WO2021064151A1

WO2021064151A1 - Combination of the ethyl esters of docosahexaenoic and eicosapentaenoic acid plus vitamin d3 for prevention of age-related diseases

Info

Publication number: WO2021064151A1
Application number: PCT/EP2020/077606
Authority: WO
Inventors: Heike A. BISCHOFF-FERRARI
Original assignee: Zurich Universitaet Institut fuer Medizinische Virologie
Current assignee: Zurich Universitaet Institut fuer Medizinische Virologie
Priority date: 2019-10-01
Filing date: 2020-10-01
Publication date: 2021-04-08
Anticipated expiration: 2022-04-01

Abstract

The present invention relates to the use of eicosapentaenoic acid ethyl ester and docosahexaenoic acid ethyl ester, optionally in combination with vitamin D3, in prevention of decline in lean muscle mass, falls with and without an injury including fractures, high blood pressure, cognitive decline based on orientation, gastro-intestinal symptoms, and infection, or invasive cancer.

Description

COMBINATION OF THE ETHYL ESTERS OF DOCOSAHEXAENOIC AND EICOSAPENTAENOIC ACID PLUS VITAMIN D3 FOR PREVENTION OF AGE-RELATED DISEASES

The present invention relates to the use of a combination of docosahexaenoicacid and eicosapentaenoicacid , optionally in combination with vitamin D, in prevention of age related diseases induding but not limited to dedine in lean musde mass, falls with and without an injury induding fractures, high blood pressure, cognitive dedine, gastro-intestinal symptoms, infection, or inddent invasive cancer in a patient of age above 69.

Background

The European population is ageing, and the number of adults of age 70 and older is predicted to double by 2030. Concurrently, the number of people with age-related chronic diseases is expected to increase as well. Thus, interventions that reduce age-related diseases and prolong the number of years during which older adults are in good health and free from disabilities will have a striking impact on public health. Among the most promising interventions that are effective, affordable, and well-tolerated with benefits on several common age-related diseases are vitamin D, marine omega- 3 fatty acids and exercise. However, their individual and additive benefit on key age-related chronic diseases has yet to be confirmed in a large clinical trial.

Based on the above-mentioned state of the art, the objective of the present invention is to provide means and methods to prevent age-related diseases and thereby allow adults age 70 and older to stay healthy and active longer. This objective is attained by the subject-matter of the independent daims of the present specification.

Summary of the Invention

The invention relates to a pharmaceutical composition in prevention of decline in lean musde mass, falls with and without an injury induding fractures, high blood pressure, cognitive dedine, gastrointestinal symptoms, infection, or inddent invasive cancer. The composition of the invention is particularly advantageous when it is administered to a patient of age above 69.

Of note, the composition according to the invention was found to exert positive effects to all groups assessed in the dinical study on which the present specification is based: to the male subgroup, the female subgroup, to the subgroup younger than 75 years of age, to the subgroup older than 75 years of age, to the subgroup characterized by baseline low blood levels of omega- 3 (DHA + EPA <100μg/ml), to the subgroup characterized by baseline high blood levels of omega-3 (≥100μg/ml), to the subgroup characterized by baseline ≥ 20ng/ml Vitamin D (No Vitamin D defidency subgroup), and to the subgroup characterized by baseline < 20ng/ml Vitamin D (Vitamin D defidency subgroup). A first aspect of the invention relates to a pharmaceutical composition comprising ethyl esters of eicosapentaenoicacid and docosahexaenoicacid for use in prevention of a condition selected from decline in lean muscle mass, suffering from a tendency to have falls, injury after falling [fractures], low HDL blood levels, particularly HDL blood levels of below 1.7 mmol/L, more particularly HDL blood levels of below 1.55 mmol/L, more particularly HDL blood levels of below 1.3 mmol/L, most particularly HDL blood levels of below 1.0 mmol/L, high triglyceride blood levels, particularly triglyceride blood levels of above 1.1 mmol/L, more particularly triglyceride blood levels of above 1.7 mmol/L, more particularly triglyceride blood levels of above 2.2 mmol/L, most particularly triglyceride blood levels of above 5.6 mmol/L, cognitive decline based on orientation, gastro-intestinal symptoms, and infection (any infection, upper respiratory infection, influenza-like illness, plus evidence for an inflammatory state based on the biomarker IL-6).

A second aspect of the invention relates to a pharmaceutical composition comprising a. ethyl esters of eicosapentaenoic acid and docosahexaenoicacid , and b. vitamin D, particularly vitamin D3, for use in prevention of a condition selected from suffering from a tendency to have falls, injury after falling [fractures], high blood pressure, low HDL blood levels, particularly HDL blood levels of below 1.7 mmol/L, more particularly HDL blood levels of below 1.55 mmol/L, more particularly HDL blood levels of below 1.3 mmol/L, most particularly HDL blood levels of below 1.0 mmol/L, high triglyceride blood levels, particularly triglyceride blood levels of above 1.1 mmol/L, more particularly triglyceride blood levels of above 1.7 mmol/L, more particularly triglyceride blood levels of above 2.2 mmol/L, most particularly triglyceride blood levels of above 5.6 mmol/L, cognitive dedine based on orientation, infection (any infection, upper respiratory infection and influenza-like illness), and inddent invasive cancer.

In certain embodiments, ethyl esters of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are used at a ratio (mass/mass) of approximately 1 part EPA to 2 parts DHA.

The invention further relates to combination administration forms comprising ethyl esters of DHA, EPA and optionally, vitamin D, particularly vitamin D3 as well as to methods for treatment or prevention of age related diseases by administering the combination medicament according to the invention.

Terms and definitions

The term eicosapentaenoicacid (CAS No. 10417-94-4) in the context of the present specification is abbreviated as EPA. Eicosapentaenoiaccid is ((5Z,8Z,11Z,14Z,17Z)-eicosa- 5,8,11 ,14,17- pentenoicacid ).

The term docosahexaenoic acid (CAS No. 6217-54-5) in the context of the present specification is abbreviated as DHA. Docosahexaenoic acid is ((4Z,7Z,10Z,13Z,16Z,19Z)-docosa- 4,7,10,13,16,19-hexaenoicacid ). EPA and DHA are 20 and 22-carbon omega-3 fattyacid s, respectively, with four and six double bonds (also referred to as n-3), EPA is designated 20:5ω3 or 20:5n-3, DHA is designated 22:6ω3 or 22:6n-3. It is considered an omega-3 or n-3 fattyacid because its first double bond occurs on the third carbon from the methyl or “omega" end of the molecule. EPA and DHA are highly lipophilic, due to the large number of double bonds, has a low melting temperature and is a liquid (oil) rather than solid (wax) at room temperature. The molecular weight of EPA is 302.45 and DHA is 328.49.

Algae-based omega- 3, tested in the DO-HEALTH trial, are employed in a 2:1 ratio (mass/mass) for DHA to EPA. In contrast, fish oil as a source of omega-3 is characterized by a 1 :2 ratio (mass/mass) for DHA to EPA.

The term vitamin D in the context of the present specification relates to cholecaldferol (Vitamin D3, CAS No. 67-97-0). Other forms of vitamin D such as ergocaldferol (vitamin D2, ergocaldferol, CAS 50-14-6) may be employed to substitute vitamin D3 to achieve the same physiological effect. The amount of vitamin D is measured in International Units (IU); 1 IU is the biological equivalent of 25 ng cholecalciferol/ergocalciferol.

Tocopherols are natural antioxidants and comprise, but are not limited to, alpha-, beta-, gamma- and delta-tocopherol.

The term enteric coating in the context of the current specification refers to an oral medication coated with a polymer barrier that prevents the medication's dissolution or disintegration in the gastric environment. This helps by either protecting drugs from theacid ity of the stomach, the stomach from the detrimental effects of the drug, or to release the drug after the stomach (usually in the upper tract of the intestine). In certain embodiments, enteric coatings work by presenting a surface that is stable at the intenselyacid ic pH found in the stomach, but breaks down rapidly at a higher pH (alkaline pH). The time required for an enteric-coated dosage form to reach the intestine mostly depends on the presence and type of food in the stomach. It varies from 30 minutes up to 7 hours, with an average time of 6 hours. Detailed Description of the Invention

A first aspect of the invention relates to a pharmaceutical composition comprising eicosapentaenoic add and docosahexaenoicacid for use in prevention of a condition selected from decline in lean muscle mass, suffering from a tendency to have falls, injury after falling [fractures], low HDL blood levels, particularly HDL blood levels of below 1.7 mmol/L, more particularly HDL blood levels of below 1.55 mmol/L, more particularly HDL blood levels of below 1.3 mmol/L, most particularly HDL blood levels of below 1.0 mmol/L, high triglyceride blood levels, particularly triglyceride blood levels of above 1.1 mmol/L, more particularly triglyceride blood levels of above 1.7 mmol/L, more particularly triglyceride blood levels of above 2.2 mmol/L, most particularly triglyceride blood levels of above 5.6 mmol/L, cognitive decline based on orientation, gastro-intestinal symptoms, and infection (any infection, upper respiratory infection, influenza-like illness; plus evidence for an inflammatory state based on the biomarker IL-6).

In certain embodiments, ethyl esters of eicosapentaenoic acid and docosahexaenoic acid are used at a ratio (mass/mass) of 1 :4 to 2:1. In certain embodiments, ethyl esters of eicosapentaenoic acid and docosahexaenoic acid are used at a ratio (mass/mass) of 1 :3 to 1 :1. In certain embodiments, ethyl esters of eicosapentaenoic acId and docosahexaenoicacid are used at a ratio (mass/mass) of 1 :2. In certain embodiments, deviations from the 2:1 DHA to EPA ratio (mass/mass) of ≤10% are possible and encompassed by the present invention. In certain embodiments, the ratio of DHA to EPA is strictly ≥2,0. In certain embodiments, the pharmaceutical composition comprising eicosapentaenoicacid and docosahexaenoiaccid is for use in prevention of dedine in lean musde mass.

In certain embodiments, the pharmaceutical composition comprising eicosapentaenoicacid and docosahexaenoiaccid is for use in prevention of suffering from a tendency to have falls.

In certain embodiments, the pharmaceutical composition comprising eicosapentaenoicacid and docosahexaenoiaccid is for use in prevention of injury after falling [fractures].

In certain embodiments, the pharmaceutical composition comprising eicosapentaenoicacid and docosahexaenoiaccid is for use in prevention of low HDL blood levels, particularly HDL blood levels of below 1.7 mmol/L, more particularly HDL blood levels of below 1.55 mmol/L, more particularly HDL blood levels of below 1.3 mmol/L, most particularly HDL blood levels of below 1.0 mmol/L.

In certain embodiments, the pharmaceutical composition comprising eicosapentaenoicacid and docosahexaenoiaccid is for use in prevention of high triglyceride blood levels, particularly triglyceride blood levels of above 1.1 mmol/L, more particularly triglyceride blood levels of above 1.7 mmol/L, more particularly triglyceride blood levels of above 2.2 mmol/L, most particularly triglyceride blood levels of above 5.6 mmol/L.

In certain embodiments, the pharmaceutical composition comprising eicosapentaenoic acid and docosahexaenoicacid is for use in prevention of cognitive dedine based on orientation.

In certain embodiments, the pharmaceutical composition comprising eicosapentaenoic acid and docosahexaenoicacid is for use in prevention of gastro-intestinal symptoms.

In certain embodiments, the pharmaceutical composition comprising eicosapentaenoic acid and docosahexaenoicacid is for use in prevention of infection (any infection, upper respiratory infection, influenza-like illness; plus evidence for an inflammatory state based on the biomarker IL-6).

A second aspect of the invention relates to a pharmaceutical composition comprising a. ethyl esters of eicosapentaenoic acid and docosahexaenoicacid , and b. vitamin D, particularly vitamin D3, for use in prevention of a condition selected from suffering from a tendency to have falls, injury after falling [fractures], low HDL blood levels, particularly HDL blood levels of below 1.7 mmol/L, more particularly HDL blood levels of below 1.55 mmol/L, more particularly HDL blood levels of below 1.3 mmol/L, most particularly HDL blood levels of below 1.0 mmol/L, high triglyceride blood levels, particularly triglyceride blood levels of above 1.1 mmol/L, more particularly triglyceride blood levels of above 1.7 mmol/L, more particularly triglyceride blood levels of above 2.2 mmol/L, most particularly triglyceride blood levels of above 5.6 mmol/L, high blood pressure, cognitive dedine based on orientation, infection (any infection, upper respiratory infection and influenza-like ilness), and inddent invasive cancer.

In certain embodiments, ethyl esters of eicosapentaenoic acid and docosahexaenoicacid are used at a ratio (mass/mass) of 1 :4 to 2:1. In certain embodiments, ethyl esters of eicosapentaenoic acid and docosahexaenoicacid are used at a ratio (mass/mass) of 1 :3 to 1 :1. In certain embodiments, ethyl esters of eicosapentaenoic acid and docosahexaenoicacid are used at a ratio (mass/mass) of 1 :2.

In certain embodiments, the pharmaceutical composition comprising ethyl esters of eicosapentaenoicacid and docosahexaenoicacid , and vitamin D, particularly vitamin D3, is for use in prevention of suffering from a tendency to have falls. In certain embodiments, the pharmaceutical composition comprising ethyl esters of eicosapentaenoic acid and docosahexaenoic acid, and vitamin D, particularly vitamin D3, is for use in prevention of injury after falling [fractures].

In certain embodiments, the pharmaceutical composition comprising ethyl esters of eicosapentaenoic acid and docosahexaenoic acid, and vitamin D, particularly vitamin D3, is for use in prevention of low HDL blood levels, particularly HDL blood levels of below 1.7 mmol/L, more particularly HDL blood levels of below 1.55 mmol/L, more particularly HDL blood levels of below 1.3 mmol/L, most particularly HDL blood levels of below 1.0 mmol/L.

In certain embodiments, the pharmaceutical composition comprising ethyl esters of eicosapentaenoic acid and docosahexaenoic acid, and vitamin D, particularly vitamin D3, is for use in prevention of high triglyceride blood levels, particularly triglyceride blood levels of above 1.1 mmol/L, more particularly triglyceride blood levels of above 1.7 mmol/L, more particularly triglyceride blood levels of above 2.2 mmol/L, most particularly triglyceride blood levels of above 5.6 mmol/L.

In certain embodiments, the pharmaceutical composition comprising ethyl esters of eicosapentaenoic acid and docosahexaenoic acid, and vitamin D, particularly vitamin D3, is for use in prevention of high blood pressure.

In certain embodiments, the pharmaceutical composition comprising ethyl esters of eicosapentaenoic acid and docosahexaenoic acid, and vitamin D, particularly vitamin D3, is for use in prevention of cognitive decline based on orientation.

In certain embodiments, the pharmaceutical composition comprising ethyl esters of eicosapentaenoic acid and docosahexaenoic acid, and vitamin D, particularly vitamin D3, is for use in prevention of infection (any infection, upper respiratory infection and influenza-like ilness).

In certain embodiments, the pharmaceutical composition comprising ethyl esters of eicosapentaenoic acid and docosahexaenoic acid, and vitamin D, particularly vitamin D3, is for use in prevention of incident invasive cancer.

An alterative aspect of the invention relates to a pharmaceutical composition comprising a. ethyl esters of eicosapentaenoic acid and docosahexaenoic acid, and b. vitamin D, particularly vitamin D3, for use in prevention of invasive cancer, particularly invasive cancer excluding non-melanoma skin cancer, wherein the composition is administered to a male patient.

An alterative aspect of the invention relates to a pharmaceutical composition comprising a. ethyl esters of eicosapentaenoic acid and docosahexaenoic acid, and b. vitamin D, particularly vitamin D3, for use in prevention of an age-related injury after falling [fractures], wherein said pharmaceutical composition is administered to a female patient.

An alterative aspect of the invention relates to a pharmaceutical composition comprising a. ethyl esters of eicosapentaenoic acid and docosahexaenoic acid, and b. vitamin D, particularly vitamin D3, for use in prevention of an age-related suffering from a tendency to have falls, wherein said pharmaceutical composition is administered to a female patient.

An alterative aspect of the invention relates to a pharmaceutical composition comprising eicosapentaenoic acid and docosahexaenoic acid for use in prevention of age-related decline in lean muscle mass, wherein said pharmaceutical composition is administered to a female patient and/or a patient between 70 and 74 years of age.

An alterative aspect of the invention relates to a pharmaceutical composition comprising eicosapentaenoic acid and docosahexaenoaiccid for use in prevention of age-related gastrointestinal symptoms, wherein said pharmaceutical composition is administered to a male patient.

An alterative aspect of the invention relates to a pharmaceutical composition comprising eicosapentaenoiaccid and docosahexaenoiaccid for use in prevention of age-related high systolic blood pressure, wherein said pharmaceutical composition is administered to a patient between 70 and 74 years of age.

The composition of batches of algal oil employed to provide the ethyl esters of EPA and DHA may vary, but will always comprise at least 10% ethyl ester of EPA and 22% ethyl ester of DHA. Exemplary batches analysed in the preparation of the manufacturing protocol were shown to contain (figures give % m/m):

Batch 98-5807: DHA 35.1 ; EPA: 15.9

Batch 98-5814E: DHA 33.9; EPA: 14.9 Batch 98-5828E: DHA 32.7; EPA: 17.7

The measured parameters in the study on which the present application is based, were parameters of major health domains related to bone (injurious falls), musde (falls and lean musde mass), heart (systolic blood pressure), brain (cognitive function based on orientation), gastro-intestinal tract (new gastro-intestinal symptoms), and immunity (any infections, respiratory infections, IL-6, and invasive cancer). The skilled person is aware that these parameters give a direct indication for the propensity of a patient suffering from certain diseases.

The lean muscle mass of patients is measured by Dual Energy X-Ray Absorptiometry (DEXA), which is a measurement of the appendicular lean muscle mass determining the muscle mass of arms and legs. n certain embodiments, the decline in lean muscle mass results in or is associated with a condition selected from sarcopenia, and frailty syndrome. The condition of suffering from a tendency to have falls relates to falling more often. This tendency to fall is mitigated by the pharmaceutical composition.

Injury after felling relates to fractures of any bone or joint.

Cognitive abilities are measured based on orientation. Cognitive decline is assessed by the Montreal Cognitive Assessment (MoCA). Subscale “orientation" of the MoCA with reduced learning effect determines the orientation with regards to year, month, exact date, and day of the week.

In certain embodiments, the cognitive decline results in or is associated with a condition selected from mild cognitive impairment, and dementia. In certain embodiments, the gastro-intestinal symptoms result in or are associated with a condition selected from gastric disease, and intestinal disease.

A lowered systolic blood pressure decreases the risk of suffering from cardiovascular diseases. In certain embodiments, the high blood pressure results in or is associated with a cardiovascular disease, particularly a cardiovascular disease selected from

● myocardial infarction

● cardiomyopathy

● hypertensive heart disease. In certain embodiments, the infection is a condition selected from respiratory infection, and systemic infection.

The composition according to the invention reduced the occurrence of any invasive cancer (nonmelanoma skin cancer excluded). The inventors examined the occurrence of new cases of invasive cancer over the follow-up.

In certain embodiments, the combination of ethyl esters of eicosapentaenoic acid and docosahexaenoic acid is administered at a daily dose of 150 mg to 750 mg (mass of the two components combined). In certain particular embodiments, the combination of ethyl esters of eicosapentaenoicacid and docosahexaenoicacid is administered at a daily dose of 500 mg to 1300 mg (mass of the two components combined).

In certain particular embodiments, the combination of ethyl esters of eicosapentaenoic acid and docosahexaenoic acid is administered at a daily dose of 350 mg to 600 mg (mass of the two components combined). In certain particular embodiments, the combination of ethyl esters of eicosapentaenoic acid and docosahexaenoicacid is administered at a daily dose of 700 mg to 1100 mg (mass of the two components combined).

In certain embodiments, the ethyl esters of eicosapentaenoicacid and docosahexaenoicacid is administered at a daily dose of 0,5 g to 2 g, particularly about 1 gram of algae derived fatty acid composition.

In certain embodiments, the ethyl ester of eicosapentaenoic acid is administered at a daily dose of 50 mg to 150 mg, particularly at a daily dose of about 100 mg. In certain particular embodiments, the ethyl ester of eicosapentaenoicacid is administered at a daily dose of 200 mg to 320 mg, particularly at a daily dose of about 260 mg.

In certain embodiments, the ethyl ester of docosahexaenoic acid is administered at a daily dose of 100 mg to 300 mg, particularly at a daily dose of about 200 mg. In certain particular embodiments, the ethyl ester of docosahexaenoicacid is administered at a daily dose of 600 mg to 700 mg, particularly at a daily dose of about 640 mg. In certain embodiments, the ethyl ester of eicosapentaenoic acid is administered at a daily dose of 50 mg to 150 mg and the ethyl ester of docosahexaenoicacid is administered at a daily dose of 100 mg to 300 mg, particularly the ethyl ester of eicosapentaenoic acid is administered at a daily dose of about 100 mg and the ethyl ester of docosahexaenoicacid is administered at a daily dose of about 200 mg. In certain particular embodiments, the ethyl ester of eicosapentaenoic acid is administered at a daily dose of 200 mg to 320 mg and the ethyl ester of docosahexaenoicacid is administered at a daily dose of 600 mg to 700 mg, particularly the ethyl ester of eicosapentaenoicacid is administered at a daily dose of about 260 mg and the ethyl ester of docosahexaenoicacid is administered at a daily dose of about 640 mg.

In certain embodiments, the ethyl ester of eicosapentaenoicacid and the ethyl ester of docosahexaenoicacid are administered comprised in algal oil, particularly in an oil derived from marine algae.

In certain embodiments, the algal oil preparation is the only source of ethyl esters of eicosapentaenoicacid and docosahexaenoicacid in the pharmaceutical composition.

In certain embodiments, ethyl esters of eicosapentaenoicacid and docosahexaenoicacid are administered comprised in algal oil derived from Schizochytrium sp.

In certain embodiments, the algal oil further comprises palmitic acid and oleic aci.d In certain embodiments, the content of ethyl ester of DHA within the algal oil is 15 to 30% (m/m) and the content of ethyl ester of EPA within the algal oil is 7 to 15% (m/m), particularly wherein the content of ethyl ester of DHA within the algal oil is approx. 22% (m/m) and the content of ethyl ester of EPA within the algal oil is approx. 10% (m/m). In certain embodiments, vitamin D, particularly vitamin D3, is administered in combination with EPA and DHA at a daily dose of 1000 to 3000 IU. In certain embodiments, vitamin D, particularly vitamin D3, is administered in combination with EPA and DHA at a daily dose of 2000 IU.

In certain embodiments, the pharmaceutical composition comprises 990mg of algal oil comprising a total of 500mg of DHA and EPA at a ratio (mass/mass) of 1 :2, and the pharmaceutical composition comprises 1 ,25 mg of vitamin D3. In certain embodiments, the pharmaceutical composition is administered twice a day.

The pharmaceutical administration form or combination medicament of the invention may advantageously comprise an antioxidant, particularly a tocopherol, to increase shelf life.

In certain embodiments, the pharmaceutical composition is administered for at least 6 months. In certain embodiments, the pharmaceutical composition is administered for at least 12 months. In certain embodiments, the pharmaceutical composition is administered for at least 24 months. In certain embodiments, the pharmaceutical composition is administered for at least 36 months.

In certain embodiments, the patient is of age above 69 years of age (the patient is 70 years old or older). Pharmaceutical Composition and Administration

Another aspect of the invention relates to a pharmaceutical composition comprising ethyl esters of EPA and DHA, and/or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In certain embodiments of the invention, the compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product.

The pharmaceutical composition can be formulated for oral administration, parenteral administration, or rectal administration. In addition, the pharmaceutical compositions of the present invention can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions).

In certain particular embodiments, the pharmaceutical composition is formulated as a enterically coated capsule. The pharmaceutical composition can be formulated as two separate dosage forms, one containing the vitamin D3 component and the other one containing ethyl esters of EPA and DHA in the ratio and dosage as described herein.

In a certain particular embodiment, the administration form of the invention is provided as an enteric coated capsule that contains 500 mg of ethyl esters of eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA) in a ratio (mass/mass) of 1 :2. The formulation according to this embodiment is an oily liquid containing at least 75% n-3 polyunsaturated fatty acids in the form of ethyl esters predominantly as EPA and DHA. It is stabilized with mixed tocopherols and ascorbyl palmitate. Rosemary extract is used as a processing aid. In another certain particular embodiment, the administration form of the invention is provided as an enteric coated capsule that contains 500 mg of ethyl esters of eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA) in a ratio (mass/mass) of 1 :2. The formulation according to this embodiment is an oily liquid containing at least 75% n-3 polyunsaturated fatty acids in the form of ethyl esters predominantly as EPA and DHA. It is stabilized with mixed tocopherols and ascorbyl palmitate. The capsule according to this embodiment additionally comprises 1 Ό00 lU/capsule vitamin D3, an oily liquid consisting of crystalline Vitamin D3 (cholecalciferol) in medium chain triglycerides, stabilized with dl-α-tocopherol (vitamin E, 2.5 promille). Again, rosemary extract is used as a processing aid.

The dosage regimen for the compounds of the present invention will vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. In certain embodiments, the compounds of the invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.

In certain embodiments, the pharmaceutical composition or combination of the present invention can be in unit dosage of about 0,5 to 2 grams of unsaturated fatty acid for a subject of about 50-70 kg. The therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.

The pharmaceutical compositions of the present invention can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc. They may be produced by standard processes, for instance by conventional mixing, granulating, dissolving or lyophilizing processes. Many such procedures and methods for preparing pharmaceutical compositions are known in the art, see for example L. Lachman et al. The Theory and Practice of Industrial Pharmacy, 4th Ed, 2013 (ISBN 8123922892). As used herein, the term pharmaceutical composition refers to a compound of the invention, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier.

As used herein, the term pharmaceutically acceptable carrier indudes any solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (for example, antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, exdpients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington: the Sdence and Practice of Pharmacy, ISBN 0857110624).

Dosage forms may be for enteral administration, particularly for oral administration. Wherever alteratives for single separable features such as, for example, a dietary supplement or a medical indication are laid out herein as “embodiments", it is to be understood that such alteratives may be combined freely to form discrete embodiments of the invention disclosed herein.

Items

1. A pharmaceutical composition comprising: the ethyl ester of eicosapentaenoic acid, and the ethyl ester of docosahexaenoic acid, at a ratio of 1 :4 to 2:1 (EPA/DHA; mass/mass), particularly at a ratio of 1 :3 to 1 :1 (mass/mass), more particularly at a ratio of 1 :2 (mass/mass), for use in the prevention of an age-related condition selected from: suffering from a tendency to have falls, injury after falling [fractures], low HDL blood levels, particularly HDL blood levels of below 1.7 mmol/L, more particularly HDL blood levels of below 1.55 mmol/L, more particularly HDL blood levels of below 1.3 mmol/L, most particularly HDL blood levels of below 1.0 mmol/L, high triglyceride blood levels, particularly triglyceride blood levels of above 1.1 mmol/L, more particularly triglyceride blood levels of above 1.7 mmol/L, more particularly triglyceride blood levels of above 2.2 mmol/L, most particularly triglyceride blood levels of above 5.6 mmol/L, cognitive dedine based on orientation, and infection (any infection, upper respiratory infection, influenza-like illness; plus evidence for an inflammatory state based on the biomarker IL-6).

2. A pharmaceutical composition comprising a. ethyl esters of eicosapentaenoic acid and docosahexaenoic acid at a ratio of 1 :4 to 2:1 (mass/mass), particularly at a ratio of 1 :3 to 1 :1 (mass/mass), more particularly at a ratio of 1 :2 (mass/mass), and b. vitamin D3, particularly at 2.000 lU/day for use in the prevention of an age-related condition selected from

- suffering from a tendency to have falls, high systolic blood pressure, low HDL blood levels, particularly HDL blood levels of below 1.7 mmol/L, more particularly HDL blood levels of below 1.55 mmol/L, more particularly HDL blood levels of below 1.3 mmol/L, most particularly HDL blood levels of below 1.0 mmol/L, high triglyceride blood levels, particularly triglyceride blood levels of above 1.1 mmol/L, more particularly triglyceride blood levels of above 1.7 mmol/L, more particularly triglyceride blood levels of above 2.2 mmol/L, most particularly triglyceride blood levels of above 5.6 mmol/L,

- cognitive dedine based on orientation, infection (upper respiratory infection and influenza-like illness), and invasive cancer, particularly invasive cancer exduding non-melanoma skin cancer.

3. A pharmaceutical composition comprising a. ethyl esters of eicosapentaenoic acid and docosahexaenoic acid at a ratio of 1 :4 to 2:1 (mass/mass), particularly at a ratio of 1 :3 to 1 :1 (mass/mass), more particularly at a ratio of 1 :2 (mass/mass), and b. vitamin D3, particularly at 2.000 lU/day for use in the prevention of an age-related injury after falling [fractures], wherein said pharmaceutical composition is administered to a female patient.

4. A pharmaceutical composition comprising ethyl esters of eicosapentaenoic ac (idEPA) and docosahexaenoicacid (DHA) at a ratio of 1 :4 to 2:1 (mass/mass), particularly at a ratio of 1 :3 to 1 :1 (mass/mass), more particularly at a ratio of 1 :2 (mass/mass), for use in the prevention of age-related dedine in lean musde mass, wherein said pharmaceutical composition is administered to a female patient and/or a patient between 70 and 74 years of age.

5. A pharmaceutical composition comprising ethyl esters of eicosapentaenoic ac (idEPA) and docosahexaenoicacid (DHA) at a ratio of 1 :4 to 2:1 (mass/mass), particularly at a ratio of 1 :3 to 1 :1 (mass/mass), more particularly at a ratio of 1 :2 (mass/mass), for use in the prevention of age-related gastro-intestinal symptoms, wherein said pharmaceutical composition is administered to a male patient.

6. A pharmaceutical composition comprising ethyl esters of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) at a ratio of 1 :4 to 2:1 (mass/mass), particularly at a ratio of 1 :3 to 1 :1 (mass/mass), more particularly at a ratio of 1 :2 (mass/mass), for use in the prevention of age-related high systolic blood pressure, wherein said pharmaceutical composition is administered to a patient between 70 and 74 years of age.

7. The pharmaceutical composition for use in use in the prevention of decline in lean muscle mass and for use in the prevention of falls and injurious falls according to item 1 to 4, wherein the decline in lean muscle mass and the tendency to have falls and injurious falls results in a condition selected from sarcopenia, and frailty syndrome.

8. The pharmaceutical composition for use in the prevention of cognitive decline based on orientation according to item 1 or 2, wherein the cognitive decline results in a condition selected from mild cognitive impairment, and dementia.

9. The pharmaceutical composition for use in the prevention of gastro-intestinal symptoms according to item 6, wherein the gastro-intestinal symptoms result in a condition selected from gastric disease, and intestinal disease.

10. The pharmaceutical composition for use in the prevention of high blood pressure according to item 1 or 2, wherein the high blood pressure results in a condition selected from cardiovascular disease, particularly a cardiovascular disease selected from

● myocardial infarction

● cardiomyopathy

● hypertensive heart disease.

11. The pharmaceutical composition for use in the prevention of infection according to item 1 or 2, wherein the infection is a condition selected from respiratory infection, and systemic infection. 12. The pharmaceutical composition for use in the prevention of an age-related condition according to any one of the previous items, wherein the ethyl ester of eicosapentaenoic acid is administered at a daily dose of 50 mg to 150 mg and the ethyl ester of docosahexaenoicacid is administered at a daily dose of 100 mg to 300 mg, particularly the ethyl ester of eicosapentaenoicacid is administered at a daily dose of about 100 mg and the ethyl ester of docosahexaenoicacid is administered at a daily dose of about 200 mg.

13. The pharmaceutical composition for use in the prevention of an age-related condition according to any one of the previous items, wherein the ethyl esters of eicosapentaenoic acid and docosahexaenoic acid are comprised in algal oil, in other words the acid ethyl esters are part of an algal oil preparation, particularly in an algal oil preparation derived from marine algae.

14. The pharmaceutical composition for use in the prevention of an age-related condition according to item 13, wherein the algal oil further comprises palmitic ac aidnd oleic ac.id

15. The pharmaceutical composition for use in the prevention of an age-related condition according to item 13 or 14, wherein the content of the ethyl ester of DHA within the algal oil is 15 to 30% (m/m) and the content of the ethyl ester of EPA within the algal oil is 7 to 15% (m/m), particularly wherein the content of the ethyl ester of DHA within the algal oil is approx. 22% (m/m) and the content of the ethyl ester of EPA within the algal oil is approx. 10% (m/m).

16. The pharmaceutical composition for use in the prevention of an age-related condition according to any one of items 2, 3, 7, 8, 10 - 15, wherein vitamin D3 is administered at a daily dose of 1000 to 3000 IU, particularly 2000 IU.

17. The pharmaceutical composition for use in the prevention of an age-related condition according to anyone of the previous items, wherein the pharmaceutical composition further comprises an antioxidant, particularly a tocopherol.

18. The pharmaceutical composition for use in the prevention of an age-related condition according to any one of the previous items, wherein the pharmaceutical composition is administered for at least 6 months, particularly at least 12 months, more particularly at least 24 months, most particularly at least 36 months.

19. The pharmaceutical composition for use in the prevention of an age-related condition according to any one of the previous items, wherein the pharmaceutical composition is administered to a patient above 69 years of age.

20. The pharmaceutical composition for according to any one of the previous items, wherein the pharmaceutical composition comprises 990mg of algal oil comprising a total of 500mg of the ethyl ester of DHA and EPA at a ratio of 1 :2 (m/m), and 1 ,25 mg of vitamin D3. 21. The pharmaceutical composition for use according to any one of the preceding items, wherein the pharmaceutical composition comprises 990mg of algal oil comprising a total of 500mg of DHA and EPA at a ratio (mass/mass) of 1 :2, and wherein the pharmaceutical composition comprises 1 ,25 mg of vitamin D3. The invention is further illustrated by the following examples and figures, from which further embodiments and advantages can be drawn. These examples are meant to illustrate the invention but not to limit its scope.

Examples

The data on which the present specification is based are derived from a high-quality large clinical trial designated “DO-HEALTH" that investigated the effect of algae-based omega-3 fatty acids with and without vitamin D on 6 age-related chronic diseases.

The DO-HEALTH trial enrolled 2Ί57 adults aged 70 and older, who were required to take daily supplements of vitamin D and/or omega 3 and/or placebo plus perform a simple home exercise program (strength = interventional group or joint mobility = control, sham exercise) for three years. Participants were followed over the three years by yearly comprehensive clinical visits (baseline visit, 1-, 2- and 3-year follow-up visit) and in person phone calls every 3 months (at month 3, 6, 9, 15, 18, 21 , 27, 30 and 33). DO-HEALTH aimed to established evidence of the interventions for 5 primary endpoints: (1) the risk of incident non-vertebral fractures; (2) the risk of functional decline; (3) the risk of blood pressure increase; (4) the risk of cognitive decline; (5) and the rate of any infection. Key secondary and exploratory endpoints included incident invasive cancer, respiratory and gastro intestinal infections, bone mineral density and appendicular lean mass and biomarkers.

Adherence of the study is as follows: At year 1 , 2 and 3 more than 70% percent of participants took at least 80% of their study pills if they received vitamin D (90.6%, 80.3%, 76.1%), Omega-3 (88.8%, 78.8%, 74.4%), or mere placebo (88.3%, 77.9%, 71.5%). The evidence collected in the referenced clinical trial with regard to the effect of algae-based omega-3 fatty acids with and without vitamin D on 6 age-related chronic diseases is structured into the following outcome parameters:

(1) Age-related chronic disease context disability resulting from sarcopenia and physical frailty: evidence for the prevention of decline in lean muscle mass, prevention of falls with and without an injury including fractures

(2) Age-related chronic disease context cardio-vascular disease resulting from high blood pressure: evidence for the reduction in systolic blood pressure

(3) Age-related chronic disease context dementia resulting from a decline in cognitive function: evidence for the prevention of cognitive decline with regard to orientation (4) Age-related chronic disease context gastro-intestinal disease resulting from any cause (i.e. Gl ulcer disease, inflammatory bowel disease, constipation, gastro-intestinal cancer) and leading to malnutrition and/or anemia: evidence for the reduction of the incidence of any new gastrointestinal symptom.

(5) Age-related chronic disease context increased risk of infections resulting from reduced immune function: evidence for the reduction of risk for any infection, for respiratory infections and for influenza-like illness - plus evidence for a reduced inflammatory state based on a reduction in the biomarker IL-6.

(6) Age-related chronic disease context cancer resulting from reduced age-related DNA-repair and immune function: evidence for the reduction of the incidence of any new invasive cancer (excluding non-melanoma skin cancers). DO-HEALTH followed all 2157 participants in yearly whole-day clinical visits and in-person phone calls every 3 months between these visits, allowing a comprehensive phenotyping and high-quality endpoint assessment in DO-HEALTH. Importantly, this hands-on study design of DO-HEALTH was chosen for primary endpoints focussed on early diseases outcomes, i.e. systolic blood pressure reduction and cognitive decline instead of major cardiovascular events and dementia. Notably, the early disease endpoints chosen in DO-HEALTH are well-established in clinical care. For example, it is well-known that blood pressure rises with age and high blood pressure (BP) is a major risk factor for cardiovascular events and is the biggest single contributor to the global burden of disease and mortality. In fact, it has been predicted that by 2025 a total of 560 million new cases of hypertension are expected globally. Regarding effect sizes of blood pressure reduction and cardio- vascular disease prevention, a meta-analysis of 61 observational studies concluded that a 2 mm Hg lower systolic blood pressure was associated with a 10% lower stroke mortality and 7% lower mortality from ischaemic heart disease. Thus, reducing blood pressure with omega-3 plus vitamin D to the extend found in DO-HEALTH is highly relevant in terms of cardiovascular mortality.

The main objective of the DO-HEALTH large randomized-controlled clinical trial was to establish whether vitamin D, omega-3 fatty acids, and a simple home exercise program, individually and in combination, will prevent age-related diseases among adults age 70 years and older.

For this objective, DO-HEALTH enrolled 2157 community-dwelling men and women age 70 years and older in a multi-centre clinical trial. The target age group of 70 years an older was chosen as this age 70 is an age at which rates of chronic disease increase substantially. The trial tested the individual and the additive benefit of 2000 IU vitamin D per day, 1 g of algae-based omega-3 fatty acids (DHA:EPA ratio = 2:1 ) per day and a simple home exercise program. Each treatment modality has shown considerable promise in improving 6 common age-related chronic diseases, but definitive data from a large trial are missing.

Unique to DO-HEALTH trial, all participants unden/vent comprehensive standardized whole-day yearly examinations with regard to multiple-organ functions, physical and mental health, as well as new health events. These detailed yearly exams at baseline, year 1 , year 2 and year 3 in all 2157 participants of DO-HEALTH were further complemented by in person phone calls every 3 months between the yearly clinical visits to have high-quality assessments of safety of the interventions as well as high-quality endpoint documentation with regard to falls, infections, medication use, and any new health events during the 3-year course of the trial. Also, unique to DO-HEALTH is that algae-based omega-3 instead offish-oil-based omega-3 was used. This may be relevant in 2 ways: first, better blinding in DO-HEALTH compared to other trials due to the absent fishy after-taste (which was further improved in DO-HEALTH by enteric coating of the study capsules), second algae-based omega-3 has a different DHA:EPA ratio than fish oil omega-3 (2:1 in algae, 1 :2 in fish- oil).

The specific experiments to prove the principle of the invention were carried out within DO- HEALTH, a randomized, double-blind, placebo-controlled, 2x2x2 factorial design clinical trial. The DO-HEALTH RCT tested the individual and the additive (“multi-modal") benefit of 2000 IU vitamin D/day, 1 gram of omega-3 fatty acids per day, and a simple home exercise program, in an efficient factorial trial design.

Once follow-up of all study participants was completed and the collected data cleaned, the electronic data collection system was frozen, and a final data extraction was performed. This data was merged with data from other sources (e.g. lab data) into a master data set using SAS v.9.4 statistical software. The master data set was used as a source of all statistical analyses from that point on, according to DO-HEALTH statistical manual (including data coding (SAS) manuals and data dictionaries) developed by the team of Prof. H.A. Bischoff-Ferrari at UZH/USZ. All the statistical analyses were performed centrally by the team of Prof. H.A. Bischoff-Ferrari at UZH/USZ as per protocol.

Progress beyond the state-of-the-art

The purported health benefits of vitamin D, marine omega-3 fatty acids and exercise have been receiving increasing attention in the medical literature and the popular press. However, as definitive data on health benefits and risks of these interventions are missing, broad recommendations for their use in medical care cannot be substantiated. This is, for example, reflected by the most recent guidelines by the AHA/ACC that do not support the use of vitamin D or omega-3 in the prevention or treatment of hypertension (Whelton etal. Circulation. 2018 Oct 23; 138(17)).

DO-HEALTH is the first large clinical trial to provide evidence with regard to the effect of algae- based omega-3 fatty acids with and without vitamin D on 6 age-related chronic diseases. Notably, with regard to evidence from large clinical trials, the 2019 published VITAL trial findings among 25'871 men and women age 50 years and older living in the US, showed no benefit for 1g omega-3 fatty acids per day or 2000 IU vitamin D per day with regard to their primary endpoints of major cardiovascular events and invasive cancer. Distinguishing the VITAL trial as the only other large trial to date that tested both daily 1g omega-3 and daily 2000 IU vitamin D from the DO- HEALTH trial, VITAL enrolled younger adults in a lower age-related chronic disease risk profile (age 50+) and tested a fish-oil-based omega-3 intervention, while DO-HEALTH enrolled older adults with a higher age-related chronic disease risk profile (age 70+) and tested an algae-based omega-3. Further, while VITAL base its endpoint assessment primarily on yearly mail-based questionnaires, DO-HEALTH followed all 2157 partidpants in yearly whole-day dinical visits and in-person phone calls every 3 months between these visits, allowing a comprehensive phenotyping and high-quality endpoint assessment in DO-HEALTH. Importantly, this hands-on study design of DO-HEALTH was chosen for primary endpoints focussed on early diseases outcomes, i.e. systolic blood pressure reduction and cognitive dedine instead of major cardiovascular events and dementia. Notably, the early disease endpoints chosen in DO-HEALTH are well-established in dinical care. For example, it is well-known that blood pressure rises with age and high blood pressure (BP) is a major risk factor for cardiovascular events and is the biggest single contributor to the global burden of disease and mortality. In fact, it has been predicted that by 2025 a total of 560 million new cases of hypertension are expected globally. Regarding effect sizes of blood pressure reduction and cardio-vascular disease prevention, a meta-analysis of 61 observational studies conduded that a 2 mm Hg lower systolic blood pressure was assodated with a 10% lower stroke mortality and 7% lower mortality from ischaemic heart disease. Thus, redudng blood pressure with omega-3 plus vitamin D to the extend found in DO-HEALTH is highly relevant in terms of cardiovascular mortality.

Materials and methods

Production of trial compounds

Crystalline cholecaldferol was produced synthetically using cholesterol as a starting material. Cholecaldferol was dissolved in medium chain triglycerides and then filled into the containers.

The DHA and EPA algal oil is produced using the microalga Schizochytrium sp., a thraustochytrid. The organism used is an improved strain of the original wild-type culture. The improved strain was derived using a classical mutagenesis/screening program, which employed well-accepted techniques commonly used in industrial microbial strain improvement programs. Therefore, the strain is not genetically-engineered; i.e., it is not a genetically-modified organism (GMO). Schizochytrium sp. is nonpathogenic in humans and other animals, and the organism does not produce any known toxins.

To produce DHA and EPA algal oil, Schizochytrium algae are grown in a pure culture heterotrophic fed-batch fermentation process, recovered from the fermentation broth, and dried. The resulting dried algae are extracted to produce a crude oil that is further refined, bleached and deodorized using process operations commonly employed in the vegetable oil industry, and under US Dietary Supplement current Good Manufacturing Practices. Only food-grade materials are used in the fermentation process, ensuring the highest quality and purest product.

The EPA and DHA algal oil contains a mixture of fatty acids as triglycerides derived from marine algae. Of principle nutritional interest are the fatty acids eicosapentaenoic acid (EPA) and docosahexaenoicacid (DHA) which are present at not less than 10% and 22.5% respectively. A wide range of other dietary fatty acids are also present at lower concentrations, notably palmitic and oleic acids.

Algal oil (Martek DHA TM, produced using the microalga Schizochytrium sp.: contains a mixture of fatty acids as triglycerides, notably EPA and DHA which are present at not less than 10% and 22.5%, respectively; omega-3 fatty acids are stabilized with tocopherol to avoid any potential oxidation).

Specifications of the DHA and EPA content in the Algal oil, as based on "Certificate of analysis", are:

990.00 mg of this algal oil is added in the soft gelatine capsule (specific gravity of the algal oil: 0.94).

Measured DHA and EPA content in the Algal oil (Certificate of analysis Algal oil)

990.00 mg of this algal oil is added in the soft gelatine capsule (specific gravity of the algal oil: 0.94)

Manufacture of capsules

Vitamin D3 and or Omega-3 fatty acids are stabilized with mixed tocopherols to avoid any potential oxidation. In addition, the capsule was treated with an enteric coating which further protects the capsules from humidity and lipid peroxidation.

Enteric coating a one-step film coating system provides a protective film with excellent moisture sealing and enteric properties. With its superior taste and moisture protection it is recommended for the coating of natural extracts, fatty oils and substances with bad taste and odor. Enteric coating of omega-3 fatty acids capsules reported no influence on the bioavailability of EPA and DHA compared to non-coated capsules. Each active combination capsule contains 1000 IU of Vitamin D3 and 500 mg of eicosapentaenoic acid (EPA) and/or dososahexanoic acid (DHA) in a ratio of 1 :2.

Table 4: Components of capsules

Clinical trial

The specific experiments to prove the principle of the invention were carried out within DOHEALTH, a randomized, double-blind, placebo-controlled, 2x2x2 factorial design clinical trial. The trial tested the individual benefit and the additive (“multi-modal”) benefit of 2000 IU vitamin D/day, 1 gram of omega-3 fatty acids per day, and a simple home exercise program, in an efficient factorial trial design.

Participants were instructed to take orally 2 study capsules - preferentially with dinner - or - when participants take all of their interventions (breakfast or lunch or even at bedtime).

The DO-HEALTH trial enrolled 2Ί57 adults aged 70 and older recruited from seven study sites in

Switzerland, Germany, Austria, France and Portugal who were required to take daily supplements of vitamin D and/or omega 3 and/or placebo plus perform a simple home exercise program (strength = interventional group or joint mobility = control, sham exercise) for three years. Participants were followed over the three years by yearly comprehensive clinical visits (baseline visit, 1-, 2- and 3-year follow-up visit) and in person phone calls every 3 months (at month 3, 6, 9, 15, 18, 21 , 27, 30 and 33). DO-HEALTH aimed to established evidence of the interventions for 5 primary endpoints: (1) the risk of incident non-vertebral fractures; (2) the risk of functional decline; (3) the risk of blood pressure increase; (4) the risk of cognitive decline; (5) and the rate of any infection. Key secondary and exploratory endpoints included incident invasive cancer, respiratory and gastro intestinal infections, bone mineral density and appendicular lean mass and biomarkers. Statistical analysis

Poisson regression models or negative binomial regression models were used to evaluate the impact of each intervention and their combinations for count-based endpoints (falls and injurious falls, non-vertebral fractures, any infections, respiratory infections, influenza-like illness, and gastro-intestinal symptoms). Longitudinal regression models were used to evaluate the impact of each intervention and their combinations on the continuous endpoints (bone mineral density, PTH, blood pressure, blood lipids, SPPB (short physical performance battery), muscle mass, MoCA, orientation, HDL, LDL, total cholesterol, triglycerides, and IL-6). Cox proportional hazards models were used to evaluate the impact of each intervention and their combinations on incident cancer. All analyses were adjusted for age, gender, taller status before baseline, body mass index, and center. For continuous endpoints analyses, the models were also adjusted for baseline values.

For an updated analysis, the inventors fixed 8 missing values for body mass index derived from Dual-energy X-ray absorptiometry (DXA). For falls and injurious falls, the inventors ran negative binomial regression models to better fit the distribution of the data (overdispersion). For systolic blood pressure, any infections, upper respiratory infections, and influenza-like illness, the inventors added the 99% Confidence Intervals as pre-specified in the DO-HEALTH protocol. For cognitive function based on orientation, the inventors changed the dependence structure of the original model. For invasive cancer, the inventors included a random effect for study site (generalizability of the results). The updated analysis is shown in the application, the previous analysis is highlighted as “previous analysis". Example 1 : Study population

The inventors enrolled 2157 adults with a mean age of 74.9 (SD 4.5), and 61.7% were women. In the Table 1 (see attachment 1 IP Tables), the inventors list the key results by the 6 health domains. In contrast to the original assumption, the inventors did find a significant interaction between treatments for the following endpoints in DO-HEALTH:

SPPB: significant interaction between treatment (vitamin D * omega-3 * exercise, p=0.09),

Falls: significant interaction between treatment (vitamin D * omega-3 * exercise, p= 0.08),

Triglyceride cholesterol levels: significant interaction between treatment (omega3 * exercise , p=0.04), Any infections: Significant treatment interaction between vitamin D and omega-3, p-value=0.008,

IL-6: significant treatment interaction (vitamin D * omega-3 * exercise, p=0.06).

In summary, DO-HEALTH provides evidence for the interventions omega-3 alone or its combination with vitamin D regarding all 6 health domains relevant to healthy and active aging. The following text summarizes results by health domain consistent with Table 1. Example 2: Bona health domain

For the bone health domain, the interventions did not reduce fracture risk (NVFxs), which may in part be explained by the lower fracture rate observed in DO-HEALTH than originally expected. In the study cohort across 3 years 256 non-vertebral fractures were recorded for an overall incidence rate of 0.043 (95%CI [0.038, 0.048]) by person and year, which was below the expected overall incidence rate of 0.140 in the cohort.

However, with regard to the more prevalent endpoint injurious falls (falls with an injury including fractures) omega-3 alone reduced the risk of injurious falls in the baseline high blood level of omega-3 (DHA + EPA ≥100μg/ml) subgroup by significant 19% (IRR = 0.81 ; 95% Cl 0.69 to 0.95; p = 0.0009). In the study cohort across 3 years 2141 injurious falls were recorded for an overall incidence rate of 0.359 (95%CI [0.344, 0.374]) by person and year.

According to a previous analysis, omega-3 alone reduced the risk of injurious falls in all groups by significant 9% (IRR = 0.91 ; 95% Cl 0.83 to 0.99; p = 0.03), in the older age subgroup (age 75+) by significant 14% (IRR = 0.86; 95% Cl 0.76 to 0.98; p = 0.02)all group by significant 9% (IRR = 0.91 ; 95% Cl 0.83 to 0.99; p = 0.03), and in the older age subgroup (age 75+) by significant 14% (IRR = 0.86; 95% Cl 0.76 to 0.98; p = 0.02). Similarly, the combination of omega-3 plus vitamin D reduced the risk of injurious falls by significant 14% (IRR = 0.86; 95% IC 0.74 to 0.99; p = 0.036) in the Women subgroup only.

Further, vitamin D alone, reduced the decline in total bone mineral density at the hip significantly (mean difference = 0.003; 95% Cl 0.0003 to 0.005, p = 0.020) and reduced parathyroid hormone levels (PTH) significantly by - 4.65 ng/L (95% Cl - 5.58 to - 3.73, p < 0.0001 ), this remained significant and almost to the same extend with regard to the effect size if vitamin D was combined with omega-3 (reduction of PTH by - 3.03 ng/L, 95% Cl - 4.4 to - 1.7, p < 0.001) or with all 3 interventions including omega-3 + vitamin D + exercise (reduction of PTH by - 3.49 ng/L, 95% Cl - 5.1 to - 1.8, p < 0.001) Risk: Only for omega-3 alone, there was a small but significant increase in PTH levels by 1.63 ng/L (95% Cl 0.70 to 2.56, p = 0.001 ).

According to a previous analysis, for vitamin D alone, there was an increased risk by 20% of injurious falls in the Men subgroup (IRR = 1.2; 95% Cl 1.02 to 1.4; p = 0.028).

Example 3: Muscle health domain For the muscle health domain, the interventions did not improve lower extremity function measured by SPPB. This may be explained by the fact that, at baseline, the participants had good lower extremity function with an average baseline SPPB score of 10.9 (SD 1.5), close to the maximum of 12. Over the 3-year follow-up, there was only a small decline in SPPB across all participants (- 0.065, 95%CI [-0.104, - 0.025]; p = 0.001), without significant differences due to any of the 3 individual interventions.

However, as an endpoint with high incidence among older adults, related to enormous health care costs, omega-3 alone reduced in all group the rate of falling by significant by 10% (IRR=0.902, 95% Cl 0.81 , 1.00, p=0.043), vitamin D alone and the combination of omega-3 plus vitamin D had no significant effect.

In the subgroups Women, Older age (75+), and baseline high omega-3 (DHA+EPA ≥100 pg/ml), omega-3 alone reduced the rate of falling by significant 12% (IRR=0.88; 95% Cl 0.77 to 1.00; p=0.049), 19% (IRR=0.81 ; 95% Cl 0.69 to 0.95; p=0.011), and 17% (IRR=0.83; 95% Cl 0.71 to 0.97; p=0.017) respectively.

In the subgroups Women, the combination of omega-3 plus vitamin D reduced the rate of falling by significant 19% (IRR=0.81 ; 95% Cl 0.68 to 0.97; p=0.021 ).

According to a previous analysis, vitamin D alone reduced in all group the rate of falling by significant 14% (IRR=0.858, 95% Cl 0.75 , 0.982, p=0.0262), and the combination of omega-3 plus vitamin D reduced the rate of falling by significant 15% (IRR=0.85, Cl 0.739 , 0.978, p=0.0231).

In the study cohort across 3 years 3333 falls were recorded for an overall incidence rate of 0.558 (95%CI [0.539, 0.577]) by person and year.

Further, in the subgroups Women and Younger age (age<75), omega-3 alone significantly reduced the decline in appendicular lean muscle mass (muscle mass arms and legs) by a significant mean difference of 27.78 grams (95%CI 0.030 to 55.59; p=0.0502) and a significant mean difference of 34.91 grams (95% Cl 6.95 to 62.88; p=0.0145). Risk: Unexpectedly, the combination of omega-3 plus vitamin D plus simple home exercise program (SHEP) increased the rate of falls in the subgroup Men significantly by 38% (IRR = 1.38, 95% Cl 1.00 to 1.91 , p = 0.048). One hypothesis is that the exercise program increased physical activity of participants giving them more opportunity to fall. Example 4: Heart health domain

For the heart health domain, in all group, only the combination of omega-3 plus vitamin D led to a relative decrease in systolic blood pressure (SBP) of 1.0% over the baseline mean 143.5 mmHg by - 1.39 mmHG, (95% Cl -2.57 to - 0.22, 99%CI -2.94 to 0.15; p = 0.02).

In the subgroup Younger age (age <75), omega-3 alone led to a relative decrease in SPB of 1.2 % over the baseline mean 143.5 mmHg by -1.7 mmHg (95% IC -3.0 to -0. 4, 99%CI -3.39 to -0.01 ; p=0.0095), while the combination of omega-3 plus vitamin D led to a relative decrease in SPB over the baseline mean 143.5 mmHg by 2.17 mmHg 95% Cl -4.0 to -0.6, 99%CI -4.55 to 0.21 ; p=0.0189), and by 3.16 mmHg (95% Cl -5.4 to -0.9, 99%CI -6.1 to -0.2; p=0.006) for the Men group and by 1.82 mmHg (95% Cl -3.6 to -0.02, 99%CI -4.2 to 0.5; p=0.0474) for the baseline no vitamin D deficient group ((≥ 20ng/ml).

Further, in all group, Omega-3 alone significantly increased the advantageous lipid HDL by 0.08 mmol/l (95% Cl 0.07 to 0.09, p < 0.001 ), a relative benefit 4.8% over the baseline mean HDL of 1.71 mmol/L compared to non-omega-3 group; and the combination with vitamin D by 0.07 mmol/l (95% Cl 0.04 to 0.10, p < 0.001 ), a relative benefit of 4.1 % over the baseline mean HDL compared to non-omega-3 and non-vitamin D group; and all 3 interventions by 0.07 mmol/l (95% Cl 0.04 to 0.10, p < 0.001 ), a relative benefit of 3.1 % over the baseline mean HDL compared to placebo. Also advantageous to heart health, in all group, omega-3 alone reduced triglyceride levels significantly by 0.08 mmol/L (95% Cl -0.13 to -0.03], p=0.001) a relative benefit of 7.2% over the baseline mean triglyceride levels of 1.15 mmol/L compared to non-omega-3 group; and in combination with vitamin D by -0.055 mmol/L (95% Cl -0.106, -0.005], p=0.032), a relative benefit of 4.8% over the baseline mean triglyceride levels compared to non-omega-3 and non-vitamin D group; and all 3 interventions by 0.077 mmol/L (95% Cl -0.128 to -0.026, p=0.003), a relative benefit of 6.7% over the baseline mean triglyceride levels compared to placebo.

Risk. Consistent with the literature, in all group, the benefit of omega-3 on HDL is accompanied by an increase in the undesirable LDL levels by 0.11 mmol/l (95% Cl 0.06 to 0.16, p < 0.001 ), a relative increase of 3.2% over the baseline mean LDL of 3.35 mmol/L compared to non-omega-3 group, and in combination with vitamin D by 0.139 mmol I (95% IC 0.068 to 0.211 ; p=0.0001), a relative increase of 4.2% over the baseline mean LDL compared non-vitamin D, and all 3 interventions by 0.115 mmol/L (95% IC 0.027 to 0.202, p=0.01), a relative increase of 1.8% over baseline mean LDL compared to placebo). Example 5: Brain health domain

For the brain health domain, over the 3-year follow-up, there was a small, but significant improvement in MoCA across all participants (0.45, 95%CI [0.37, 0.53]; p < 0.0001 ), and in each treatment group at each year of follow-up. There were no significant differences in the degree of improvement for any of the 3 individual interventions compared to their respective controls in all group. This may be explained by the fact that, at baseline, participants started with a good cognitive function with an average baseline MoCA score of 25.67 (SD 3.35), close to the maximum of 30.

However, in the baseline non-Vitamin D deficient subgroup, omega-3 alone showed effects on one of the MoCA components, orientation with regards to year, month, exact date, and day of the week, and reduced the decline of orientation by a significant 1.25% (mean reduction in decline compared to non-omega-3 group of 0.049 (95% Cl 0.049 to 0.094, p-value = 0.00342).

According to a previous analysis, omega-3 in combination with vitamin D showed effects on one of the MoCA components and reduced the decline of orientation by a significant 1.10% (mean reduction in decline compared to placebo group of 0.043 (95% Cl 0.005 to0.082, p = 0.027). In the subgroup Men, omega-3 alone led to a relative decrease of 1.42% in the decline of orientation compared to non-omega3 subgroup (mean reduction in decline of 0.056 (95% IC 0.014 to 0.098], p=0.0091), and combined with vitamin D, to relative decrease of 2.13% in the decline in orientation compared to placebo group (mean increase of 0.084 (95% IC 0.024 to 0.143], p=0.0061). In the baseline no vitamin D deficient subgroup (≥ 20ng/ml), omega-3 alone led to a relative decrease of 0.87% in the decline of orientation compared to non-omega3 group (mean reduction in decline of 0.034 (95% Cl 0 to 0.069], p=0.0522).

Notably, orientation was a predefined alterative endpoint for cognitive function because this component has the least potential for a learning effect.

Risk: Vitamin D alone led to a small but significant relative decrease of 1.13% in the improvement of MoCA scores compared to non-Vitamin D deficient subgroup (mean difference: -0.285 -95% Cl -0.552 to -0.017, p=0.0372) in the older age subgroup (age 75+), and to a small but significant relative decrease of 1.14% in the improvement of MoCa scores compared to baseline non-Vitamin D deficient subgroup (mean difference: -0.285 (95% Cl -0.563 to -0.008, p=0.0441 ) in the baseline vitamin D deficient subgroup (< 20 ng/ml). No significant effects were observed for the alterative endpoint orientation in the older age and baseline non-Vitamin D deficient subgroups.

Example 6: Gastno-intestinal health domain

For the gastro-intestinal health domain, across 3 year of DO-HEALTH, a total of 3284 new gastrointestinal symptoms were recorded. In all group, there were no significant differences in the incidence of any new gastro-intestinal symptom for any of the 3 individual interventions and their combinations compared to their respective controls. However, in the subgroup Men, Omega-3 alone reduced the incidence of any new gastro-intestinal symptom by a significant 27% (IRR =0.73, 95% Cl 0.53 to 0.98, p =0.04). Vitamin D and the simple home exercise program individually, had no effect on gastrointestinal symptoms.

Example 7: Immunity health domain

For the immunity health domain, across 3 years, 6233 infections were recorded for an overall incidence rate of 1.044 (95%CI [1.018, 1.070]) by person and year. Of the 6233 infections, 2755 were classified upper respiratory infections, and 2533 were classified influenza-like illness. In all group, Omega-3 alone significantly reduced the average number of infections from 1.04 per year to 0.93 per year. Thereby, omega-3 significantly reduced the incidence of any infection by 11 % (incidence rate ratio IRR =0.89, 99%CI 0.78 to 1.01 , 95% Cl 0.80 to 0.98, p=0.02) in all group, by 22% in the subgroup Men (IRR=0.78, 99%CI 0.62 to 0.99, 95% Cl 0.65 to 0.94, p=0.008), by 13% in the subgroup Younger age (age<75) (IRR=0.87, 99%CI 0.74 to 1.02, 95% Cl 0.77 to 0.98, p=0.02), and by 18% in the subgroup baseline high blood levels of omega-3 (DMA + EPA ≥100μg/ml) (IRR=0.82, 99%CI 0.68 to 0.99, 95% Cl 0.71 to 0.95, p=0.007). In the subgroup Younger age (age <75), vitamin D significantly reduced the incidence of any infections by 16% (IRR=0.84, 99%CI 0.71 to 0.99, 95% Cl 0.74 to 0.95, p=0.007), and in combination with omega-3, by 12% (IRR=0.88, 99%CI 0.74 to 1.03, 95% Cl 0.77 to 0.99, p=0.04).

Additionally, omega-3 alone reduced upper respiratory infections by 10% in all group (IRR = 0.90, 99%CI 0.81 to 0.99, 95%CI 0.83 to 0.97, p = 0.005), by 12% in the subgroup Men (IRR=0.88, 99%CI 0.74 to 1.03, 95%IC 0.77 to 0.99, p=0.04), by 21 % in the subgroup Older age (age 75+) (IRR=0.79, 99%CI 0.67 to 0.94, 95% IC 0.70 to 0.90, p=0.0003), by 12% in the subgroup baseline high blood levels of omega-3 (≥100μg/ml) (IRR=0.88, 99%CI 0.76 to 1.02, 95% IC 0.79 to 0.98, p=0.02), and by 14% in the subgroup baseline vitamin D deficiency (<20ng/mL) (IRR=0.86, 99%CI 0.74 to 1.00, 95% IC 0.76 to 0.97, p=0.01). Omega-3 also reduced influenza-like illness by 12% (IRR = 0.88, 95%CI 0.81 to 0.95, p = 0.001) in all group, by 15% in the subgroup Men (IRR=0.85, 95% IC 0.75 to 0.97, p=0.01 ), by 23% in the subgroup Older age (age 75+) (IRR=0.77, 95% IC 0.67 to 0.88, p<=0.0001), by 14% in the subgroup baseline high blood levels of omega-3 (≥100μg/ml) (IRR=0.86, 95% IC 0.77 to 0.97, p=0.01), by 10% in the subgroup no baseline vitamin D deficiency (≥20 ng/mL) (IRR=0.90, 95% IC 0.81 to 0.99, p=0.04) , and by 15% in the subgroup baseline vitamin D deficiency (<20ng/mL) (IRR=0.85, 95% IC 0.75 to 0.96], p=0.008).

Further, omega-3 in combination with vitamin D reduced upper respiratory infections by 11 % in all group (IRR=0.89, 99%CI 0.77 to 1.02, 95% Cl 0.80 to 0.99, p=0.03), by 18% in the subgroup Men (IRR=0.82, 99%CI 0.65 to 1.04, 95% Cl 0.69 to 0.98, p=0.03), by 16% in the subgroup baseline high blood levels of omega-3 (≥100μg/ml) (IRR=0.84, 99%CI 0.69 to 1.04, 95% Cl 0.72 to 0.99, p=0.03), by 17% in the subgroup Vitamin D deficiency (<20 ng/mL) (IRR=0.83, 99%CI 0.66 to 1.04, 95%CI 0.10 to 0.98, p=0.03).

Omega-3 in combination with vitamin D also reduced influenza-like illness by 15% in all group (IRR=0.85, 95% Cl 0.76 to 0.95, p=0.004), by 22% in the subgroup Men (IRR=0.78, 95% Cl 0.65 to 0.93, p=0.007), by 22% in the subgroup Older age (age 75+) (IRR=0.78, 95% Cl 0.65 to 0.94, p=0.009), by 21% in the subgroup baseline high blood levels of omega-3 (≥100μg/ml) (IRR=0.79, 95% Cl 0.67 to 0.93, p=0.004), by 20% in the subgroup vitamin D deficiency (<20ng/mL) (IRR=0.80, 95% IC 0.67 to 0.95], p=0.01). As a mechanistic support for these benefits, in all group, omega-3 alone led to a relative decrease in the anti-inflammatory biomarker IL-6 of 26.3% over the baseline mean IL6 of 3.80 ng/L by 1.00 ng/L (95%CI [-1.66,-0.35], p-value=0.003), and vitamin D alone to a relative decrease in IL6 of 17.4 % by 0.66 ng/L (95%CI [-1.31 ,-0.01], p-value=0.04)

Neither vitamin D alone nor the simple home exercise program alone had a significant effect on the incidence of any infections, upper respiratory infections, and influenza-like illness (all group).

Risk: Exercise and the combination of omega-3 and vitamin D increased the incidence of any infections by 27% (IRR=1.27, 99%CI 1.03 to 1.56, 95% IC 1.08 to 1.49, p=0.003) and by 19% (IRR=1.19, 99%CI 0.96 to 1.48, 95% IC 1.01 to 1.40, p=0.04) respectively in the subgroup Older age (age 75+).

Regarding confirmed invasive cancer (excluding non-melanoma skin cancer), there were 64 new confirmed cases by medical records and none of the interventions were effective individually to reduce cancer risk. However, all 3 treatments together (combination of omega 3 with vitamin D and with the simple home exercise program) reduced the risk of invasive cancer by 66% (HR = 0.34, 95%CI 0.14 to 0.82, p=0.02), in all group. In the subgroup Men, the combination of omega-3 with vitamin D reduced the risk of confirmed invasive cancer by 66% (HR=0.34, 95%CI 0.12 to 0.93,p=0.03) and all treatments together by 86% (HR=0.14, 95%CI 0.04 to 0.54, p=0.004).

According to a previous analysis, the combination of omega-3 with vitamin D reduced the risk of confirmed invasive cancer by 51 % (HR=0.49, 95%CI 0.24 to 1.00, p=0.049).

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Claims

1. A pharmaceutical composition comprising a. eicosapentaenoic add ethyl ester and docosahexaenoic add ethyl ester at a ratio (mass/mass) of 1 :4 to 2:1 , particularly at a ratio (mass/mass) of 1 :3 to 1 :1 , more particularly at a ratio (mass/mass) of 1 :2, and b. vitamin D3, particularly at 2.000 lU/day for use in prevention of age-related invasive cancer, particularly invasive cancer excluding non-melanoma skin cancer.

2. The pharmaceutical composition for use according to claim 1 , wherein the pharmaceutical composition comprises 990mg of algal oil comprising a total of 500mg of DHA and EPA at a ratio (mass/mass) of 1 :2, and wherein the pharmaceutical composition comprises 1 ,25 mg of vitamin D3.

3. The pharmaceutical composition for use according to claim 1 or 2, wherein the composition is administered to a male patient.

4. A pharmaceutical composition comprising a. ethyl esters of eicosapentaenoic acid and docosahexaenoic acid at a ratio (mass/mass) of 1 :4 to 2:1 , particularly at a ratio (mass/mass) of 1 :3 to 1 :1 , more particularly at a ratio (mass/mass) of 1 :2, and b. vitamin D3, particularly at 2.000 lU/day for use in prevention of an age-related injury after falling [fractures], wherein said pharmaceutical composition is administered to a female patient.

5. The pharmaceutical composition for use in prevention of age-related injury after falling according to claim 4, wherein the age-related injury after falling is the result of a condition selected from sarcopenia, and frailty syndrome.

6. A pharmaceutical composition comprising a. ethyl esters of eicosapentaenoic acid and docosahexaenoic acid at a ratio (mass/mass) of 1 :4 to 2:1 , particularly at a ratio (mass/mass) of 1 :3 to 1 :1 , more particularly at a ratio (mass/mass) of 1 :2, and b. vitamin D3, particularly at 2.000 lU/day for use in prevention of an age-related condition selected from high systolic blood pressure, low HDL blood levels, particularly HDL blood levels of below 1.7 mmol/L, more particularly HDL blood levels of below 1.55 mmol/L, more particularly HDL blood levels of below 1.3 mmol/L, most particularly HDL blood levels of below 1.0 mmol/L, high triglyceride blood levels, particularly triglyceride blood levels of above 1.1 mmol/L, more particularly triglyceride blood levels of above 1.7 mmol/L, more particularly triglyceride blood levels of above 2.2 mmol/L, most particularly triglyceride blood levels of above 5.6 mmol/L, and infection (upper respiratory infection and influenza-like illness).

7. A pharmaceutical composition comprising a. ethyl esters of eicosapentaenoic acid and docosahexaenoic acid at a ratio (mass/mass) of 1 :4 to 2:1 , particularly at a ratio (mass/mass) of 1 :3 to 1 :1 , more particularly at a ratio (mass/mass) of 1 :2, and b. vitamin D3, particularly at 2.000 lU/day for use in prevention of an age-related suffering from a tendency to have fells.

8. The pharmaceutical composition for use according to claim 7, wherein said pharmaceutical composition is administered to a female patient.

9. A pharmaceutical composition comprising ethyl esters of eicosapentaenoic add (EPA) and docosahexaenoic add (DHA) at a ratio (mass/mass) of 1 :4 to 2:1 , particularly at a ratio (mass/mass) of 1 :3 to 1 :1 , more particularly at a ratio (mass/mass) of 1 :2, for use in prevention of an age-related condition selected from

- suffering from a tendency to have falls, injury after falling [fractures], low HDL blood levels, particularly HDL blood levels of below 1.7 mmol/L, more particularly HDL blood levels of below 1.55 mmol/L, more particularly HDL blood levels of below 1.3 mmol/L, most particularly HDL blood levels of below 1.0 mmol/L, high triglyceride blood levels, particularly triglyceride blood levels of above 1.1 mmol/L, more particularly triglyceride blood levels of above 1.7 mmol/L, more particularly triglyceride blood levels of above 2.2 mmol/L, most particularly triglyceride blood levels of above 5.6 mmol/L,

- cognitive decline based on orientation, and infection (any infection, upper respiratory infection, influenza-like illness; plus evidence for an inflammatory state based on the biomarker IL-6).

10. A pharmaceutical composition comprising ethyl esters of eicosapentaenoic acid (EPA) and docosahexaenoic add (DHA) at a ratio (mass/mass) of 1 :4 to 2:1 , particularly at a ratio (mass/mass) of 1 :3 to 1 :1 , more particularly at a ratio (mass/mass) of 1 :2, for use in prevention of age-related dedine in lean musde mass, wherein said pharmaceutical composition is administered to a female patient and/or a patient between 70 and 74 years of age.

11. A pharmaceutical composition comprising ethyl esters of eicosapentaenoic add (EPA) and docosahexaenoic add (DHA) at a ratio (mass/mass) of 1 :4 to 2:1 , particularly at a ratio (mass/mass) of 1 :3 to 1 :1 , more particularly at a ratio (mass/mass) of 1 :2, for use in prevention of age-related gastro-intestinal symptoms, wherein said pharmaceutical composition is administered to a male patient.

12. A pharmaceutical composition comprising ethyl esters of eicosapentaenoic acid (EPA) and docosahexaenoic add (DHA) at a ratio (mass/mass) of 1 :4 to 2:1 , particularly at a ratio (mass/mass) of 1 :3 to 1 :1 , more particularly at a ratio (mass/mass) of 1 :2, for prevention of age-related high systolic blood pressure, wherein said pharmaceutical composition is administered to a patient between 70 and 74 years of age.

13. The pharmaceutical composition for use in prevention of an age-related condition according to any one of the previous daims, wherein the ethyl ester of eicosapentaenoic add is administered at a daily dose of 50 mg to 150 mg and the ethyl ester of docosahexaenoic add is administered at a daily dose of 100 mg to 300 mg, particularly the ethyl ester of eicosapentaenoic add is administered at a daily dose of about 100 mg and the ethyl ester of docosahexaenoic add is administered at a daily dose of about 200 mg.

14. The pharmaceutical composition for use in prevention of an age-related condition according to any one of the previous daims, wherein the ethyl ester of eicosapentaenoic add and the ethyl ester of docosahexaenoic add are administered comprised in algal oil, in other words the add ethyl esters are part of an algal oil preparation, particularly in an algal oil preparation derived from marine algae.

15. The pharmaceutical composition for use in prevention of an age-related condition according to daim 14, wherein the content of the ethyl ester of DHA within the algal oil is 15 to 30% (m/m) and the content of the ethyl ester of EPA within the algal oil is 7 to 15% (m/m), particularly wherein the content of the ethyl ester of DHA within the algal oil is approx. 22% (m/m) and the content of the ethyl ester of EPA within the algal oil is approx. 10% (m/m).

16. The pharmaceutical composition for use in prevention of an age-related condition according to any one of daims 1-8, and 13-15, wherein vitamin D3 is administered at a daily dose of 1000 to 3000 IU, particularly 2000 IU.

17. The pharmaceutical composition for use in prevention of an age-related condition according to any one of the previous daims, wherein the pharmaceutical composition further comprises an antioxidant, particularly a tocopherol.

18. The pharmaceutical composition for use in prevention of an age-related condition according to any one of the previous daims, wherein the pharmaceutical composition is administered for at least 6 months, particularly at least 12 months, more particularly at least 24 months, most particularly at least 36 months.

19. The pharmaceutical composition for use in prevention of an age-related condition according to any one of the previous claims, wherein the pharmaceutical composition is administered to a patient above 69 years of age.

20. The pharmaceutical composition for use according to any one of the preceding claims, wherein the pharmaceutical composition comprises 990mg of algal oil comprising a total of 500mg of DHA and EPA at a ratio (mass/mass) of 1 :2, and wherein the pharmaceutical composition comprises 1 ,25 mg of vitamin D3.