Compositions of n 1- dihydrocaffeoyl-n 10- caffeoylspermidine for maintaining and / or improving bone health

Abstract

Described herein are compositions for maintaining and / or improving bone health in a subject, such as an aging subject, including N1-dihydrocaffeoyl-N10-caffeoylspermidine and an additive. Also, described herein are methods for maintaining and / or improving bone health in a subject, such as an aging subject. Also, described here are methods for preventing and / or treating bone diseases in a subject, such as an aging subject.

Description

COMPOSITIONS OF V'-l)lin i)R()( I I E() L- V"'- CAFFEOYLSPERMIDINE FOR MAINTAINING AND / OR IMPROVING BONE HEALTH RELATED APPLICATIONS

[0001] The present patent document claims the benefit of priority to Chinese Patent Application No. 202510241348.8, filed February 28, 2025, which is hereby incorporated by reference.BACKGROUND

[0002] The present application relates to compositions of compounds, as well as uses thereof for maintaining and / or improving bone health, and / or treating and / or preventing bone diseases in subjects, e.g., aging subjects.

[0003] Spermidine is the most abundant polyamine in a majority of different human tissues. Spermidine results from amino acid metabolism and includes essential cellular functions, including regulation of cell growth, proliferation, tissue regeneration, DNA and RNA stabilization, enzymatic modulation, regulation of translation, and autophagy.Further, spermidine exhibits anti-inflammatory and antioxidant properties, enhances mitochondrial metabolic function and respiration, promotes chaperone activity, and improves proteostasis. Intracellular spermidine concentrations decline during the normal course of aging. Conversely, the administration of spermidine is linked to an increase in the survival of yeast, worms, flies, and human immune cells, and to a reduction in age-associated mortality in mice. Very high spermidine concentrations in sperm fluid may prevent cell senescence and confer long-term survival to germ cell lines. Spermidine homeostasis is influenced by nutritional uptake, intestinal sources, endogenous biosynthesis, degradation, and active transporter systems between compartments.

[0004] Many anti-aging properties of spermidine have been causally linked to the capacity of spermidine to ensure proteostasis through the stimulation of cytoprotective macroautophagy. Spermidine induces autophagy through the inhibition of several acetyltransferases. The optimal concentration of spermidine in humans to maintain optimal autophagy levels for healthy aging is a topic of ongoing investigation. The age-induced spermidine decline may involve the alteration of one or several of the distinctfactors that determine systemic availability of spermidine. Spermidine bioavailability is determined by different sources of this polyamine: (i) cellular biosynthesis, (ii) production by intestinal microorganisms, and (iii) nutritional supply, as well as (iv) catabolism and (v) urinary excretion.

[0005] Lycium ruthenicum is a flowering plant commonly known as “Russian box thorn.” L. ruthenicum is a member of Solanaceae Juss. that can be found in Central Asia, southern Russia, northwest China, Northern India, and Pakistan. L. ruthenicum grows in Nubra Valley in India, and at elevations of 400 - 3000 meters in saline deserts, sands, and roadsides in Central Asia and northwest China. An extract L. ruthenicum is a source of spermidine.

[0006] Bone diseases, including osteoporosis, Paget’s disease of the bone, osteogenesis imperfecta, rickets, osteomalacia, renal osteodystrophy, and hyperparathyroidism, remain a major public health problem in this country. They cause approximately 1.5 million fractures each year, fractures that impose tremendous physical and emotional costs on those who suffer them and their family members. They represent a significant financial burden to both individuals and society at large. Many of these costs are avoidable, since much is already known about how to effectively prevent, diagnose, and treat bone disease throughout the life span. However, much of what could be done to reduce this burden is not being done today, due to a lack of awareness of the problem and the failure to apply current knowledge. In fact, many in the public and even the medical community believe that osteoporosis is a natural consequence of aging and that nothing can be done about it.

[0007] Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in fracture risk. It is the most common reason for a broken bone among the elderly. Bones that commonly break include the vertebrae in the spine, the bones of the forearm, the wrist, and the hip. Until a broken bone occurs there are typically no symptoms. Bones may weaken to such a degree that a break may occur with minor stress or spontaneously. After the broken bone heals, some people may have chronic pain and a decreased ability to carry out normal activities.

[0008] Osteoporosis may be due to lower-than-normal maximum bone mass and greater-than-normal bone loss. Bone loss increases after the menopause due to lower levels of estrogen, and after “andropause” due to lower levelsof testosterone. Osteoporosis may also occur due to a number of diseases or treatments, including alcoholism, anorexia, hyperthyroidism, kidney disease, and surgical removal of the ovaries. Certain medications increase the rate of bone loss, including some antiseizure medications, chemotherapy, proton pump inhibitors, selective serotonin reuptake inhibitors, and glucocorticosteroids. Smoking and getting an inadequate amount of exercise are also risk factors. Osteoporosis is defined as a bone density of 2.5 standard deviations below that of a young adult. This is typically measured by dual-energy X-ray absorptiometry (DXA or DEXA) (“Prevention and management of osteoporosis,” World Health Organization Technical Report Series, World Health Organization, Vol. 921, pp. 1-164 (2003))

[0009] Although osteoporosis can be defined as low bone mass leading to structural fragility, it is difficult to determine the extent of the condition described in these qualitative terms. Using the World Health Organization’s quantitative definition based on bone density measurement, there are roughly 10 million Americans over age 50 with osteoporosis and an additional 34 million with low bone mass or “osteopenia” of the hip, which puts them at risk for osteoporosis, fractures, and their potential complications later in life (National Osteoporosis Foundation. America’s Bone Health: The State of Osteoporosis and Low Bone Mass in Our Nation. Washington, DC: National Osteoporosis Foundation (2002)).

[0010] Left unchecked, the bone health status of Americans is only going to get worse, due primarily to the aging of the population. In fact, the prevalence of osteoporosis and osteoporotic-related fractures will increase significantly unless the underlying bone health status of Americans is significantly improved. While much less is known about the prevalence and treatment of other bone diseases, they too can have a severe impact on the health and well-being of those who suffer from them, especially if they are not diagnosed and treated in a timely manner.

[0011] While aging cannot be prevented, treatment can reduce levels of deformity and suffering due to osteoporosis. Further research on osteoporosis is likely to yield additionalimprovements in the treatment of these bone diseases and may even yield insights into how they can be prevented.

[0012] Osteoporosis has no symptoms and the person usually does not know that they have osteoporosis until a bone is broken. Osteoporotic fractures occur in situations where healthy people would not normally break a bone; they are therefore regarded as fragility fractures. Examples of situations where people would not normally break a bone include a fall from standing height, normal day-to-day activities such as lifting, bending, or coughing.

[0013] As well as susceptibility to breaks and fractures, osteoporosis can lead to other complications. Bone fractures from osteoporosis can lead to disability and an increased risk of death after the injury in elderly people. Osteoporosis can decrease the quality of life, increase disabilities, and increase the financial costs to health care systems.

[0014] Proper nutrition, physical exercise, including physical exercise prescription for elderly, physical therapy and hormone therapy have been used for prevention of osteoporosis and improving bone health.

[0015] Nonetheless, there still exists a need for composition and methods for improving bone health. Compositions including dicaffeoylspermidine derivatives to improve bone health would represent a useful contribution to the art.SUMMARY

[0016] In an embodiment, described herein is a composition for improving bone health in a subject comprising Al-dihydrocaffeoyl-Al0-caffeoylspermidine and an additive. The composition maintains and / or improves bone health in a subject administered the composition relative to a subject not administered the composition by: increasing bone volume fraction (BVF), increasing trabecular thickness (Tb.Th), decreasing trabecular separation (Tb.Sp), increasing trabecular number (Tb.N), increasing bone mineral density (BMD), increasing bone mineral content (BMC); and / or increasing bone surface density (BS / TV) expression. The subject is an aging subject. The composition increases spermidine content in the subject within 1 hour after administration of the composition. The composition can comprise at least 10% by weight of N1-dihydrocaffeoyl-M°-caffeoylspermidine, or at least 25% by weight of N1-dihydrocaffeoyl-A10-caffeoylspermidine, or at least 45% by weight of 7V1-dihydrocaffeoyl-A10-caffeoylspermidine. The composition is formulated for oral administration, wherein the dosage of A1-dihydrocaffeoyl-A10-caffeoylspermidine is in the range of 1.5 mg / kg to 50 mg / kg of body weight of the subject. The composition may be in a form of a tablet, a ready-to-drink beverage, a concentrate, powder, granules, gel, solid, semi-solid, frozen liquid, lozenges or hard candies, dissolving strips, and chewing gum. The composition may be a nutritional supplement.

[0017] Another embodiment relates to the use of the composition comprising N1-dihydrocaffeoyl-7V10-caffeoylspermidine and an additive to improve bone health in the subject.

[0018] Yet another embodiment relates to a method for maintaining and / or improving bone health in an aging subject, comprising administering to the subject an effective amount of a composition comprising Al-dihydrocaffeoyl-Al0-caffeoylspermidine and an additive. The composition maintains and / or improves bone health in an aging subject relative to an aging subject not administered the composition by: increasing bone volume fraction (BVF), increasing trabecular thickness (Tb.Th), decreasing trabecular separation (Tb.Sp), increasing trabecular number (Tb.N), increasing bone mineral density (BMD), increasing bone mineral content (BMC); and / or increasing bone surface density (BS / TV) expression. The composition increases spermidine content in the subject within 1 hour after administration of the composition. The composition comprises at least 10% by weight of 7V1-dihydrocaffeoyl-7V10-caffeoylspermidine, or at least 25% by weight of N1-dihydrocaffeoyl-7V10-caffeoylspermidine, or at least 45% by weight of N1-dihydrocaffeoyl-7V10-caffeoylspermidine. The composition is administered orally, wherein the dosage of 7V1-dihydrocaffeoyl-7V10-caffeoylspermidine is in the range of 1.5 mg / kg to 50 mg / kg of body weight of the subject.

[0019] Yet another embodiment relates to a method for preventing and / or treating bone diseases in a subject comprising administering to the subject an effective amount of a composition comprising 7V1-dihydrocaffeoyl-7V10-caffeoylspermidine and an additive. The bone disease is osteoporosis, Paget’s disease of the bone, osteogenesis imperfecta, rickets, osteomalacia, renal osteodystrophy, or hyperparathyroidism. The composition comprises at least 10% by weight of 7V1-dihydrocaffeoyl-7V10-caffeoylspermidine, or atleast 25% by weight of N1-di hydrocaffeoy I -Nl0-caffeoy I spermidine, or at least 45% by weight of A%dihydrocaffeoyl-Al0-caffeoyl spermidine. The composition is administered orally, wherein the dosage of M-dihydrocaffeoyl-.V10-caffeoylsperrnidine is in the range of 1.5 mg / kg to 50 mg / kg of body weight of the subject. The composition is a nutritional supplement.

[0020] Further areas of applicability will become apparent from the description provided herein. It should be understood that the description and specific examples are intended for purposes of illustration only and are not intended to limit the scope of the present disclosure.BRIEF DESCRIPTION OF THE DRAWINGS

[0021] In order that the present disclosure may be well understood, there will now be described various forms thereof, given by way of example, reference being made to the accompanying drawings. The components in the figures are not necessarily to scale. Moreover, in the figures, like-referenced numerals designate corresponding parts through the different views.

[0022] FIG. 1 illustrates the structure of Nl-dihydrocaffeoyl-Nl0-caffeoylspermidine.

[0023] FIG. 2 depicts images of bone in SAMP8 vehicle group and N1-dihydrocaffeoyl-Nl0-caffeoylspermidine treated group: (a) images of cortical bone, (b) images of trabecular, (c) merge of cortical bone and trabecular, and (d) images of bone.

[0024] FIG. 3 illustrates depicts graphs of bone analysis: (a) bone volume fraction (BV7TV), (b) trabecular thickness (Tb.Th), (c) trabecular separation (Tb.Sp), (d) trabecular number (Tb.N), (e) bone mineral density (BMD), (f) bone mineral content (BMC), (g) bone surface density (BS / TV). Values are represented as the means ± SE. * indicates p < 0.05 compared with SAMP8 group. ** indicates p < 0.001 compared with SAMP8 group.DETAILED DESCRIPTION OF THE DRAWINGS AND THE PRESENTLY PREFERRED EMBODIMENTS

[0025] The present invention will now be described more fully herein after. For the purposes of the following detailed description, it is to be understood that the invention may assume various alternative variations and step sequences, except where expresslyspecified to the contrary. Thus, before describing the present invention in detail, it is to be understood that this invention is not limited to particularly exemplified embodiments that may of course, vary. The following description is merely exemplary in nature and is not intended to limit the present disclosure, applications, or uses.

[0026] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meanings as those generally understood by those skilled in the art to which the present disclosure pertains. Such terms as those defined in a generally used dictionary are to be interpreted as having meanings equal to the contextual meanings in the relevant field of art.

[0027] Definitions

[0028] The uses of the terms “a” and “an” and “the” and similar referents in the context of describing the present disclosure (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The use of the term “plurality of’ is defined by the Applicant in the broadest sense, superseding any other implied definitions or limitations hereinabove or hereinafter unless expressly asserted by Applicant to the contrary, to mean a quantity of more than one. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.

[0029] The terms “preferred” and “preferably” refer to embodiments of the invention that may afford certain benefits, under certain circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful and is not intended to exclude other embodiments from the scope of the invention.

[0030] As used herein, “around,” “about” or “approximately” shall generally mean within 20 percent, preferably within 10 percent, and more preferably within 5 percent of a given value or range. Numerical quantities given herein are approximate; meaning thatthe terms “around,” “about” or “approximately” can be inferred if not expressly stated. When the term “about” is used in describing a value or an endpoint of a range, the disclosure should be understood to include both the specific value and endpoint referred to.

[0031] As used herein the terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The present description also contemplates other examples “comprising,” “consisting of,” and “consisting essentially of,” the examples or elements presented herein, whether explicitly set forth or not.

[0032] In describing elements of the present disclosure, the terms 1st, 2nd, first, second, A, B, (a), (b), and the like may be used herein. These terms are only used to distinguish one element from another element, but do not limit the corresponding elements irrespective of the nature or order of the corresponding elements.

[0033] The term “composition” is used herein to describe a formulation that includes at least A1-dihydrocaffeoyl-A10-caffeoylspermidine. The term refers to a comestible formulation that may be suitable for oral ingestion by the subject (e.g., an aging human subject). Exemplary compositions that include but are not limited to: sprays (e.g., aerosols), powders, chewing gum, ingestible solids, gels, aqueous beverages, dry powder (e.g., a powder that can be directly consumed or that can be reconstituted with liquid to provide a beverage as defined herein), nutritional bars, lozenges, tablets, capsules, wafers, pastes, and the like. Other compositions are described herein. In certain preferred embodiments, the composition described herein is in a form of tablets.

[0034] As used herein, the terms “A1-dihydrocaffeoyl-A10-caffeoylspermidine” or “DHCS” refer to a compound of L. ruthenicum fruits having the Chemical Abstracts Service (“CAS”) Registry No. 121850-61-1, a molecular formula of C25H33N3O6, and the following structural formula:A^1-di hydrocaffeoy I -A^'°-caffeoy I spermidine may also be referred to as “ / V'-hydrocaffeoyl- / Vl0-Caffeoylspermidine.”

[0035] In an example, a composition may include at least about 0.5% by weight of 7V1-dihydrocaffeoyl-7V10-caffeoylspermidine, or at least about 1.0% by weight, or at least about 1.5% by weight, or at least about 2.0% by weight, or at least about 2.5% by weight, or at least about 3.0% by weight, or at least about 3.5% by weight, or at least about 4.0% by weight, or at least about 4.5% by weight, or at least about 5.0% by weight, or at least about 5.5% by weight, or at least about 6.0% by weight, or at least about 6.5% by weight, or at least about 7.0% by weight, or at least about 7.5% by weight, or at least about 8.0% by weight, or at least about 8.5% by weight, or at least about 9.0% by weight, or at least about 9.5% by weight, or at least about 10.0% by weight, or at least about 10.5% by weight, or at least about 11.0% by weight, or at least about 11.5% by weight, or at least about 12.0% by weight, or at least about 12.5% by weight, or at least about 13.0% by weight, or at least about 13.5% by weight, or at least about 14.0% by weight, or at least about 14.5% by weight, or at least about 15.0% by weight, or at least about 15.5% by weight, or at least about 16.0% by weight, or at least about 16.5% by weight, or at least about 17.0% by weight, or at least about 17.5% by weight, or at least about 18.0% by weight, or at least about 18.5% by weight, or at least about 19.0% by weight, or at least about 19.5% by weight, or at least about 20.0% by weight, or at least about 20.5% by weight, or at least about 21.0% by weight, or at least about 21.5% by weight, or at least about 22.0% by weight, or at least about 22.5% by weight, or at least about 23.0% by weight, or at least about 23.5% by weight, or at least about 24.0% by weight, or at least about 24.5% by weight, or at least about 25.0% by weight, or at least about 25.5% by weight, or at least about 26.0% by weight, or at least about 26.5% by weight, or at least about 27.0% by weight, or at least about 27.5% by weight, or at least about 28.0% by weight, or at least about 28.5% by weight, or at least about 29.0% by weight, at leastabout 29.5% by weight, at least about 30.0% by weight, at least about 35.0% by weight, at least about 40.0% by weight, at least about 45.0% by weight, or at least about 50.0% by weight, or more. In certain embodiments, the dosage of / V'-dihydrocaffeoyl-ZV10-caffeoylspermidine may be in the range of 1.5 mg / kg to 50 mg / kg of body weight. In certain other embodiments, the dosage of A4-dihydrocaffeoyl V10-caffeoylspermidine may be at least 1.5 mg / kg of body weight; at least 2 mg / kg of body weight; at least 3 mg / kg of body weight; at least 4 mg / kg of body weight; at least 5 mg / kg of body weight; at least 6 mg / kg of body weight; at least 7 mg / kg of body weight; at least 8 mg / kg of body weight; at least 9 mg / kg of body weight; at least 10 mg / kg of body weight; at least 11 mg / kg of body weight; at least 12 mg / kg of body weight; at least 13 mg / kg of body weight; at least 14 mg / kg of body weight; at least 15 mg / kg of body weight; at least 16 mg / kg of body weight; at least 17 mg / kg of body weight; at least 18 mg / kg of body weight; at least 19 mg / kg of body weight; at least 20 mg / kg of body weight; at least 21 mg / kg of body weight; at least 22 mg / kg of body weight; at least 23 mg / kg of body weight; at least 24 mg / kg of body weight; at least 25 mg / kg of body weight; at least 16 mg / kg of body weight; at least 27 mg / kg of body weight; at least 28 mg / kg of body weight; at least 29 mg / kg of body weight; at least 30 mg / kg of body weight; at least 31 mg / kg of body weight; at least 32 mg / kg of body weight; at least 33 mg / kg of body weight; at least 34 mg / kg of body weight; at least 35 mg / kg of body weight; at least 36 mg / kg of body weight; at least 37 mg / kg of body weight; at least 38 mg / kg of body weight; at least 39 mg / kg of body weight; at least 40 mg / kg of body weight; at least 41 mg / kg of body weight; at least 42 mg / kg of body weight; at least 43 mg / kg of body weight; at least 44 mg / kg of body weight; at least 45 mg / kg of body weight; at least 46 mg / kg of body weight; at least 47 mg / kg of body weight; at least 48 mg / kg of body weight; at least 49 mg / kg of body weight; or at least 50 mg / kg of body weight; or more. In certain preferred embodiments, the dosage is 30 mg / kg of body weight.

[0036] As used herein, the terms “effective amount” or “pharmaceutically or therapeutically effective amount” refer to the amount of the active ingredient(s), the extract(s), to be administered orally to the subject to trigger the desired effect (e.g., maintaining and / or improving bone health) without or causing minimal toxic adverse effect against the subject, and / or without undesirable side-effects. One skilled in the artshould know that the effective amount can vary from one individual to another due to the external factors such as age, sex, diseased state, races, body weight, formulation of the composition, availability of other active ingredients in the formulation, and so on. For instance, as shown below in the Examples, an effective ratio of Ad-dihydrocaffeoyl-A10-caffeoylspermidine to mouse feed was 25 mg Al-dihydrocaffeoyl-Al0-caffeoylspermidine mixed in 1 kg of mice feed (0.25 g / kg ).

[0037] The term “bone health” refers to the strength and condition of the skeletal system of a subject, e.g., an aging subject, which is important for mobility, preventing fractures, and overall well-being. Healthy bones are dense and strong and are made of living tissue that is constantly being renewed. Healthy bones provide the body with a frame that allow for mobility and for protection against injury. Bones serve as a storehouse for minerals that are vital to the functioning of many other life-sustaining systems in the body. Unhealthy bones, however, perform poorly in executing these functions and can lead to debilitating fractures. Bones naturally become weaker and less dense with age. Women have less bone tissue than men and are at greater risk of osteoporosis.

[0038] The terms “improved,” “improving,” “improved” in the context of the effect A1-dihydrocaffeoyl-A10-caffeoylspermidine on bone health means that compared with the “vector group” or “blank group,” the treatment group (i.e., the group being administered the described composition comprising TV1-dihydrocaffeoy 1- / Vl0-caffeoy 1 spermidine) was statistically significant, and the statistical result P value was <0.001 or <0.05 compared to blank group. For example, as shown herein, compared with “blank group” (e.g., SAMP8 mice ), Al-dihydrocaffeoyl-Al0-caffeoylspermidine treated group (e.g., SAMP8 mice administrated with A1-dihydrocaffeoyl-A10-caffeoylspermidine) showed a significantly increased bone volume fraction (BVF), a significantly increased trabecular thickness (Tb.Th), a significantly decreased trabecular Separation (Tb.Sp), a significantly increased trabecular number (Tb.N), a significantly increased bone mineral density (BMD), a significantly increased bone mineral content (BMC); and / or a significantly increased bone surface density (BS / TV) expression (Figure 3).

[0039] The terms “increasing” and “increased” in the context of the effect N1-dihydrocaffeoyl-Al0-caffeoylspermidine (e.g., SAMP8 mice administrated with A1-dihydrocaffeoyl-A10-caffeoylspermidine) on bone means that compared with the “vector group” or “blank group” (e.g., SAMP8 mice), the treatment with the described composition comprising A1-dihydrocaffeoyl-A10-caffeoylspermidine resulted in statistically significant increase, and the statistical result P value was <0.05 or <0.001 for the studied indicators of bone health (i.e., bone volume fraction, trabecular thickness, trabecular number, bone mineral density, bone mineral content, and bone surface density).

[0040] The terms “decreasing” or “decreased” in the context of the effect N1-dihydrocaffeoyl-Al0-caffeoylspermidine on bone means that compared with the “vector group” or “blank group,” the treatment with the described composition comprising N1-dihydrocaffeoyl-Al0-caffeoylspermidine resulted in a statistically significant decrease, and the statistical result P value was <0.05 for the studied indicator of bone health, e.g., trabecular separation.

[0041] The term “additive” means a substance which is added in the formulation along the therapeutic agent to impart specific qualities in the formulation. Additives have little or no therapeutic value but are necessary in the manufacture of various dosage forms. Additives include excipients and carriers.

[0042] The term “excipient” refers to a substance which helps to absorb any of the components of the composition, stabilizes said components or helps in the preparation of the composition. Thus, excipients can have the function of keeping the components bound together, such as for example starches, sugars or celluloses, a sweetening function, a colorant function, the function of protecting the medicament from the external medium, such as for example isolating it from the air and / or moisture, a filler function for a tablet, capsule or any other form of formulation, such as for example di basic calcium phosphate, a disintegrating function to facilitate the dissolution of the components and their absorption in the intestine, without excluding other types of excipients not mentioned in this paragraph. Therefore, the term “excipient” is defined as the substance which, included in dosage forms, is added to the active substances or their associations to enable their preparation and stability, modify their organoleptic properties or determine the physical / chemical properties of the pharmaceutical composition and its bioavailability. The “pharmaceutically acceptable” excipient should not interact with the activity of theactive compounds of the described composition. Examples of excipients are binding agents, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, and colorants. More specific, non-limiting examples of acceptable excipients are starches, sugars, xylitol, sorbitol, calcium phosphate, steroid fats, talc, silica, or glycerin, among others.

[0043] By “administering” and “administration” is meant a mode of delivery. A daily dosage can be divided into one, two, three or more doses in a suitable form to be administered one, two, three or more times throughout a time period, such as a day, week, month.

[0044] By ‘ ‘treating” or “ameliorating” or “alleviating” is meant administering a composition for therapeutic purposes or administering treatment to a subject already suffering from a disorder to improve the subject's condition. As compared with an equivalent untreated control, such amelioration or degree of treatment is at least 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100%, as measured by any standard, suitable technique.

[0045] As described herein, the term “subject” is equivalent to the terms “individual” and “patient” whereby the terms can be used interchangeably. “Subject” means any animal belonging to any species. Examples of subjects include, but are not limited to, commercially bred animals such as birds (hens, ostriches, chickens, geese, partridges, etc.), rabbits, hares, domestic animals (dogs, cats, etc.), livestock such as sheep and goat livestock, pigs, wild boars, horses, ponies, etc., and cattle (bulls, oxen, etc.). In a particular embodiment, the subject is a mammal, preferably a primate, more preferably a human being of any race, sex, or age. In certain preferred embodiments, the subject is an aging subject.

[0046] The term “aging subject” means a subject that exhibits the time-related deterioration of the physiological functions necessary for survival and fertility. The age at which aging starts varies, and can depend on several factors, including genetics, lifestyle, and environment. For example, from around the age of twenty-five for humans the first signs of aging start to become apparent on the surface of the skin; muscle strength and endurance typically peak in the mid-thirties, and then gradually decline. For human subjects, bones start to age around age 35, when bone breakdown starts to occur faster than bone replacement. Bones are thickest and strongest in early adulthood, until latetwenties. From about age 25 to age 50, bone density tends to stay stable. After age 50, bone breakdown outpaces bone formation. (Osteoporosis: What You Need to Know as You Age I Johns Hopkins Medicine.) The body is continually removing old bone and replacing it with new bone through a process called remodeling. Up to about age 40, all the bone removed is replaced. After age 40, less bone is replaced. In the context of this invention, an aging subject is a subject that is at least 35 years old; preferably, at least 40 years old; more preferably, at least 45 years old; more preferably, at least 50 years old.

[0047] Compositions

[0048] In one embodiment, described herein are compositions for maintaining and / or improving bone health in a subject, the compositions comprising A'-dihydrocaffeoyl-A10-caffeoylspermidine and an additive.

[0049] In another embodiment, described herein are compositions for maintaining and / or improving bone health in an aging subject, the compositions comprising N1-dihydrocaffeoyl-Al0-caffeoylspermidine and an additive.

[0050] In one embodiment, the described compositions maintain and / or improve bone health in a subject, such as an aging subject, relative to a subject not administered the compositions by at least one of: increasing bone volume fraction (BVF), increasing trabecular thickness (Tb.Th), decreasing trabecular Separation (Tb.Sp), increasing trabecular number (Tb.N), increasing bone mineral density (BMD), increasing bone mineral content (BMC), and / or increasing bone surface density (BS / TV) expression.

[0051] In one embodiment, the described compositions can comprise at least 10% by weight of Al-dihydrocaffeoyl-Al0-caffeoylspermidine; alternatively, at least 25% by weight of Al-dihydrocaffeoyl-Al0-caffeoylspermidine; or alternatively, at least 45% by weight of Al-dihydrocaffeoyl-Al0-caffeoylspermidine.

[0052] In one embodiment, the compositions can be formulated for oral administration.

[0053] In an example, for oral administration, the described A'-dihydrocaffeoyl-A10-caffeoylspermidine compositions may be formulated as ready-to-drink beverages, concentrates (e.g., syrups), dry compositions (e.g., powders, granules, or tablets that may be reconstituted with a liquid (e.g., with water), gels, solids, semi-solids (e.g., ice cream, pudding, or yogurt), frozen liquids (e.g., ice pops), lozenges or hard candies, dissolvingstrips (e.g., an edible strip containing pullulan and compositions of the invention), and chewing gum. Other knows formulations are also contemplated.

[0054] In an example, for oral administration, A^-dihydrocaffeoyl-TV10-caffeoylspermidine may be combined with one or more solid inactive ingredients for the preparation of tablets, capsules, pills, powders, granules, or other suitable solid dosage forms of a composition. For example, A71-dihydrocaffeoyl-A710-caffeoylspermidine may be combined with at least one excipient selected from the group consisting of fillers, binders, humectants, disintegrating agents, solution retarders, absorption accelerators, wetting agents, absorbents, or lubricating agents. Other useful excipients may include magnesium stearate, calcium stearate, mannitol, xylitol, sweeteners, starch, carboxymethylcellulose, microcrystalline cellulose, silica, gelatin, silicon dioxide, and the like.

[0055] The term “preparation” may be intended to include the formulation of 7V1-dihydrocaffeoyl-7V10-caffeoylspermidine with encapsulating material as a carrier, providing a capsule in which the extract or compound, with or without other carriers, is surrounded by a carrier, which is thus in association with N^dihydrocaffeoyl-N10-caffeoylspermidine.

[0056] In certain examples in which a preparation includes TV^dihydrocaffeoyl-TV10-caffeoylspermidine in the form of a powder or a tablet, the powder or the tablet may include an extract or compound of the present disclosure in an amount of from about 5 weight %, or from about 10 weight %, or from about 15 weight %, or from about 20 weight %, or from about 25 weight %, or from about 30 weight %, or from about 35 weight %, or form about 40 weight %, or form about 45 weight %, or from about 50 weight %, or from about 55 weight %, or from about 60 weight %, or from about 65 weight %, to about 70 weight %; or from about 10 weight % to about 15 weight %, or to about 20 weight %, or to about 25 weight %, or to about 30 weight %, or to about 35 weight %, or to about 40 weight %, or to about 45 weight %, or to about 50 weight %, or to about 55 weight %, or to about 60 weight %, or to about 65 weight %, or from any one of the above minima or any one of the above maxima, including any subranges therebetween. In certain embodiments, the dosage of TV'-dihydrocaffeoyl-TV10-caffeoylspermidine may be in the range of 1.5 mg / kg to 50 mg / kg of body weight or including any subranges therebetween.

[0057] Examples of suitable carriers may include microcrystalline cellulose, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, and cocoa butter. Examples of other excipients may include magnesium stearate, stearic acid, talc, and silicon dioxide.

[0058] In certain examples, a binder may be included in a composition. Examples of binders may include disaccharides such as sucrose or lactose; polysaccharides and derivatives thereof such as starches, cellulose, modified cellulose (such as microcrystalline cellulose or cellulose ethers, such as hydroxypropyl cellulose); sugar alcohols such as xylitol, sorbitol, or mannitol; proteins such as gelatin; synthetic polymers such as polyvinylpyrrolidone (PVP) or a polyethylene glycol (PEG).

[0059] In certain examples, a humectant may be included in a composition. Examples of humectants may include propylene glycol, hexylene glycol, butylene glycol, aloe vera gel, an alpha hydroxy acid such as lactic acid, egg yolk or egg white, glycerol triacetate, honey, lithium chloride, molasses, a polymeric polyol such as polydextrose, quillaia, sodium hexametaphosphate E452i, urea, or castor oil.

[0060] In certain examples, a disintegrating agent may be included in a composition. Examples of disintegrating agents may include crosslinked polymers such as crosslinked polyvinylpyrrolidone (crospovidone) or crosslinked sodium carboxymethyl cellulose (croscarmellose sodium), or a modified starch such as sodium starch glycolate.

[0061] In certain examples, a wetting agent may be included in a composition.Examples of wetting agents may include benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, Poloxamer 188, Poloxamer 407, Polyoxyl 40 Stearate, Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 80, sodium lauryl sulfate, sorbitan monooleate, or sorbitan monostearate.

[0062] In certain examples, a lubricating agent may be included in a composition. Examples of lubricating agents may include talc, silica, or a fat, such as vegetable stearin, magnesium stearate, or stearic acid.

[0063] In certain examples, a sweetener may be included in a composition. Examples of sweeteners may include sugar, corn syrup, aspartame, sucralose, acesulfame K, saccharin, or xylitol.

[0064] In an example, examples of liquid preparations of the described compositions may include compositions in combination with a carrier in a form such as solutions, suspensions, or emulsions, in which the carrier may be a fluid such as a solvent, or an emulsifying agent. In certain examples, a liquid preparation may be a water or water-propylene glycol solution. In other examples, parenteral injection liquid preparations may be formulated as solutions in aqueous polyethylene glycol solution. The described compositions may thus be formulated for parenteral administration (for example, by injection, for example bolus injection or continuous infusion) and may be presented in unit dose or in ampoules, pre-filled syringes, small- volume infusion, or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents, such as suspending, stabilizing, and / or dispersing agents.Alternatively, the described composition may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for reconstitution with a suitable vehicle, for example, sterile, pyrogen-free water, before use.

[0065] In certain examples, aqueous solutions suitable for oral use may be prepared by dissolving the described compositions in water and adding suitable colorants, flavors, stabilizing and thickening agents, as preferred. Aqueous suspensions suitable for oral use may be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.

[0066] In certain examples, an emulsifying agent may be included in a composition that provides for combining two or more immiscible fluids in a single mixture and maintains the mixture as stable. Examples of emulsifying agents may include acacia, carbomer copolymer, carbomer interpolymer, cholesterol, coconut oil, diethylene glycol stearates, ethylene glycol stearates, glyceryl distearate, glyceryl monolinoleate, glyceryl monooleate, glyceryl monostearate, lanolin alcohols, lecithin, mono- and di-glycerides, Polaxamer, polyoxyethylene 50 stearate, polyoxyl 10 oleyl ether, polyoxyl 20 cetostearyl ether, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearate, polyoxyl lauryl ether, polyoxyl stearyl ether, Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 80, propylene glycol monostearate, sodium cetostearyl sulfate, sodiumlauryl sulfate, sodium stearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, stearic acid, and wax.

[0067] The preparations may preferably be in unit dosage forms. In such form, the preparation may be subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form may be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form may be a capsule, tablet, cachet, or lozenge itself, or the unit dosage form may be the appropriate number of any of such unit dosage forms in packaged form.

[0068] Further details on techniques for formulation and administration may be found in the latest edition of Remington’s Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.).

[0069] Forms and Uses

[0070] In an example, the described composition may be used for improving bone health in a subject. The subject may be an aging subject.

[0071] In another example, the described composition may be used for maintaining bone health in a subject. The subject may be an aging subject.

[0072] The composition maintains and / or improves bone health in an aging subject relative to an aging subject not administered the composition by: increasing bone volume fraction (BVF), increasing trabecular thickness (Tb.Th), decreasing trabecular separation (Tb.Sp), increasing trabecular number (Tb.N), increasing bone mineral density (BMD), increasing bone mineral content (BMC); and / or increasing bone surface density (BS / TV) expression.

[0073] In an example, suitable dosage forms of the described compositions may include tablets, capsules, solutions, suspensions, powders, gums, and confectionaries. Examples of compositions may include supplements. Sublingual delivery systems may include, but are not limited to, dissolvable tabs under and on the tongue, liquid drops, and beverages. Edible films, hydrophilic polymers, oral dissolvable films, or oral dissolvable strips may be used. Examples of compositions may include an additive such as an excipient or a carrier.

[0074] In yet another example, the described composition may be used for an oral administration.

[0075] In yet another embodiment, the described composition may be a tablet.

[0076] In yet another example, the described composition may be used as a nutritional supplement.

[0077] Methods

[0078] In an example, the present disclosure provides a method of maintaining and / or improving bone health in a subject, including administering to the subject a composition including A71-dihydrocaffeoyl-A710-caffeoylspermidine. The subject may be an aging subject. The composition maintains and / or improves bone health in an aging subject relative to an aging subject not administered the composition by: increasing bone volume fraction (BVF), increasing trabecular thickness (Tb.Th), decreasing trabecular separation (Tb.Sp), increasing trabecular number (Tb.N), increasing bone mineral density (BMD), increasing bone mineral content (BMC); and / or increasing bone surface density (BS / TV) expression. The composition increases spermidine content in the subject within 1 hour after administration of the composition. The composition comprises at least 10% by weight of A71-dihydrocaffeoyl-A710-caffeoylspermidine; alternatively, the composition comprises at least 25% by weight of A71-dihydrocaffeoyl-A710-caffeoylspermidine; or alternatively, the composition comprises at least 45% by weight of / V'-dihydrocaffeoyl-7V10-caffeoylspermidine. The composition may be administered orally.

[0079] In another embodiment, the present disclosure provides a method for preventing and / or treating bone diseases in a subject comprising administering to the subject an effective amount of a composition comprising A^-dihydrocaffeoyl-TV10-caffeoylspermidine and an additive. The bone disease may be osteoporosis, Paget’s disease of the bone, osteogenesis imperfecta, rickets, osteomalacia, renal osteodystrophy, or hyperparathyroidism. The composition comprises at least 10% by weight of 7V1-dihydrocaffeoyl-7V10-caffeoylspermidine; alternatively, the composition comprises at least 25% by weight of A4-dihydrocaffeoyl-7V10-caffeoylspermidine; or alternatively, the composition comprises at least 45% by weight of TV'-dihydrocaffeoyl-TV10-caffeoylspermidine. The composition may be administered orally. The composition may be a nutritional supplement.

[0080] In an example, the present disclosure provides a supplement of spermidine, including: i) a compound selected from the group consisting of A^-dihydrocaffeoyl-TV10-caffeoylspermidine; and ii) an additive. In certain examples, the compound may at least partially hydrolyzed in vivo to provide spermidine.

[0081] The compositions and methods described above may be better understood in connection with the following Examples. In addition, the following non-limiting examples are an illustration. The illustrated methods are applicable to other examples of compositions of matter to be screened and evaluated of the present disclosure. The procedures described as general methods describe what is believed will be typically effective to screen and evaluate compositions of matter. However, the person skilled in the art will appreciate that it may be necessary to vary the procedures for any given example of the present disclosure, e.g., vary the order or steps and / or the chemical reagents used.

[0082] EXAMPLES

[0083] Senescence Accelerated Mouse-Prone 8 (SAMP8) is a mouse line that displays a phenotype of accelerated aging. SAMP8 develops various aging-related phenotypes such as disruption of autonomic nervous function and neurodegenerative disorders (Chikamoto, A., et al., “Early attenuation of autonomic nervous function in senescence accelerated mouse-prone 8 (SAMP8),” Exp Anim., 68(4):511 (2019)), and sarcopenia (Guo, A.Y., et al., “Muscle mass, structural and functional investigations of senescence-accelerated mouse P8 (SAMP8),” Exp Anim., 64(4):425 (2015)). It is widely used in bone health detection (Sanada, Y., et al., “Senescence-accelerated mice prone 8 (SAMP8) in male as a spontaneous osteoarthritis model,” Arthritis Res Ther., 24(1):235 (2022)).

[0084] Example 1: A1-dihvdrocaffeoyl-A10-caffeoylspermidine Improves Bone Health During Aging

[0085] (1) Methods and Procedures

[0086] SAMP8 mice were used to study the effects of A4-dihydrocaffeoyl-A10-caffeoylspermidine on bone health. Lifespan of the SAMP8 mice used in the study was around 12-13 months. The experiment started with 3-month-old SAMP8 mice and endedwhen the mice were 8-month-old. SAMP8 mice were obtained from Beijing HFK Bioscience, China.

[0087] A1-dihydrocaffeoyl-A10-caffeoylspermidine was obtained from Laboratory Amway I&S, China.

[0088] S AMP8 mice were administered mice feed with or without N1-dihydrocaffeoyl-A10-caffeoylspermidine.

[0089] A1-dihydrocaffeoyl-A10-caffeoylspermidine to mouse feed was 25 mg N1-dihydrocaffeoyl-A10-caffeoylspermidine mixed in 1 kg of mice feed (0.25 g / kg).

[0090] At the end of the treatment period, histology and microcomputed tomography (mCT) was used to determine changes in the SAMP8 mice that were administered N1-dihydrocaffeoyl-A10-caffeoylspermidine (AA001 treatment) as compared to the mice that were not administered A1-dihydrocaffeoyl-A10-caffeoylspermidine.

[0091] (2) Results

[0092] Figure 2 shows images of bone in S AMP8 vehicle group and N1-dihydrocaffeoyl-A10-caffeoylspermidine treated group: (a) images of cortical bone; (b) images of trabecular; (c) merge of cortical bone and trabecular; (d) images of bone.

[0093] The AA001 treatment increased the density of trabecular bone, the thickness of cortical bone, and the integrity of the overall bone structure compared with the control group, suggesting its effectiveness in improving the skeletal health and stability of SAMP8 mice. The results were statistically significant.

[0094] As shown in Figure 3, A1-dihydrocaffeoyl-A10-caffeoylspermidine administered to the SAMP8 mice increased bone volume fraction (BVF), increased trabecular thickness (Tb.Th), decreased trabecular separation (Tb.Sp), increased trabecular number(Tb.N), increased bone mineral density (BMD), increased bone mineral content (BMC) and increased bone surface density (BS / TV) expression as compared to SAMP8 vehicle mice (S AMP8 mouse without administration of Ahdihydrocaffeoyl-A10-caffeoylspermidine). The results were statistically significant.

[0095] (3) Conclusion

[0096] These results indicate that administration of Ahdihydrocaffeoyl-A10-caffeoylspermidine (AA001) can effectively improve the skeletal health of aging mice.

[0097] Further, this study demonstrates that A'-dihydrocaffeoyl-A10-caffeoylspermidine can at least maintain and, surprisingly, improve bone health during aging.

[0098] In summary, the study showed that A^-dihydrocaffeoyl-TV10-caffeoylspermidine, which can be found in L. ruthenicum can maintain and / or improve bone health during aging.

[0099] Although the present disclosure has been described with reference to examples and the accompanying drawings, the present disclosure is not limited thereto, but may be variously modified and altered by those skilled in the art to which the present disclosure pertains without departing from the spirit and scope of the present disclosure.

[0100] The subject-matter of the disclosure may also relate, among others, to the following aspects:

[0101] A first aspect relates to a composition for improving bone health in a subject comprising A1-dihydrocaffeoyl-A10-caffeoylspermidine and an additive.

[0102] A second aspect relates to the composition of aspect 1, wherein the composition maintains and / or improves bone health in the subject administered the composition relative to a subject not administered the composition by: increasing bone volume fraction (B VF), increasing trabecular thickness (Tb.Th), decreasing trabecular separation (Tb.Sp), increasing trabecular number (Tb.N), increasing bone mineral density (BMD), increasing bone mineral content (BMC); and / or increasing bone surface density (BS / TV) expression.

[0103] A third aspect relates to the composition of aspect 1 or 2, wherein the subject is an aging subject.

[0104] A fourth aspect relates to the composition of aspects 1 to 3, wherein the composition increases spermidine content in the subject within 1 hour after administration of the composition.

[0105] A fifth aspect relates to the composition of aspects 1 to 4, comprising at least 10% by weight of A1-dihydrocaffeoyl-A10-caffeoylspermidine.

[0106] A sixth aspects relates to the composition of aspects 1 to 4, comprising at least 25% by weight of A1-dihydrocaffeoyl-A10-caffeoylspermidine.

[0107] A seventh aspects relates to the composition of aspects 1 to 4, comprising at least 45% by weight of A1-dihydrocaffeoyl-A10-caffeoylspermidine.

[0108] An eighth aspect relates to the composition of aspects 1 to 7, wherein the composition is formulated for oral administration.

[0109] A nineth aspect relates to the composition of aspects 1 to 8, wherein the composition is in a form of a tablet, a ready-to-drink beverage, a concentrate, powder, granules, gel, solid, semi-solid, frozen liquid, lozenges or hard candies, dissolving strips, and chewing gum.

[0110] A tenth aspect relates to the composition of aspects 1 to 9, wherein the composition is a nutritional supplement.

[0111] An eleventh aspect relates to the use of the composition of aspects 1 to 10 to improve bone health in the subject.

[0112] A twelfth aspect relates to a method for maintaining and / or improving bone health in an aging subject, comprising administering to the subject an effective amount of a composition comprising A1-dihydrocaffeoyl-A10-caffeoylspermidine and an additive.

[0113] A thirteenth aspect relates to the method of aspect 12, wherein the composition maintains and / or improves bone health in an aging subject relative to an aging subject not administered the composition by: increasing bone volume fraction (BVF), increasing trabecular thickness (Tb.Th), decreasing trabecular separation (Tb.Sp), increasing trabecular number (Tb.N), increasing bone mineral density (BMD), increasing bone mineral content (BMC); and / or increasing bone surface density (BS / TV) expression.

[0114] A fourteenth aspect relates to the method of aspect 12 or aspect 13, wherein the composition increases spermidine content in the subject within 1 hour after administration of the composition.

[0115] A fifteenth aspect relates to the method of aspects 12 to 14, wherein the composition comprises at least 10% by weight of Ahdihydrocaffeoyl-A10-caffeoylspermidine.

[0116] A sixteenth aspect relates to the method of aspects 12 to 14, wherein the composition comprises at least 25% by weight of Ahdihydrocaffeoyl-A10-caffeoylspermidine.

[0117] A seventeenth aspect relates to the method of aspects 12 to 14, wherein the composition comprises at least 45% by weight of 4-dihydrocaffeoyl-A10-caffeoylspermidine.

[0118] An eighteenth aspect relates to the method of aspects 12 to 17, wherein the composition is administered orally.

[0119] A nineteenth aspect relates to a method for preventing and / or treating bone diseases in a subject comprising administering to the subject an effective amount of a composition comprising A1-dihydrocaffeoyl-A10-caffeoylspermidine and an additive.

[0120] A twentieth aspect relates to the method of aspect 19, wherein the bone disease is osteoporosis, Paget’s disease of the bone, osteogenesis imperfecta, rickets, osteomalacia, renal osteodystrophy, and / or hyperparathyroidism.

[0121] A twenty first aspect relates to the method of aspect 19 or aspect 20, wherein the composition comprises at least 10% by weight of Ad-dihydrocaffeoyl-A10-caffeoylspermidine.

[0122] A twenty second aspect relates to the method of aspect 19 or aspect 20, wherein the composition comprises at least 25% by weight of Ahdihydrocaffeoyl-A10-caffeoylspermidine.

[0123] A twenty third aspect relates to the method of aspect 19 or aspect 20, wherein the composition comprises at least 45% by weight of Ad-dihydrocaffeoyl-A10-caffeoylspermidine.

[0124] A twenty fourth aspect relates to the method of aspects 19 to 23, wherein the composition is administered orally.

[0125] A twenty fifth aspect relates to the method of aspects 19 to 24, wherein the composition is a nutritional supplement.

[0126] A twenty sixth aspect relates to the method of aspects 19 to 25, wherein the subject is an aging subject.

[0127] In addition to the features mentioned in each of the independent aspects enumerated above, some examples may show, alone or in combination, the optional features mentioned in the dependent aspects and / or as disclosed in the description above and shown in the figures.

Claims

1. CLAIMSWhat is claimed is:

1. A composition for maintaining and / or improving bone health in a subject comprising A1-dihydrocaffeoyl-A10-caffeoylspermidine and an additive.

2. The composition of claim 1, wherein the composition maintains and / or improves bone health in a subject administered the composition relative to a subject not administered the composition by:increasing bone volume fraction (BVF),increasing trabecular thickness (Tb.Th),decreasing trabecular separation (Tb.Sp),increasing trabecular number (Tb.N),increasing bone mineral density (BMD),increasing bone mineral content (BMC); and / orincreasing bone surface density (BS / TV) expression.

3. The composition of claim 1, where the subject is an aging subject.

4. The composition of claim 1 or claim 2, wherein the composition increases spermidine content in the subject within 1 hour after administration of the composition.

5. The composition of any of claims 1-3, comprising at least 10% by weight of A1-dihydrocaffeoyl-A10-caffeoylspermidine.

6. The composition of any of claims 1-3, comprising at least 25% by weight of A1-dihydrocaffeoyl-A10-caffeoylspermidine.

7. The composition of any of claims 1-3, comprising at least 45% by weight of A4-dihydrocaffeoyl-A4°-caffeoylspermidine.

8. The composition of any of claims 1-3, wherein the composition is formulated for oral administration, wherein the dosage of A1-dihydrocaffeoyl-A10-caffeoylspermidine is in the range of 1.5 mg / kg to 50 mg / kg of body weight of the subject.

9. The composition of any of claims 1-8, wherein the composition is in a form of a tablet, a ready-to-drink beverage, a concentrate, powder, granules, gel, solid, semi-solid, frozen liquid, lozenges or hard candies, dissolving strips, and chewing gum.

10. The composition of any of claims 1-9, wherein the composition is a nutritional supplement.

11. Use of the composition of any of claims 1-10 to maintain and / or improve bone health in the subject.

12. A method for maintaining and / or improving bone health in an aging subject, comprising administering to the subject an effective amount of a composition comprising A1-dihydrocaffeoyl-A10-caffeoylspermidine and an additive.

13. The method of claim 12, wherein the composition maintains and / or improves bone health in an aging subject relative to an aging subject not administered the composition by:increasing bone volume fraction (BVF),increasing trabecular thickness (Tb.Th),decreasing trabecular separation (Tb.Sp),increasing trabecular number (Tb.N),increasing bone mineral density (BMD),increasing bone mineral content (BMC); and / orincreasing bone surface density (BS / TV) expression.

14. The method of claim 12 or claim 13, wherein the composition increases spermidine content in the subject within 1 hour after administration of the composition.

15. The method of any of claims 12-14, wherein the composition comprises at least 10% by weight of A1-dihydrocaffeoyl-A10-caffeoylspermidine.

16. The method of any of claims 12-14, wherein the composition comprises at least 25% by weight of A1-dihydrocaffeoyl-A10-caffeoylspermidine.

17. The method of any of claims 12-14, wherein the composition comprises at least 45% by weight of A1-dihydrocaffeoyl-A10-caffeoylspermidine.

18. The method of any of claims 12-14, wherein the composition is administered orally, wherein the dosage of 4-dihydrocaffeoyl- 4°-caffeoylspermidine is in the range of 1.5 mg / kg to 50 mg / kg of body weight of the subject.

19. A method for preventing and / or treating bone diseases in a subject comprising administering to the subject an effective amount of a composition comprising N1-dihydrocaffeoyl-Al0-caffeoylspermidine and an additive.

20. The method of claim 19, wherein the bone disease is osteoporosis, Paget’s disease of the bone, osteogenesis imperfecta, rickets, osteomalacia, renal osteodystrophy, or hyperparathyroidism.

21. The method of claim 19 or claim 20, wherein the composition comprises at least 10% by weight of A1-dihydrocaffeoyl-A10-caffeoylspermidine.

22. The method of claim 19 or claim 20, wherein the composition comprises at least 25% by weight of A1-dihydrocaffeoyl-A10-caffeoylspermidine.

23. The method of claim 19 or claim 20, wherein the composition comprises at least 45% by weight of A1-dihydrocaffeoyl-A10-caffeoylspermidine.

24. The method of claim 19 or claim 20, wherein the composition is administered orally, wherein the dosage of A^1-dihydrocaffeoyl-A^10-caffeoylspermidine is in the range of 1.5 mg / kg to 50 mg / kg of body weight of the subject.

25. The method of any of claims 19-24, wherein the composition is a nutritional supplement.

26. The method of any of claims 19-25, wherein the subject is an aging subject.

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