Figure 27 showing the results for the standard concentration, and Table 79 and Figure 28 showing the results for the low concentration. As can be readily seen from the results, the inhibition against the reference inhibitor was unexpectedly strong against the known reference inhibitor POM-1. Notably, the composition had an IC50 concentration of 0.000044%. When the colored fractions were tested for inhibitory activity, the inhibitory activity was partially, but not completely, distributed to selected fractions, as can be seen from the results in Table 80 and Figure 29. JPEG2025004025000086.jpg62166JPEG2025004025000087.jpg71166JPEG2025004025000088.jpg121166

[0171] Next, the inventors further investigated whether one or more particular plant materials and their polyphenols are associated with inhibitory activity against CD39. To that end, the inventors tested two components of the red blend, namely apple extract (DCH-IC50X) and pomegranate extract (DCH-IC50Y), at a low concentration range as shown in Table 81, but under otherwise identical assay conditions. The results are shown in Table 82 and Figure 30. JPEG2025004025000089.jpg49166JPEG2025004025000090.jpg96166

[0172] In yet another experiment, the inventors also investigated whether CD39 could also be inhibited by the multivitamin mixture. To this end, a comparison was performed between the multivitamin mixture (designated DCH-TIV-1.0 (Centrum Multivitamin for Adults)) and a representative composition (designated DCH-TIC-0.5) using the same CD39 experimental procedure described above. Such compositions are shown in Table 83. JPEG2025004025000091.jpg43166

[0173] The results of this comparison are shown in Table 84 and Figure 31. As can be seen from the results, the representative composition had a very strong inhibitory effect on CD39, while the multivitamin composition had essentially no significant inhibitory effect. JPEG2025004025000092.jpg81166 CD73:

[0174] In yet another experiment, the inventors further sought to determine whether the representative compositions affected the enzymatic activity of recombinant human CD73 using an in vitro enzyme assay.

[0175] The reagents used are shown in Tables 85-89 below and were tested as described unless otherwise stated (*AMPCP or quercetin was used as the reference compound). Table 85 shows the representative composition at standard concentrations, and Table 86 shows the colored fractions of the representative composition at standard concentrations, where D5 is the yellow blend, D9 is the purple blend, D21 is the green blend, D13 is the red blend, and D31 is CBD, respectively. Here, as above, the red blend included apple extract, pomegranate extract, tomato powder, and beet, the green blend included olive extract, rosemary extract, green coffee bean extract, and kale, the orange-yellow blend included onion extract, ginger extract, grapefruit extract, and carrot, and the purple-blue blend included grape extract, blueberry extract, currant, and elderberry. Table 87 shows CD73. JPEG2025004025000093.jpg33166JPEG2025004025000094.jpg47166JPEG2025004025000095.jpg25166

[0176] Assay conditions: In general, all assay points were performed according to the CD39 and CD73 inhibitor screening assay kit protocols (BPS Bioscience, #79278 and 72055, respectively). CD73 enzyme reactions were performed in duplicate for 30 min at room temperature in a 50 μl mixture containing assay buffer, ATP, CD73 enzyme, and test compound. Test compounds were pre-incubated with the enzyme for 30 min. The reaction was initiated by the addition of substrate. 50 μl reactions were performed in 96-well clear plates. After the enzyme reaction, 100 μl of colorimetric detection reagent was added to the reaction mixture. After 15 min incubation, absorbance was measured at 630 nm using a Tecan plate reader.

[0177] Data Analysis: Enzyme activity assays were performed in duplicate at each concentration. Absorbance data were analyzed and compared. In the absence of compound, the intensity of each data set was defined as 100% (Ce) activity. In the absence of enzyme, the intensity of each data set was defined as 0% (C0) activity. Percent activity in the presence of each compound was calculated according to the following formula: % activity = (C-C0) / (Ce-C0), where C is the intensity in the presence of compound (all percent activities less than zero are denoted as zero in the table).

[0178] As can be seen from the results in Tables 88-90, the inhibition of CD73 by the representative compositions and fractions thereof was significantly higher, especially compared to the current reference standard. Table 88 and Figure 32 show the results of CD73 inhibition at standard concentrations, while Table 89 and Figure 33 show the results of CD73 inhibition at lower concentrations, where the IC50 for the representative compositions is about 0.000044%. Moreover, as can be seen from these results and the results for the pigmented fractions shown in Table 90 and Figure 34, a strong synergistic effect of the pigmented fractions when used in combination (as in the representative compositions) was observed with respect to inhibition of CD73. JPEG2025004025000096.jpg61166JPEG2025004025000097.jpg72166JPEG2025004025000098.jpg123166

[0179] To further investigate whether CD73 can also be inhibited by multivitamin formulations, the inventors conducted a comparative study between the representative composition and the multivitamin composition using the same test procedure outlined above. Table 91 shows the reagents used in this study (DCH-TIV-0.5 represents the representative composition, and DCH-TIV-1.0 represents Centrum Multivitamin for Adults). JPEG2025004025000099.jpg45166

[0180] As can be readily seen from the results in Table 92 and FIG. 35, the representative compositions had substantial inhibitory activity with respect to CD73, while only slight inhibitory activity was observed with the multivitamin composition. JPEG2025004025000100.jpg81166

[0181] In some embodiments, the numbers expressing properties such as amounts and concentrations of ingredients, reaction conditions, etc., used to describe and claim certain embodiments of the present invention should be understood to be modified in some cases by the term "about". Thus, in some embodiments, the numerical parameters set forth in the written description and the accompanying claims are approximations that may vary depending on the desired properties sought to be obtained by a particular embodiment. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of individually referencing each individual value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.

[0182] As used herein, the term "administering" a pharmaceutical or nutraceutical composition refers to both direct and indirect administration of a pharmaceutical or nutraceutical composition, where direct administration of a pharmaceutical or nutraceutical composition is typically performed by a medical professional (e.g., a doctor, a nurse, a nutritionist, etc.) and indirect administration involves providing or making available a pharmaceutical or nutraceutical composition to a health care professional or individual in need thereof for direct administration (e.g., by injection, infusion, oral delivery, topical delivery, etc.). Additionally, it is noted that the term "predicting" a condition, susceptibility to development of a disease, or response to an intended treatment is meant to cover the act or prediction (but not treatment or diagnosis) of predicting the condition, susceptibility and / or response, including the progression, improvement, and / or duration of the condition in a subject.

[0183] All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "etc.") provided with respect to specific embodiments herein is intended merely to better illustrate the invention and does not limit the scope of the invention as otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0184] As used throughout this specification and claims, the meanings of "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Also, as used in this description, the meaning of "in" includes "in" and "on," unless the context clearly dictates otherwise. Also, as used herein, the term "coupled" is intended to include both direct coupling (where the two elements coupled to each other are in contact with each other) and indirect coupling (where at least one additional element is in contact with each other), unless the context clearly dictates otherwise. Thus, the terms "coupled to" and "coupled with" are used synonymously.

[0185] It will be apparent to those skilled in the art that many variations beyond those already described are possible without departing from the concept of the present invention. Thus, the subject matter of the present invention should not be limited except as set forth in the appended claims. Moreover, in interpreting both the specification and the claims, all terms should be interpreted in the broadest possible manner consistent with the context. In particular, the term "comprises" should be interpreted to refer to an element, component, or step in a non-exclusive manner indicating that the referenced element, component, or step may be present or utilized or may be combined with other elements, components, or steps not expressly referenced. If the specification or claims refer to at least one selected from the group consisting of A, B, C... and N, the statement should be interpreted as requiring only one element from the group, not A and N, B and N, etc.

Claims

1. a nutritionally acceptable carrier in combination with a plurality of chemically distinct polyphenols derived from plant material having red, green, orange-yellow, and purple-blue colors; A nutritional composition characterized in that the chemically distinct polyphenols derived from the plant material are a synergistic combination with respect to inhibition of at least one biochemical marker selected from the group consisting of BACE1, CD38, CD73, CDK5, JAK1, JAK2, and JAK3.

2. 2. The composition of claim 1, wherein the plant material having a red color comprises at least one of apple extract, pomegranate extract, tomato powder, and beet root powder, the plant material having a green color comprises at least one of olive extract, rosemary extract, green coffee bean extract, and kale powder, the plant material having an orange-yellow color comprises at least one of onion extract, ginger extract, grapefruit extract, and carrot powder, and the plant material having a purple-blue color comprises at least one of grape extract, blueberry extract, gooseberry powder, and elderberry powder.

3. 2. The composition of claim 1, wherein the plant material having a red color includes at least two of apple extract, pomegranate extract, tomato powder, and beet root powder, the plant material having a green color includes at least two of olive extract, rosemary extract, green coffee bean extract, and kale powder, the plant material having an orange-yellow color includes at least two of onion extract, ginger extract, grapefruit extract, and carrot powder, and the plant material having a purple-blue color includes at least two of grape extract, blueberry extract, gooseberry powder, and elderberry powder.

4. 2. The composition of claim 1, wherein the plant materials having a red color include apple extract, pomegranate extract, tomato powder, and beet root powder, the plant materials having a green color include olive extract, rosemary extract, green coffee bean extract, and kale powder, the plant materials having an orange-yellow color include onion extract, ginger extract, grapefruit extract, and carrot powder, and the plant materials having a purple-blue color include grape extract, blueberry extract, gooseberry powder, and elderberry powder.

5. 2. The composition of claim 1, wherein the chemically distinct polyphenol further inhibits at least one additional biochemical marker selected from the group consisting of ARG-1, ARG-2, SIRT-1, CD39, IDO1, IDO2, NAMPT, PCSK9, CD47, and Cathepsin S.

6. The composition of claim 1, which further inhibits Keap / Nrf2 binding and / or ACE2 / Spike binding.

7. The composition of claim 1 , wherein the composition is formulated in a single dosage unit for oral administration.

8. The composition of claim 7, wherein the single dosage unit contains 50 to 1,000 mg of the composition.

9. 8. The composition of claim 7, wherein the single dosage unit is formulated as a capsule, gummy, or powder.

10. 10. The composition of claim 1, wherein the composition further comprises vitamins, dietary trace elements or minerals, nicotinamide riboside, probiotics, and / or prebiotics.

11. a nutritionally acceptable carrier in combination with a plurality of chemically distinct polyphenols derived from plant material having red, green, orange-yellow, and purple-blue colors; said plant materials having a red color include apple extract, pomegranate extract, tomato powder, and beet root powder; the plant material having a green color includes olive extract, rosemary extract, green coffee bean extract, and kale powder; The plant materials having an orange-yellow color include onion extract, ginger extract, grapefruit extract, and carrot powder; the plant material having a violet-blue color comprises at least one of grape extract, blueberry extract, currant powder, and elder powder; A nutritional composition, wherein the combination of plant materials is a synergistic combination with respect to inhibition of at least one biochemical marker selected from the group consisting of BACE1, CD38, CD73, CDK5, JAK1, JAK2, and JAK3.

12. The composition of claim 11 , wherein the combination of the plant materials is a synergistic combination with respect to inhibition of BACE1, CD38, and CD73.

13. 12. The composition of claim 11, further inhibiting at least one additional biochemical marker selected from the group consisting of ARG-1, ARG-2, SIRT-1, CD39, IDO1, IDO2, NAMPT, PCSK9, CD47, and cathepsin S.

14. The composition of claim 11, which further inhibits Keap / Nrf2 binding and / or ACE2 / Spike binding.

15. The composition of claim 11 , wherein the composition is formulated in a single dosage unit for oral administration.

16. The composition of claim 15, wherein the single dosage unit contains 50 to 1,000 mg of the composition.

17. 16. The composition of claim 15, wherein the single dosage unit is formulated as a capsule, gummy, or powder.

18. 16. The composition of claim 15, wherein the composition further comprises vitamins, dietary trace elements or minerals, nicotinamide riboside, probiotics, and / or prebiotics.

19. 12. The composition of claim 11, wherein the composition is effective to treat and / or alleviate symptoms of inflammatory conditions, cardiovascular conditions, neurological conditions, metabolic conditions, and cancer.

20. 12. The composition of claim 11, wherein the apple extract, pomegranate extract, olive extract, rosemary extract, green coffee bean extract, onion extract, ginger extract, grapefruit extract, grape extract, and blueberry extract are ethanol extracts or ethanol / water extracts.

21. A method of supporting the health of an individual, comprising administering to said individual a composition according to any one of claims 1 to 10 or 11 to 20.

22. 22. The method of claim 21, wherein the composition is administered to provide immune support, metabolic support, longevity support, support for central nervous system (CNS) function, reduce inflammatory responses, reduce the effects of cardiovascular disease, and reduce the rate of amyloid beta plaque formation.

23. 22. The method of claim 21, wherein the composition is administered orally for at least 30 days.

24. 22. The method of claim 21, wherein the composition is administered orally in a daily dose of 50 to 1,000 mg.

25. 22. The method of claim 21, further comprising co-administering vitamins, dietary trace elements or minerals, nicotinamide riboside, probiotics, and / or prebiotics.

26. 26. The method of claim 25, wherein the dietary trace elements or minerals, the nicotinamide riboside, the probiotics, and / or the prebiotics are co-administered in the same dosage unit.

27. 1. A method for reducing NAD+ depletion in an individual, comprising: administering to an individual a synergistic combination of polyphenols derived from plant materials having red, green, orange-yellow, and purple-blue colors; The method, wherein the combination synergistically inhibits CD38.

28. 28. The method of claim 27, wherein the polyphenol is provided in the form of the plant material.

29. 29. The method of claim 27 or 28, wherein the plant material having a red color is selected from the group consisting of apple extract, pomegranate extract, tomato powder, and beet root powder, the plant material having a green color is selected from the group consisting of olive extract, rosemary extract, green coffee bean extract, and kale powder, the plant material having an orange-yellow color is selected from the group consisting of onion extract, ginger extract, grapefruit extract, and carrot powder, and the plant material having a purple-blue color is selected from the group consisting of grape extract, blueberry extract, gooseberry powder, and elderberry powder.

30. 28. The method of claim 27, wherein the decrease in NAD+ is an age-related decrease in NAD+.

31. 1. A method of supporting the longevity of an individual, comprising: administering to an individual a synergistic combination of polyphenols derived from plant materials having red, green, orange-yellow, and purple-blue colors; The method, wherein the combination synergistically inhibits CD73.

32. 32. The method of claim 31 , wherein the polyphenol is provided in the form of the plant material.

33. 33. The method of claim 31 or 32, wherein the plant material having a red color is selected from the group consisting of apple extract, pomegranate extract, tomato powder, and beet root powder, the plant material having a green color is selected from the group consisting of olive extract, rosemary extract, green coffee bean extract, and kale powder, the plant material having an orange-yellow color is selected from the group consisting of onion extract, ginger extract, grapefruit extract, and carrot powder, and the plant material having a purple-blue color is selected from the group consisting of grape extract, blueberry extract, gooseberry powder, and elderberry powder.

34. 32. The method of claim 31, wherein said administration increases immune function, thereby preserving longevity.

35. 1. A method of supporting cognitive function in an individual, comprising: administering a synergistic combination of polyphenols derived from plant materials having red, green, orange-yellow, and purple-blue colors; The method, wherein the combination synergistically inhibits BACE1.

36. 36. The method of claim 35, wherein the polyphenol is provided in the form of the plant material.

37. 37. The method of claim 35 or 36, wherein the plant material having a red color is selected from the group consisting of apple extract, pomegranate extract, tomato powder, and beet root powder, the plant material having a green color is selected from the group consisting of olive extract, rosemary extract, green coffee bean extract, and kale powder, the plant material having an orange-yellow color is selected from the group consisting of onion extract, ginger extract, grapefruit extract, and carrot powder, and the plant material having a purple-blue color is selected from the group consisting of grape extract, blueberry extract, gooseberry powder, and elderberry powder.

38. 36. The method of claim 35, wherein said administering reduces the rate of amyloid-beta plaque formation.

39. 1. A method of supporting central nervous system (CNS) function in an individual, comprising: administering a synergistic combination of polyphenols derived from plant materials having red, green, orange-yellow, and purple-blue colors; The method, wherein the combination synergistically inhibits CDK5.

40. 40. The method of claim 39, wherein the polyphenol is provided in the form of the plant material.

41. 41. The method of claim 39 or 40, wherein the plant material having a red color is selected from the group consisting of apple extract, pomegranate extract, tomato powder, and beet root powder, the plant material having a green color is selected from the group consisting of olive extract, rosemary extract, green coffee bean extract, and kale powder, the plant material having an orange-yellow color is selected from the group consisting of onion extract, ginger extract, grapefruit extract, and carrot powder, and the plant material having a purple-blue color is selected from the group consisting of grape extract, blueberry extract, gooseberry powder, and elderberry powder.

42. 40. The method of claim 39, wherein said administration reduces age-related cognitive decline.

43. 1. A method of supporting immune function in an individual, comprising: administering a synergistic combination of polyphenols derived from plant materials having red, green, orange-yellow, and purple-blue colors; The method, wherein the combination synergistically inhibits at least one of JAK1, JAK2, and JAK3.

44. 44. The method of claim 43, wherein the polyphenol is provided in the form of the plant material.

45. 45. The method of claim 43 or 44, wherein the plant material having a red color is selected from the group consisting of apple extract, pomegranate extract, tomato powder, and beet root powder, the plant material having a green color is selected from the group consisting of olive extract, rosemary extract, green coffee bean extract, and kale powder, the plant material having an orange-yellow color is selected from the group consisting of onion extract, ginger extract, grapefruit extract, and carrot powder, and the plant material having a purple-blue color is selected from the group consisting of grape extract, blueberry extract, gooseberry powder, and elderberry powder.

46. 44. The method of claim 43, wherein said administering relieves a symptom of rheumatoid arthritis, psoriasis, or inflammatory bowel disease.

47. 1. A method of inhibiting at least one of BACE1, CD38, CD73, CDK5, JAK1, JAK2, and JAK3, comprising: contacting at least one of BACE1, CD38, CD73, CDK5, JAK1, JAK2, and JAK3 with a plurality of chemically distinct polyphenols derived from plant material having red, green, orange-yellow, and purple-blue colors; The method of claim 1, wherein the chemically distinct polyphenols derived from the plant material are a synergistic combination with respect to inhibition of at least one biochemical marker selected from the group consisting of BACE1, CD38, CD73, CDK5, JAK1, JAK2, and JAK3.

48. 48. The method of claim 47, wherein the polyphenol is provided in the form of the plant material.

49. 49. The method of claim 47 or 48, wherein the plant material having a red color is selected from the group consisting of apple extract, pomegranate extract, tomato powder, and beet root powder, the plant material having a green color is selected from the group consisting of olive extract, rosemary extract, green coffee bean extract, and kale powder, the plant material having an orange-yellow color is selected from the group consisting of onion extract, ginger extract, grapefruit extract, and carrot powder, and the plant material having a purple-blue color is selected from the group consisting of grape extract, blueberry extract, gooseberry powder, and elderberry powder.

50. 48. The method of claim 47, wherein the contacting step occurs in vivo.

51. 48. The method of claim 47, wherein the contacting step comprises oral administration to the mammal.

52. 52. The method of claim 51, wherein the composition is administered to provide immune support, metabolic support, longevity support, support for central nervous system (CNS) function, reduce inflammatory responses, reduce the effects of cardiovascular disease, and reduce the rate of amyloid beta plaque formation.

53. 1. A method of treating a condition associated with activity of at least one of BACE1, CD38, CD73, CDK5, JAK1, JAK2, JAK3, ARG-1, ARG-2, SIRT-1, CD39, IDO1, IDO2, NAMPT, PCSK9, CD47, and cathepsin S in a mammal, comprising:

20. A method comprising administering to the mammal a plurality of chemically distinct polyphenols in an amount effective to inhibit at least one of BACE1, CD38, CD73, CDK5, JAK1, JAK2, JAK3, ARG-1, ARG-2, SIRT-1, CD39, IDO1, IDO2, NAMPT, PCSK9, CD47, and cathepsin S.

54. 54. The method of claim 53, wherein the condition is an inflammatory condition, a cardiovascular condition, a neurological condition, a metabolic condition, and cancer.

55. 54. The method of claim 53, wherein the plurality of chemically distinct polyphenols is derived from plant material having red, green, orange-yellow, and purple-blue colors.

56. 56. The method of claim 55, wherein the plant material having a red color is selected from the group consisting of apple extract, pomegranate extract, tomato powder, and beet root powder, the plant material having a green color is selected from the group consisting of olive extract, rosemary extract, green coffee bean extract, and kale powder, the plant material having an orange-yellow color is selected from the group consisting of onion extract, ginger extract, grapefruit extract, and carrot powder, and the plant material having a purple-blue color is selected from the group consisting of grape extract, blueberry extract, gooseberry powder, and elderberry powder.

57. 57. The method of claim 55 or 56, wherein the polyphenol is provided in the form of the plant material.

58. 54. The method of claim 53, wherein the chemically distinct polyphenols synergistically inhibit BACE1, CD38, CD73, CDK5, JAK1, JAK2, and / or JAK3.

59. 54. The method of claim 53, wherein the plurality of chemically distinct polyphenols is orally administered to the mammal.

60. 60. The method of claim 59, wherein the plurality of chemically distinct polyphenols is administered in a daily dose of 50-1,000 mg.

61. 54. The method of claim 53, further comprising the step of co-administering to the mammal vitamins, dietary trace elements or minerals, nicotinamide riboside, probiotics, and / or prebiotics.

62. 54. The method of claim 53, wherein the chemically distinct polyphenol is administered in an amount effective to inhibit at least three of BACE1, CD38, CD73, CDK5, JAK1, JAK2, JAK3, ARG-1, ARG-2, SIRT-1, CD39, IDO1, IDO2, NAMPT, PCSK9, CD47, and cathepsin S.

63. 54. The method of claim 53, wherein the chemically distinct polyphenol is administered in an amount effective to inhibit at least five of BACE1, CD38, CD73, CDK5, JAK1, JAK2, JAK3, ARG-1, ARG-2, SIRT-1, CD39, IDO1, IDO2, NAMPT, PCSK9, CD47, and cathepsin S.

64. 54. The method of claim 53, wherein the chemically distinct polyphenol is administered in an amount effective to inhibit at least ten of the following biochemical markers: BACE1, CD38, CD73, CDK5, JAK1, JAK2, JAK3, ARG-1, ARG-2, SIRT-1, CD39, IDO1, IDO2, NAMPT, PCSK9, CD47, and cathepsin S.

65. 54. The method of claim 53, wherein the chemically distinct polyphenol is administered in an amount effective to inhibit BACE1, CD38, CD73, CDK5, JAK1, JAK2, JAK3, ARG-1, ARG-2, SIRT-1, CD39, IDO1, IDO2, NAMPT, PCSK9, CD47, and cathepsin S.

66. 1. The use of chemically distinct polyphenols to support healthy aging, comprising: the chemically distinct polyphenols are present in plant material having red, green, orange-yellow, and purple-blue colors; The chemically distinct polyphenols inhibit CD38, CD39, CD73, ARG-1, ARG-2, BACE1, CDK5, cathepsin S, JAK1, JAK2, and JAK3.

67. 67. The use of claim 66, wherein the multiple chemically distinct polyphenols further inhibit SIRT-1, IDO1, IDO2, NAMPT, PCSK9, CD47, Keap / Nrf2 binding, and / or ACE2 / Spike binding.

68. 67. The use of claim 66, wherein the chemically distinct polyphenols synergistically inhibit BACE1, CD38, CD73, CDK5, JAK1, JAK2, and / or JAK3.

69. 67. The use of claim 66, wherein the polyphenol is provided in the form of plant material.

70. 70. The use of claim 66 or 69, wherein the plant material having a red color is selected from the group consisting of apple extract, pomegranate extract, tomato powder, and beet root powder, the plant material having a green color is selected from the group consisting of olive extract, rosemary extract, green coffee bean extract, and kale powder, the plant material having an orange-yellow color is selected from the group consisting of onion extract, ginger extract, grapefruit extract, and carrot powder, and the plant material having a purple-blue color is selected from the group consisting of grape extract, blueberry extract, gooseberry powder, and elderberry powder.

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