阅读说明：本技术 具有抗衰老/逆转衰老作用的用于激活沉默调节蛋白的营养药物性组合物 (Nutraceutical composition for activation of sirtuin with anti-aging/anti-aging effects ) 是由 乔凡尼·恰莱拉 柳德米拉·扎波罗热 于 2019-01-08 设计创作，主要内容包括：用于在人体内激活沉默调节蛋白的营养药物性组合物,其特征在于,所述组合物包含10-15wt％的和厚朴酚；12-40wt％的紫檀芪；22-32wt％的虎杖苷；25-40wt％的鞣花酸和1.5-3wt％的锌、硒、铬和烟酰胺的混合物,所述组合物促进对于细胞降解和衰老现象的抑制。(A nutraceutical composition for activating sirtuin in humans, wherein said composition comprises 10-15 wt% honokiol; 12-40 wt% pterostilbene; 22-32 wt% of polydatin; a mixture of ellagic acid in an amount of 25 to 40% by weight and zinc, selenium, chromium and nicotinamide in an amount of 1.5 to 3% by weight, said composition promoting the inhibition of cellular degradation and the phenomenon of senescence.)

1. Nutraceutical composition for the activation of sirtuin in humans, characterized in that it comprises 10-15 wt% of honokiol, 12-40 wt% of pterostilbene, 22-32 wt% of polydatin, 25-40 wt% of ellagic acid and 1.5-3 wt% of a mixture of zinc, selenium, chromium and nicotinamide, all of which make up 100 wt% of the composition.

2. The nutraceutical composition according to the preceding claims, wherein excipients are also present.

3. The nutraceutical composition according to any of the preceding claims, wherein the total weight of the composition is between 900mg and 1200 mg.

4. The nutraceutical composition according to the preceding claims, wherein the total weight of said composition is 1076g, wherein 16mg is niacinamide vitamin B3; 150mg is a dried magnolia extract, 20% measured by honokiol titration, comprising 30mg honokiol; 300mg of dry blueberry extract, 20% pterostilbene by titration, comprising 60mg of pterostilbene; 200mg of resveratrol from polygonum cuspidatum, with a polydatin titration of 20%, containing 40mg of polydatin; 400mg of a dry pomegranate extract, 20% ellagic acid titration, comprising 80mg ellagic acid; 10mg of zinc ion, in the form of zinc gluconate; 0.055mg selenium ion, in the form of selenium methionine; 0.040mg of chromium ions, in the form of chromium picolinate.

5. The nutraceutical composition of any of the preceding claims, comprising an excipient selected from the group consisting of: microcrystalline cellulose, dibasic calcium phosphate, hydroxypropyl methylcellulose, vegetable magnesium stearate, and mixtures thereof.

6. The nutraceutical compositions of claims 3, 4 and 5, formulated as oblong tablets.

7. The nutraceutical composition of any of the preceding claims, for use in a method of treating cellular aging, said composition promoting the activation of sirtuin.

8. The nutraceutical composition according to the preceding claims, which is administered in a daily dose of 2 g.

9. The nutraceutical composition according to any one of claims 1 to 6, for use in a method of treating a neurodegenerative disease.

Technical Field

The present invention relates to the field of nutraceutical and, more particularly, to a unique composition comprising ingredients that, in addition to being beneficial to humans when taken alone, when present at specific concentrations (as in the compositions of the present invention), also involve sustained activation of sirtuins (sirtuins) to produce all anti-degenerative, anti-aging and anti-aging effects triggered by activation.

Background

Without doubt, the average human life has been increasing for centuries. This significant difference cannot be attributed to genetic variation in human species, but can certainly be traced back to changes in environmental properties, such as improvements in living conditions and medical advances.

Aging can be defined as a complex of all physiological, genetic and molecular changes that occur over time. Age-related changes can be attributed to natural growth processes, genetic defects associated with individuals, and the relationship of genotype to environment. Our body is constantly subjected to oxidative stress due to oxidative substances (free radicals) produced as a result of environmental factors (ultraviolet rays) or substances introduced with diet or produced intracellularly during cellular respiration. Free radicals are formed at each moment of our life and from birth, and are associated with the normal life processes of cellular respiration and other factors such as excessive physical exercise, active and passive smoking, electromagnetic pollution, atmospheric pollution, a wide variety of chemicals in the air and food.

In general, oxidative stress causes intense damage to proteins, lipids and DNA, increasing the risk of tumors, cardiovascular diseases and degenerative diseases. Once damaged, cells protect themselves from damage by activating repair mechanisms, or, if damaged excessively, programmed death programs (i.e. apoptosis) are activated with the aim of permanently eliminating the diseased cells. Human beingIt has long been known that during the aging process, cell damage gradually increases due to oxidative stress. From a molecular point of view, the increase in age-related oxidative stress can be traced back to three different factors, an increase in the rate of production of reactive oxygen metabolites, a decrease in the antioxidant defense system, and a decrease in the efficiency of degradation and repair of damaged molecules. ROS (reactive oxygen species) are very reactive chemical species present in the environment and also produced in vivo as metabolic byproducts, especially during mitochondrial respiration. ROS are involved in the pathogenesis of a variety of diseases, from inflammation to immunosuppression, from diabetes to alzheimer's disease, from cirrhosis to atherosclerosis and various types of cancer (Lyras l. halliwell b. et al, 1998). ROS pathology is caused by "oxidative stress", i.e. a balance between ROS production and antioxidant defense is lost: the most serious pathologies that may result from this are atherosclerosis and various types of tumors. Free radicals are chemical species with unpaired electrons on their outermost orbitals and are characterized by their high reactivity and chemical instability. Of great importance from a biological point of view are free radical species of oxygen and nitrogen, such as the superoxide anion O₂-, a hydroxyl radical OH, nitrogen monoxide NO and the peroxynitrite anion ONOO- (which may be formed by O)₂The combined generation of NO radicals). Among the oxygen species mentioned, the most active is the OH radical, which reacts a few angstroms away from its point of generation and which forms from H₂O₂The onset may be catalyzed by some transition metals. Although there are many sites for free radical formation within the cell, mitochondria appear to be the primary source. In particular, superoxide radicals are produced at the level of ubiquinone and NADH dehydrogenase. Cells have developed a number of protective mechanisms to limit the production of oxidants and eliminate excess oxidants. In particular, there are antioxidant enzymes that can convert active oxygen into smaller species. The three major antioxidant enzymes are superoxide dismutase (SOD), Catalase (CAT), and glutathione peroxidase (GPx). In addition to endogenous antioxidants, free radicals are also inactivated by exogenous or food antioxidants.

It is now generally accepted that the diet used is the basis of an absolutely healthy life, especially when the diet involves the intake of all those substances which are considered to have antioxidant properties.

In the context of antioxidant and anti-aging processes, relatively recently, a unique class of substances known as sirtuins, which are present in the human organism, is of particular interest.

It is a class of enzyme activator proteins that act as histone deacetylases or mononucleotransferases. They regulate important metabolic pathways in prokaryotes and eukaryotes. Their name is derived from a silent regulatory gene of yeast (involved in the regulation of cell development).

Sirtuins mediate phenomena such as aging, transcriptional regulation, apoptosis, stress resistance, and affect energy efficiency and alertness in the presence of low caloric intake.

Briefly, these materials: exhibit enzymatic properties, regulate metabolic processes associated with insulin resistance, control immunity, play an important role in epigenetics, and participate in the defense against cancer diseases.

Their action is similar to that of the "sentinel" structure, when it is detected that the DNA damage caused by degradation and the consequent phenomenon of senescence are mainly dependent on free radicals, they are ready to intervene to activate the repair mechanisms of the intervention.

Numerous studies have also shown that there is a direct proportional important link between activation of the mechanisms leading to the production and activation of sirtuins and caloric restriction: in more detail, it was found through experimentation that the heat limitation may be: reducing the incidence and slowing the onset of age-related diseases (by way of non-limiting example of cardiovascular disease and neurodegenerative disease); the anti-stress capability is improved; and generally increases life expectancy.

The reduction in caloric intake actually favors the expression of genes involved in cell repair, protein turnover and synthesis, antioxidant stress and glucose metabolism.

Genes activated by caloric restriction include those encoding sirtuins. As mentioned above, these substances have deacetylation activity and, on a biological level, their activation involves keeping the body healthy during food shortages. In higher organisms, sirtuins activate lipolysis and gluconeogenesis and control cell proliferation, inflammatory phenomena, telomere aging and stress responses. Sirtuins are the expression of SIRT genes, which are usually present in human chromosomes. One of the major substrates of sirtuins is histones, which are part of the chromosomal makeup where they bind to DNA, keeping it tight, organizing it and thus regulating gene expression. Acetylation/deacetylation of histones alters the binding of these proteins to DNA, allowing genetic material to interact with other proteins. Sirtuins are activated by so-called sirtuin activators in addition to their natural activation by caloric restriction. Among these, resveratrol is undoubtedly known, belongs to the family of polyphenolic compounds and is found in grape berries, wine, some berries and oilseeds (peanuts) and in specific plants.

It is worth mentioning that in order to obtain medically relevant amounts of such substances it is not sufficient to eat the specified food containing them in a daily diet, since in this case the person should include a few kilograms or liters of that particular food in the menu. For these reasons, as will be explained below, it is an object of the present invention to provide a food product containing a natural extract of a STACs-SIRT activator compound in a necessary amount. The Sir2 (sirtuin 2) gene, from which the entire family name originates, is one of the first longevity genes identified in lower organisms such as nematodes (nematodes) and midges. A wide variety of species (from yeast to humans) express variants of this gene, the activation of which extends life expectancy. 7 genes belonging to this family (SIRT 1-7) have been identified in mammals. In particular, the gene homologous to Sir2 is SIRT1(Sir2 homolog 1). It encodes the Sirt1 protein, which is capable of deacetylating nuclear and cytoplasmic proteins that control key cellular processes such as apoptosis and metabolism. SIRT1 regulates insulin and glucose production, lipid metabolism, and cell survival, thus concluding that sirtuins can mediate the effects of heat flux limitation in mammals (Cohen, Miller et al, 2004). Thus, the potential anti-aging effects of the Sir2 gene found in yeast appear to be applicable to mammals with more complex mechanisms involving abundant protein patterns. Thus, caloric restriction promotes cell survival by inducing Sirt1 deacetylase.

Even if it is certain that humans can benefit from the caloric restricted anti-aging effect, a diet with a long-term dietary regime is not a viable approach. For some time, researchers have been working on the identification of molecules that mimic the effects of caloric restriction.

The Sinclair team described 18 plant-derived molecules capable of activating sirtuins in yeast and investigated their effect on SIRT1 (a human homolog of Sir 2). The flavonoids quercetin and fisetin, stilbenes piceatannol and resveratrol, and chalcone butin stimulate SIRT 15 to 13 times. Most of these compounds present a hydroxyl group in the meta position of the phenolic ring a, which is trans-oriented to ring B. When ring a does not present OH in the meta position (fisetin), the catechol B ring is essential to maintain significant activity. Another important factor for activity is the co-planarity between the hydroxylated rings a and B.

The most powerful activator is considered to be resveratrol, a compound synthesized by a large number of plants in response to stress, in appreciable amounts in grapes and red wine. It is well known that such molecules have protective effects on a number of diseases, including cardiovascular diseases, neoplastic diseases and neurodegenerative diseases.

Some authors hypothesize that plants synthesize compounds (such as resveratrol) in response to stress and nutrient limitations, thereby activating metabolic pathways involving sirtuins, and that plants symbiotic fungi and animals stimulate sirtuins with phenolic derivatives from the plant itself.

Resveratrol and other STACs (SIR-activating compounds) activate sirtuins in the nematodes caenorhabditis elegans (caenorhabditis elegans) and Drosophila melanogaster (Drosophila melanogaster), as well as in saccharomyces cerevisiae (s.

With respect to age-related diseases, recent studies have revealed neuroprotective activity of sirtuins. Resveratrol appears to promote a non-amyloidogenic pathway of amyloid precursor protein, which regulates the pathogenesis of alzheimer's disease (Thimmappa and Anekonda, 2006).

Recent studies have shown that resveratrol-like molecules have higher resveratrol activity than the substrate. It is pterostilbene, or a stilbene compound chemically combined with resveratrol, and is also present in blueberries and grapes.

As mentioned above, the use of dietary therapies, in particular caloric restriction, to promote sirtuin activation and indirectly inhibit cellular degradation processes due to the action of highly oxidative chemicals (such as free radicals) has led to questionable feasibility in view of the persistence of the application of the method, which may be carried out in a relatively limited time.

In this connection, the object of the present patent application is to propose a unique nutraceutical composition (dietary composition) which is not generally considered as a meal or a substitute for food, but as a supplement, in order to provide those substances for which preliminary studies, which have led to the definition of the present invention, have shown to be particularly effective: promoting sirtuin activation; sustained slowing of cellular degradation effects; and triggering of cellular repair mechanisms that macroscopically manifest very distinct physical rejuvenation phenomena.

Disclosure of Invention

The present invention relates to a unique nutraceutical composition suitable for promoting cellular repair in the human body after degradation phenomena promoted by oxidative substances and aging-related effects. The use of the composition under certain protocols and as disclosed hereinafter results in an anti-aging effect that is visible in the subject in which the composition is employed. All this is due to the unique combination of substances present in the composition, which synergistically produce an overall effect in terms of antioxidant and anti-cell aging properties. In more detail, the nutraceutical compositions according to the present invention are able to achieve the above-mentioned effects due to the activation of sirtuins, which, as mentioned above, mediate phenomena such as aging, transcriptional regulation, apoptosis, stress resistance, etc., and they also affect energy efficiency and alertness in low-calorie intake situations.

In more detail, the composition comprises ingredients that provide beneficial effects to the body even when taken alone and that exhibit enhanced effects in inducing cell, tissue repair and macroscopically body rejuvenation when they coexist at specific concentrations.

In particular, the nutraceutical compositions according to the present invention comprise ingredients such as honokiol (honokiol), pterostilbene (pterostilbene), polydatin (polydatin), ellagic acid (ellagic acid), zinc, selenium, chromium, vitamin B3.

Honokiol is a well known compound that can be extracted from magnolia bark and it exhibits many beneficial properties in relation to its strong antioxidant action, being able to counteract lipid peroxidation and protect mitochondria from free radical attack. It is also a substance that has a protective effect on brain function. Some studies also revealed that it is able to inhibit the mTor pathway (i.e. the mTor pathway of the rapamycin receptor, which is essential for tumor growth), without acting in the same direction as new T lymphocytes used to counteract the tumor itself.

Pterostilbene is a stilbene compound mainly existing in blueberry and grape, belongs to phytoalexins, and is an anti-infective substance generated by plants. Its structure and properties are similar to those of resveratrol (belonging to the same family). In the latter case, it has two methoxy groups and shows a higher bioavailability; easy transport within the cell; the degradation and elimination speed in the organism is slower, that is, the half-life period in the organism is about 7 times higher than that of the resveratrol. Pterostilbene also shows beneficial effects on cardiovascular health, cholesterol levels and cognitive function, improving attention and memory, and has sedative and anti-stress effects to improve anxiety and nervous tone. Its strong antioxidant properties also enable it to deactivate free radicals associated with oxidative stress.

Polydatin is a stilbene glucoside (stilbenoid glucoside) derived from resveratrol, and is mainly present in grape juice. It is more stable than resveratrol and more bioavailable because it is more resistant than enzymatic oxidation, it permeates into cells through an active transport mechanism that utilizes glucose transporters, and because it is soluble in water, it is more easily absorbed in the intestinal tract.

It also shows strong anti-radical action and, therefore, anti-oxidant, as well as anti-inflammatory. It can inhibit lipid peroxidation, and is very effective on oxidative stress. This molecule is 50 times more effective than resveratrol in that it is water soluble and therefore it is fully absorbable, unlike resveratrol which is hardly absorbed, thus reducing its bioavailability. Polydatin is a natural molecule that reaches all cells, even skin cells, at very high concentrations due to the active transport mechanism using glucose transporters.

Ellagic acid is an antioxidant natural phenolic present in a variety of fruits and vegetables.

The antiproliferative and antioxidant properties of ellagic acid have prompted research aimed at determining its potential positive health effects. It is well known that zinc is a constituent element of many enzymes in the human body. It is particularly important for the function of enzymes that regulate cellular respiration, and its ability to combat free radicals and reduce the effects of aging is also well known.

In addition, selenium is present in small amounts in the human body, mainly through food intake, and its content depends on the content of selenium in the soil, as in the case of plants. It can be used as a prophylactic agent for a number of diseases including cancer, cardiac circulatory dysfunction, arteriosclerosis, cirrhosis, arthritis and emphysema.

Chromium is trivalent chromium and is known to promote a decrease in insulin resistance, a decrease in circulating glucose (improving optimal blood glucose levels), a decrease in blood triglycerides and cholesterol, and a decrease in fat mass due to the lower availability of circulating glucose (an inhibitor of sirtuin activity).

Finally, niacinamide is an effective antidote that, in addition to being an effective agent for the prevention of many diseases, is also effective in the circulation and lowering of cholesterol in the blood. It is essential for proper functioning of the nervous system, maintenance of skin health and formation of digestive system tissues. Niacinamide (Vit B3) is also an active catalyst for substances such as pterostilbene, polydatin, and honokiol.

In view of the above properties of the substances comprised in the nutraceutical compositions according to the present invention, it is clear that the latter is undoubtedly a combination of substances having a benefit to the organism.

However, it is unique not in the individual characteristics of its components (also known), but in those derived from their association, including a significant ability to activate cellular repair mechanisms due to damage (in particular caused by the action of free radicals). In particular, this effect is due to the synergistic effect of the components (especially those of stilbenes) in the sustained activation of the sirtuin protein.

Advantageously, the sustained sirtuin activation results in a repair effect that is also sustained due to oxidation/degradation and cellular senescence processes. All this results in a significant anti-ageing effect being observed macroscopically.

Advantageously, the effect can be verified after a relatively short time following the application of a particular regimen of the composition.

Advantageously, the composition is capable of promoting the activation of all sirtuins (SIRT 1, 2, 3, 4, 5, 6, 7) present in an organism, due to the presence of its stilbenes component in the presence of catalysts such as selenium, chromium, zinc and vitamin B3, and at the same time of promoting the inhibition of the onset of all neurodegenerative diseases.

Thus, it is noteworthy that since the metal elements are in ionic form in the composition, they contribute to the trans-cell membrane transport of SIRT activator extracts. The ionic form of these elements is therefore of strategic importance, since it facilitates their interaction with the transported molecule, thus facilitating transport across the cell membrane.

The result is a composition in which the normal efficiency that can be achieved with each component alone is enhanced in the composition.

Detailed Description

The compositions according to the invention comprise the above-mentioned ingredients and active ingredients in variable but specific concentration ranges, the values of which are translated into the definition of a composition, which can be defined as a drug or a supplement. In any event, the subject composition can be defined as a nutraceutical because it exhibits therapeutic and prophylactic properties.

More specifically, the composition comprises 10-15 wt% honokiol; 12-40 wt% pterostilbene; 22-32 wt% of polydatin; 25-40 wt% ellagic acid and 1.5-3 wt% of a mixture of zinc, selenium, chromium and nicotinamide. In addition, the following excipients may be present.

Preferably, the composition is administered in an amount of about 2g per day, which corresponds to the content of two tablets (typically two oval tablets).

In more detail, in one of its embodiments, the composition is such that the total amount of the composition is between 900mg and 1200mg for a tablet.

In one of its preferred embodiments, the weight of said composition formulated as an oval tablet is 1076g, wherein 16mg is niacinamide vitamin B3; 150mg of dried magnolia extract (20% measured by honokiol titration, containing 30mg of honokiol); 300mg of dry blueberry extract (20% pterostilbene titration, containing 60mg of pterostilbene); 200mg of resveratrol from Polygonum Cuspidatum (Polygonum Cuspidatum) (20% by polydatin titration, containing 40mg polydatin); 400mg of dry pomegranate extract (20% ellagic acid titration, containing 80mg of ellagic acid); 10mg of zinc (in the form of zinc gluconate); 0.055mg selenium (as selenium methionine); 0.040mg of chromium (in the form of chromium picolinate).

Excipients, such as microcrystalline cellulose, dibasic calcium phosphate, hydroxypropyl methylcellulose, vegetable magnesium stearate, and mixtures thereof, may also be included.

By way of non-limiting example, coating agents that may be used to prepare the tablets are hydroxypropyl methylcellulose, microcrystalline cellulose, stearic acid, titanium dioxide.