FR2979543A1 - Composition, useful e.g. for reducing neurodegenerative disorders associated with aging, comprises vitamin B6, vitamin B9 and/or folate, vitamin B12, oil e.g. docosahexaenoic acid and standardized extract of red fruit in e.g. anthocyanins - Google Patents

Abstract

Composition comprises vitamin B6, vitamin B9 and/or at least one folate, vitamin B12, an oil containing docosahexaenoic acid and eicosapentaenoic acid, and a standardized extract of red fruit in anthocyanins, and/or anthocyanidins. ACTIVITY : Neuroprotective; Nootropic; Dermatological; Anabolic. MECHANISM OF ACTION : None given.

Description

The invention relates to a composition, in particular a pharmaceutical, nutraceutical or food composition comprising vitamin B6, vitamin B9 and / or at least one folate, vitamin B12, an oil containing docosahexaenoic acid (DHA). and eicosapentaenoic acid (EPA) and at least one red fruit extract standardized to anthocyanins, anthocyanins and / or anthocyanins. The invention also relates to the use of such a composition for delaying or reducing neurodegenerative disorders and cognitive impairment related to age. The aging of the population is accompanied by an increase in neurodegenerative disorders (Alzheimer's disease for example) as well as by frequent cognitive impairment, including memory. The memory disorder is indeed one of the main cognitive changes felt by the elderly and expressed in medical consultations ("amnesic complaint" of the elderly). Among memory disorders, aging mainly affects the declarative memory as well as the working memory, while the semantic memory remains more stable and seems less affected (Park and Reuter-Lorenz 2009). Declarative memory and working memory require strong cognitive flexibility that relies mainly (but not exclusively) on the activity of two brain structures, the hippocampus and the prefrontal cortex. Numerous studies have shown that aging induces an alteration of the activity of these two cerebral structures. On the one hand, we note the emergence in the elderly of an overactivity of the frontal cortex which is accompanied by a reduction of the hippocampal activity (Sperling 2007). Many positive correlations have been established between frontal overactivity and memory impairment in the elderly (Davis et al., 2008). The gradual emergence of memory impairment in the elderly makes it all the more necessary to use nutritional compounds to prevent and / or slow the onset of cognitive decline, or even to compensate for the deterioration of the memory. upstream memory of the use of pharmacological compounds. - 2 - The European Food Safety Agency, under Regulation 1924/2006 recognizes the role of omega-3 fatty acids and especially docosahexaenoic acid (DHA), vitamins B6, B9 (or folates) and B12 in the maintenance of brain, psychological and neurological functions (European Food Safety Authority (EFSA) 2010a, European Food Safety Authority (EFSA) 2010b, European Food Safety Authority (EFSA) 2010c, European Food Safety Authority (EFSA) 2010d). Many studies have been conducted to demonstrate a positive impact of B vitamins, antioxidants such as plant polyphenols and more particularly anthocyanins, found in red fruits, and omega-3 fatty acids which are classified as essential fatty acids polyunsaturated and that it is found in large quantities in certain oily fish, in linseeds, nuts, or rapeseed, for example. Largely studied in isolation (Balk et al 2006, Lavialle 2007, Yao and Vieira 2007, Jia et al., 2008), some of these compounds have also been studied in combination: B vitamins (Lewerin et al., 2005, Stott et al. 2005), omega 3s and B vitamins (Andreeva et al., 2011). However, these studies show conflicting results. B vitamins combined with one another or with omega-3s do not appear to have a significant effect on cognitive functions (Andreeva et al., 2011, Balk et al., 2006, Lewerin et al., 2005). The same is true for the red fruit extracts studied in isolation (Balk et al., 2006). The Applicant Company has itself been able to demonstrate that an association of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), vitamins B6, B9 and B12 or a blueberry extract (Vaccinum myrtillus L) standardized in anthocyanins, anthocyanins and / or anthocyanidins had no significant promnesic effect in the aged mouse (see section EXAMPLES). There is therefore still a need for an association of assets to improve cognitive functions, especially among the elderly. An object of the invention is therefore to propose a novel composition having a promnesic effect and thus making it possible to reduce or delay age-related cognitive disorders and to improve the quality of life of persons suffering from these disorders. Other aims and advantages will become apparent on reading the nonlimiting description that follows. It is the merit of the inventors to have found, after lengthy and intense research, that it was possible to optimize the effectiveness of DHA, vitamins B6, B9 (or folate) and B12 through the addition of a red fruit extract containing anthocyanins, anthocyanins and / or anthocyanidins.

An object of the invention is therefore a composition, in particular pharmaceutical, nutraceutical, veterinary or food composition comprising - vitamin B6, - vitamin B9 and / or at least one folate, - vitamin B12, - an oil containing docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) and at least one red fruit extract standardized to anthocyanins, anthocyanins and / or anthocyanins. Within the meaning of the invention, the term "standardized" or "standardized" means the notion of controlling an extract, an oil or any other ingredient in order to make it conform to a standard or a minimum content defined in certain molecules such as anthocyanins, anthocyanins and / or anthocyanidins in the case of red fruit extract. A red fruit extract standardized to anthocyanins, anthocyanins and / or anthocyanidins is therefore a red fruit extract having a defined minimum content of anthocyanins, anthocyanins and / or anthocyanins. The addition of a standardized red fruit extract to anthocyanins, anthocyanins and / or anthocyanins to a composition comprising vitamins B6, B9 (and / or folate (s)) and B12, DHA and EPA achieves a significant improvement in cognitive function in subjects with age-related cognitive impairment. It improves the quality of life of people affected by age-related degeneration.

The oil can be selected from fish oils. Preferably, sardine, anchovy or tuna oil or a mixture of two or more of these oils will be used. Advantageously, the weight ratio DHA / EPA of the oil is between 2.5 and 8, preferably between 3 and 7, more preferably between 3.5 and 6, and even more preferably about 4.

The oil content of the composition according to the invention is advantageously from 74.00 to 89.80%, preferably from 76.00 to 85.00%, more preferably from 79.00 to 80.00% and even more preferably from approximately 79.70% by weight relative to the total weight of the whole of oil, vitamin B6, vitamin B9 and / or folate (s), vitamin B12 and red fruit extract.

The content of red fruit extract of the composition according to the invention is advantageously from 0.00 to 25.98%, preferably from 14.85 to 23.95%, more preferably 19.90 to 20.93% and more. preferably still about 20.22% by weight relative to the total weight of the set of oil, vitamin B6, vitamin B9 and / or folate (s), vitamin B12 and red fruit extract. Advantageously, the red fruit extract standardized to anthocyanins, anthocyanins and / or anthocyanidins is used in the form of a powder. The water content is preferably less than 8%, by weight, relative to the total weight of the extract. According to a preferred embodiment of the invention, the red fruit extract contains at least 23% of anthocyanins, anthocyanins and / or anthocyanidins expressed as cyanidin 3-O-glucoside equivalent, with, preferably, a minimum of 2% cyanidin 3-O-glucoside, a minimum of 0.1% of peonidine 3-O-galactoside and a minimum of 0.8% of peonidine 3-O-glucoside. The antioxidant capacity of the red fruit extract, determined in Trolox equivalent by the ORAC method (Prior et al., 2005), is preferably at least 9000 jamol Trolox equivalent per gram of extract powder. According to a preferred embodiment of the invention, the red fruit extract standardized in anthocyanins, anthocyanins and / or anthocyanidins. This red fruit extract can be chosen from extracts of blueberry (Vaccinum myrtillus L), blackberry, blueberry, strawberry, raspberry, blackcurrant, cranberry; very good results have been obtained with bilberry extract (Vaccinum myrtillus L). The content of vitamins B (B6, B9 and / or folate (s), B12) of the composition according to the invention is advantageously from approximately 0.02% to 0.2%, in particular from 0.02045% to 0, 1953%, preferably from 0.05 to 0.15%, more preferably from 0.07 to 0.1% and even more preferentially from approximately 0.08% by weight relative to the total weight of the oil assembly, vitamin B6, vitamin B9 and / or folate (s), vitamin B12 and red fruit extract. The vitamin B6 content is advantageously from 0.02 to 0.17%, preferably from 0.025 to 0.125%, more preferably from 0.045 to 0.075% and even more preferentially from about 0.053% by weight relative to the total weight of the product. set of oil, vitamin B6, vitamin B9 and / or folate (s), vitamin B12 and red fruit extract. The content of vitamin B9 and / or at least one folate is advantageously from 0.0004 to 0.025%, and preferably from about 0.025% by weight relative to the total weight of the whole of oil, vitamin B6, vitamin B9 and / or folate (s), vitamin B12 and red fruit extract. The vitamin B12 content is advantageously 0.00005 to 0.0003%, and preferably about 0.0003% by weight relative to the total weight of the whole of oil, vitamin B6, vitamin B9 and / or folate (s). ), vitamin B12 and red fruit extract. In a particularly advantageous embodiment, the composition according to the invention comprises: from about 0.02% to 0.2%, especially from 0.02045% to 0.1%, and preferably from 0.20% to 0.2%; , 0.5 to 0.15%, more preferably 0.07 to 0.1% and more preferably still about 0.08% by weight of vitamins B (B6, B9 and / or folate (s), B12) relative to the total weight of the whole of fish oil, vitamin B6, vitamin B9 and / or folate (s), vitamin B12 and red fruit extract, - from 74.00 to 89.80%, preferably from 76.00 to at 85.00%, more preferably 79.00 to 80.00% and even more preferably about 79.7% by weight of fish oil relative to the total weight of the whole fish oil, vitamin B6, vitamin B9 and / or folate (s), vitamin B12 and red fruit extract. from 10.00 to 25.98%, preferably from 14.85 to 23.95%, more preferably 19.90 to 20.93% and even more preferentially from about 20.22% by weight of fruit extract red, preferably blueberry (Vaccinum myrtillus L), based on the total weight of the whole fish oil, vitamin B6, vitamin B9 and / or folate (s), vitamin B12 and red fruit extract. In one variant of this embodiment, the different B vitamins are present in the following contents: from 0.02 to 0.17%, preferably from 0.025 to 0.125%, more preferably 0.045 to 0.075% and even more preferentially from 0.053% by weight of viatmine B6 based on the total weight of the whole fish oil, vitamin B6, vitamin B9 and / or folate (s), vitamin B12 and red fruit extract; from 0.0004 to 0.025%, and still more preferably from about 0.025% by weight of vitamin B9 and / or at least one folate relative to the total weight of the whole of fish oil, vitamin B6, vitamin B9 and / or folate (s), vitamin B12 and red fruit extract; from 0.00005 to 0.0003%, and even more preferentially from about 0.0003% by weight of vitamin B12 relative to the total weight of the whole of fish oil, vitamin B6, vitamin B9 and / or folate (s), vitamin B12 and red fruit extract; The composition according to the invention can be in different forms depending on how it will be administered.

It may for example be a concentrate consisting essentially of the five components defined above. The composition according to the invention may be in the form of a composition of pharmaceutical, nutraceutical or veterinary type, in which the five components (oil, vitamin B6, vitamin B9 and / or folate (s), vitamin B12, red fruit extract ) are associated with a pharmaceutically acceptable carrier, more particularly for oral administration, in such forms as tablets, hard or soft capsules (soft capsules), powders, granules and oral suspensions or solutions. When a solid composition in the form of tablets is prepared, the combination of the five components according to the invention is mixed with a vehicle such as starch, magnesium stearate, lactose, gum arabic, talc or the like. . A preparation in capsules is obtained by mixing the five components according to the invention with the appropriate excipients and pouring the resulting mixture into hard or soft capsules (soft capsules). A syrup or oral solution preparation may contain the combination of the five components of the invention together with a sweetener, a preservative, as well as a flavoring agent and a suitable colorant. The water-dispersible powders or granules may contain the combination of the five components according to the invention in admixture with dispersants or wetting agents, or suspending agents, as well as with correcting agents. taste or sweeteners. It can also be a food-type composition in which the combination of the five components according to the invention is integrated into a usual food composition, such as for example cereal bars, drinks, food dishes. and any type of food preparation usually consumed.

As already indicated above, the composition according to the invention makes it possible to significantly improve cognitive functions in subjects with age-related cognitive impairment. The invention therefore also relates to a composition as defined above for use as a medicament, more particularly for delaying or reducing neurodegenerative disorders and age-related cognitive impairment.

The invention also relates to a dietary supplement comprising the composition according to the invention. The amount of each of the five components of the composition in a drug or food supplement according to the invention will depend on the mode of administration (1, 2 or more intakes) and the daily amount.

In the composition of the invention, the daily quantity of oil administered to individuals is 630 mg with a minimum of docosahexaenoic acid (DHA) of 250 mg and a quantity of eicosapentaenoic acid (EPA) of between 31 mg and 100 mg. mg. Preferably the amount of DHA is 250 mg and the amount of EPA 60 mg. For vitamins B6, B9 (and / or folate (s)) and B12 the daily amounts in the composition of the invention correspond to a minimum of 15% of the recommended daily intakes (RDA - Directive 2008/100 / EC) namely 210 μg, 30 μg and 0.375 μg, respectively. Preferably, the daily amount of vitamin B6 is 420 μg, the daily amount of vitamin B9 is 200 μg and the daily amount of vitamin B12 25 is 2.5 jag. In the composition of the invention, the daily amount of red fruit extract administered to individuals ranges from 80 to 160 mg with a minimum amount of anthocyanins, anthocyanins and / or anthocyanidins ranging from 18.4 mg to 36 mg. , 8 mg. Preferably, the amount of red fruit extract amounts to 160 mg with a minimum of anthocyanins, anthocyanins and / or anthocyanidins of 36.8 mg.

The invention is described in more detail below, with the aid of the following examples which are in no way limiting but are given by way of example only. EXAMPLES The efficacy of the composition according to the invention was demonstrated by an in vivo study. This study aimed to determine and compare the promising potential on working memory. Mice of the C57B1 / 6 line aged 4-5 months ("young adult" group) or 17-18 months (C. Rivers, France) were used. This "rodent" model represents a validated model of working memory during aging. Indeed, aged mice (17-18 months) show increased sensitivity to delay-dependent proactive interferences in a spontaneous alternation test compared to young mice (4-5 months) (Vandesquille 2011). The effectiveness of the composition of the invention was verified on the model of C57B1 / 6 mice aged 17-18 months by a sequential alternation test. The sequential alternation test is widely used to evaluate spatial working memory in mice (Grant 1981, Beracochea et al., 1987, Beracochea et al., 1995). Sequential alternation is a protocol by which one evaluates sensitivity to interference, one of the main factors of forgetting. In this test, the mouse is subjected to several successive tests separated by a constant time interval. The quantitative increase in the number of trials (6 successive trials) causes a gradual fall in performance, from the 2nd trial to the 6th trial. In the 6th test (test N) for example, the animal must refer to the choice made in the 5th test (test N-1), without taking into account the previous choices (1st to 4th test, tests N-2, N-3 , etc.) that exert a strong proactive interference (Roberts and Dale 1981). The mouse must therefore permanently ignore the information that has become irrelevant from one test to another ("resetting mechanisms" (Olton and Samuelson 1976)) (Figure 1). The memory test was performed in an automated T-shaped labyrinth built in gray Plexiglas. The central aisle (35 cm long X 15 cm wide x 10 cm high) is connected to a starting compartment and two arrival compartments (left or right) of comparable dimensions (15cm x 10cm). A computer controls the automatic opening and closing of the doors, based on the signals emitted by photocells placed at the beginning of each arrival compartment and the departure compartment. The background noise (30dB) and lighting (30 lux) of the room were kept constant.

The labyrinth was thoroughly cleaned with 95% alcohol and then water between each mouse. The experimental rooms are air-conditioned and ventilated. In order to determine on the working memory during aging the effectiveness and the synergy of the nutritional compounds used in the composition according to the invention, several solutions have been realized: either a solution below called "Base" consisting of a suspension mixture of the following ingredients: fish oil standardized to DHA and EPA + vitamin B9 + vitamin B6 + vitamin B12. - The so-called "Base" solution associated with 3 different concentrations (dose 1, dose 2, dose 3) of blueberry extract standardized in anthocyanins, anthocyanins and / or anthocyanidins. - Or a solution of blueberry extract alone at the highest concentration (dose 3). COMPOSITION OF DIFFERENT SOLUTIONS To prepare the "Base" solution, 0.315 mg of fish oil with a DHA / EPA ratio of 4, 0.000306 mg vitamin B6, 0.00013 mg vitamin B9 and 0.0015 mg of a powder containing 0.1% vitamin B12 were mixed. The solutions "Base + dose 1", "Base + dose 2" and "Base + dose 3" were obtained by mixing 0.315 mg of fish oil with a ratio of DHA / EPA equal to 4, 0.000306 mg of vitamin B6, 0.00013 mg of vitamin B9 and 0.0015 mg of a powder containing 0.1% of vitamin B12 with 0.08 mg, 0.80 mg, 0.160 mg of blueberry extract, standardized at 23%, respectively at least anthocyanins, anthocyanins and / or anthocyanidins for doses 1, 2 and 3 The solution of blueberry extract alone at dose 3 was obtained by mixing 0.160 mg of blueberry extract, standardized to a minimum of 23% anthocyanins, anthocyanins and / or anthocyanidins, at 0.315 mg of water. These solutions were administered daily per os by gastric intubations (2 gavages per day). The concentrations administered daily by gastric intubation (2 gavages per day) and the comparison with humans are specified in Table 1. Table 1: Amount of base solution and red fruit extract administered by gastric intubation (2 gavages a day) to the mice. Correspondence with an example of quantity administered in humans. Male (70kg) Male (70kg) Mouse (35g) Mouse (35g) Mouse (35g) Basic solution mg / day mg / day mg / day mg / day mg / day (Example 1) (Example 2) Fish oil 630 630 0.315 '0.315' 0.315 'Vitamin B9 0.26 0.26 0.000131 0.000131 0.000131 Vitamin B6 0.612 0.612 0.0003061 0.0003061 0.0003061 Vitamin B12 (Powder 0.1% B12) 3 3 0.00151 0.0015 1 0.00151 Red fruit extract 160 80 / / / Dose 1 / 0.081 / / Dose 2 3 / / 0.8 3 / Dose 3 2 / / / 1.6 2 I Dose calculated on the basis of the relationship between human mass (70kg) and mass of the mouse (35g) 2: Dose calculated on the basis of the quantities of dry matter ingested by humans (160 mg of blueberry extract per 500 g of dry matter) and amounts of dry matter ingested by the mouse (5 g of dry matter). 3: Dose calculated on the basis of the quantities of dry matter ingested by man (80 mg of blueberry extract per 500 g of dry matter) and the quantities of dry matter ingested by the mouse (5 g of dry matter). The administration of the solutions was carried out per os by gastric intubations (force-feeding with 2 daily gavages) carried out in the morning and in the afternoon. During the behavioral sessions (sequential alternation test), the solutions are administered 1 hour before the beginning of the session. The feeding is always done in a room different from that where the behavioral test takes place. The mice were divided into independent groups according to the following treatments: - Group 1: "Young adult", C57B1 / 6 mice aged 4-5 months (not gavaged); N = 12 - Group 2: "Aged", C57B1 / 6 mice aged 17-18 months (not gavaged); N = 12 - Group 3: "Aged-Base": C57B1 / 6 mice aged 17-18 months fed with the so-called Base solution (see Table 1); N = 12 - Group 4: "Aged-Base + water": C57B1 / 6 mice aged 17-18 months force-fed with the so-called Base solution and with water (1 gavage "base" in the morning + 1 gavage "water " the afternoon); N = 12 - Group 5: "Age-Base + Dose 1": C57B1 / 6 mice aged 17-18 months fed with the so-called base solution associated with blueberry extract at dose 1 (see Table 1); N = 12 - Group 6: "Aged-Base + Dose 2": C57B1 / 6 mice aged 17-18 months fed with the so-called base solution associated with blueberry extract at dose 2 (see Table 1); N = 12 - Group 7: "Aged-Base + Dose 3": C57B1 / 6 mice aged 17-18 months fed with the so-called base solution associated with blueberry extract at dose 3 (see Table 1) ; N = 12 - Group 8: "Aged-Dose 3 of Bilberry" only; 17-18 month old C57B1 / 6 mice fed with the solution of blueberry extract alone at dose 3 (see Table 1), N = 13 Comparison of groups 1 and 2 makes it possible to measure the deleterious effect of aging in the untreated mouse. The comparison of groups 2, 3 and 4 makes it possible to determine whether the possible stress induced by the gastric intubation procedure interferes with the performance of the aged mice and whether the administration of the base induces a promnesiant effect according to the quantity administered daily. (1 dose versus 2 doses) The comparison of the 3,5,6 and 7 groups makes it possible to determine - if the blueberry extract associated with the so-called base solution induces a promissant effect compared to the so-called base solution alone (comparison with group 3) and at which concentration this bilberry extract is effective (comparison between groups 5,6 and 7). Group 8 makes it possible to determine whether or not the effective dose of the bilberry extract in combination with the "Base" product has a promnesiant effect on administration alone (ie without the so-called Base solution).

For each group of mice, the administration of the different solutions lasts 30 days consecutively. The behavioral test is performed repeatedly on the same groups of animals either after 1 day, 15 days or 30 days of treatment. Each mouse is thus evaluated with 3 different treatment durations, which makes it possible to assess the evolution of the performances as a function of the duration of the treatment on the same animal. RUNNING OF THE TESTS - Habituation. The mice were manipulated several days before the onset of behavioral tests, to familiarize them with the manipulation and reduce stress in contact with the experimenter. - Free exploration. The mice were placed daily for 10 minutes in the T-labyrinth for 2 successive days, for free exploration of the apparatus (i.e. without closing the doors). During each session, the animal was therefore free to browse the entire labyrinth, to become familiar with the device and above all, to constitute the "spatial and environmental map" (spatial references) essential to alternate. Training Phase: The mice were subjected the next day to a session consisting of 7 successive trials separated by a 30-second test interval. This session allows the animal to become familiar with the opening and closing of doors in the labyrinth. Each test was conducted as follows. The animal was first placed in the departure compartment for 30 seconds. At the end of this period of confinement, the door was opened and the animal could choose to enter the arrival compartment (left or right) of his choice. As soon as the animal entered the compartment of arrival, the door of this compartment was closed, the mouse remaining 30 seconds in the arrival arm. Then at the end of this period of confinement, the mouse was manually returned to the starting compartment for a new test, identical to the first. At each test, the animal was free to enter each of the two arrival compartments. During the confinement period in the departure compartment, the center aisle and the arrival arms were cleaned. - Test phase. 1 hour before the test, the mice received oral treatment, in a room different from that where the behavioral test took place. Each mouse was then subjected to seven successive trials each separated by an interval of 90 seconds. We have shown in our previous studies, that this time interval caused a gradual and significant fall of the alternation in the aged mouse. The procedure is identical to that of the "training" phase, except for increasing the time between tests. STATISTICS The comparison of the groups was carried out by analysis of variance (Fisher PLSD ANOVA) with one or more factors, followed according to the case by a Bonferroni-Dunn post-hoc test. Intra-group comparisons were performed by Student's t-test. The statistical significance level is set at p <0.05. EFFECT AFTER 1 DAY OF TREATMENT (Figure 2) Only ungated "young adult" mice have a high% alternation and significantly higher than the theoretical chance (50%), now throughout the series. trials. On the other hand, the "Aged" mice of the groups treated or not, have percentages of alternation which do not differ significantly from chance, and which are significantly lower than those of the "young adult" mice not stuffed. This result confirms the mouse model used in this study. The treatment of one day by the so-called "Base" solution, with or without red fruit extract, does not cause any particular promnesiant effect on the performance of "aged" mice, which remain deficient compared to "young adult" mice (Figure 2).

EFFECT AFTER 15 DAYS OF TREATMENT (Figure 3) The solutions "Base + Blueberry dose 2" and "Base + Blueberry dose 3" allow old mice to recover after 15 days of supplementation a working memory equivalent (not significantly different) to that measured in young adults.

The groups receiving the product "Base" and "Base + water" showed no improvement in performance compared to older mice without supplementation. The groups receiving the product "Base" and "Base + water" showed no improvement in performance compared to older mice "Base + Bilberry Extract - Dose 1". The groups receiving the product "Base" and "Base + water" showed no improvement in performance compared to older mice "Base + bilberry extract - Dose 2". The group receiving only the product "Bilberry extract alone - Dose 3" showed no improvement in performance over aged mice without supplementation. The group receiving only the product "Bilberry extract alone - Dose - 17 - 3" showed no improvement in performance compared to the older mice "Base + water", "Base", "Base + bilberry extract - Dose 1" and "Base + bilberry extract - Dose 2", The group receiving the product "Base + Blueberry dose 3" has a significantly increased working memory compared to older mice without supplementation (p <0.0037). The group receiving the product "Base + Blueberry dose 3" has a significantly increased working memory compared to aged "Base + Water" mice (p = 0.011).

The group receiving the product "Base + Blueberry dose 3" has a significantly increased working memory compared to older "Base" mice (p <0.01). The group receiving the product "Base + Blueberry dose 3" has a significantly increased working memory compared to aged mice "Bilberry extract alone - Dose 3" (p <0.01). The combination according to the invention thus allows after 15 days of treatment a potentiation of the promnesiant effect compared to the solution consisting of a suspension mixture of fish oil standardized in DHA and EPA, vitamin B9, vitamin B6 and vitamin B12 called "Base" and bilberry extract solution alone at the strongest concentration called "Blueberry extract alone - Dose 3", administered separately, and they are devoid of promnesiant effect. EFFECT AFTER 30 DAYS OF TREATMENT (Figure 4) The products "Base + Blueberry dose 1", "Base + Blueberry dose 2" and "Base + Blueberry dose 3" allow old mice to recover after 30 days of supplementation a working memory equivalent (not significantly different) to that measured in young adults. The group receiving the "Base + water" product showed no improvement in performance compared to elderly mice without supplementation. The group receiving the product "Base + water" showed no improvement in performance compared to aged mice "Bilberry extract alone - Dose 3". The group receiving the "Base" product showed a significant decrease in performance compared to "young adult" mice (p <0.043). The group receiving the product "Base" has a slight improvement in performance compared to elderly mice without supplementation and aged mice "Base + water", this improvement is however not significant. The group receiving the "Base" product showed no improvement in performance compared to older mice "Base + bilberry extract - Dose 1". The group receiving the product "Base + Blueberry dose 1" has a slight improvement in performance compared to elderly mice without supplementation and aged mice "Base + water", this improvement is not significant but does not differ significantly either. "young adult" mice. The group receiving the product "Base + Blueberry dose 2" has a significantly increased working memory compared to aged mice without supplementation p <0.01. The group receiving the product "Base + Blueberry dose 2" has a significantly increased working memory compared to older "Base + water" mice p <0.01. The group receiving the product "Base + Blueberry dose 2" has a significantly increased working memory compared to aged "Base" mice 2 p <0.05. The group receiving the product "Base + Blueberry dose 2" has a significantly increased working memory compared to the older mice "Base + Blueberry dose 1" p <0.05. The group receiving the product "Base + Blueberry dose 2" has a working memory equivalent to older mice "Base + Blueberry dose 3". The group receiving the product "Base + Blueberry dose 2" has a significantly increased working memory compared to aged mice "Bilberry extract alone - Dose 3" p <0.01. The group receiving the product "Base + Blueberry dose 3" has a significantly increased working memory compared to older mice without supplementation (p <0.01). The group receiving the product "Base + Blueberry dose 3" has a significantly increased working memory compared to older "Base + water" mice (p <0.01).

The group receiving the product "Base + Blueberry dose 3" has a working memory that tends to be increased (p = 0.07) compared to older "Base" mice. The group receiving the product "Base + Blueberry dose 3" has a significantly increased working memory compared to older mice "Base + Blueberry dose 1" (p <0.05). The group receiving the product "Base + Blueberry dose 3" has a significantly increased working memory compared to aged mice "Bilberry extract alone - Dose 3" (p <0.01). The combination according to the invention thus allows, after 30 days of treatment, a potentiation of the promnesiant effect compared to the solution consisting of a suspension mixture of fish oil standardized with DHA and EPA + vitamin B9 + - vitamin B6 + vitamin B12 called "Base" and blueberry extract solution alone at the strongest concentration called "Bilberry extract alone - Dose 3", administered separately, and they are devoid of promnesiant effect.

EVOLUTION OF EFFICACY ACCORDING TO TIME (Figure 5) After 15 days, the most important evolution concerns the group "Base + blueberry dose 3" whose performances evolve from 50 ± 2.9% in J1 to 73.6 ± 4.3%; t = 5.45; p = 0.0002 then the group "Base + blueberry dose 2" whose% of alternation evolves from 47.2 ± 3.4% in J1 to 62.5 ± 5.8% after 15 days; t = 1.95; p = 0.07. The other groups "Aged" treated or untreated show% alternation close to chance (50%) and very comparable in J1 and J15. After 30 days, only two groups showed a significant improvement in their performance: the older group "Base + bilberry dose 2" which changed from 47.2 ± 3.4% in J1 to 76.3 ± 3.2%; t = 8.04; p <0.0001 and the older group "Base + blueberry dose 3" which changes from 50 ± 2.9% in J1 to 73.6 ± 3.8%; t = 6.18; p <0.0001). DESCRIPTION OF THE FIGURES FIG. 1 illustrates the diagram of the analytical potential of the sequential alternation test determining the working memory. Figure 2 illustrates the effects of the different treatments after one day of oral gastric intubation administration on the general% sequential alternation. FIG. 3 illustrates the effects of the various treatments after 15 days of administration by oral gastric intubation on the average alternation of tests 2-7. FIG. 4 illustrates the effects of the various treatments after 30 days of administration by oral gastric intubation on the average alternation of the tests 2-7. FIG. 5 illustrates the evolution of performances as a function of the duration of the treatment. - 22 - BIBLIOGRAPHIC REFERENCES Andreeva, V. A., et al. (2011). "Cognitive function alter supplementation with vitamins and long-chain omega-3 fatty acids: ancillary findings from the SU.FOL.0M3 randomized trial." Am J Clin Nutr 94 (1): 278-86.

Balk, E., et al. (2006). "B vitamins and berries and age-related neurodegenerative disorders." Evid Rep Technol Assess (Full Rep). (134): 1-161. Beracochea, D., et al. (1995). "B-CCM reverses the memory deficits caused by a chronic ethanol administration and mammillary bodies lesions in mice." Psychobiology 23: 52-58.

Beracochea, D., et al. (1987). "Build-up and release from proactive interference in chronic ethanol consumption in mice: a behavioral and neuroanatomical study." Behav Brain Res 25 (1): 63-74. Davis, S. W., et al. (2008). "What PASA? The posterior-anterior shift in aging." Cereb Cortex 18 (5): 1201-9.

European Food Safety Authority (EFSA) (2010a). "Scientific Opinion on the maintenance of docosahexaenoic acid (DHA) and maintenance of normal (fasting) blood concentrations of triglycerides (ID 533, 691, 3150), protection of blood lipids from oxidative damage (ID 630), contribution to the maintenance of a normal body weight (ID 629), brain, eye and development (ID 627, 689, 704, 742, 3148, 3151), maintenance of normal brain function (ID 565, 626, 631, 689, 690, 704, 742, 3148, 3151), maintenance of normal vision (ID 627, 632, 743, 3149) and maintenance of normal spermatozoa motility (ID 628) pursuant to Article 13 (1) of Regulation (EC) No. 1924 / 2006 "EFSA Journal 8 (10): 1734.

European Food Safety Authority (EFSA) (2010b). "(81, 85, 86, 88), maintenance of normal vision (ID 83, 87), reduction of fatigue and fatigue (ID 84), cell division (ID 195, 2881) and contribution to normal amino acid synthesis (ID 195, 2881) pursuant to Article 13 (1) of Regulation (EC) No 1924/2006. " EFSA Journal 8 (10): 1760. - 23 - European Food Safety Authority (EFSA) (2010c). B6 and contribution to normal homocysteine metabolism (ID 73, 76, 199), maintenance of normal bone (ID 74), maintenance of normal teeth (ID 74), maintenance of normal hair (ID 74), maintenance of normal skin (ID 74), maintenance of normal nails (ID 74), contribution to normal energy-yielding metabolism (ID 75,214), contribution to normal psychological functions (ID 77), reduction of tiredness and fatigue (ID 788), and contribution to normal cysteine synthesis (ID 4283) pursuant to Article 13 (1) of Regulation (EC) No 1924/2006 "EFSA Journal 8 (10): 1759.

European Food Safety Authority (EFSA) (2010d). B12 and contribution to normal neurological and psychological functions (ID 95, 97, 98, 100, 102, 109), contribution to normal homocysteine metabolism (ID 96, 103, 106), maintenance of normal bone (ID 104), maintenance of normal teeth (ID 104), maintenance of normal hair (ID 104), maintenance of normal skin (ID 104), maintenance of normal nails (ID 104), reduction of fatigue and fatigue (ID 108), and cell division (ID 212) pursuant to Article 13 (1) of Regulation (EC) No. 1924/2006 "EFSA Journal 8 (10): 1756. Grant, D. (1981). "Intertrial interference in the rat's short term memory." Journal of Experimental Psychology 7: 217-227. Jia, X., et al. (2008). "Does taking vitamin, mineral and fatty acid supplements prevent cognitive decline? A systematic review of randomized controlled trials." J Hum Nutr Diet 21 (4): 317-36. Lavialle, M. (2007). "DHA in neurotransmission." Oilseeds, Fatty Bodies, 25 Lipids. 14 (1): 11-15. Lewerin, C., et al. (2005). "Significant correlations of plasma homocysteine and serum methylmalonic acid with movement and cognitive performance in the elderly subjects no change from a short-term vitamin therapy: a placebo-controlled randomized study." Am J Clin Nutr. 81 (5): 1155-62.

Olton, D. and R. Samuelson (1976). "Remembrance of places passed: spatial memory in rats." J Exp Psychol Anim Behav Processes 2: 97-116. Park, D.C. and P. Reuter-Lorenz (2009). "The adaptive brain: aging and neurocognitive scaffolding." Annu Rev Psychol 60: 173-96. Prior, R., et al. (2005). "Standardized methods for the determination of antioxidant capacity and phenolics in foods and dietary supplements." J Agric Food Chem 53 (10): 4290-302. Roberts, A. and R. Dale (1981). "Remembrance of places lasts: Proactive inhibition and patterns of choice in space memory." Learning and motivation 12: 261-281. Sperling, R. (2007). "Functional MRI studies of associative encoding in normal aging, mild cognitive impairment, and Alzheimer's disease." Ann N Y Acad Sci 1097: 146-155. Stott, D., et al. (2005). "Randomized controlled trial of homocysteine-lowering vitamin treatment in elderly patients with vascular disease." Am J Clin Nutr. 82 (6): 13206. Vandesquille, M. (2011) Involvement of the cholinergic system in the alteration of working memory during aging in mice. University of Bordeaux 1. Bordeaux. Yao, Y. and A. Vieira (2007). "Protective activities of Vaccinium antioxidants with potential relevance to mitochondrial dysfunction and neurotoxicity." Neurotoxicolo gy 28 (1): 93-100.20

Claims (10)

CLAIMS1 Composition comprising - vitamin B6, - vitamin B9 and / or at least one folate, - vitamin B12, - an oil containing docosahexanoic acid (DHA) and eicosapentaenoic acid (EPA) and - a red fruit extract standardized in anthocyanins, anthocyanins and / or anthocyanidins. 2. Composition according to claim 1, characterized in that the oil is a fish oil. 3. Composition according to claim 1 or 2, characterized in that the red fruit extract is an extract of blueberry. 4. Composition according to any one of the preceding claims, characterized in that the oil content is 74 to 89.80% by weight relative to the total weight of the set of oil, vitamin B6, vitamin B9 and / or folate, vitamin B12 and plant extract. 5. Composition according to any one of the preceding claims, characterized in that the content of plant extract is 10 to 25.98% by weight relative to the total weight of the set of oil, vitamin B6, vitamin B9 and / or folate, vitamin B12 and plant extract. 6. Composition according to any one of the preceding claims, characterized in that the vitamin B content is 0.02 to 0.2% by weight relative to the total weight of the set of oil, vitamin B6, vitamin B9 and / or folate, vitamin B12 and vegetable extract. 7. Composition according to any one of the preceding claims, characterized in that the weight ratio docosahexanoic acid (DHA) / eicosapentaenoic acid (EPA) is from 2.5 to 8. Composition according to any one of the preceding claims for use as a medicament. 9. A composition according to any one of the preceding claims for delaying or reducing neurodegenerative disorders and age-related cognitive impairment. 10. Food supplement or food comprising a composition according to any one of claims 1 to 7.