RU2738644C2 - Agent for reducing biological age - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: group of inventions relates to an agent for reducing biological age. An agent for reducing biological age, including nicotinamide riboside, white grapefruit seed extract, containing spermidine, bubbly fucus extract, containing fucoxanthin taken in a certain amount. Capsule for reducing biological age, containing an effective amount of agent.

EFFECT: agent and capsule described above are effective for reducing biological age.

8 cl, 1 ex

Description

The invention relates to a composition made from natural raw materials that improves health, quality and longevity.

LEVEL OF TECHNOLOGY

With age, in addition to the weakening of vital functions, age-dependent diseases debut, in particular:

- cardiovascular diseases (in 1st place as the cause of death);

- oncological diseases (in 2nd place);

- neurodegenerative (Alzheimer's disease, Parkinson's disease, multiple sclerosis)

- metabolic and endocrine disorders (diabetes mellitus).

In most cases, the treatment of these diseases is symptomatic and palliative, that is, it does not imply a cure precisely because of older age.

In this regard, it remains relevant to create means that prevent, slow down and / or alleviate the course of these diseases, characterized by the absence of a toxic effect on a weakened organism, not containing potent substances and not causing side effects that reduce adherence to treatment.

From the prior art, various extracts of medicinal plants, phyto-assemblies and vitamin complexes are known, included in the State Pharmacopoeia of the Russian Federation.

The disadvantage of phyto-assemblies and vitamin-mineral complexes is that they belong to medicines and require medical prescription and control, strict adherence to dosage and taking into account contraindications.

In addition, herbal tea can cause an allergic reaction in some patients.

Thus, the creation of alternative means of the same purpose for the treatment of patients with allergic reactions to known herbal remedies and vitamin complexes remains relevant.

DISCLOSURE OF THE INVENTION

The objective of the invention is to create a food supplement based on natural raw materials for independent use and as an adjuvant in the complex therapy of age-related diseases in geriatrics and gerontology. The result of using the additive according to the invention is an improvement in at least one of the indicators associated with aging, in particular,

blood markers (see Jones P.A. (2012) Nat. Rev. Genet. 13, 484–492), metabolic

markers (see The Journals of Gerontology: Series A, 8 October 2018, 73 (11): 1482–90),

the level of end products of glycation (see Practical Medicine (2018) 3 (114): 110-13)).

In accordance with the present invention, there is provided an agent for reducing biological age, comprising the following ingredients in parts by weight, based on dry matter:

nicotinamide riboside 1.0 part,

white grapefruit seed extract containing spermidine, 19.0 to 28.4 parts,

the extract of fucus vesiculosus, containing fucoxanthin, from 6.6 to 9.9 parts.

The additive according to the invention can be used in the prevention, preparation of the body for treatment, simultaneously with the treatment of the main age-related disease, to smooth out the negative consequences of the treatment of the main age-related disease.

In one embodiment, the additive may further include at least one functional additive, carrier, filler, diluent, flavoring, anti-caking agent, thickener, sweetener, or preservative.

In yet another embodiment, the additive comprises, on a dry weight (mg) basis:

white grapefruit seed extract 215 mg,

bladder fucus extract 75 mg,

nicotinamide riboside 9.1 mg.

In one preferred embodiment, the supplement comprises at least one B vitamin.

In another preferred embodiment, the additive is for use by individuals over 30 years of age.

In another preferred embodiment, the additive is for use as an adaptogen

In accordance with another aspect of the present invention, there is provided a capsule containing an effective amount of the above-described nutritional supplement.

Said capsule in one of its particular embodiments may contain 600 mg of the above-described food additive.

The biological activity of the individual components of the composition has previously been well studied. However, attempts to combine the action of these components in a combined supplement have not been made, the compatibility and toxicity of the components have not been studied. At the same time, the authors found that the components of the composition are not only compatible with each other, non-toxic, do not cause tangible side effects, but the total effect of the combination of these components in a given ratio exceeds the effect of the individual components of the composition and the expected effect from the summation of the effects of several components. This is due to the fact that the components of the composition affect various biochemical pathways and mutually compensate for unwanted side effects.

White Grapefruit Seed Extract contains natural polyamine spermidine.

Dietary supplementation with spermidine is known to reduce overall mortality and, in particular, mortality from cardiovascular disease and cancer in humans (Kiechl S et al. Am J Clin Nutr. 2018 Aug 1; 108 (2): 371-380) ...

The molecular mechanism of the geroprotective action of spermidine is that it inhibits the activity of EP300 acetyltransferase, which suppresses autophagy (Madeo F. et al. Aging (Albany NY). 2018 Aug; 10 (8): 2209-2211 https: //www.ncbi .nlm.nih.gov / pmc / articles / PMC6128428 /). This target is a common anti-inflammatory drug known as aspirin. By the mechanism of action, it is also a mimetic of low-calorie nutrition (Minois N. Gerontology 2014; 60: 319-326).

Recent epidemiological evidence suggests that increased absorption of spermidine-containing foods also reduces overall, cardiovascular and cancer mortality in humans (Madeo F et al. Aging (Albany NY). 2018; 10: 2209-2211).

Spermidine is associated with reduced mortality and longer life: a 6-year difference between 33% of patients with the highest intakes and 33% with the lowest (Am J Clin Nutr. 2018 Aug 1; 108 (2): 371-380).

Experiments in mice have shown that spermidine can prolong lifespan, prevent the development of liver fibrosis and malignant hepatoma, one of the most common forms of liver cancer through the induction of MAP1S-mediated autophagy (Cancer Res. 2017 Jun 1; 77 (11): 2938-2951) ...

Spermidine delays the onset of tumors in a mouse model of induced lung cancer (Cancer Cell. 2016 Jul 11; 30 (1): 147-160).

Spermidine, activates autophagy, protects against neurodegeneration and cognitive decline in model animals (Cell Cycle. 2014 Dec 15; 13 (24): 3903-3908; Investigative Ophthalmology & Visual Science July 2015, Vol. 56, 5012-5019; Cell Cycle. 2015 Mar 1; 14 (5): 697-698).

Spermidine has cardioprotective effects (Nat Med. 2016 Dec; 22 (12): 1428-1438).

Spermidine lowers blood pressure and has vasoprotective effects (Autophagy. 2017 Apr 3; 13 (4): 767-769).

Spermidine increases the lifespan of mice and inhibits the production of trimethylamine produced by the intestinal microbiota, which can be used to treat atherosclerosis (Matsumoto M. et al. (2011). PLoS ONE, 6 (8), e23652; Matsumoto M. et al. (2017) Journal of Functional Foods, 36, 94-101; Wang Z. et al. (2015) Cell, 163 (7), 1585-1595).

Spermidine promotes hair growth (PLoS One. 2011; 6 (7): e22564).

Bladder fucus contains fucoxanthin, a natural compound derived from xanthophylls, auxiliary pigments in the chloroplasts of brown, diatoms and some other algae, which give them a brown or olive-green color.

Fucoxanthin increases the lifespan of various animal models (Pharmacol Res. 2015 Oct; 100: 228-41).

Fucoxanthin inhibits mTOR and induces autophagy (Acta Pharmacol Sin. 2013 Nov 5; 34 (11): 1403-1410)

In experimental models, fucoxanthin reduces age-dependent intestinal permeability, contributes to the preservation of fertility in the age dynamics (BMC Genomics. 2018; 19 (Suppl 3): 77). The same study showed changes in the activity of 57 genes in molecular pathways associated with longevity, such as those associated with longevity, including MAPK, mTOR, Wnt, Notch and Hippo, autophagy, translation, glycolysis, oxidative phosphorylation, apoptosis, immune response, neurogenesis, circadian rhythms and DNA damage response (BMC Genomics. 2018; 19 (Suppl 3): 77).

In mouse skin cells, fucoxanthin activates the NRF2 signaling pathway responsible for antioxidant protection and detoxification of xenobiotics (AAPS J. 2018 Feb 20; 20 (2): 32).

In white adipose tissue of mice, fucoxanthin activates the enzyme UCP1, which may promote lipolysis and normalization of body weight (Biochem Biophys Res Commun. 2005 Jul 1; 332 (2): 392-7).

In mice, there were no acute or chronic toxicity effects at high doses (500, 1000, 2000 mg / kg body weight) of fucoxanthin (J Toxicol Sci. 2009 Oct; 34 (5): 501-10).

Colorectal cancer is one of the most common types of malignant neoplastic diseases. Fucoxanthin has an inhibitory effect on tumor cells and colorectal cancer tissues (Oncol Lett. 2015 Sep; 10 (3): 1463-1467).

Various studies have noted its antidiabetic, anti-inflammatory, hepatoprotective, cardiovascular, cerebrovascular effects, and a role in the prevention of obesity (Evid Based Complement Alternat Med. 2015; 2015: 723515).

Nicotinamide riboside (NR) is a natural form of vitamin B3.

Nicotinamide riboside supplementation is well tolerated and increases NAD + levels in healthy middle-aged and older adults.

Nicotinamide adenine dinucleotide (NAD +) is a critical coenzyme for enzymes involved in the health benefits of regular calorie restriction. Thus, the use of NAD + precursors to increase the bioavailability of NAD + has been proposed as a strategy for improving cardiovascular and other physiological functions with aging in humans.

Oral administration of NR effectively increased NAD + levels in PBMCs by ~ 60% compared with placebo (mean change = 6.2 pmol / mg protein, one-sided 95% CI (0.074, ∞)) (Nature Communicationsvolume 9, Article number: 1286 ( 2018)).

Nicotinamide adenine dinucleotide (NAD +) is a precursor to NAD +, a sirtuin activator and low calorie diet mimetic (Nat Commun. 2018 Mar 29; 9 (1): 1286).

Nicotinamide riboside is a precursor of NAD + and increases its level in the human body (Nat Commun. 2016; 7: 12948; NPJ Aging Mech Dis. 2017; 3:17).

At the same time, the bioavailability of NAD + decreases with age, which results in chronic age-related diseases.

Nicotinamide riboside does not exhibit genotoxicity, does not increase the mortality of mice at a dosage of 5000 mg per kg of body weight, does not lead to changes in the liver, kidneys, ovaries and testes of mice when taken chronically in high doses (Hum Exp Toxicol. 2016 Nov; 35 (11) : 1149-1160). Its toxicity does not exceed that of niacin. A 2 × 6-week randomized, double-blind, placebo-controlled, crossover clinical trial in which chronic supplementation of vitamin NAD + with nicotinamide riboside (NR) is well tolerated and effectively stimulates NAD + metabolism in healthy middle-aged and older people (Nat Commun. 2018 Mar 29 ; 9 (1): 1286).

Nicotinamide riboside acts as a neuroprotective agent to reduce axonal degeneration in excitotoxicity (FASEB J. 2017 Dec; 31 (12): 5440-5452).

Nicotinamide riboside in a mouse model with degeneration of skeletal muscle tissue restored muscle mass and its functional ability - strength and endurance (Cell Metab. 2016 Aug 9; 24 (2): 269-82). Nicotinamide riboside has cardioprotective effects (Circulation. 2018 May 22; 137 (21): 2256-2273).

Nicotinamide riboside reduces the risk of obesity through an increase in oxidative phosphorylation in mitochondria (Cell Metab. 2012 Jun 6; 15 (6): 838-847). Nicotinamide adenine dinucleotide (NAD +) is a co-substrate for several enzymes, including the sirtuin family of NAD + -dependent protein deacylases. The beneficial effects of elevated NAD + levels and activation of sirtuin on mitochondrial homeostasis, metabolism and lifespan have been established in different animal species. Shown here that α-amino-β-carboxyconate-ε-semialdehyde decarboxylase (ACMSD), an enzyme that limits the spontaneous cyclization of α-amino-β-carboxymoconate-ε-semialdehyde in the de novo NAD + synthesis pathway, controls NAD + cell levels via an evolutionarily conserved mechanism in Caenorhabditis elegans and the mouse. Genetic and pharmacological inhibition of ACMSD enhances de novo NAD + synthesis and sirtuin 1 activity, ultimately enhancing mitochondrial function (Naturevolume 563, pages 354–359 (2018)). Increasing NAD metabolism can extend the lifespan of various organisms (Aging Research Reviews, Volume 47, November 2018, Pages 1-17).

Restoring NAD + levels in aged or sick animals can help protect health and prolong life (Cell Metabolism, Volume 27, Issue 3, 6 March 2018, Pages 529-547).

NAD + levels decrease with age in animals ranging from Caenorhabditis elegans to mice. Increasing NAD + levels through dietary supplementation with NAD + precursors, nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN), improves mitochondrial, muscle, nerve, and melanocytic stem cell function in mice, and also increases mouse lifespan (Rejuvenation Research Vol. 20 , No. 3).

Recent studies have shown that the level of production of NAD + decreases with age in the human body, and if you restore the "young" level of production of this molecule, you can prolong not only life, but also health (Naturevolume 563, pages354–359 (2018)).

CARRYING OUT THE INVENTION

EXAMPLE 1

A group of 20 volunteers from 30 to 45 years old were randomly divided into two groups, the volunteers of the first group received the study drug so that neither the researcher nor the volunteers knew whether they were receiving the study drug or a placebo. The second group received a placebo.

The food supplement contains, on a dry basis (mg):

white grapefruit seed extract 215 mg,

bladder fucus extract 75 mg,

nicotinamide riboside 9.1 mg,

functional additives (microcrystalline cellulose, talc (anti-caking agent), glycerin (water-retaining agent)) up to a total weight of 600 mg.

The composition was administered orally in the form of hard gelatin capsules, two capsules containing 600 mg of the composition twice a day.

To assess the biological age and the rate of aging, studies were carried out:

1) Epigenome according to the model of the so-called. The Horvath Watch (see Jones P.A. (2012) Nat. Rev. Genet. 13, 484–492). To do this, the subjects were sampled saliva for DNA analysis for methylation using the technology of the Trumelabs laboratory (Harvard, USA).

2) Metabolome - blood markers made in the Chromolab laboratory (RF) and processed according to the Aging.AI 3.0 algorithm based on the original model (see description in The Journals of Gerontology: Series A, 8 October 2018, 73 (11): 1482–90 ).

3) The level of accumulation of CNG (end products of glycation) in the epidermis of Advanced Glycosylation End-products (AGE) using special equipment for calculating the stages of the Maillard Truage reaction by the fluorescent method (see Practical Medicine (2018) 3 (114): 110-13)

4) The elasticity of blood vessels was assessed using the Russian medical device "Cardioscan" with the Pulse Trace processing algorithm and the analysis of the following parameters:

i) the stiffness of the arterial wall;

ii) elasticity of the aorta;

iii) tone of small resistive arteries;

iv) the value of central blood pressure, pressure in the aorta

v) the state of endothelial function in the area of small resistive arteries (microcirculation system) and large arteries of the muscular type;

vi) the ability of endothelial cells to synthesize nitrogen monoxide, the most potent antiatherogenic agent;

vii) duration of systole, duration of expulsion of blood by the left ventricle;

viii) amplitude and time relationships of early and late systolic waves;

ix) augmentation index (contribution of the late or reflected wave to the pulse pressure value);

x) saturation index (saturation of hemoglobin with oxygen).

Analysis of the data obtained shows a decrease in biological age (integrated processing of the data obtained) by 1.5-2 times in the group receiving the study drug, while no significant changes were observed in the control group.

Claims (10)

1. Means for reducing biological age, including the following ingredients in parts by weight, calculated on dry matter, including: nicotinamide riboside 1.0 white grapefruit seed extract containing spermidine, from 19.0 to 28.4 Fucus vesiculosus extract containing fucoxanthin, 6.6 to 9.9 2. An agent according to claim 1, further comprising a carrier, filler, diluent, humectant, flavor, anti-caking agent, thickener, sweetener and / or preservative. 3. Means according to claim 1, which includes, based on dry weight, mg: white grapefruit seed extract 215 bladder fucus extract 75 nicotinamide riboside 9.1 4. The agent according to claim 1, further comprising at least one B vitamin. 5. The agent according to claim 1, characterized in that it is intended for use by individuals over 30 years of age. 6. The agent according to claim 1, characterized in that it is additionally intended as an adaptogen. 7. A capsule for reducing biological age, containing an effective amount of the agent according to any one of claims. 1-5. 8. A capsule according to claim 7, characterized in that it contains 600 mg of the agent according to claim 1.