Compositions and methods for enhancing healthspan

Abstract

Compositions and methods are presented in which a plurality of chemically distinct polyphenols modulate the health span of a subject when administered at a later stage of life. Preferred compositions are formulated for oral administration and are derived from colored plant materials commonly found in the Mediterranean diet.

Description

COMPOSITIONS AND METHODS FOR ENHANCING HEALTHSPAN

[0001] This application claims priority to our copending US provisional Patent application with the application number 63 / 585,503 filed on 09 / 26 / 2023, which is incorporated by reference herein.Field of the Invention

[0002] The field of the invention is compositions and methods for nutritional supplements, especially as it relates to polyphenols and polyphenol mixtures commonly associated with a diet rich in fruits and vegetables such as the Mediterranean diet, and their use in modulating health span when administered at a later stage of life.Background of the Invention

[0003] The background description includes information that may be useful in understanding the present invention. It is not an 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 herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.

[0005] “Youthfulness is not determined by age. It is determined by one’s life force.” (Daisaku Ikeda). Likewise, what matters is not years of one’s life but rather the life lived within those years. But the life that one can live within each year may be restricted by physical and mental capabilities. Both of which tend to deteriorate as the years pass by. Many people in later stages of life are privy to the debilitating effects of older age. Such physical and / or mental limitations have even been accepted as being a part of “getting old.” However, as advances in aging research and regenerative medicine continue to add more years to people’s lives, more years may be spent in an unhealthy, limited way.

[0006] This is the problem today: lifespans are getting longer, and health span is not keeping pace. In other words, although people are tending to have more years of life, they have insufficient health to fully enjoy those extra years of life. Within the past few years, globally, life expectancy has increased from 66.8 years in 2000 to 73.4 years in 2019. (World Health Organization (WHO) Global Health Estimates: Life Expectancy and Leading Causes of Death and Disability). Although healthy life expectancy has also increased from 58.3 years to 63.7 years, respectively, such an increase was due to declining mortality as opposed to reduced years living without disability or disease. (WHO). People are tending to live more years, but the years of potentially living with disability or disease has also increased. This inability of health span to keep up with increasing lifespan results in many people no longer having the desire to live longer lives. For example, in recent years, a small number of studies have investigated how long people would prefer to live and how various ailments or life situations would impact that number. In one study done amongst the American public, it was discovered that people want to live long, but healthy, lives. (Desire for Extended Life. 2016 Jan 20; 6:353; p. l. doi: 10.3389 / fgene.2015.00353). In the study, 1000 individuals were surveyed about how long they wished to live (age 85, 120, 150, or indefinitely) under a few different scenarios. (See above). With guaranteed mental and physical health as a scenario, 797 of 1000 people wanted to live to 120 or longer. (See above). In another survey of 1500 respondents, using a different platform, the study found that 74.4% wished to live to 120 or longer if health was guaranteed. (See above; p. 2). As shown, many people wish to live far longer than the average human lifespan so long as they stay healthy. Furthermore, a Norwegian study of individuals aged 60+ sought to investigate how long older individuals prefer to live given hypothetical adverse changes in health and living conditions. The results indicated that the fear of living under what is typically perceived as adverse age-related conditions likely outweighs the fear of death. In the study, participants were asked “If you could choose freely, until what age would you wish to live?” (Age and Ageing 2021; 50: 2012-2018; p. 2013. Doi: 10.1093 / ageing / afabl 13). The average preferred life expectancy in response to the question was 91.4 years. (See above; p. 2015). But when introduced to the hypothetical scenario of being diagnosed with dementia, 89% of participants reduced their preferred life expectancy. (See above). Additionally, when the hypothetical scenario of experiencing chronic pain was posed, 85% of participants also lowered their preferred life expectancy. (See above).

[0007] Health span matters just as much as, if not more than, lifespan. However, there is only a small body of evidence that substantiates a way in which health span alone can be modulated.There is a considerable variety of vitamins and other isolated nutritional or molecular compounds that allege to provide immune support, cardiac support, digestive support, antiinflammatory effects, longevity, and anti-ageing effects.

[0008] In an effort to increase selected metrics associated with life span or health, few compositions and methods are known. For example, in WO 2021 / 158825, it was discovered that specific combinations of polyphenols and / or polyphenol-rich materials (e.g., extracts and powders) commonly found in food items of the Mediterranean diet had substantial effect on a variety of molecular biomarkers associated with longevity, inflammation, immune function, NAD / energy metabolism, and the gut microbiome. The tested biomarkers included BACE1, CD38, CD73, CDK5, JAK1, JAK2, and JAK3. Further biochemical markers that were inhibited included ARG-1, ARG-2, SIRT-2, CD39, IDO1, IDO2, NAMPT, PCSK9, CD47, and Cathepsin S. While mechanistically intriguing, the ‘825 reference did not establish a correlation between inhibition of the biomarkers and an increase in health span. Rather, these biomarkers were associated with the ‘Blue Zones’, populations with increased lifespan.

[0009] Similarly, in US Patent Application 2023 / 0263746, it was discovered that metabolic modulation could occur using a plurality of chemically distinct polyamines as shown in C. elegans. The contemplated compositions demonstrated reduced mortality rates and increase in overall lifespan, particularly in the second half of life, as seen in a C. elegans model. Nonetheless, the specific combination of a first and second polyamine composition again did not target modulation of the C. elegans" health span in isolation from lifespan. Improvements in health span were seen to improve only with improvements in lifespan. Lastly, in a study done on the ability of phycoerythrin in extending the life span and health span of C. elegans (AGE (2014) 36:9717), it was discovered that the antioxidant activity of phycoerythrin conferred increased resistance to cellular stress that resulted in improved life span and health span. Although interesting, the lifespan and health span of the C. elegans were, again, jointly improved in populations where phycoerythrin was present from day 1 of the experiment.

[0010] Thus, even though various compositions and methods for potentially modulating health span are known in the art, all or almost all of them suffer from several drawbacks. There is more to life than just ensuring it does not end. Therefore, there remains a need for modulation of health span, especially in the later stages of life where it matters most.Summary of The Invention

[0011] The inventive subject matter is directed to compositions and methods for assisting healthy aging of a subject through administration of a combination of polyphenols and / or polyphenol-rich materials (e.g. extracts and powders) commonly found in food items of the Mediterranean diet. Notably, and as is shown in more detail herein below, the compositions presented herein exhibited significant improvements in health span in a well-recognized animal model, improving the health span even above a potent positive control.

[0012] In one aspect of the inventive subject matter, the inventor contemplates a nutritional composition for administration to a subject to assist healthy aging of the subject that includes a nutritionally acceptable carrier in combination with a plurality of chemically distinct polyphenols from plant materials having a red color, a green color, an orange-yellow color, and a purple-blue color; most preferably the composition has been demonstrated to increase locomotor activity in a C. elegans nematode in vivo model relative to a control composition not containing the plurality of chemically distinct polyphenols; additionally, it is preferred that the increase in locomotor activity is demonstrated in the latter half of lifespan of the in vivo model to thereby increase health span.

[0013] In some embodiments, the red colored plant materials comprise at least one of an apple extract, a pomegranate extract, a tomato powder, and a beet root powder; wherein the green colored plant materials comprise at least one of an olive extract, a rosemary extract, a green coffee bean extract, and a kale powder; wherein the orange-yellow colored plant materials comprise at least one of an onion extract, a ginger extract, a grapefruit extract, and a carrot powder; and wherein the purple-blue colored plant materials comprise at least one of a grape extract, a blueberry extract, a currant powder, and an elderberry powder. Alternatively, the red colored plant materials comprise at least two of an apple extract, a pomegranate extract, a tomato powder, and a beet root powder; wherein the green colored plant materials comprise at least two of an olive extract, a rosemary extract, a green coffee bean extract, and a kale powder; wherein the orange-yellow colored plant materials comprise at least two of an onion extract, a ginger extract, a grapefruit extract, and a carrot powder; and wherein the purple-blue colored plant materials comprise at least two of a grape extract, a blueberry extract, a currant powder, and an elderberry powder. Nonetheless, the red colored plant materials comprise an apple extract, a pomegranate extract, a tomato powder, and a beet root powder; wherein the green colored plant materials comprise an olive extract, a rosemary extract, a green coffee beanextract, and a kale powder; wherein the orange-yellow colored plant materials comprise an onion extract, a ginger extract, a grapefruit extract, and a carrot powder; and wherein the purple-blue colored plant materials comprise a grape extract, a blueberry extract, a currant powder, and an elderberry powder.

[0014] In a further aspect of the inventive subject matter, the modulation of the health span of a subject is associated with maintenance of physical and / or mental function as compared to the subject not having been administered the composition and / or improvement of physical and / or mental function as compared to the subject not having been administered the composition. In addition, the health span of a subject is in respect to the group consisting of C. elegans, humans, and / or non-human mammals at a later stage in life. Moreover, a later stage in life comprises at least the latter third of lifespan of the in vivo model a C. elegans. or the human, or non-human mammal. . .In some embodiments, the chemically distinct polyphenols are present in quantities sufficient to effect (a) modulation of health span of a subject by delaying or preventing a chronic disease; (b) modulation of health span of a subject by delaying or preventing an age- related disability; (c) modulation of health span of a subject by increasing locomotor activity; (d) modulation of health span of a subject by preserving or increasing the health of thin or thick filaments of cellular muscle fibers; (e) modulation of health span of a subject by preserving or increasing the stimulation of regions of the brain associated with reward or happiness; (f) modulation of health span of a subject by decreasing concentrations of cortisol in the nervous system; (g) modulation of health span of a subject by preserving or increasing the energy yield of metabolic processes; (h) modulation of health span of a subject by preserving or increasing the health of extracellular matrices; (i) modulation of health span of a subject by preserving or increasing intracellular NAD+ or ATP concentration; (j) modulation of health span of a subject by preserving or increasing the mitochondrial biogenesis; and / or (k) modulation of health span of a subject by preserving or increasing glucose uptake into cells. Additionally, the delay or prevention of the chronic disease includes conditions that are a leading cause of death, that last one year or more, that require ongoing medical attention, and / or that limit daily activities of living. Whereas the age-related disability includes physical and / or mental impairments that substantially limit one or more significant life activity.

[0015] Most typically, but not necessarily, the composition is formulated in single dosage units for oral administration (e.g., each containing between 50 and 1,500 mg of the composition),which may be formulated as a capsule, a gummy, or a powder. Where desired, the composition may further comprise an additional nutritionally acceptable functional ingredient.

[0016] In other preferred embodiments, the composition has been further demonstrated to inhibit enzymes associated with age related health decline. In such embodiments, it is typically preferred that the enzymes are ARG-1, ARG-2, SIRT1, BACE1, Cathepsin S, CDK5, IDO1, IDO2, NAMPT, PCSK9, CD47, CD38, JAK1, JAK2, JAK3, CD39, and CD73, and / or Keap / Nrf2, and / or a combination thereof. As such, it should be appreciated that the compositions presented herein will positively modulate certain pathways (and pathway elements) associated with healthy ageing.

[0017] Viewed from a different perspective, the inventor additionally contemplates a method of modulating the health span of a subject which comprises orally administering to the subject the compositions presented herein. It is further contemplated that the combination of plant materials modulates the health span of a subject.

[0018] Particularly, modulation of the health span of a subject is associated with maintenance of physical and / or mental function as compared to subject not having been administered the composition and / or improvement of physical and / or mental function as compared to subject not having been administered the composition. Furthermore, the health span of a subject is in respect to the group consisting of C. elegans, humans, and / or non-mammals at a later stage in life. Additionally, a later stage in life comprises administering to a subject a combination of polyphenols from plant materials after at least 30 years of life.

[0019] Among other uses, the combination of plant materials is present in quantities sufficient to effect modulation of health span of a subject by delaying or preventing a chronic disease; modulation of health span of a subject by delaying or preventing an age-related disability; modulation of health span of a subject by increasing locomotor activity; modulation of health span of a subject by preserving or increasing the health of thin or thick filaments of cellular muscle fibers; modulation of health span of a subject by preserving or increasing the stimulation of regions of the brain associated with reward or happiness; modulation of health span of a subject by decreasing concentrations of cortisol in the nervous system; modulation of health span of a subject by preserving or increasing the energy yield of metabolic processes; modulation of health span of a subject by preserving or increasing the health of extracellular matrices; modulation of health span of a subj ect by preserving or increasing intracellular NAD+or ATP concentration; modulation of health span of a subject by preserving or increasing the mitochondrial biogenesis; and / or modulation of health span of a subject by preserving or increasing glucose uptake into cells. As noted earlier, the delay or prevention of the chronic disease includes conditions that are a leading cause of death, that last one year or more, that require ongoing medical attention, and / or that limit daily activities of living. In addition, the delay or prevention of the age-related disability includes physical and / or mental impairments that substantially limit one or more significant life activity. Furthermore, the combination of plant materials is comprised of chemically distinct polyphenol-containing plant materials having a red color, a green color, an orange-yellow color, and a purple-blue color.

[0020] Preferably, the chemically distinct polyphenol-containing plant materials having a red color comprise an apple extract, a pomegranate extract, a tomato powder, and a beet root powder; wherein the green colored plant materials comprise an olive extract, a rosemary extract, a green coffee bean extract, and a kale powder; wherein the orange-yellow colored plant materials comprise an onion extract, a ginger extract, a grapefruit extract, and a carrot powder; wherein the purple-blue colored plant materials comprise a grape extract, a blueberry extract, a currant powder, and an elderberry powder; and wherein the combination of plant materials modulates the health span of a subject.

[0021] In essence, the method of modulating the health span delays or prevents chronic diseases, delays or prevents age-related disabilities, preserves or increases locomotor activity, health of thin or thick filaments of cellular muscle fibers, stimulation of brain regions associated with reward or happiness, energy yield of metabolic processes, health of extracellular matrices, intracellular concentration of NAD+ or ATP, mitochondrial biogenesis, and / or glucose uptake into cells, and / or decreases concentration of cortisol in the nervous system.

[0022] Moreover, it is preferred that the composition is orally administered over at least 30 days with a daily dose of between 50 and 1,500 mg. Most typically, but not necessarily, the composition further comprises an additional nutritionally acceptable functional ingredient which is co-administered in the same dosage unit.

[0023] Additionally viewed from a different perspective, the inventor also contemplates the use of a plurality of chemically distinct polyphenols to modulate health span of a subject, wherein the chemically distinct polyphenols are present in plant materials having a red color,a green color, an orange-yellow color, and a purple-blue color, and wherein the chemically distinct polyphenols delays or prevents chronic diseases, delays or prevents age-related disabilities, preserves or increases locomotor activity, health of thin or thick filaments of cellular muscle fibers, stimulation of brain regions associated with reward or happiness, energy yield of metabolic processes, health of extracellular matrices, intracellular concentration of NAD+ or ATP, mitochondrial biogenesis, and / or glucose uptake into cells, and / or decreases concentration of cortisol in the nervous system. Therefore, the chemically distinct polyphenols are contemplated to modulate the health span of a subject.

[0024] As before, the modulation of the health span of a subject is associated with maintenance of physical and / or mental function as compared to the subject not having been administered the composition and / or improvement of physical and / or mental function as compared to the subject not having been administered the composition. Also, the health span of a subject is in respect to the group consisting of C. elegans, humans, and / or non-mammals at a later stage in life. In addition, a later stage in life comprises administering to a subject a combination of polyphenols from plant materials after at least 30 years of life.

[0025] In some embodiments, the combination of plant materials is present in quantities sufficient to effectmodulation of health span of a subject by delaying or preventing a chronic disease; modulation of health span of a subject by delaying or preventing an age-related disability; modulation of health span of a subject by increasing locomotor activity; modulation of health span of a subject by preserving or increasing the health of thin or thick filaments of cellular muscle fibers; modulation of health span of a subject by preserving or increasing the stimulation of regions of the brain associated with reward or happiness; modulation of health span of a subject by decreasing concentrations of cortisol in the nervous system; modulation of health span of a subject by preserving or increasing the energy yield of metabolic processes; modulation of health span of a subject by preserving or increasing the health of extracellular matrices; modulation of health span of a subj ect by preserving or increasing intracellular NAD+ or ATP concentration; modulation of health span of a subject by preserving or increasing the mitochondrial biogenesis; and / or modulation of health span of a subject by preserving or increasing glucose uptake into cells. Additionally, the delay or prevention of the chronic disease includes conditions that are a leading cause of death, that last one year or more, that require ongoing medical attention, and / or that limit daily activities of living. Whereas the delayor prevention of the age-related disability includes physical and / or mental impairments that substantially limit one or more significant life activity.

[0026] In still further contemplated embodiments, the polyphenols are provided in the form of the plant materials. As before, it is preferred that the red colored plant materials are selected from the group consisting of an apple extract, a pomegranate extract, a tomato powder, and a beet root powder; wherein the green colored plant materials are selected from the group consisting of an olive extract, a rosemary extract, a green coffee bean extract, and a kale powder; wherein the orange-yellow colored plant materials are selected from the group consisting of an onion extract, a ginger extract, a grapefruit extract, and a carrot powder; and wherein the purple-blue colored plant materials are selected from the group consisting of a grape extract, a blueberry extract, a currant powder, and an elderberry powder.

[0027] Various objects, features, aspects, and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments, along with the accompanying drawing figures in which like numerals represent like components.Brief Description of The Drawing

[0028] FIG.l is a graph depicting exemplary results for the fraction of C. elegans moving in response to administration of composition according to the inventive subject matter. As depicted, at 250 pg / mL, the fraction of worms moving was greater than control up to day 8, and then similar to control until the end of the assay. At 500 pg / mL, the fraction of worms moving was greater than both control and 250 pg / mL up to day 10, and then similar to control until the end of the assay. At 1 mg / mL, the fraction of worms moving was greater than control but lower than 250 pg / mL of formulation between day 4 and day 5, then similar to 250 pg / mL from day 5 to day 9.5, and then lower than control until the end of the assay.

[0029] FIG.2 is a graph depicting exemplary results for mean hours C. elegans spent moving from day 4 to day 8, and from day 4 to day 13 in response to administration of composition according to the inventive subject matter, along with a positive control, sulfamethoxazole, (SMX 16 pg / mL) mean hours moving for 500 pg / mL of formulation were significantly greater than SMX, and both 250 pg / mL and 1 mg / mL formulations. For the period day 4 to day 13, the effect of 250 and 500 pg / mL and SMX were significant but not the effect of Img / mL of the formulation.

[0030] FIG.3 is a graph depicting exemplary results for mean speed of all C. elegans in response to administration of composition according to the inventive subject matter. In worms transferred to control petri dishes on day 3, mean speed of all worms kept declining until day 10, then plateaued until the end of the assay. The mean speed of all SMX-treated worms was higher than control from day 4 to day 8. In worms transferred to the formulation of the inventive subject matter on day 3, mean speed of moving worms showed a dose-dependent increase, significantly higher than control and SMX treated groups.

[0031] FIG.4 is a graph depicting exemplary results for mean distance moved from day 4 to day 8, and from day 4 to day 13 in response to administration of composition according to the inventive subject matter. As depicted, between day 4 and day 8, the distances moved showed a statistically significant dose-response increase from control, to SMX, to 250 pg / mL formulation, to 500 pg / mL formulation. No further increase was observed from 500 pg / mL to 1 mg / mL formulations.

[0032] FIG.5 is a graph depicting exemplary results for the mean speed of moving C. elegans in response to administration of composition according to the inventive subject matter. As depicted, in worms transferred to the formulation of the inventive subject matter on day 3, mean speed of moving worms showed a dose-dependent increase. For example, at 250 pg / mL, the mean speed of moving worms was slightly greater than the control up to day 8, but then similar to the control until the end of the assay.

[0033] FIG.6 is a graph depicting exemplary results for the fraction of C. elegans moving in response to administration of the composition according to the inventive subject matter as compared to the positive and negative controls. As depicted, the worms transferred to the formulation of the inventive subject matter on day 3 showed a significantly higher fraction of movement compared to control up to day 8, but then similar to control at the end of the assay. Additionally, the worms transferred to the formulation showed a higher fraction of movement compared to the positive control from day 5 to day 8, but then similar toward the end of the assay.

[0034] FIG.7 is a graph depicting exemplary results for the fraction of C. elegans moving in response to administration of the composition according to the inventive subject matter as compared to the negative control. Again, the worms transferred to the formulation of theinventive subject matter on day 3 showed a significantly higher fraction of movement compared to control up to day 8, but then similar to control at the end of the assay.

[0035] FIG.8 is a graph depicting exemplary results for the fraction of C. elegans moving in response to administration of the composition according to the inventive subject matter as compared to the positive control. Again, the worms transferred to the formulation of the inventive subject matter showed a higher fraction of movement compared to the positive control from day 5 to day 8, but then similar toward the end of the assay.

[0036] FIG.9 is a graph depicting exemplary results for mean hours spent moving by C. elegans from day 4 to day 8 in response to administration of the composition according to the inventive subject matter as compared to the positive and negative controls. As depicted, the results for mean hours spent moving by worm in response to administration of the composition according to the inventive subject matter is significantly higher than both controls during this time period.

[0037] FIG.10 is a graph depicting exemplary results for mean hours spent moving by C. elegans from day 4 to day 8 in response to administration of the composition according to the inventive subject matter as compared to the negative control. Again, the results for mean hours spent moving by worm in response to administration of the composition according to the inventive subject matter is significantly higher than control during this time period.

[0038] FIG.ll is a graph depicting exemplary results for mean hours spent moving by C. elegans from day 4 to day 8 in response to administration of the composition according to the inventive subject matter as compared to the positive control. Again, the results for mean hours spent moving by worm in response to administration of the composition according to the inventive subject matter is significantly higher than positive control during this time period.

[0039] FIG.ll is a graph depicting exemplary results for mean hours spent moving by C. elegans from day 4 to day 13 in response to administration of the composition according to the inventive subject matter as compared to the positive and negative controls. As depicted, the results for mean hours spent moving by worm in response to administration of the composition according to the inventive subject matter is statistically similar to the positive control, but significantly higher than control during this time period.

[0040] FIG.13 is a graph depicting exemplary results for mean hours spent moving by C. elegans from day 4 to day 13 in response to administration of the composition according to the inventive subject matter as compared to the negative control.

[0041] FIG.14 is a graph depicting exemplary results for mean hours spent moving by C. elegans from day 4 to day 13 in response to administration of the composition according to the inventive subject matter as compared to the positive control.

[0042] FIG.15 is a graph depicting exemplary results for mean speed of all C. elegans in response to administration of the composition according to the inventive subject matter as compared to the positive and negative controls. As depicted, the worms transferred to the formulation of the inventive subject matter showed a statistically significant increase from control and positive control from day 4 to day 8, but then similar toward the end of the assay.

[0043] FIG.16 is a graph depicting exemplary results for mean speed of all C. elegans in response to administration of the composition according to the inventive subject matter as compared to the negative control.

[0044] FIG.17 is a graph depicting exemplary results for mean speed of all C. elegans in response to administration of the composition according to the inventive subject matter as compared to the positive control.

[0045] FIG.18 is a graph depicting exemplary results for mean distance moved by C. elegans from day 4 to day 8 in response to administration of the composition according to the inventive subject matter as compared to the positive and negative controls. As depicted, the worms transferred to the formulation of the inventive subject matter showed a statistically significant increase in distance moved compared to both positive and negative control during this time period.

[0046] FIG.19 is a graph depicting exemplary results for mean distance moved by C. elegans from day 4 to day 8 in response to administration of the composition according to the inventive subject matter as compared to the negative control.

[0047] FIG.20 is a graph depicting exemplary results for mean distance moved by C. elegans from day 4 to day 8 in response to administration of the composition according to the inventive subject matter as compared to the positive control.

[0048] FIG.21 is a graph depicting exemplary results for mean distance moved by C. elegans from day 4 to day 13 in response to administration of the composition according to the inventive subject matter as compared to the positive and negative controls. As depicted, the worms transferred to the formulation of the inventive subject matter showed a statistically significant increase in distance moved compared to both positive and negative control during this time period.

[0049] FIG.22 is a graph depicting exemplary results for mean distance moved by C. elegans from day 4 to day 13 in response to administration of the composition according to the inventive subject matter as compared to the negative control.

[0050] FIG.23 is a graph depicting exemplary results for mean distance moved by C. elegans from day 4 to day 13 in response to administration of the composition according to the inventive subject matter as compared to the positive control.

[0051] FIG.24 is a graph depicting exemplary results for mean speed of moving C. elegans in response to administration of the composition according to the inventive subject matter as compared to the positive and negative controls. As depicted, the worms transferred to the formulation of the inventive subject matter showed a statistically significant and consistent increase in mean speed compared to both positive and negative control.

[0052] FIG.25 is a graph depicting exemplary results for mean speed of moving C. elegans in response to administration of the composition according to the inventive subject matter as compared to the negative control.

[0053] FIG.26 is a graph depicting exemplary results for mean speed of moving C. elegans in response to administration of the composition according to the inventive subject matter as compared to the positive control.Detailed Description

[0054] The inventors have discovered various compositions and methods of modulating health span in a simple and effective manner using nutritionally acceptable compounds and compositions that, maintain or even improve various aspects of a prolonged health span as seen in a Caenorhabditis elegans (C. elegans) model.

[0055] The C. elegans in vivo model was selected especially because it shares fundamental biological mechanisms such as muscle contraction, nervous system signaling, and cell death, with humans and many other species. In fact, many C. elegans genes have orthologs in humans, meaning they perform similar functions in both organisms, making it possible to study the effects of various compositions, methods, or conditions on the human gene function using C. elegans models. As such, where the compositions and methods disclosed herein demonstrate beneficial effects on C. elegans in vivo models, especially the increase of locomotor activity later in life, the inventors contemplate that such effects will have health span benefits on humans, non-human mammals, and non-mammals.

[0056] The relation between increased locomotor activity in a C. elegans in vivo model and health span in organisms such as humans is especially evidenced by the sarcomere, the fundamental unit of muscle contraction, being conserved between C. elegans and humans. The molecules that regulate muscle contraction, assembly, and maintenance are also largely conserved between C. elegans and humans. Further, C. elegans uses mechanosensory neurons to regulate locomotion, which is similar to how humans use mechanosensory neurons to regulate their behavior and movement. Still further, the proteins observed in C. elegans and their human orthologs are, on average, 49.1% identical and 69.3% similar. Their cognate coding sequences are, on average, 49.8% identical. Therefore, and in view of the disclosure herein, the inventors contemplate that benefits to locomotion (and other health span aspects) in C. elegans later in life have a nexus with health span benefits to humans, non-human mammals, and non-mammals, potentially later in life as well. As used herein, the term “health span” refers to healthy aging. Health span, or healthy aging, can be observed and quantified through a variety of systemic phenomena or metrics, and especially locomotor activity, which in turn is influenced by one or more underlying physiological processes or conditions that include delay and / or prevention of chronic disease, delay and / or prevention of age-related disability, health state and / or functioning of thin or thick filaments of cellular muscle fibers, stimulation of brain regions associated with reward or happiness, energy yield of metabolic processes, health state and / or functioning of thin or thick filaments of cellular muscle fibers, stimulation of brain regions associated with reward or happiness, energy yield of metabolic processes, health state and / or functioning of extracellular matrices, intracellular concentration of NAD+ or ATP, mitochondrial biogenesis, glucose uptake into cells, and concentration of cortisol in the circulatory and / or nervous system. Further examples associated with health span or healthy aging include longevity, gut health, intestinal barrier integrity, skin health, dermal barrierintegrity, cognition, memory, and / or energy metabolism. As expressed here, chronic disease includes conditions that are a leading cause of death as determined by the most current statistical data. For example, in the United States, as provided by the Center for Disease Control and Prevention, in 2019, some leading causes of death included heart disease, malignant neoplasms, accidents (unintentional injuries), chronic lower respiratory disease, cerebrovascular diseases, and Alzheimer disease. (National Vital Statistics Reports, Vol. 70, No. 9, Jul. 26, 2021; p.9). Chronic disease may also include a condition or disease that lasts one year or more, in either effects or treatment. Ongoing medical attention is required, from either a trained medical professional or a competent individual, for treatment of the chronic disease and / or daily activities of living are subjectively limited from the effects of said chronic disease. However, use of chronic disease in the latter context does not necessitate that the condition or disease is also a leading cause of death. The applicable definitions of the term chronic disease are not mutually exclusive to each other.

[0057] As expressed here, age-related disability includes physical and / or mental impairments that substantially limit one or more significant life activity. A substantial limitation includes impairments that may be minor or major in nature but, nonetheless, have an impact on a person’s daily life such that the presence of the disability results in an increase in difficulty for completion of tasks. In other words, the threshold for performing subjectively “normal” tasks decreases with age-related disability, which results in a limitation in what a person may do without increased challenge. A significant life activity varies person to person but includes those activities that a person of normal health, without an age-related disability, would be able to engage in without any increased difficulty.

[0058] In this context, it should be appreciated that health span is to be distinguished from survivability, lifespan, and life expectancy. Survivability, lifespan, and life expectancy depend upon a quantifiable amount of time that a subject may live. In contract, health span depends upon the status of physiological parameters that affect a subject’s health as the subject ages. Therefore, a subject can potentially have a relatively strong survivability and long lifespan, yet have a poor health span (for example, by having weak thin and thick filaments in muscle fibers, poor glucose uptake into cells, deficient mitochondrial biogenesis, chronic disease and so on). In especially advantageous aspects, and as shown in more detail below, contemplated compositions and methods modulate normal locomotor activity in such a way that would not otherwise occur in untreated subjects. Such modulation was especially pronounced in the latterpart of the subject’s lifespan (e.g., latter half, latter third, latter quarter, etc.), after administration at a later stage of life, which may or may not be accompanied by an increase in lifespan.

[0059] As expressed here, administration at a later stage of life is preferably provided to a subject in the latter part of the subject’s lifespan (latter half, latter third, latter quarter, etc.). In human subjects, administration is preferably provided when the subject is at least 30 years of age, or at least 40 years of age, or at least 50 years of age, or at least 60 years of age, or at least 70 years of age, or at least 80 years of age, or at least 90 years of age, or at least 100 years of age. Suitable administration ages may also be during adult years (30-39 years), or middle-aged adult years (40-59 years), or senior adult years (60+ years). In considering average life expectancy, suitable administration for women, who on average live 79 years, may occur after 35% of life, 38% of life, or 50% of life, or 60% of life, or 70% of life, or 80% of life, or 90% of life, or 100% of life. Men on average live 73 years, which would result in suitable administration occurring after 35% of life, 42% of life, or 50% of life, or 60% of life, or 70% of life, or 80% of life, or 90% of life, or 100% of life. However, and especially where a human or non-human mammal leads or attempts to lead an active or even athletic lifestyle, contemplated compositions may also be administered when the subject is a teenager, or at least 20 years of age.

[0060] In one typical embodiment, a nutritional composition comprises a nutritionally acceptable carrier in combination with a plurality of chemically distinct polyphenols from plant materials having a red color, a green color, an orange-yellow color, and a purple-blue color, wherein the chemically distinct polyphenols from the plant materials modulate the health span of a subject.

[0061] Viewed from a different perspective, the inventor therefore also contemplates a method of modulating the health span of a subject that includes a step of orally administering to the subject the compounds and / or compositions presented herein. Most typically, the combination of plant materials modulate the health span of a subject.

[0062] Consequently, it should be appreciated that a plurality of chemically distinct polyphenols as presented herein can be used to modulate health span of a subject. Preferably, the chemically distinct polyphenols are present in plant materials having a red color, a green color, an orange-yellow color, and a purple-blue color, and in especially preferred aspects, thechemically distinct polyphenols delay or prevent chronic diseases, delay or prevent age-related disabilities, preserve or increase locomotor activity, health of thin or thick filaments of cellular muscle fibers, stimulation of brain regions associated with reward or happiness, energy yield of metabolic processes, health of extracellular matrices, intracellular concentration of NAD+ or ATP, mitochondrial biogenesis, and / or glucose uptake into cells, and / or decreases concentration of cortisol in the nervous system.

[0063] In one example, specific blends of selected plant materials common in the Mediterranean diet can be prepared that modulate health span. Preferably, such blends are combinations of colored plant materials that belong to a number (e.g., at least two, at least three, or at least four) of different color groups, and particularly plant materials having a red color, green color, orange / yellow color, and / or purple / blue color. For example, in one embodiment of contemplated compositions, polyphenol-containing products / extracts were obtained from red colored source materials that included an apple extract, a pomegranate extract, tomato powder, and beet root; from green colored source materials that included an olive extract, rosemary extract, green coffee bean extract, and kale; from orange / yellow colored source materials that included an onion extract, a ginger extract, a grapefruit extract, and carrot; and from purple / blue colored source materials that included a grape extract, a blueberry extract, currant, and elderberry, and the particular ingredients and proportions are described in more detail below. Viewed from a different perspective, contemplated compositions will therefore include a large number of polyphenols that below to at least two, or at least three, or at least four different polyphenolic classes, including organic acids, phenolics, flavonols, flavanols, anthocyanins, chlorogenic acids, betacyanins, etc. As will be readily appreciated, the particular choice of a plant material will depend on the desired (polyphenolic) component in the plant material and its effect on health span.

[0064] Of course, it should also be appreciated that the plant materials may be provided in various forms, including whole plant materials or portions thereof (e.g., root, fruit, leaves, etc.) in fresh or dried form, juices or macerates from plant materials or portions thereof in fresh or dried form, and aqueous or aqueous / alcoholic extracts and chromatographic fractions of the aforementioned plant materials. Still further, it should be noted that one or more polyphenols of the plant materials may even be provided as purified (natural isolated or synthetic) chemical entities, typically with 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 materials willbe complex mixtures to provide maintenance or improvement of various aspects of prolonged health span. In other words, the inventive subject matter may be formulated to meet a particular need as related to health span.

[0065] Consequently, and viewed from a different perspective, it should be appreciated that the mechanism of action of contemplated compositions is not limited to a single specific function (e.g., antioxidant) or limited to a specific chemical category (e.g., vitamins), but in fact complementarily and synergistically provides multiple biological activities that modulate health span. As such, contemplated compositions and methods target a variety of biological systems, including energy metabolism, immune function, neural and CNS function, cardiac function, inflammation, etc. In addition, it is contemplated that the plant materials will also provide a variety of micro-nutrients to assist or complement the functions of the polyphenols and other colored pigments present in the compositions.

[0066] As an example of another function or benefit of the contemplated compositions, the beneficial effect on multiple enzymatic targets that are involved with numerous aspects of health and healthy ageing such as ARG-1, ARG-2, SIRT1, BACE1, Cathepsin S, CDK5, IDO1, IDO2, NAMPT, PCSK9, CD47, CD38, JAK1, JAK2, JAK3, CD39, and CD73, and / or Keap / Nrf2 may be observed. Viewed from a different perspective, it should be appreciated that the compositions presented herein are useful to beneficially affect multiple pathways associated with health and healthy ageing via inhibition of key signaling components and / or enzymes in these pathways. Remarkably, the observed modulation of these biomarkers using the compositions presented herein paralleled the profile of biomarkers in individuals that adhered to the Mediterranean diet and individuals with significant longevity.

[0067] Consequently, it should be appreciated that the compositions contemplated herein may be advantageously used as a stand-alone product to modulate health span such as support of proper immune function, support to reduce inflammation, support of normal NAD+ levels, support of cardiac health. In this context, it should be noted that the term ’’support” when used in conjunction with a physiological function or condition is intended to mean prevent decline of one or more components or activities of the component(s) associated with the physiological function or condition, at least partially reverse decline of one or more components or activities of the component(s) associated with the physiological function or condition, maintain normal function of one or more components or activities of the component(s) associated with the physiological function or condition, prevent abnormal overactivity (or over-expression) of oneor more components associated with the physiological function or condition, and / or at least partially reverse abnormal overactivity (or over-expression) of one or more components associated with the physiological function or condition. Alternatively, the compositions contemplated herein may also be combined with other nutritional supplements and / or vitamins to provide beneficial effects otherwise not obtainable with such supplements or vitamins. It should be recognized that the compositions presented herein present a new and different class of health support with a variety of beneficial effects that reach beyond the benefits of a multivitamin formulation.

[0068] In further contemplated aspects of the inventive subject matter, it should be appreciated that the compositions presented herein may be formulated in a variety of forms, and particularly preferred formulations include those in combination with a nutritionally or pharmaceutically acceptable carrier, most preferably for oral administration (however, parenteral administration is also expressly contemplated). Therefore, contemplated compositions can be formulated as solid or a liquid product. For example, where contemplated compositions are formulated as a solid product, suitable product forms include single dosage unit formulations such as capsules, tablets, and powders, while other solid formulations include snack bars, gummies, or other edible products onto which the composition is coated (e.g., onto cereal) or into which the composition is mixed or layered (e.g., into chewing gum). In another examples, where contemplated compositions are formulated as a liquid product, 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 product (e.g., yoghourt, kefir).

[0069] Therefore, contemplated compositions may be provided in bulk, as part of an edible or drinkable product, and / or provided in single dosage units for consumption. Most typically, the daily dosage for contemplated compositions (excluding the 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, or at least 2,000 mg, or at least 2,500 mg, or at least 3,000 mg, or at least 3,500 mg, or at least 4,000 mg, but in most cases below 10,000 mg, or below 8,000 mg, or below 6,000 mg. For example, suitable dosages will be 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 750-1,500 mg or between 750-2,000 mg, or between 1,500-2,500 mg. In still further contemplated aspects, a dosage unit will represent a recommended quantity of the compositions contemplated herein. Therefore, adosage unit may be presented as a single item of consumption (e.g., dosage unit is a single capsule or ready-to drink beverage) or as multiple items of consumption (e.g., dosage unit distributed over 2-4 capsules). Most typically, the compositions contemplated herein will constitute at least 60%, or at least 70%, or at least 80%, or at least 85%, or at least 90%, or at least 95% of a single dosage unit given to a subject.

[0070] As will be readily appreciated, contemplated compositions may further be combined with one or more additional ingredients to impart further desirable health span modulations, and suitable additional ingredients include vitamins (e.g., single vitamins, or vitamin blends such as multivitamin blends), 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 comprising nicotinamide riboside, prebiotics, human milk oligosaccharides), fatty acids, and / or one or more probiotic microorganisms (e.g., Lactobacillus spec. , Bifidobacterium spec., Leukonostoc spec., Saccharomyces boulardii, etc.).

[0071] Suitable vitamins may further include one or more vitamins, and it is contemplated that the vitamins will be present in the compositions presented herein in quantities consistent with common use in the art (which may or may not exceed the FDA recommended RDA for the specific vitamin). Therefore, and among other suitable choices, preferred vitamins include vitamin A, vitamin Bl, vitamin B3 (niacin) or derivative or metabolite thereof (e.g., nicotinamide (also known as niacinamide), nicotinamide riboside, NAD), vitamin B6, vitamin B7 (biotin), vitamin B9 (folate), vitamin B12, vitamin C, vitamin D3, vitamin E, vitamin K2, and CoQlO.

[0072] With respect to the isolated or purified compounds it is generally preferred that such compounds will have known or suspected health span-related activity, and among other suitable choices, especially contemplated compounds include 5-gamma-aminobutyric acid (GABA), alpha lipoic acid (ALA), apoaequorin, one or more betalains (e.g., betaxanthins or betacyanins), caffeine, carnitine, a ceramide, chondroitin and various derivatives thereof (e.g., chondroitin sulfate), a conjugated linoleic acid (CLA), creatine, curcumin, cysteine, a green tea catechin (EGCG, EC, EGC, GCG, GC), cytidine 5 -phosphocholine, dehydroepiandrosterone (DHEA), eicosapentaenoic Acid (EP A), a medium-chain fatty acid (MCFA), a short chain fatty acid (SCFA, typically between 4 and 8 carbon atoms in linear length), one or more omega-3 fatty acids (e.g., a-linolenic acid (ALA), fisetin and its metabolites, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)), a monounsaturated fatty acid (MUFA, andespecially oleic acid and other fatty acids having between 14-20 carbon atoms, typically with a double bond in omega-3, 6, 7, or 9 position), a polyunsaturated fatty acid (PUFA, typically including 18 or 20 carbon atoms with double bond at 3, 6, or 9 position), calcium fructoborate, glucosamine, hyaluronic acid (low as well as high-molecular weight), hydroxyproline, hydroxytryptophan (5-HTP), one or more soy isoflavones (e.g, daidzein, genistein, glycitein, etc.) and their metabolites and glycosides, inositol hexaphosphate, various ketones (e.g., beta hydroxybutyrate, acetoacetate, acetone), a lignan (sesamine, sesamolin, sesaminol), various lecithins, lycopene, lysine, mannose, melatonin, methyl sulfonylmethane (MSM), N- acetyltrosine, theanine, a phytosterol (e. , beta sitosterol), N-acetyl -carnitine, N- acetylcysteine, N-acetyltyrosine, phosphatidylserine, a phytoestrogen, a polycosanol, quercetin, resveratrol, ribose, S-adenosylmethionine (SAM), Tryptophane, tyrosine, uridine-5- monophosphate, ursolic acid, and yohimbine.

[0073] Contemplated elements include all micro- and macronutrients, and especially minerals and elements in complexed form (e.g., as chelate, complexed in a food matrix), covalently bound form (e.g., as organometallic compound), and in ionic form as an inorganic salt (e.g., zinc chloride), a mixed salt (e.g., zinc gluconate), or an oxide (e.g., ZmO). Therefore, and among other choices, boron, calcium, copper, iron, magnesium, molybdenum, manganese, selenium, silicon, strontium, and zinc.

[0074] With respect to complex organic molecules or biological structure selected it is contemplated that especially preferred compounds include collagen (e.g., type II), colostrum, demineralized bone matrix, eggshell membrane, various fibers (soluble and insoluble), various beta glucans, various mushroom polysaccharides (e.g., from turkey tail, lion’s mane, shiitake, cordyceps, reishi, etc.), plant or whey protein, prebiotics (e.g., various fructooligosaccharides, xylooligosaccharides, and human milk oligosaccharides), and keratin. As should be readily appreciated, these molecules and structures may be further processed (e.g., partial or total hydrolysis, size fractionation, etc.).

[0075] In further contemplated embodiments, suitable compounds and / or extracts will include plants, plant parts (e.g, root, fruits, seed, leaves / stems, etc.), and extracts thereof, and it should be noted that the extracts may be crude pressed juices, aqueous or hydroalcoholic extracts, etc., which may be further processed to enrich in one or more desirable components using protocols well known in the art. For example, suitable plants for the compounds or extracts include Aloe vera, Ashwagandha, Bacopa monierii, Black cohosh, Boswellia, Chamomile, Chasteberry,Cissus quadrangular! s, Coffee cherry, Cranberry, Dong Quai, Echinacea, Elderberry, Fenugreek, Garlic, Ginger, Ginkgo biloba, Ginseng, Grapefruit, Hawthorn, Horny goat, Horsetail grass, Hops, Kava, Licorice, Maca, Milk Thistle, Nettle, St. John’s wort, Tongkat Ali, Passion flower, Pumpkin, Pygeum, Red yeast rice, Rhodiola, Saw palmetto, Tribulus, Turmeric, Valerian, Wild yam, and Yohimbe.

[0076] Especially contemplated enzymes for the compounds and / or extracts include various proteases, carbohydrate hydrolases, and lipases. Therefore, suitable enzymes include amylase, galactosidase, lactase, xylanase, bromelain, papain, and lipase. Moreover, suitable additional compounds also include pharmaceutical agents know to extend lifespan or health span such as metformin, acetylsalicylic acid, GLP-1 and GLP-1 analogs, etc.

[0077] With respect to probiotics suitable for use herein, it should be appreciated that all known probiotics are deemed suitable for use herein, and especially contemplated probiotics include bacterial and yeast probiotics. For example, suitable probiotics include various lactobacilli such as Lactobacillus acidophilus, Lactobacillus brevis, Lactobacillus casei, Lactobacillus plantarum, Lactobacillus brevis, Lactobacillus gasseri, Lactobacillus plantarum, Lactobacillus paraplantarum, Lactobacillus coryniformis, Lactobacillus rhamnosus, various bifidobacterial such as Bifidobacterium lactis, Bifidobacterium breve, and Bifidobacterium longum, Leuconostoc me senter oides, Pediococcus pentosaceus, Leuconostoc citreum, Leuconostoc argentinum, Lactococcus sp., and Weissella ssp.

[0078] In further contemplated aspects, suitable quantities may also be determined by the (preferably synergistic) effect of the compounds and / or extracts in combination with the polyphenols and polyphenol mixtures. Therefore, suitable ratios of the compounds and / or extracts to the polyphenols and polyphenol mixtures will be between 1 : 50 to 1 :20, or between 1 :20 and 1 : 10, or between 1 : 10 and 1 :5, or between 1 :5 and 1 :2, or between 1 :2 and 2: 1, or between 2 : 1 and 5 : 1 , or between 5 : 1 and 10 : 1 , or between 10:1 and 20 : 1 , or between 20 : 1 and 50.

[0079] Consequently, and depending on the particular choice of compounds and / or extracts, it should be appreciated that the known or suspected modulations of health span associated with the compounds and extracts will vary considerably.

[0080] Of course, it should be recognized that the compositions according to the inventive subject matter may be administered not only to a human, but also to other non-humanmammals, and especially livestock and companion animals (e.g, dogs, cats, horses). Therefore, where a “subject” is described herein with respect to being administered the compositions disclosed herein, a “subject” may be a human, a mammal, a non-mammal, or C. elegans. Administration will typically be between once daily and three times daily (and in some cases even more) over a period of at least two days, three days, five days, 1 week, 2-4 weeks, 1-3 months, and even longer. Most typically, administration can be performed for a period sufficient to provide at least symptomatic relief of a condition (e.g., pain and swelling associated with inflammation, low energy level, frequent infections, etc.), prophylactically to avoid or help reduce severity of a health condition, and in turn modulate health span.ExamplesRepresentative Composition:

[0081] Unless indicated otherwise, all tests were performed with a defined mixture of selected polyphenol-containing products / extracts common to the Mediterranean diet. The polyphenolcontaining products / extracts were obtained from source materials characterized by 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; and Purple / blue group: grape extract, blueberry extract, currant, and elderberry. Com starch, silica, and sunflower lecithin were used as processing aids. Relative proportions are shown in Table 1 below.Table 1Phytochemical HPLC / MS / MS analysis: An HPLC / MS compositional analysis of the exemplary composition above revealed the following ingredients and proportions where the columns in each of Tables 2-8 indicate the analyte ID (col.l), chemical entity (col.2), M-H (col.3), RT (col.4), peak intensity (col.5), and MS / MS fragments (col.6) Table 2Table 3Table 4Table 5Table 6Table 7Table 8

[0082] The composition was tested on the C. elegans model to investigate its effects on and ability to modulate health span in a variety of conditions.

[0083] In the following experiment, and unless indicated otherwise, the formulation (the exemplary composition) was administered on day 3 of adulthood, after the worms experience an age-related decline in mobility. Age-related declines in mobility most typically occur from day 3 onwards. This timeframe is also more relevant to the time of expected administration to humans, as most interventions to slow aging are targeted to adults from middle-age onwards. The testing concentrations used were 250 pg / mL, 500 pg / mL and 1 mg / mL. This range of concentrations was necessary to attempt to identify the maximum efficacious concentration and / or the concentration at which the effect potentially switches from position to negative. Additionally, the duration of the assay was 14 days to allow for any longer-term effects of the formulation to be detected.

[0084] Assay conditions: A negative (1% DMSO) control is included that is added to all petri dishes. A positive control, sulfamethoxazole, (SMX 16 pg / mL), a compound known to increase C. elegans lifespan (Virk et al., 2012), is also included. For the first part of the health span assessment (Day 0-3), 3.5 cm agar plates were poured without any formulation (the exemplary composition). For the second part of the health span assessment (Day 3-14), 3.5 cm petri disheswere poured with agar media containing a concentration series of the formulation (the exemplary composition), the solvent only control, and the SMX positive control. At day 3 of adulthood, the worms were transferred to the prepared agar plates with the different exemplary concentrations (HP 250 pg / mL, or HP 500 pg / mL, or HP Img / mL) of the composition. There is a break in the data while the worms are being transferred to the agar plates with the different conditions. Plates were then loaded onto the Wormgazer Run and started. After 14 days, the run terminated, and petri dishes were removed and inspected manually for any deviations.

[0085] Data analysis - Fraction Moving: All graphs have negative control that contains only 1% of the solvent (DMSO) control and as positive control, SMX. In worms transferred to SMX on day 3, an initial increase of fraction moving was noticed, followed by a steady decline until the end of the assay. Throughout the assay, the fraction moving in SMX-treated worms was higher than for control. In worms transferred to the formulation on day 3, an initial dosedependent drop in fraction moving was noticed, followed by an increase in fraction moving above control, then a steady decline. Depicted in FIG. 1. At 250 pg / mL, the fraction of worms moving was greater than control up to day 8, and then similar to control until the end of the assay. At 500 pg / mL, the fraction of worms moving was greater than both control and 250 pg / mL up to day 10, and then similar to control until the end of the assay. At 1 mg / mL, the fraction of worms moving was greater than control but lower than 250 pg / mL of formulation between day 4 and day 5, then similar to 250 pg / mL from day 5 to day 9.5, and then lower than control until the end of the assay.

[0086] Results: Between day 4 and day 8, the mean hours moving were significantly greater for worms on all concentrations of the formulation and for SMX compared to the control. Depicted in FIG. 2, mean hours moving for 500 pg / mL of formulation were significantly greater than SMX, and both 250 pg / mL and 1 mg / mL formulations. For the period day 4 to day 13, the effect of 250 and 500 pg / mL and SMX were significant but not the effect of 1 mg / mL of the formulation.

[0087] Data analysis - Mean Speed: The mean speed of moving worms records the average speed of only the worms that are moving at any given time point. Whereas, the mean speed of all worms records the average speed over the whole worm population, including the worms that stop moving over time. It is generated by multiplying the mean speed of moving worms by the fraction of moving worms. In worms transferred to control petri dishes on day 3, mean speed of all worms kept declining until day 10, then plateaued until the end of the assay.Depicted in FIG. 3. In worms transferred to SMX on day 3, mean speed of moving worms was similar to the control, except between day 5 to day 8, when the speed of moving SMX-treated worms was slightly higher. Depicted in FIG. 5. The mean speed of all SMX-treated worms was higher than control from day 4 to day 8. In worms transferred to the formulation on day 3, mean speed of moving worms showed a dose-dependent increase. For example, at 250 pg / mL, the mean speed of moving worms was slightly greater than the control up to day 8, but then similar to the control until the end of the assay. Depicted in FIG. 5. The mean speed of all worms was greater than control up to day 8, then similar to control until the end of the assay. Depicted in FIG. 3. At 500 pg / mL, the mean speed of moving worms was greater than at 250 pg / mL up to day 11, then similar to the control until the end of the assay. The mean speed of all worms was greater than at 250 pg / mL up to day 6, then similar to 250 pg / mL until the end of the assay. At 1 mg / mL, the mean speed of moving worms was greater than at 500pg / mL up to day 8, then similar to 500 pg / mL until the end of the assay. The mean speed of all worms was similar to 500 pg / mL throughout the assay.

[0088] Results: Between day 4 and day 8, the distances moved showed a statistically significant does-response increase from control, to SMX, to 250 pg / mL formulation, to 500 pg / mL formulation. Depicted in FIG. 4. No further increase was observed from 500 pg / mL to 1 mg / mL formulations. Measuring between day 4 and day 13, the distance moved was greatest on the 500 pg / mL formulation. Depicted in FIG. 4.

[0089] Notably, adding worms to the formulation at day 3, a day that corresponds to the later stages of fertility of the worms, can result in a strong effect that makes the worms stay healthier for longer. It has also been observed that a greater effect was present when the formulation was administered at 500 pg / mL. While the effect of Img / mL of the formulation on the speed of moving worms was greater than that observed for 500 pg / mL, the positive effect of 1 mg / mL of formulation on fraction moving was less than that observed for 500 pg / mL. Such a result may suggest that there is a dose-dependent increase in mean speed of moving worms but that at high concentrations, there is an activity that suppresses the fraction moving. Nonetheless, a delayed dosage of 250 pg / mL, or 500 pg / mL, or 1 mg / mL was also efficacious in producing beneficial effects in relation to health span, with 500 pg / mL seeming to produce the greatest benefits.

[0090] Depicted in FIG.6 is a graph showing exemplary results for the fraction of C. elegans moving in response to administration of the composition according to the inventive subjectmatter as compared to the positive and negative controls. As can be readily seen, the worms exposed to the formulation of the inventive subject matter on day 3 showed a significantly higher fraction of movement compared to control up to day 10, and then similar to control at the end of the assay. Additionally, the worms exposed to the formulation showed a higher fraction of movement compared to the positive control from day 5 to day 10, and then similar toward the end of the assay. FIG.7 is a graph depicting exemplary results for the fraction of C. elegans moving in response to administration of the composition according to the inventive subject matter as compared to only the negative control. Again, the worms exposed to the formulation of the inventive subject matter on day 3 showed a significantly higher fraction of movement compared to control up to day 10, and then similar to the negative control at the end of the assay. FIG.8 is a graph depicting exemplary results for the fraction of C. elegans moving in response to administration of the composition according to the inventive subject matter as compared to only the positive control. Notably, even when compared to the well-known positive control standard SMX, it can be seen that worms exposed to the formulation of the inventive subject matter showed a substantially higher fraction of movement compared to the positive control from day 5 to day 8, and then similar toward the end of the assay.

[0091] FIG.9 is a graph depicting exemplary results for mean hours spent moving by C. elegans from day 4 to day 8 in response to administration of the composition according to the inventive subject matter as compared to the positive and negative controls. As shown in FIG.9, the results for mean hours spent moving by worm in response to administration of the composition according to the inventive subject matter was significantly higher than both controls during this time period. FIG.10 is a graph depicting exemplary results for mean hours spent moving by C. elegans from day 4 to day 8 in response to administration of the composition according to the inventive subject matter as compared to only the negative control. Again, the results for mean hours spent moving by worms in response to administration of the composition according to the inventive subject matter was significantly higher than control during this time period. FIG.ll is a graph depicting exemplary results for mean hours spent moving by C. elegans from day 4 to day 8 in response to administration of the composition according to the inventive subject matter as compared to only the positive control. Once more, the results for mean hours spent moving by worms in response to administration of the composition according to the inventive subject matter was significantly higher than positive control during this time period.

[0092] FIG.12 is a bar graph depicting exemplary results for mean hours spent moving by C. elegans from day 4 to day 13 in response to administration of the composition according to the inventive subject matter as compared to the positive and negative controls. As shown, the results for mean hours spent moving by worms in response to administration of the composition according to the inventive subject matter was similar to the positive control, but significantly higher than control during this time period. FIG.13 is a graph depicting exemplary results for mean hours spent moving by C. elegans from day 4 to day 13 in response to administration of the composition according to the inventive subject matter as compared to the negative control. Once again, the exposure to the composition as presented herein resulted in a substantial increase in hours spent moving. FIG.14 is a graph depicting exemplary results for mean hours spent moving by C. elegans from day 4 to day 13 in response to administration of the composition according to the inventive subject matter as compared to the positive control, indicating an at least equal performance to the well-established positive control SMX.

[0093] FIG.15 is a graph depicting exemplary results for mean speed of all C. elegans in response to administration of the composition according to the inventive subject matter as compared to the positive and negative controls. As can be readily seen, the worms exposed to the formulation of the inventive subject matter showed a statistically significant increase from control and even positive control from day 4 to day 8, which then had similar performance past day 8. FIG.16 is a graph depicting exemplary results for mean speed of all C. elegans in response to administration of the composition according to the inventive subject matter as compared to the negative control. FIG.17 is a graph depicting exemplary results for mean speed of all C. elegans in response to administration of the composition according to the inventive subject matter as compared to the positive control. Once more, the effect on mean speed of the worms above positive control was substantial and unexpected.

[0094] Notably, depicted in FIG.18 is a graph depicting exemplary results for mean distance moved by C. elegans from day 4 to day 8 in response to administration of the composition according to the inventive subject matter as compared to the positive and negative controls. As can be readily seen, the worms exposed to the formulation of the inventive subject matter showed a statistically significant increase in distance moved compared to both positive and negative controls during this time period. FIG.19 is a graph depicting exemplary results for mean distance moved by C. elegans from day 4 to day 8 in response to administration of the composition according to the inventive subject matter as compared to the negative control, andFIG.20 is a graph depicting exemplary results for mean distance moved by C. elegans from day 4 to day 8 in response to administration of the composition according to the inventive subject matter as compared to the positive control. These results regarding increase in mean distance moved from day 4 to day 8 are particularly noteworthy, as they demonstrate the significant beneficial effects of the compositions disclosed herein on health span by modulation of locomotor activity.

[0095] Further investigation into the increase in mean distance moved is seen in FIG.21, FIG.22, and FIG.23, which depict exemplary results for mean distance moved by C. elegans from day 4 to day 13 in response to administration of the composition according to the inventive subject matter as compared to the positive and / or the negative controls. FIG.21 is a graph depicting exemplary results for mean distance moved by C. elegans from day 4 to day 13 in response to administration of the composition according to the inventive subject matter as compared to the positive and negative controls. As depicted, the worms exposed to the formulation of the inventive subject matter showed a statistically significant increase in distance moved compared to both positive and negative control during this time period. FIG.22 is a graph depicting exemplary results for mean distance moved by C. elegans from day 4 to day 13 in response to administration of the composition according to the inventive subject matter as compared to the negative control. FIG.23 is a graph depicting exemplary results for mean distance moved by C. elegans from day 4 to day 13 in response to administration of the composition according to the inventive subject matter as compared to the positive control. In this context, it is especially notable that when measuring mean distance moved from day 4 to day 13, the increase in mean distance moved observed in the C. elegans in response to administration of the composition disclosed herein compared to the respective controls remained significant beyond day 8.

[0096] FIG.24 is a graph depicting exemplary results for mean speed of moving C. elegans in response to administration of the composition according to the inventive subject matter as compared to the positive and negative controls. As depicted, the worms exposed to the formulation of the inventive subject matter showed a statistically significant increase in mean speed compared to both positive and negative control. FIG.25 is a graph depicting exemplary results for mean speed of moving C. elegans in response to administration of the composition according to the inventive subject matter as compared to the negative control, and FIG.26 is a graph depicting exemplary results for mean speed of moving C. elegans in response toadministration of the composition according to the inventive subject matter as compared to the positive control.

[0097] In view of the above, it should therefore be appreciated that the contemplated compositions were effective in positively affecting multiple metrics of health span as can be seen form the changes in mean distance moved, mean speed of moving, the fraction worms moving, means hours moving, and mean speed of all worms. Further, the most significant increases in health span were observed until day 8 in the C. elegans lifespan, and sometimes until day 13 (thus extending in some cases throughout the entire lifespan).

[0098] Finally, it should be noted that in some embodiments the combination of the plurality of chemically distinct polyphenols from the plant materials having a red color, a green color, an orange-yellow color, and a purple-blue color may be a synergistic combination. As such, at least two of the polyphenols within one or more of the color groups may have a synergistic effect on at least one aspect of health span, or at least two color groups of the compositions as presented herein may have a synergistic effect on at least one aspect of health span.

[0099] As used herein, the term “administering” a pharmaceutical or nutraceutical composition refers to both direct and indirect administration of the pharmaceutical or nutraceutical composition, wherein direct administration of the pharmaceutical or nutraceutical composition is typically performed by a health care professional (e.g., physician, nurse, dietitian, etc.), and wherein indirect administration includes a step of providing or making available the pharmaceutical or nutraceutical composition to the health care professional or individual in need thereof for direct administration (e.g., via injection, infusion, oral delivery, topical delivery, etc.). It should further be noted that the terms “prognosing” or “predicting” a condition, a susceptibility for development of a disease, or a response to an intended treatment is meant to cover the act of predicting or the prediction (but not treatment or diagnosis of) the condition, susceptibility and / or response, including the rate of progression, improvement, and / or duration of the condition in a subject.

[0100] In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” As used herein, the terms "about" and "approximately", when referring to a specified, measurable value (such as a parameter, an amount, a temporal duration, and the like),is meant to encompass the specified value and variations of and from the specified value, such as variations of + / -10% or less, alternatively + / -5% or less, alternatively + / -1% or less, alternatively + / -0.1% or less of and from the specified value, insofar as such variations are appropriate to perform in the disclosed embodiments. Thus, the value to which the modifier "about" or "approximately" refers is itself also specifically disclosed. The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.

[0101] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0102] As used in the description herein and throughout the claims that follow, the meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise. As also used herein, and unless the context dictates otherwise, the term "coupled to" is intended to include both direct coupling (in which two elements that are coupled to each other contact each other) and indirect coupling (in which at least one additional element is located between the two elements). Therefore, the terms "coupled to" and "coupled with" are used synonymously.

[0103] It should be apparent to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein. The inventive subject matter, therefore, is not to be restricted except in the scope of 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 terms “comprises” and “comprising” should be interpreted as referring to elements, components, or steps in a non-exclusive manner, indicating that the referenced elements, components, or steps may be present, or utilized, or combined with other elements, components, or steps that are not expressly referenced. Where the specification or claims referto at least one of something selected from the group consisting of A, B, C . . . . and N, the text should be interpreted as requiring only one element from the group, not A plus N, or B plus N, etc.

Claims

CLAIMSWhat is claimed is:

1. A nutritional composition for administration to a subject to assist healthy aging of the subject, comprising: a nutritionally acceptable carrier in combination with a plurality of chemically distinct polyphenols from plant materials having a red color, a green color, an orangeyellow color, and a purple-blue color; wherein the composition has been demonstrated to increase health span in a C. elegans in vivo model relative to a control composition not containing the plurality of chemically distinct polyphenols; and wherein the increase in health span is demonstrated in the latter half of lifespan of the in vivo model, and wherein the increase in health span comprises an increase in locomotor activity relative to the control.

2. The composition of claim 1 wherein the red colored plant materials comprise at least one of an apple extract, a pomegranate extract, a tomato powder, and a beet root powder; wherein the green colored plant materials comprise at least one of an olive extract, a rosemary extract, a green coffee bean extract, and a kale powder; wherein the orangeyellow colored plant materials comprise at least one of an onion extract, a ginger extract, a grapefruit extract, and a carrot powder; and wherein the purple-blue colored plant materials comprise at least one of a grape extract, a blueberry extract, a currant powder, and an elderberry powder.

3. The composition of claim 1 wherein the red colored plant materials comprise at least two of an apple extract, a pomegranate extract, a tomato powder, and a beet root powder; wherein the green colored plant materials comprise at least two of an olive extract, a rosemary extract, a green coffee bean extract, and a kale powder; wherein the orangeyellow colored plant materials comprise at least two of an onion extract, a ginger extract, a grapefruit extract, and a carrot powder; and wherein the purple-blue colored plant materials comprise at least two of a grape extract, a blueberry extract, a currant powder, and an elderberry powder.

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

5. The composition of claim 1 wherein the increase of the health span is associated with increase of physical and / or mental function as compared to the control.

6. The composition of claim 1 wherein the health span is in respect to the group consisting of C. elegans, humans, non-human mammals, and / or non-mammals at a later stage in life.

7. The composition of claim 6 wherein the increase in health span has been demonstrated in the final third of the lifespan.

8. The composition of claim 1 wherein the chemically distinct polyphenols are further present in quantities sufficient to(a) delay or prevent a chronic disease;(b) delay or prevent an age-related disability;(d) preserve or increase health of thin or thick filaments of cellular muscle fibers;(e) preserve or increase stimulation of regions of the brain associated with reward or happiness;(f) decrease concentrations of cortisol in the nervous system;(g) preserve or increase energy yield of metabolic processes;(h) preserve or increase health of extracellular matrices;(i) modulation of health span of a subject by preserving or increasing intracellularNAD+ or ATP concentration;(j) preserve or increase mitochondrial biogenesis; and / or(k) preserve or increase glucose uptake into cells.

9. The composition of claim 8 wherein the delay or prevention of the chronic disease includes conditions that are a leading cause of death, that last one year or more, that require ongoing medical attention, and / or that limit daily activities of living.

10. The composition of claim 8 wherein the delay or prevention of the age-related disability includes physical and / or mental impairments that substantially limit one or more significant life activity.

11. The composition of claim 1 wherein the composition is formulated in single dosage units for oral administration.

12. The composition of claim 11 wherein the dosage unit contains between 50 and 1,500 mg of the composition.

13. The composition of claim 11 wherein the dosage unit is formulated as a capsule, a gummy, or a powder.

14. The composition of claim 1 wherein the composition further comprises an additional nutritionally acceptable functional ingredient.

15. The composition of claim 1 wherein the composition has been further demonstrated to inhibit enzymes associated with health decline in aging.

16. The composition of claim 15 wherein the enzymes are ARG-1, ARG-2, SIRT1, BACE1, Cathepsin S, CDK5, IDO1, IDO2, NAMPT, PCSK9, CD47, CD38, JAK1, JAK2, JAK3, CD39, and CD73, and / or Keap / Nrf2, and / or a combination thereof.

17. A method of modulating the health span of a subject, comprising: orally administering to the subject, a composition according to any one of claims 1-16.

18. The method of claim 17 wherein modulation of the health span of the subject is associated with maintenance of physical and / or mental function as compared to a subject not having been administered the composition and / or improvement of physical and / or mental function as compared to the subject not having been administered the composition.

19. The method of claim 17 wherein the subject is selected from the group consisting of C. elegans. a human, and a non-human mammal.

20. The method of claim 17 wherein the composition is orally administered over at least 30 days.

21. The method of claim 17 wherein the composition is orally administered at a daily dose of between 50 and 1,000 mg.

22. The method of claim 17 wherein the composition further comprises an additional nutritionally acceptable functional ingredient.

23. The method of claim 22 wherein the additional nutritionally acceptable functional ingredient is co-administered in the same dosage unit.

24. A nutritional composition, comprising a plurality of chemically distinct polyphenols, for modulation of a health span of a subject, wherein the chemically distinct polyphenols are present in plant materials having a red color, a green color, an orange-yellow color, and a purple-blue color, wherein the composition has been demonstrated to increase health span in a C. elegans in vivo model relative to a control composition not containing the plurality of chemically distinct polyphenols; and wherein the increase in health span is demonstrated in the latter half of lifespan of the in vivo model, and wherein the increase in health span comprises an increase in locomotor activity relative to the control.

25. The use of claim 24 wherein modulation of the health span of a subject is associated with maintenance of physical and / or mental function as compared to subject not having been administered the composition and / or improvement of physical and / or mental function as compared to subject not having been administered the composition.

26. The use of claim 24 wherein the subject is selected from the group consisting of C. elegans, a human, and a non-human mammal.

27. The use of claim 24 wherein the increase in health span is demonstrated in the latter third of lifespan of the in vivo modell.

28. The use of claim 24 wherein the combination of plant materials is present in quantities sufficient to(a) delay or prevent a chronic disease;(b) delay or prevent an age-related disability;(d) preserve or increase health of thin or thick filaments of cellular muscle fibers;(e) preserve or increasestimulation of regions of the brain associated with reward or happiness;(f) decrease concentrations of cortisol in the nervous system;(g) preserve or increaseenergy yield of metabolic processes;(h) preserve or increasethe health of extracellular matrices;(i) preserve or increaseintracellular NAD+ or ATP concentration;(j) preserve or increasemitochondrial biogenesis; and / or(k) preserve or increaseglucose uptake into cells.

29. The use of claim 28 wherein the delay or prevention of the chronic disease includes conditions that are a leading cause of death, that last one year or more, that require ongoing medical attention, and / or that limit daily activities of living.

30. The use of claim 28 wherein the delay or prevention of the age-related disability includes physical and / or mental impairments that substantially limit one or more significant life activity.

31. The use of claim 24 wherein the polyphenols are provided in the form of the plant materials.

32. The use of claim 24 or claim 31 wherein the red colored plant materials are selected from the group consisting of an apple extract, a pomegranate extract, a tomato powder, and a beet root powder; wherein the green colored plant materials are selected from the group consisting of an olive extract, a rosemary extract, a green coffee bean extract, and a kale powder; wherein the orange-yellow colored plant materials are selected from the group consisting of an onion extract, a ginger extract, a grapefruit extract, and a carrot powder; and wherein the purple-blue colored plant materials are selected from the group consisting of a grape extract, a blueberry extract, a currant powder, and an elderberry powder.

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