WO2026008342A1 - Composition for improving sleep - Google Patents

Abstract

The invention pertains to a non-therapeutic method for improving sleep and/or improving physical activity in a healthy human subject, said method comprising administering to said subject a combination of: i) uridine, or salts, phosphates, acyl derivatives or esters thereof; ii) at least one of docosahexaenoic acid (22:6; DHA) and eicosapentaenoic acid (20:5; EPA), or esters thereof, preferably at least DHA, more preferably DHA and EPA; iii) choline, or salts or esters thereof; and iv) at least one vitamin B selected from vitamins B6, B9 and B12 including their functional equivalents; and v) optionally at least one of vitamin C, vitamin E and selenium.

Description

Composition for improving sleep

Field of the invention

The invention is the field of nutrition and more particularly relates to nutritional compositions for improving sleep and/or improving physical activity in a healthy subject. The composition is in particular used in adults, preferably elderly in need of improved sleep quality.

Background

The amount of sleep and the sleep quality generally decreases during aging and may be caused by many different physiological, psychological, lifestyle, and social changes. Sleep disturbances are common in older adults and poor sleep quality can impact both mental wellbeing and physical health. Older adults often engage in less physical activity, which can negatively impact sleep quality. Also, changes in living situations, such as moving to assisted living facilities, can disrupt familiar sleep environments and routines. These factors contribute to a decline in sleep quality with age, affecting overall health and well-being.

Current treatments like sleep medication or melatonin may promote sleep, but can also have side effects like drowsiness or impaired focus. Thus, there remains a need to further investigate whether dietetic and nutritional intervention helps to improve and support sleep quality in subjects in need thereof.

WO2022240286 describes a composition comprising high protein matter in the range of 5 to 25g per 100 calories for preserving or increasing muscle mass during sleep and improving sleep quality by taking the composition shortly before going to sleep. The composition can further comprise choline and DHA/EPA, vitamins and minerals.

CN110250288 describes the beneficial effect of a composition comprising among others whey powder, DHA, MCT fat, inulin on improving sleep, in particular on improving sleep latency and sleep duration, in breastfeeding mothers.

US2010/331275 describes a composition comprising DHA and/or EPA and uridine for supporting activities of daily living in subjects suffering from Alzheimer’s disease or dementia. It furthers mentions a disturbed sleeping pattern in rats given a vitamin B-deficient diet while locomotor activity was decreased and time spent at rest increased. Activities of daily living is a medical terminology for which tests are available assessing the subject’s ability to perform such activities.

JP 2012/051865 describes the use of a seafood extract such as krill extract comprising phospholipids, DHA and EPA for promoting a sedative effect. It shows less exercise activity while being awake and becoming ‘sleepy’ (sleep prolongation), thus implying reduced physical activity.

Overall, studies of improved nutrition have shown contrasting effects in intervention groups, but whether increased nutritional intake may improve sleep quality and/or physical activity in healthy subjects, or subjects in need of improved sleep has not been adequately studied. Thus, there remains a need to further investigate whether dietetic and nutritional intervention helps to improve and support sleep in subjects in need thereof.

Summary of the invention

The inventors have observed that upon administering a combination or product comprising (i) uridine, or salts, phosphates, acyl derivatives or esters thereof; (ii) at least one of docosahexaenoic acid (22:6; DHA) and eicosapentaenoic acid (20:5; EPA), or esters thereof; (iii) choline, or salts or esters thereof; and (iv) at least one vitamin B selected from vitamins B6, B9 and B 12 including their functional equivalents; and optionally (v) at least one of vitamin C, vitamin E and selenium, to a healthy human subject, the sleep (quality) and physical activity in said subject was improved. Sleep and physical activity can be improved using the composition of the invention, in particular in a healthy elderly subject of at least 50 years of age. The subjects were healthy and not diagnosed with neurological impairment or diseases, but merely subject to normal ageing. The present inventors surprisingly found, through clinical study, that administration of a composition containing (i) - (iv) (and optionally (v)) showed a significant reduction in sleep disturbances and a significant increase in exercise frequency as part of physical activity. In addition, a trend was visible towards increased exercise duration. Compliance and tolerability were very high and side effects were relatively low. The results of the clinical study are summarized in the examples section. The combination of improved sleep and increased physical exercise frequency shows that the subjects did not only spend increased time in bed or asleep but further suggests that the subjects were more rested and more active which emphasizes the benefits for older adults to have a more active lifestyle. Based on those results, the invention thus pertains to the (non-therapeutic) method for improving sleep and/or improving physical activity in a healthy human subject, said method comprising administering to said subject a combination of (i) uridine, or salts, phosphates, acyl derivatives or esters thereof; (ii) at least one of docosahexaenoic acid (22:6; DHA) and eicosapentaenoic acid (20:5; EPA), or esters thereof; (iii) choline, or salts or esters thereof; and

(iv) at least one vitamin B selected from vitamins B6, B9 and B12 including their functional equivalents, and optionally (v) at least one of vitamin C, vitamin E and selenium.

Worded differently, the invention pertains to the non-therapeutic use of a combination of (i) uridine, or salts, phosphates, acyl derivatives or esters thereof; (ii) at least one of docosahexaenoic acid (22:6; DHA) and eicosapentaenoic acid (20:5; EPA), or esters thereof; (iii) choline, or salts or esters thereof; and (iv) at least one vitamin B selected from vitamins B6, B9 and B 12 including their functional equivalents, and optionally (v) at least one of vitamin C, vitamin E and selenium, for improving sleep and/or improving physical activity in a healthy human subject, said use comprising administering to said subject the aforementioned combination.

The invention also pertains to a combination of (i) - (iv) and optionally (v) in the manufacture of a nutritional composition for improving sleep and/or improving physical activity in a healthy human subject in need thereof. It is preferred that therapeutically effective amounts of (i) - (iv) and optionally (v) are part of a composition to be administered to said healthy human subjects. Worded differently, the invention also pertains to a composition for use in (therapeutically) improving sleep and/or (therapeutically) improving physical activity in a (healthy) human subject in need thereof, said composition comprising a combination of (i) - (iv) and optionally

(v).

Outside the scope of physical activity of healthy subjects, let alone sleep behavior, it is noted that during the last decennium, uridine, choline and omega-3 fatty acids such as DHA have attracted attention as active components in supporting memory and/or cognitive function in subjects in need thereof, also often in context of age-associated neurodegenerative processes such as MCI and dementia, but also in the context of neurotrauma. These compounds have been found rate-limiting precursors for membrane phosphatide synthesis. The multi -nutrient combination ‘Fortasyn Connect’ (DHA, EPA, UMP, choline, phospholipids, vitamins B6, B9, B12, C, E, and selenium) is known to support endogenous phospholipid synthesis and to slow down cognitive decline (e.g. memory loss) in early stages of Alzheimer’s disease.

List of figures

Figure 1 shows the changes from baseline in sleep disturbance scores wherein subjects were randomized to either the placebo group (n = 24) or nutritional supplementation with a composition according to the present invention (n = 24). A significant decrease (p<0.05) in sleep disturbances was observed in the group that received the active composition.

Figure 2 shows the changes from baseline in exercise frequency scores wherein subjects were randomized to either the placebo group (n = 24) or nutritional supplementation with a composition according to the present invention (n = 24). A significant increase (p<0.05) in physical exercise frequency was observed in the group that received the active composition.

Figure 3 shows the changes from baseline in exercise duration scores wherein the subjects were randomized to either the placebo group (n = 24) or nutritional supplementation with a composition according to the present invention (n = 24). A non-significant increase (p<0.10) in physical exercise duration was observed in the group that received the active composition.

List of preferred embodiments

1. A (non-therapeutic) method for improving sleep and/or improving physical activity in a healthy human subject, said method comprising administering to said subject a combination of: i. uridine, or salts, phosphates, acyl derivatives or esters thereof; ii. at least one of docosahexaenoic acid (22:6; DHA) and eicosapentaenoic acid (20:5; EPA), or esters thereof, preferably at least DHA, more preferably DHA and EPA; iii. choline, or salts or esters thereof; and iv. at least one vitamin B selected from vitamins B6, B9 and B12 including their functional equivalents; and v. optionally at least one of vitamin C, vitamin E and selenium.

2. The method according to embodiment 1, wherein the healthy human subject is an adult, preferably an elderly person, preferably at least 50 years of age, more preferably at least 55 years of age; and/or the subject is a subject that self-reports a subjective age-related cognitive decline but has no neurodegenerative disease diagnosis. 3. The method according to embodiment 1 or 2, wherein improving sleep and/or improving physical activity comprises one or more of: improving sleep quality, reducing sleeping problems or disturbances, increasing sleep duration, increasing frequency of physical activity or exercises, increasing duration of physical activity or exercises, reducing muscle fatigue, reducing mental fatigue.

4. The method according to any one of the preceding embodiments, wherein improving sleep and/or improving physical activity is assessed on the basis of Patient Reported Outcomes Measurement Information System (PROMIS) or Physical Activity Questionnaire for Older Adults (CHAMPS).

5. The method according to any one of the preceding embodiments, wherein the combination administered to said subject further comprises at least one or more of vitamin C, vitamin E and selenium, preferably all of vitamin C, vitamin E and selenium.

6. The method according to any one of the preceding claims, wherein the combination administered to said subject further comprises at least one phospholipid.

7. The method according to any one of the preceding embodiments, wherein DHA is administered in an amount of at least 0.5 g per 100 g, preferably 0.5 - 5 g per 100 g of the composition or per day.

8. The method according to any one of the preceding embodiments, wherein uridine, as the cumulative amount of uridine, deoxyuridine, uridine phosphates, nucleobase uracil and acylated uridine derivatives, is administered in an amount of 0.1-5 g, preferably 0.2-2.5 g, more preferably 0.25-1 g per 100 g of the composition or per day.

9. The method according to any one of the preceding embodiments, wherein choline or salts or esters thereof, calculated as choline, is administered in an amount more than 0.1 g, preferably 0.1 to 1 g choline per 100 g of the composition or per day.

10. The method according to any one of the preceding embodiments, wherein selenium is administered in an amount of 0.01 - 0.5 mg, preferably 0.02 - 0.1 mg per 100 g of the composition or per day.

11. The method according to any of the preceding embodiments, wherein vitamin C is administered in an amount of 20 to 1000 mg, in particular in the range of 30 to 500 mg, more in particular in the range of 50 to 150 mg per 100 g of the composition or per day.

12. The method according to any one of the preceding embodiments, wherein the combination is comprised in a liquid nutritional supplement.

13. The method according to any one of the preceding embodiments, wherein the composition comprises, per 100 ml of liquid: 100 - 500 mg EPA,

1000 - 1500 mg DHA,

80 - 600 mg phospholipids,

200 - 600 mg choline,

400 - 800 mg uridine monophosphate (UMP),

20 - 60 mg alpha-TE (vitamin E),

60 - 100 mg vitamin C,

40 - 80 pg selenium,

1 - 5 pg vitamin Bl 2,

0.5 - 2 mg vitamin B6, and

200 - 600 pg folic acid.

14. Use of a combination of: i. uridine, or salts, phosphates, acyl derivatives or esters thereof; ii. at least one of docosahexaenoic acid (22:6; DHA) and eicosapentaenoic acid (20:5; EPA), or esters thereof, preferably at least DHA, more preferably DHA and EPA; iii. choline, or salts or esters thereof; and iv. at least one vitamin B selected from vitamins B6, B9 and B12 including their functional equivalents; and v. optionally at least one of vitamin C, vitamin E and selenium, for the manufacture of a nutritional composition for improving sleep and/or improving physical activity in a healthy human subject in need thereof.

15. A composition for use in improving sleep and/or improving physical activity in a subject in need thereof, said composition comprising: i. uridine, or salts, phosphates, acyl derivatives or esters thereof; ii. at least one of docosahexaenoic acid (22:6; DHA) and eicosapentaenoic acid (20:5; EPA), or esters thereof, preferably at least DHA, more preferably DHA and EPA; iii. choline, or salts or esters thereof; and iv. at least one vitamin B selected from vitamins B6, B9 and B12 including their functional equivalents; and v. optionally at least one of vitamin C, vitamin E and selenium.

Detailed description of the invention Throughout this application, the following terminology and abbreviations may be used:

Patient-Reported Outcomes Measurement Information System Short Form vl.O Sleep Disturbance 8b (PROMIS Short Form vl.O Sleep Disturbance 8b) or in short “PROMIS” refers to the self-reported questionnaire used to assess sleep disturbances and in general sleep quality. The questionnaire measures quality of sleep on a 5-point scale for 8 different items focusing on sleep quality.

Community Healthy Activities Model Program for Seniors or in short “CHAMPS” refers to the self-reported questionnaire used to assess physical activity. The questionnaire is about activities that may have been done by the subject in the past 4 weeks, how many times the subject performed said activity and how many hours the subject spent on that activity.

Subjective Cognitive Decline Questionnaire 9 or in short “SCD-Q9” refers to the self-reported questionnaire and serves as a brief screening tool for early detection of subjective cognitive decline by (healthy) aging.

With ‘administration’ it is preferably oral administration which is intended.

In one aspect of the present invention, (i) - (iv) and optional (v) are part of a composition according to the invention which is used as a pharmaceutical product comprising one or more pharmaceutically acceptable carrier materials.

In a preferred aspect of the invention, (i) - (iv) and optional (v) are part of a composition which is used as a nutritional product, for example as a nutritional supplement, e.g., as an additive to a normal diet, as a fortifier, to add to a normal diet, or as a complete nutrition. The nutritional product preferably comprises at least one component selected from the group of fats, proteins, and carbohydrates. It preferably comprises between 30 - 60 en% carbohydrates, between 30 and 60 en% fat, and between 1 and 20 en% protein. This is based on the assumption that lipid, carbohydrates and protein generate approximately 9, 4 and 4 kcal/g, respectively, the 3 together making up for all caloric contributions of the composition. In one embodiment, the food product is a liquid composition containing between 0.8 and 1.4 kcal per ml. It is understood that a nutritional product differs from a pharmaceutical product by the presence of nutrients which provide nutrition to the subject to which the composition is administered, in particular the presence of protein, fat, digestible carbohydrates and dietary fibres. It is preferably a composition complying with food for special medical purposes requirements, preferably according to EC directive FSMP 1999/21ZEC which is herewith incorporated by reference. It may further contain ingredients such as minerals, vitamins, organic acids, and flavouring agents.

According to another embodiment of the invention, the composition is provided as a nutritional product or nutritional supplement. The product of the invention is an enteral composition, intended for oral administration. It is preferably administered in liquid form. In one embodiment, the food product is a liquid composition containing between 50 and 250 kcal per 100 ml, more preferably between 75 and 125 kcal per 100 ml.

A first aspect of the invention provides for a (non-therapeutic) method for improving sleep and/or improving physical activity (increasing frequency and/or duration of physical activity), preferably improving sleep and improving physical activity (increasing frequency and duration of physical activity) in a healthy human subject, said method comprising administering to said subject a combination of: i. uridine, or salts, phosphates, acyl derivatives or esters thereof; ii. at least one of docosahexaenoic acid (22:6; DHA), eicosapentaenoic acid (20:5; EPA) and docosapentaenoic acid (22:5; DPA), or esters thereof, preferably at least DHA, more preferably DHA and EPA; iii. choline, or salts or esters thereof; and iv. at least one vitamin B selected from vitamins B6, B9 and B12 including their functional equivalents; and v. optionally at least one of vitamin C, vitamin E and selenium.

Alternatively, the invention provides for a (non-therapeutic) use of the aforementioned combination for improving sleep and/or improving physical activity (increasing frequency and/or duration of physical activity), preferably improving sleep and improving physical activity (increasing frequency and duration of physical activity) in a healthy human subject, including oral administration. The subject preferably suffers from impaired physical activity and/or impaired sleep behavior, preferably the subject suffers from one or more of insomnia, sleep apnea, narcolepsy, circadian rhythm sleep-wake disorder or parasomnia. Nutrient combination (i) - (iv) and optionally (v) significantly improves sleep quality and physical activity scores in human being subject to (healthy) aging as shown in an experimental study with Souvenaid intervention. Also, a trend towards increased physical exercise duration was observed. The subjects were healthy and not diagnosed with neurological impairment or diseases. In one embodiment, the subjects may be characterized as suffering from or at increased risk of Age associated memory impairment (AAMI) which typically describes loss of memory function in otherwise healthy persons of age 50 and over. This is a relatively modest cognitive impairment thought to be common enough to be a feature of normal aging. It has been surprisingly found that supplementation of the nutrient combination to these older adults in particular improves sleep quality by reducing sleeping problems/disturbances as assessed by PROMIS questionnaire and also improves physical activity by increasing frequency and/or duration of physical exercise as assessed by the CHAMPS questionnaire. These effects are both associated to contribute to a healthier life in this ageing population. Moreover, the effects as shown were observed in a relatively healthy population, but subject to healthy cognitive ageing as indicated by a subjective cognitive decline questionnaire (SCD-Q9).

Thus, in an embodiment, the subject is a healthy human subject, preferably an elderly person, preferably at least 50 years of age, more preferably at least 55 years of age. Preferably, the method of the invention is a non-therapeutic method of improving sleep and/or physical activity, in particular in a healthy subject, in particular in a healthy elderly person subject to healthy cognitive aging. The subject is preferably a subject that self-reports a subjective age- related cognitive decline but has no neurodegenerative disease diagnosis. The subject is not diagnosed with or suffering from any underlying conditions from the following list: dementia (according to the Diagnostic and Statistical Manual of Mental Disorders 5th Edition and/or the National Institute on Ageing and Alzheimer ’s Association criteria), prior stroke, cancer, untreated major depressive disorder, any concurrent major medical or neurological illness, or history of abuse of illegal drugs and substances, or any neurotrauma including traumatic brain injury, and spinal cord injury. In further preferred embodiment, the subject is a subject that selfreports healthy cognitive aging but is not diagnosed with or suffering from any underlying conditions from the following list: dementia (according to the Diagnostic and Statistical Manual of Mental Disorders 5th Edition and/or the National Institute on Ageing and Alzheimer ’s Association criteria), prior stroke, cancer, untreated major depressive disorder, any concurrent major medical or neurological illness, or history of abuse of illegal drugs and substances, or any neurotrauma including traumatic brain injury, and spinal cord injury.

In a preferred embodiment of the invention, improving sleep and/or improving physical activity comprises one or more of: improving sleep quality, reducing sleeping problems or disturbances, increasing sleep duration, increasing frequency of physical activity or exercises, increasing duration of physical activity or exercises, reducing muscle fatigue, reducing mental fatigue, preferably reducing sleeping problems or disturbances, increasing frequency of physical activity or exercises and increasing duration of physical activity or exercises, most preferably reducing sleeping problems or disturbances and increasing frequency of physical activity or exercises. In a most preferred embodiment, improving sleep comprises reducing sleeping problems or disturbances, and improving physical activity comprises increasing frequency of physical activity or exercises. In a further preferred embodiment of the invention, improving sleep and/or improving physical activity is assessed on the basis of Patient Reported Outcomes Measurement Information System (PROMIS) or Physical Activity Questionnaire for Older Adults (CHAMPS).

The method or use of the invention comprises administering the composition comprising the aforementioned ingredients(i)-(iv) and optionally (v), and as further outlined below, to a subject in need thereof. Preferably, the composition is enterally (orally) administered to the subject at least one time per day for a period of at least 12 weeks, preferably at least 26 weeks, more preferably at least 1 year or at least 2 years.

Uridine and/or equivalents thereof

The method or use, combination and composition according to the invention comprise uridine and/or an equivalent thereof, including salts, phosphates, acyl derivatives and/or esters. The method or use, combination and composition preferably comprises at least one uridine or an equivalent thereof selected from the group consisting of uridine (i.e. ribosyl uracil), deoxyuridine (deoxyribosyl uracil), uridine phosphates (UMP, dUMP, UDP, UTP), nucleobase uracil and acylated uridine derivatives. Preferably, the composition or combination to be administered according to the present invention comprises a source of uridine selected from the group consisting of uridine, deoxyuridine, uridine phosphates, uracil, and acylated uridine. Preferably, the method or use, combination and composition according to the invention comprise an uridine phosphate selected from the group consisting of uridine monophosphate (UMP), uridine diphosphate (UDP) and uridine triphosphate (UTP). In a preferred embodiment, the composition or combination comprises at least one of the aforementioned uridine phosphates. Most preferably the present composition or combination comprises UMP, as UMP is most efficiently being taken up by the body. Hence, inclusion of UMP in the present method or use, combination and composition enables a high effectivity or efficacy at the lowest dosage and/or the administration of a low volume to the subject. Preferably at least 50 weight% of the uridine in the present method or use, combination and composition is provided by UMP, more preferably at least 75 weight%, most preferably at least 95 weight%. Doses administered are given as UMP. The amount of uracil sources can be calculated taking the molar equivalent to the UMP amount (molecular weight 324 Dalton).

The present method preferably comprises the administration of uridine (the cumulative amount of uridine, deoxyuridine, uridine phosphates, nucleobase uracil and acylated uridine derivatives) in an amount of 0.1-5 g, preferably 0.2-2.5 g, more preferably 0.25-1 g per 100 g of the composition, or in terms of daily dosage, in the range of 0.1-5 g, preferably 0.2-2.5 g, more preferably 0.25-1 g per day. In one embodiment, the present method or use, combination and composition may comprise the administration a uridine source in a concentration of 0.1-5 g, preferably 0.2-2.5 g, more preferably 0.25-1 g per, calculated as UMP, per 100 kcal product. The terms product, composition and combination are used interchangeably. co-3 LC-PUFAs

The method, composition or combination of the invention comprise at least one omega-3 long- chain polyunsaturated fatty acid (LC PUFA; having a chain length of 18 and more carbon atoms) selected from the group consisting of docosahexaenoic acid (22:6; DHA) and eicosapentaenoic acid (20:5; EPA). Preferably the present composition or combination contains at least DHA, more preferably DHA and EPA. EPA is converted to DPA (co-3), increasing subsequent conversion of DPA to DHA in the brain. Hence, the present composition or combination preferably also contains a significant amount of EPA in addition to DHA, so to further stimulate in vivo DHA formation.

The LCPUFAs (DHA and/or EPA) are preferably provided as triglycerides, diglycerides, monoglycerides, free fatty acids or their salts or esters, phospholipids, lysophospholipids, glycerol ethers, lipoproteins, ceramides, glycolipids or combinations thereof. Preferably, the present composition or combination comprises at least DHA in triglyceride form. Suitable co-3 LCPUFA and/or DHA sources include tuna oil, (other) fish oils, DHA-rich alkyl esters, algae oil, egg yolk, or phospholipids enriched with co-3 LCPUFA e.g. phosphatidylserine-DHA. Preferably, a composition or combination according to the invention comprises fish oil providing the omega-3 LCPUFA(s). Another particularly suitable source for the omega-3 LCPUFA(s) is algae oil.

When EPA and/or DHA are present, the total daily dosage of DHA+EPA taken together is in the range of 0.25 - 5 g, preferably 0.5 - 5 g, more preferably 0.75 - 2.5 g, per 100 g of the composition, or in terms of daily dosage, in the range of 0.25 - 5 g, preferably 0.5 - 5 g, more preferably 0.75 - 2.5 g, per day. In a preferred embodiment, these amounts are based on the total sum of DHA and EPA if present. DHA is preferably administered in an amount of at least 0.5 g per 100 g, more preferably 0.5 - 5 g per 100 g, most preferably 0.75 - 2 g per 100 g of the composition, or in terms of daily dosage, in the range of at least 0.5 g per day, more preferably 0.5 - 5 g per day, most preferably 0.75 - 2 g per day.

In terms of the composition, combination or method, the proportion of co-3 LCPUFA (more preferably DHA+EPA) of the total fatty acids in the composition is preferably 5 to 95 wt%, more preferably 10 to 80 wt%, most preferably 15 to 70 wt%, even more preferably 20 to 60 wt% of the total fatty acids. The present composition or combination preferably comprises 5 to 95 wt% DHA based on total fatty acids, preferably 10 to 75 wt% DHA based on total fatty acids, more preferably 10 to 60 wt%, even more preferably 10 - 50 wt%, more preferably 10 - 40 wt%, especially at least 20 wt% DHA, based on total fatty acids of the composition or combination. The present composition or combination preferably comprises 5 to 95 wt% EPA based on total fatty acids, preferably 5 to 75 wt% EPA, even more preferably 5 - 50 wt%, more preferably 5 - 25 wt%, most preferably 5 - 15 wt%, based on total fatty acids of the composition or combination.

In the method, combination or composition of the invention, the ratio of the weight of DHA to EPA is preferably larger than 1, more preferably 2:1 to 10: 1, more preferably 2: 1 to 5: 1. The ratios take into account and optimize the balance between DHA and precursors thereof to ensure optimal effectiveness while maintaining low-volume formulations. If arachidonic acid (AA) is present or administered, it preferably concerns a very low amount of AA, expressed in terms of a DHA/AA weight ratio in the present composition, combination or method of at least 5, preferably at least 6. If AA is administered, it preferably amounts to less than 5 g per 100 ml liquid product and/or less than 300 mg per 100 g dry weight of the composition or combination.

Choline

In a preferred embodiment, the method or use, combination and composition according to the present invention comprise choline, a choline salt and/or choline ester. Herein, the term ‘choline’ shall be considered to encompass all these equivalents. Choline salts are preferred. The choline salt is preferably selected from choline chloride, choline bitartrate, or choline stearate. The choline ester is preferably selected from the group consisting of phosphatidylcholine and lyso-phosphatidylcholine. The present method preferably comprises the administration of more than 0.1 g choline per 100 g, preferably 0.1 to 1 g choline per 100 g, more preferably 0.2 to 0.5 g choline per 100 g of the composition or combination, or in terms of daily dosage, more than 0.1 g choline per day, preferably 0.1 to 1 g choline per day, more preferably 0.2 to 0.5 g choline per day. The above numbers are based on choline, the amounts of choline equivalents or sources can be calculated taking the molar equivalent to choline into account, based on the molar mass of 104 g/mol choline.

B Vitamins

In a preferred embodiment, the method or use, combination and composition according to the present invention comprises at least one B vitamin selected from the group consisting of vitamin B6 (pyridoxine, pyridoxal, or pyridoxamine, or pyridoxine hydrochloride), vitamin B9 (folic acid or folate), and vitamin B12 (cobalamins). Functional equivalents are encompassed within these terms. Preferably the present composition comprises at least vitamin B6 and/or vitamin B9, more preferably at least vitamins B6 and B9, most preferably vitamins B6, B9 and B12. Vitamin B6 is preferably administered to provide an amount of 100 - 500 mcg, preferably 150 - 300 mcg, based on 100 g of the composition or per day. Vitamin B9 is preferably administered to provide an amount to provide 50 to 1000 pg, in particular in the range of 100 to 1000 pg, more in particular in the range of 200 to 800 pg per 100 g of the composition or per day. Vitamin B9 may be present as folate, which includes folic acid, folinic acid, methylated, methenylated and formylated forms of folates, their salts or esters (e.g. Cl -6 alkyl ester), as well as their derivatives with one or more glutamic acid, and all in either reduced or oxidized form. Preferably, vitamin B9 is provided as folic acid. Vitamin B12 is preferably administered to provide an amount in the range of 0.5 to 20 pg, in particular in the range of 1 to 10 pg per 100 g of the composition or per day. The term “vitamin Bl 2” incorporates all cobalamin equivalents known in the art.

In a preferred embodiment, the method or use, combination and composition according to the present invention further comprises choline and at least vitamin B6 and/or vitamin B9, more preferably at least vitamins B6 and B9, most preferably vitamins B6, B9 and B12.

Vitamin C. selenium and vitamin E

The method or use, combination and composition according to the invention preferably comprise one or more of the antioxidants vitamin C, vitamin E and selenium. It is especially preferred that the composition comprises both vitamin C and selenium, and optionally further comprises vitamin E, most preferably the composition according to the invention comprises vitamin C, vitamin E and selenium.

Vitamin C includes functional equivalents thereof, and may be present in an amount in the range of 20 to 1000 mg, in particular in the range of 30 to 500 mg, more in particular in the range of 50 to 150 mg per 100 g of the composition, or in terms of daily dosage, in the range of 20 to 1000 mg, in particular in the range of 30 to 500 mg, more in particular in the range of 50 tol50 mg per day.

Selenium may be present in an amount of 0.01 - 0.5 mg, preferably 0.02 - 0.1 mg per 100 g of the composition, or in terms of daily dosage, in the range of 0.01 - 0.5 mg, preferably 0.02 - 0.1 mg per day.

Vitamin E refers to compounds having vitamin E activity as known in the art, typically tocopherol and/or an equivalent thereof. Vitamin E may be present as tocopherol and tocopherol equivalents in an amount in the range of 10 to 200 mg, in particular in the range of 10 to 100 mg, more in particular in the range of 20 to 50 mg per 100 g of the composition, or in terms of daily dosage, in an amount in the range of 10 to 200 mg, in particular in the range of 10 to 100 mg, more in particular in the range of 20 to 50 mg per day. The term ‘tocopherol and equivalent thereof’, as used in this description, comprises tocopherols (e.g. alpha- and gamma-), tocotrienols, pharmaceutical and/or nutritional acceptable derivatives thereof and any combination thereof. The above numbers are based on alpha-tocopherol equivalents (alpha- TE), as recognized in the art.

Phospholipids

It is preferred to incorporate at least one phospholipid in the method or use, combination and composition according to the invention. The term “phospholipid” excludes phosphatidylcholine (PC) that is already accounted for in the choline fraction. The present composition preferably comprises at least one phospholipid in an amount of 0.01 to 1 gram per 100 ml, more preferably between 0.05 and 0.5 gram per 100 ml, most preferably 80 to 600 mg per 100 ml. The at least one phospholipid is preferably provided for using lecithin, more preferably soy lecithin.

The composition may further comprise a digestible carbohydrate fraction, preferably including a source of lactose and a source of polysaccharide.

In one embodiment, it is preferred that the method or use, combination and composition has a protein content of less than 15 en%, more preferably less than 10 en%, most preferably less than 5 en% of the total energy content of the composition. The energy percentages of the components are calculated using the calculation factors 9 kcal per g lipid, 4 kcal per g protein or g digestible carbohydrates, 2 kcal per g dietary fibers and zero kcal for the other components in the composition. In one embodiment, it is preferred that the composition comprises less than 0.5 to 10 g protein per 100 ml, more preferably less than 1 to 6 gram protein per 100 ml, most preferably 2 to 6 gram protein/ 100 ml.

In one embodiment, the method or use, combination and composition according to the invention comprises, per 100 ml of liquid: 100 - 500 mg EPA, preferably 200 - 400 mg;

1000 - 1500 mg DHA, preferably 950 - 1300 mg;

80 - 600 mg phospholipids, preferably 60 - 200 mg phospholipids;

200 - 600 mg choline, preferably 300 - 500 mg choline;

400 - 800 mg uridine monophosphate (UMP), preferably 500 - 700 mg UMP;

20 - 60 mg alpha-TE (vitamin E), preferably 30 - 50 mg vitamin E;

60 - 100 mg vitamin C, preferably 60 - 90 mg vitamin C;

40 - 80 pg selenium, preferably 45 - 65 pg selenium; 1 - 5 pg vitamin B 12, preferably 2 - 4 pg vitamin B 12;

0.5 - 2 mg vitamin B6, preferably 0.5 - 2 mg vitamin B6; and 200 - 600 pg folic acid, preferably 300 - 500 pg folic acid.

Examples

For a more complete understanding of the present disclosure, reference is now made to the following examples taken in conjunction with the accompanying drawings.

Example 1

Objective

The present experimental study was performed using a virtual assessment to study the effects of the composition according to the invention on the sleep quality and physical activity in healthy ageing.

Study summary

A randomized, double-blind, placebo-controlled, parallel group virtual pilot trial was performed over 6 months in a single-center. Participants were screened for eligibility and randomly allocated to receive the test product (specific multinutrient composition; n= 24) or placebo (isocaloric and similar in appearance and flavor to the test product, n=24), both as a 125 mL once-daily drink, on a 1 : 1 basis. Neuropsychological tests were done at baseline and after 6 months of intervention. Self-reported questionnaires were used to assess sleep quality, physical exercise and in general the quality of life.

Test product

Souvenaid (Fortasyn Connect; Nutricia, Zoetermeer, the Netherlands) is a multinutrient developed to support phospholipid synthesis. It comprises nutrients and cofactors (long-chain omega-3 fatty acids, uridine, choline, B vitamins, vitamin C, vitamin E, and selenium as described in example 2.

Study design

Participants were English or Spanish speaking people aged 55-89 years from all ethnic groups and considered to have age-related cognitive decline. Participants were eligible when scoring within the 25th - 75th percentile in the subjective cognitive decline questionnaire9 (SCD-Q9) to determine the presence of subjective age-related cognitive decline. The study excluded subjects diagnosed with dementia (according to the Diagnostic and Statistical Manual of Mental Disorders 5th Edition and/or the National Institute on Ageing and Alzheimer ’s Association criteria), prior stroke, cancer, untreated major depressive disorder that has not been in remission for at least 6 months prior to the study, any concurrent major medical or neurological illness, or history of abuse of illegal drugs and substances. Other exclusion criteria include enrolment in other cognitive therapeutic trials, the use of the nutritional supplements for cognitive improvements in the 24 days (folate, vitamins B6, B12, C, and E) or 30 days (omega-3 fatty acids) prior to participation, and treatment with any anti-AD medication or over- the-counter supplements or ‘cognitive/memory’ enhancers.

Participants were assessed at baseline and 6 months. In addition, they were contacted monthly by telephone to monitor safety, assess motivation, and promote compliance. Sleep quality was measured by the Patient-Reported Outcomes Measurement Information System Short Form vl.O Sleep Disturbance 8b (PROMIS Short Form vl.O Sleep Disturbance 8b). The questionnaire measured quality of sleep on a 5-point scale and the outcome measure was calculated by averaging the ratings across all 8 items present on the questionnaire. In addition, physical exercise frequency and duration were measured using the Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire. In total six outcomes, among which exercise frequency and exercise duration, were reported based on the questionnaire and analysis was performed on each outcome separately.

Results

Oral supplementation of Fortasyn Connect (daily consumption for 6 months) significantly improved sleep (p<0.05) as assessed by the PROMIS questionnaire and physical activity (p<0.05) as assessed by the CHAMPS questionnaire, see Figures 1 and 2 respectively. Physical exercise duration tended to improve, es evidenced by a non-significant (p<0.10) increase in physical exercise duration, see Figure 3. Statistical analysis was performed using a one-sided t-test. Furthermore, the test product was well tolerated and had no side effects.

Conclusion

The findings show that Fortasyn Connect improved sleep quality in older adults. It not only reduced sleep disturbances as measured by PROMIS questionnaire, but also increased the frequency of physical exercises as measured by the CHAMPS questionnaire and potentially increased the duration of the physical exercises. Example 2

A liquid composition according to the invention, comprising per 125 mL serving:

• 4.9 g fat 40 mg vitamin E (alpha-TE) • 300 mg EPA 80 mg vitamin C

• 1200 mg DHA 60 pg selenium

• 106 mg phospholipids 3 pg vitamin B12

• 400 mg choline • 1 mg vitamin B6

• 625 mg UMP • 400 pg folic acid

Claims

Claims

1. A (non-therapeutic) method for improving sleep and/or improving physical activity in a healthy human subject, said method comprising administering to said subject a combination of: i. uridine, or salts, phosphates, acyl derivatives or esters thereof; ii. at least one of docosahexaenoic acid (22:6; DHA) and eicosapentaenoic acid (20:5; EPA), or esters thereof, preferably at least DHA, more preferably DHA and EPA; iii. choline, or salts or esters thereof; and iv. at least one vitamin B selected from vitamins B6, B9 and B12 including their functional equivalents; and v. optionally at least one of vitamin C, vitamin E and selenium.

2. The method according to claim 1, wherein the healthy human subject is an adult, preferably an elderly person, preferably at least 50 years of age, more preferably at least 55 years of age; and/or the subject is a subject that self-reports a subjective age-related cognitive decline but has no neurodegenerative disease diagnosis.

3. The method according to claim 1 or 2, wherein improving sleep and/or improving physical activity comprises one or more of: improving sleep quality, reducing sleeping problems or disturbances, increasing sleep duration, increasing frequency of physical activity or exercises, increasing duration of physical activity or exercises, reducing muscle fatigue, reducing mental fatigue.

4. The method according to any one of the preceding claims, wherein improving sleep and/or improving physical activity is assessed on the basis of Patient Reported Outcomes Measurement Information System (PROMIS) or Physical Activity Questionnaire for Older Adults (CHAMPS).

5. The method according to any one of the preceding claims, wherein the combination administered to said subject further comprises at least one or more of vitamin C, vitamin E and selenium, preferably all of vitamin C, vitamin E and selenium.

6. The method according to any one of the preceding claims, wherein the combination administered to said subject further comprises at least one phospholipid.

7. The method according to any one of the preceding claims, wherein DHA is administered in an amount of at least 0.5 g per 100 g, preferably 0.5 - 5 g per 100 g of the composition or per day.

8. The method according to any one of the preceding claims, wherein uridine, as the cumulative amount of uridine, deoxyuridine, uridine phosphates, nucleobase uracil and acylated uridine derivatives, is administered in an amount of 0.1-5 g, preferably 0.2-2.5 g, more preferably 0.25-1 g per 100 g of the composition or per day.

9. The method according to any one of the preceding claims, wherein choline or salts or esters thereof, calculated as choline, is administered in an amount more than 0.1 g, preferably 0.1 to 1 g choline per 100 g of the composition or per day.

10. The method according to any one of the preceding claims, wherein selenium is administered in an amount of 0.01 - 0.5 mg, preferably 0.02 - 0.1 mg per 100 g of the composition or per day.

11. The method according to any of the preceding claims, wherein vitamin C is administered in an amount of 20 to 1000 mg, in particular in the range of 30 to 500 mg, more in particular in the range of 50 to 150 mg per 100 g of the composition or per day.

12. The method according to any one of the preceding claims, wherein the combination is comprised in a liquid nutritional supplement.

13. The method according to any one of the preceding claims, wherein the composition comprises, per 100 ml of liquid:

100 - 500 mg EPA,

1000 - 1500 mg DHA,

80 - 600 mg phospholipids,

200 - 600 mg choline,

400 - 800 mg uridine monophosphate (UMP), 20 - 60 mg alpha-TE (vitamin E),

60 - 100 mg vitamin C,

40 - 80 pg selenium,

1 - 5 pg vitamin Bl 2,

0.5 - 2 mg vitamin B6, and

200 - 600 pg folic acid.

14. Use of a combination of: i. uridine, or salts, phosphates, acyl derivatives or esters thereof; ii. at least one of docosahexaenoic acid (22:6; DHA) and eicosapentaenoic acid (20:5; EPA), or esters thereof, preferably at least DHA, more preferably DHA and EPA; iii. choline, or salts or esters thereof; and iv. at least one vitamin B selected from vitamins B6, B9 and B12 including their functional equivalents; and v. optionally at least one of vitamin C, vitamin E and selenium, for the manufacture of a nutritional composition for improving sleep and/or improving physical activity in a healthy human subject in need thereof.

15. A composition for use in (therapeutically) improving sleep and/or (therapeutically) improving physical activity in a subject in need thereof, said composition comprising: i. uridine, or salts, phosphates, acyl derivatives or esters thereof; ii. at least one of docosahexaenoic acid (22:6; DHA) and eicosapentaenoic acid (20:5; EPA), or esters thereof, preferably at least DHA, more preferably DHA and EPA; iii. choline, or salts or esters thereof; and iv. at least one vitamin B selected from vitamins B6, B9 and B12 including their functional equivalents; and v. optionally at least one of vitamin C, vitamin E and selenium, wherein the subject in need thereof is preferably a human subject subject to healthy cognitive aging, more preferably a human subject who suffers from impaired physical activity and impaired sleep behavior.