WO2009093454A1 - Food composition, feed composition comprising the food composition, and method for feeding animal by using the feed composition - Google Patents

Food composition, feed composition comprising the food composition, and method for feeding animal by using the feed composition Download PDF

Info

Publication number
WO2009093454A1
WO2009093454A1 PCT/JP2009/000223 JP2009000223W WO2009093454A1 WO 2009093454 A1 WO2009093454 A1 WO 2009093454A1 JP 2009000223 W JP2009000223 W JP 2009000223W WO 2009093454 A1 WO2009093454 A1 WO 2009093454A1
Authority
WO
WIPO (PCT)
Prior art keywords
polyamine
diamine
animal
formula
composition according
Prior art date
Application number
PCT/JP2009/000223
Other languages
French (fr)
Japanese (ja)
Inventor
Kuniyasu Soda
Original Assignee
Jichi Medical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jichi Medical University filed Critical Jichi Medical University
Priority to JP2009550472A priority Critical patent/JPWO2009093454A1/en
Publication of WO2009093454A1 publication Critical patent/WO2009093454A1/en

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/132—Amines having two or more amino groups, e.g. spermidine, putrescine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a food composition, a feed composition for extending the life of an animal, and an animal breeding method using the feed composition. More specifically, the present invention relates to a food composition containing a specific polyamine, a feed composition containing a specific polyamine for extending the life of an animal, and providing the feed composition to increase the life of the animal. It is about the breeding method to extend.
  • Patent Document 1 a functional food or wine beverage with an increased polyphenol content
  • Patent Document 3 a composition that extends the life by specific inhibition of EF-kinase
  • Patent Document 3 a specific pharmacological substance A composition for delaying aging
  • CD11a and CD18 constitute LFA-1 (leukocyte function associated antigen 1).
  • LFA-1 leukocyte function associated antigen 1
  • immune cells such as lymphocytes, monocytes, macrophages and granulocytes having the LFA-1 on their surface adhere to vascular endothelial cells that express the ligand ICAM-1. Is activated and causes inflammation in the tissue.
  • tissue inflammation begins as a result of this reaction, the production of various mediators that induce inflammation induces activation of other adhesion molecules and functional cell membrane differentiation antigen molecules, thereby enhancing inflammation.
  • Non-Patent Documents 2, 3 and 4 the occurrence and progression of inflammation can be suppressed by decreasing the expression level of LFA-1 or by reducing the adhesion function of the adhesion molecule by binding an antibody or a functional molecule to this adhesion molecule.
  • the present inventors have studied the suppression of the occurrence and progression of such inflammation, and found that specific polyamines such as spermine reduce the expression of LFA-1 and have an anti-inflammatory effect (non-patented).
  • Reference 1 an LFA-1 inhibitor based on the polyamine was developed to prevent or prevent the progression of various inflammation-derived diseases (Patent Document 2).
  • Patent Document 2 As a result of further research, the present inventors have found that LFA-1 on the surface of immune cells increases and inflammation tends to occur as age increases, and the ability to synthesize polyamines decreases with age, compared with young individuals It was found that the preferable polyamine concentration in the blood is lowered.
  • Polyamine that suppresses the increase in LFA-1 because the increase in LFA-1 with aging facilitates the progression of arteriosclerosis, heart disease, autoimmune arthritis, diabetic retinopathy, etc. caused by vascular inflammation It was thought that taking the necessary amount of food from the diet could maintain the health of the animal and prolong its lifespan.
  • the present invention relates to a functional food composition effective for preventing and reducing inflammation caused by an increase in LFA-1 accompanying aging and the like, and related diseases, a feed composition for extending the life of an animal, and It aims at providing the breeding method of the animal using this feed composition. More specifically, the present invention relates to a functional food composition that contains a specific polyamine and is effective for preventing and reducing inflammation caused by an increase in LFA-1 accompanying aging and the like, and related diseases, It aims at providing the feed composition for extending the life of an animal containing a specific polyamine, and the breeding method which extends the life of an animal by providing this feed composition.
  • the present inventors In the course of studying inflammation caused by an increase in LFA-1 with aging and the relationship between related diseases and polyamines, the present inventors have ingested a polyamine that suppresses the increase in LFA-1 from the diet. Considering the potential for maintaining animal health and prolonging life, we studied the effects of such polyamines. As a result, the inventors have obtained the knowledge that the life span of animals can be extended by ingesting polyamines that suppress the increase in LFA-1 from the diet, thereby completing the present invention.
  • S-adenosylmethionine decarboxylase AdoMet DC
  • ODC ornithine decarboxylase
  • S-adenosylmethionine is a substance that supplies a methyl group into the living body, and this increase in concentration promotes the progression of gene methylation.
  • the expression of LFA-1 is known to decrease in protein expression due to methylation of the promoter region (CpG) of the gene.
  • the present invention provides a food composition comprising at least one compound selected from the group consisting of a polyamine of the following formula (1) and a pharmaceutically acceptable salt thereof.
  • a food composition comprising at least one compound selected from the group consisting of a polyamine of the following formula (1) and a pharmaceutically acceptable salt thereof.
  • m1 to m5 are each independently an integer of 0 to 7, at least one of which is greater than 0, and the sum of m1 + m2 + m3 + m4 + m5 is 2 or more and less than 18, and p1, p2, p3 and p4 are each independently 0 or 1.
  • this invention provides the feed composition for extending the lifetime of an animal which consists of said food composition. Furthermore, the present invention provides at least one compound selected from the group consisting of a polyamine of the formula (1) and a pharmaceutically acceptable salt thereof per kg body weight of an animal in a daily dosage unit of 0.01 to 1000 mg, preferably 0.01 to The feed composition comprising 100 mg is provided.
  • the animal is administered 0.01 to 1000 mg, preferably 0.01 to 100 mg, of at least one compound selected from the group consisting of the polyamine of the formula (1) and its pharmaceutically acceptable salt per kg body weight.
  • a breeding method for extending the life of an animal which supplies the feed composition.
  • the present invention administers to an animal 0.01 to 1000 mg, preferably 0.01 to 100 mg of at least one compound selected from the group consisting of the polyamine of formula (1) and its pharmaceutically acceptable salt per kg body weight.
  • the terms used in this specification are defined as follows.
  • polyamine refers to a compound containing two or more amino groups and two or more linear or branched alkylene moieties having 2 to 7 carbon atoms in the same molecule.
  • pharmaceutically acceptable salts refers to non-toxic acid addition salts of inorganic or organic acids that can be used as pharmaceuticals.
  • animal means a warm-blooded animal, such as a mammal, to which the feed composition of the present invention is to be provided. For example, dogs, cats, rats, mice, horses, cows, sheep, and people.
  • CD11a is called as LFA-1 ⁇ -chain, gp180 / 95, ⁇ L Integrin, etc. as aliases, but in this specification and claims, these names are unified to CD11a.
  • CD18 is referred to as LFA-1 ⁇ -chain, Integrin ⁇ 2, etc. as aliases, but in the present specification and claims, these names are collectively referred to as CD18.
  • the term “daily feeding unit” refers to the amount of feed composition given as a daily feed or added to a daily feed. In the case of the feed composition to be added, it can be provided in the form of a powder, liquid, tablet or the like.
  • pets such as dogs and cats, animals such as monkeys, deer and elephants bred in zoos, dolphins, sea lions, sea otters and killer whales bred in aquariums and the like It is possible to maintain the health of marine animals such as dogs and horses such as horses, and to prolong their life. In addition, by providing humans with functional foods, the effects of maintaining their health and extending their life can be expected.
  • polyamine compounds used in the present invention are biogenic amines that exist universally in living organisms, and can be produced by extraction from living organisms.
  • the production method is disclosed in documents such as BeilsteinssteinHandbuch Der Organischen Chemie.
  • Information on polyamine compounds used in the present invention is also described in the Merck Index 9th edition and Method in Molecular Biology (Vol. 79, Polyamine Protocols, Edited by: D. Morgan, Humana Press Inc., Totowa, NJ) Has been. Therefore, those skilled in the art can produce or obtain the polyamine of the present invention based on these information.
  • the polyamine used in the present invention is preferably a polyamine represented by the following formula (1).
  • m1 to m5 are each independently an integer of 0 to 7, at least one of which is greater than 0, and the sum of m1 + m2 + m3 + m4 + m5 is 2 or more and less than 18, and p1, p2, p3 and p4 are each independently 0 or 1.
  • m1 to m5 are each independently an integer of 0 to 5, and the sum of m1 + m2 + m3 + m4 + m5 is 2 or more and less than 17.
  • the sum of m1 + m2 + m3 + m4 + m5 can be 4 or more and less than 16.
  • m1 is an integer of 2 to 7, m2, m3, m4 and m5 are 0, and p1, p2, p3 and p4 can each be 0.
  • m1 is an integer of 2 to 7
  • m2 is an integer of 2 to 7
  • m3, m4 and m5 are
  • p1 is 1, and p2, p3 and p4 are 0 and 0, respectively. can do.
  • m1 is an integer of 3 to 5
  • m2 is an integer of 2 to 5
  • m3, m4 and m5 are
  • p1 is 1
  • p2, p3 and p4 are 0 and 0, respectively. can do.
  • m1 is an integer of 2 to 7, m2 and m3 are integers of 2 to 7, m4 and m5 are 0, p1 and p2 are 1, and p3 and p4 are 0, respectively. be able to.
  • m1 is an integer of 3 to 5
  • m2 and m3 are integers of 2 to 5
  • m4 and m5 are 0, p1 and p2 are 1, and p3 and p4 are 0 and 0, respectively. can do.
  • m1, m2, m3 and m4 are integers of 2 to 7, m5 is 0, p1 to p3 are 1, and p4 can be 0.
  • m1 is an integer of 3 to 5, m2, m3 and m4 are integers of 2 to 5, m5 is 0, p1 to p3 is 1, and p4 is 0. be able to.
  • the polyamine of the formula (1) can be diamine, triamine, tetraamine, pentaamine, and hexaamine, and in the present invention, these can be used alone or in combination. Next, specific examples of the polyamine will be given.
  • diamines used in the present invention include the following. Putrescine NH 2 (CH 2 ) 4 NH 2 1,4-butanediamine Cadaverine NH 2 (CH 2 ) 5 NH 2 1,5-pentanediamine Ethylenediamine NH 2 (CH 2 ) 2 NH 2 1,2-etanediamine Trimethylenediamine NH 2 (CH 2 ) 3 NH 2 1,3-propanediamine Hexamethylenediamine NH 2 (CH 2 ) 6 NH 2 1,6-hexanediamine Preferred among these diamines is putrescine.
  • triamines used in the present invention include the following. Cardin (Norspermidine) NH 2 (CH 2 ) 3 NH (CH 2 ) 3 NH 2 3,3'-iminobispropylamine [Biochem Biophys. Res. Commun. 63. 69 (1975)]spermidine NH 2 (CH 2 ) 3 NH (CH 2 ) 4 NH 2 N-aminobutyl-1,3-diaminopropane [Beil.
  • Examples of the tetraamine used in the present invention include the following. Theremin (Norspermine) NH 2 (CH 2 ) 3 NH (CH 2 ) 3 NH (CH 2 ) 3 NH 2 4,8-diazaundecane-1,11-diamine Spermine NH 2 (CH 2 ) 3 NH (CH 2 ) 4 NH (CH 2 ) 3 NH 2 4,9-diazadodecane-1,12-diamine [Beil.
  • pentaamine used in the present invention examples include the following. Caldopentamine NH 2 (CH 2 ) 3 NH (CH 2 ) 3 NH (CH 2 ) 3 NH (CH 2 ) 3 NH 2 4,8,12-triazapentadecane-1,15-diamine Homocaldopentamine NH 2 (CH 2 ) 3 NH (CH 2 ) 3 NH (CH 2 ) 3 NH (CH 2 ) 4 NH 2 4,8,12-triazahexadecane-1,16-diamine Aminopropylcanavalmine NH 2 (CH 2 ) 3 NH (CH 2 ) 4 NH (CH 2 ) 3 NH (CH 2 ) 4 NH 2 4,9,13-triazaheptadecane-1,17-diamine Bis (aminopropyl) homospermidine NH 2 (CH 2 ) 3 NH (CH 2 ) 4 NH (CH 2 ) 4 NH (CH 2 ) 4 NH 2 4,9
  • Preferred among these pentaamines are cardopentamine and homocardopentamine.
  • hexaamine used in the present invention examples include the following. Caldohexamine NH 2 (CH 2 ) 3 NH (CH 2 ) 3 NH (CH 2 ) 3 NH (CH 2 ) 3 NH (CH 2 ) 3 NH 2 4,8,12,16-tetraazanonadecane-1,19-diamine Homocaldohexamine NH 2 (CH 2 ) 3 NH (CH 2 ) 3 NH (CH 2 ) 3 NH (CH 2 ) 3 NH (CH 2 ) 3 NH (CH 2 ) 4 NH 2 4,8,12,16-tetraazaicosane-1,20-diamine Thermohexamine NH 2 (CH 2 ) 3 NH (CH 2 ) 3 NH (CH 2 ) 3 NH (CH 2 ) 4 NH (CH 2 ) 3 NH 2 4,8,12,17-tetraazaicosane-1,20-diamine Homosermohexamine NH 2 (
  • the polyamine can be used in the form of a pharmaceutically acceptable salt.
  • the salt is an addition salt of an organic acid or an inorganic acid, and includes, for example, inorganic acid addition salts such as hydrochloric acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, and, for example, sulfonic acid, methanesulfonic acid, sulfamic acid , Tartaric acid, fumaric acid, hydrobromic acid, glycolic acid, citric acid, maleic acid, succinic acid, acetic acid, benzoic acid, ascorbic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, propionic acid, lactic acid, Organic acid addition salts such as pyruvic acid, oxalic acid, stearic acid, cinnamic acid, aspartic acid, salicylic acid and gluconic acid. Since the following the
  • the dose of the feed composition of the present invention is appropriately changed according to the type, sex, age, and body weight of the target animal. Usually, in mammals, 0.01 to 1000 mg / kg body weight, 0.01 mg of polyamine per day is used. -400 mg / Kg body weight, 0.01-100 mg / Kg body weight, 0.05-100 mg / Kg body weight, 0.05-40 mg / kg body weight, and further 0.05-4 mg / kg body weight.
  • 0.01 to 1000 mg / kg of polyamine per day as the polyamine of at least one compound selected from the group consisting of the polyamine of the formula (1) and a pharmaceutically acceptable salt thereof per 1 kg body weight of the present invention Prolong the life of animals, including administering body weight, 0.01-400 mg / Kg body weight, 0.01-100 mg / Kg body weight, 0.05-100 mg / Kg body weight, 0.05-40 mg / kg body weight, and further 0.05-4 mg / kg body weight Provide breeding methods.
  • the total amount of the polyamine and the like contained in the normal feed and the polyamine and the like provided by the feed composition of the present invention may be the above-mentioned supply amount.
  • the form of the food composition and the feed composition of the present invention can be appropriately selected according to the characteristics of the target animal.
  • it can be liquid, semi-fluid, or solid.
  • the liquid feed composition can be used by mixing or sprinkling with animal feed.
  • the semi-liquid feed composition can be used alone or in addition to other fluid, semi-kneaded product feeds.
  • the solid feed composition can be used as a pet food form such as a powder or a pellet cut into a certain size.
  • the polyamine content of the food composition and the feed composition of the present invention is 0.0025 to 100 mg / kg body weight, preferably 0.005 to 40 mg / kg body weight, more preferably 0.01 to as polyamine per dosage unit. 4 mg / kg body weight.
  • the feed composition of this invention when supplying the feed composition of this invention alone, it can manufacture with various granular solid forms.
  • the feed composition of the present invention is a dog food
  • a predetermined amount of polyamine can be added to a base feed containing meat and vegetables, and agar can be added and coagulated.
  • the meat of the base feed is beef, horse meat, chicken meat, fish meat, etc., and these meats are used alone or in combination.
  • the base feed vegetables are carrots, cabbage, corn, tomatoes, etc., and these vegetables are used alone or in combination.
  • cheese, pasta, fried chicken soup, beef consomme and the like can be added to the base feed.
  • the base feed is pulverized into a minced state, and then polyamine, water and agar are added, heated, molded, cooled and solidified.
  • the polyamine or a pharmaceutically acceptable salt thereof or a combination thereof can be used alone or in combination with other desired nutritional supplements and drugs as active ingredients.
  • the nutritional supplements include various vitamins such as vitamin C, vitamin E, garlic, and complex vitamin B, brewer's yeast, linseed oil, fish oil, brewed vinegar, protein concentrate, dairy products, and mineral agents.
  • the drug include an appetite enhancer, an antibacterial agent, a digestive enzyme, an anti-infective agent, an antifungal agent, an anti-inflammatory agent, an analgesic agent, a metabolic agent, a parasiticide agent, and other pharmaceutical agents.
  • the feed composition of the present invention starts to be fed before the animal individual's ability to synthesize and maintain polyamines with aging and the blood vessels and the like are prone to inflammation.
  • rodents such as mice are 4 to 10 weeks old
  • animals such as cats and dogs are 4 to 8 months old
  • large herbivores such as horses, cows, and elephants are 6 months to 2 years old
  • the feed composition of the present invention is fed for at least 3 months, preferably 6 months, more preferably 12 months from the start of feeding, and if necessary, the feed composition may be continuously fed throughout the life.
  • the feed composition of this invention corresponding to the required amount per day may be given once a day. However, they may be given separately at the time of each feed supply.
  • the ratio% means weight% (w / w%).
  • a basic feed composition was prepared. Hereinafter, it is referred to as a low polyamine feed composition.
  • the composition of the feed composition is as follows. Moisture 7.6% Protein 26.4% Lipid 10.2% Fiber 2.5% Ash content 6.0% Nitrogen-free extract 47.3% Calorie 397 Kcal / 100g
  • Raw materials used for the preparation of the feed composition are milk casein, white fish meat, yeast, wheat germ, pork fat, wheat bran, defatted rice bran, alfalfa coarse flour, wheat coarse flour, corn, milo, vitamin mixture, and It is a mineral mixture. These raw materials were blended so as to have the above composition, mixed with an appropriate amount of water, and molded into pellets.
  • a feed composition was prepared.
  • the amount of polyamine added was 0.015% spermine, 0.06% spermidine, and 0.015% putrescine for each feed composition. It was prepared in the same manner as the low polyamine feed composition except that the polyamine was added.
  • Example 2 Measurement of blood polyamine concentration when using the feed composition of Example 1 24-week-old mice (Jc1: ICR mouse, male) were divided into 2 groups of 8 mice, and the low polyamine of Example 1 was divided into one group.
  • the spermidine-containing polyamine feed composition prepared in Example 1 was administered to other groups, and the blood concentrations of spermidine after 26 weeks were compared.
  • the body weight of the mouse is 30 to 70 g, and about 3 to 10 g of food is consumed per day. Therefore, the intake of spermidine is about 20 to 200 mg / kg / day per mouse. As shown in FIG.
  • the blood spermidine concentration of the group ingesting the low polyamine feed composition is about 32 nmol / ml, while the blood spermidine concentration of the group ingesting the high polyamine feed composition is about 50 nmol / ml. is there. Therefore, it is understood that the blood polyamine concentration is increased by ingesting the feed composition of the present invention.
  • Example 3 Measurement of blood polyamine concentration when using the feed composition of Example 1 24-week-old mice (Jc1: ICR mouse, male) were divided into 2 groups of 9 mice, and the low polyamine of Example 1 was divided into 1 group. The feed composition was given, and the spermine-containing polyamine feed composition prepared in Example 1 was administered to the other groups, and the spermine blood concentrations after 26 weeks were compared. In this case, the body weight of the mouse is 30 to 70 g, and about 3 to 10 g of feed is consumed per day. Therefore, the intake of the spermine is about 5 to 50 mg / kg per mouse. As shown in FIG.
  • the blood spermidine concentration of the group ingesting the low polyamine feed composition is about 5 nmol / ml, while the blood spermine concentration of the group ingesting the high polyamine feed composition is about 10 nmol / ml. is there. Therefore, it is understood that the blood polyamine concentration is increased by ingesting the feed composition of the present invention.
  • Example 4 Examination of effect of high polyamine-containing feed composition of the present invention (survival rate) 24 week-old mice (Jc1: ICR mice, male) were divided into 2 groups of 9 mice, one group was given the low polyamine feed composition of Example 1, and the other group was prepared in Example 1 with spermine-containing polyamines. The feed composition was administered and the cumulative survival rate was compared up to 80 weeks of age. Mice were housed in a closed incubator with 4-6 mice in each gauge, temperature and humidity controllable and equipped with a device that sends air through a filter. Animals used in all experiments were kept in one incubator, and the same water was administered to all animals. In addition, the air in the incubator has a structure that diffuses throughout, and the animals used in the experiment were breathing with the same air.
  • the body weight of the mouse is 30 to 70 g, and about 3 to 10 g of feed is consumed per day. Therefore, the intake of the spermine is about 5 to 50 mg / kg per mouse. The intake of spermidine is about 20 to 200 mg / kg per mouse.
  • mice (Jc1: ICR mouse, male) started feeding the feed composition of the present invention from 24 weeks of age, and observation was made at 80 weeks of age. Of the 110 experimental animals, 66 mice were fed a low polyamine diet, but 37 were alive at 80 weeks of age. On the other hand, 44 mice were fed a high polyamine diet, but 37 were alive at 80 weeks of age. Of the mice that were fed a high polyamine diet that had survived at the age of 80 weeks of age, 21 of the 37 surviving mice had good fur, fleshiness, and active exercise. However, among the 37 mice in the low polyamine donating group, there were only 12 mice with good fur, fleshy and active movement, and many had poor fur.
  • Example 6 Toxicity of polyamines According to additional experiments, 0.045% spermine (contained 4.5 g in 10 kg of food), 0.115% spermidine (contained 11.5 g in 10 kg of bait) and 0.045% of putrescine ( Mice were reared with a continuous feed composition containing 4.5 g in 10 kg of feed.
  • the feed composition used here is the same as that produced in Example 1 except for the amount of polyamine. Even after 8 months (33 weeks have passed) since the start of the experiment, no changes were observed in the bred mice and no toxicity was observed.
  • natto contains about 10 to 100 mg of polyamines such as spermine and spermidine per 100 g, and is a high polyamine-containing food.
  • the blood concentration of spermine was measured 2 months after the start of the experiment, divided into a group (10 adults) who ingested 1 or more packs containing 45-50 g of natto every day and a group (7 adults) who did not take natto. As a result, as shown in FIG.
  • the blood concentration of spermine was clearly increased in the group ingesting natto every day, whereas the blood concentration of spermine was not changed in the group not ingesting natto. Therefore, it can be seen that even in primates including humans, the blood polyamine concentration is increased by ingesting the high polyamine feed composition of the present invention.
  • This LFA-1 is an important cell membrane protein for inducing inflammation, and this enhanced expression induces inflammation. Therefore, since the synthesis of polyamines decreases with age in animals, the expression of immune cells such as lymphocytes and mononuclear cells is enhanced, and chronic inflammation governed by these cells tends to occur. And that is thought to be the cause of lifestyle-related diseases. That is, it has been found that many lifestyle-related diseases such as arteriosclerosis are induced by inflammation.
  • spermine decreases LFA-1 in peripheral blood mononuclear cells.
  • the polyamine concentration in the blood is measured, and the expression of LFA-1 is suppressed (LFA-1 is decreased) depending on the concentration of polyamine (spermine) due to the relationship with the expression of LFA-1.
  • the cause of the progression of lifestyle-related diseases is inflammation
  • the knowledge that the prevention effect of lifestyle-related diseases can be expected if the polyamine concentration in the blood (whole blood including blood cells) can be increased. Obtained.
  • FIG. 11 shows the mouse blood spermidine concentration increase data obtained in Example 2.
  • FIG. 12 shows the data on the increase in mouse blood spermine concentration obtained in Example 3.
  • the concentration of polyamines (spermidine and spermine) in the blood of mice fed a high polyamine diet containing a large amount of polyamine increased at 26 weeks after administration.
  • blood polyamine levels did not increase in mice that ate normal or low polyamine levels.
  • the spermine concentration in the blood increased in about two months even when a human had a high polyamine diet (when natto as a high polyamine diet was eaten 1-2 packs a day).
  • FIG. 12 is a photograph showing the difference in appearance of 80-week-old mice. Obviously, the mice that ate a high polyamine concentration had good hair.
  • Example 5 was continued, and the kidneys of the mice were removed at 88 weeks, and the tissues of each organ were examined. However, as shown in FIG. 14B, in the low and normal polyamine-fed mice, hardening of the kidney glomeruli (organ that filters urine) (glomerulosclerosis) was prominent.
  • the glomerulosclerosis is one of the most characteristic changes as a result of aging, and is caused by the progression of lifestyle-related diseases such as arteriosclerosis.
  • the kidney was immunostained with an antibody of senescence marker protein 30 (SMP30).
  • SMP30 is a protein that decreases from the tissue with age, and is not affected by other hormones and has a function of protecting the tissue against oxidative stress. This decrease in protein lowers the defense function against oxidative stress in the body and further accelerates aging.
  • the amount of expression of SMP30 (stained in black to dark gray in the photograph) in the kidneys of the mice of the high polyamine diet group obtained in Example 5 was high, and the mice that ate the high polyamine diet Then we found that there are many SMP30.
  • the amount of SMP30 in the kidneys of low or normal polyamine-fed mice decreased (light color). Of course, the expression of SMP30 is high in the young mice shown in the comparison.
  • the liver was further immunostained using an SMP30 antibody.
  • SMP30 the expression level of SMP30 in the liver of mice with a high polyamine diet group is high (stained in a dark color in the photograph), and many SMP30 in mice that ate a high polyamine diet. Was found to exist.
  • the amount of SMP30 in the liver of low or normal polyamine-fed mice was decreased (light color).
  • the expression of SMP30 is high in the young mice shown in the comparison.
  • the high polyamine diet suppressed the histological changes of important organs accompanying aging of mice, and kept the youthful and active. That is, it can be seen that aging and glomerular hardening, which is a typical change thereof, are prevented and the life is extended.
  • the high polyamine diet that is, the food composition and feed composition of the present invention suppresses lifestyle-related diseases such as arteriosclerosis and aging, and causes lifestyle-related diseases. It is clear that a protective function against certain oxidative stress (SMP30) can be maintained.
  • cardiovascular disease causes cardiovascular diseases such as myocardial infarction and cerebral infarction, it is the leading cause of death in industrialized countries, especially Western countries, and it is thought that overcoming this disease will lead to a longer life span. Yes. Therefore, we focused on whether there is evidence that polyamines, particularly spermine, that have strong anti-inflammatory effects (suppression of inflammatory cytokine production and LFA-1 expression) suppress arteriosclerosis.
  • the target countries are European countries including Russia and the United States, Canada, Australia and New Zealand (Albania, Armenia, Australia, Austria, Azerbaijan, Belarus, Belgium, Spanish and Herzegovina, Bulgaria, Canada, Croatia, Siplus, Czech Republic, Denmark , Estonia, Finland, France, Georgia, Germany, Greece, Vietnamese, Vietnamese, Ireland, Israel, Italy, Ukraine, Norway, Norway, Norway, Norway, Norway, Switzerland, Kom, Norway, Lithuania, Malta, New Zealand, Norway, Tru, Pottgart, Romania, Russian Federation, Slovakia, Slovenia, Spain , Sweden, Tarikistan, Dunia, Yugoslavia, Turkey, Turkmenis Emissions, Ukraine, United Kingdom, United States of America, is the 49 countries of Uzbekistan), and cultural, racial makeup, food culture, a relatively similar national religious background in the subject.
  • the investigated foods are animal fats, aquatic animals, marine products, beef, butter, ghee, cephalopods, cheese, cream, crustaceans, deep sea fish, eggs, animal fat (raw), freshwater fish, honey, sea fish (others) ), Meat (other), whole milk, milk preparation butter (whole milk with dairy products converted from milk), mollusks (other), mutton and goat meat, edible internal organs, pork, chicken, whey, apples, Banana, lemon and lime, citrus (other), pineapple, grape, orange and mandarin, fruit (other), pulses (other), tree nut, ground nut, cereal (cereal (other), barley, oat, Rye, wheat, rice (mild eq)), potatoes, corn, onions, tomatoes, vegetables (others), stimulants, oil grains, sugar, coffee, beer, wine, alcoholic beverages.
  • CVD cardiovascular disease
  • spermine intake and total calories which had the strongest anti-inflammatory effects (inhibition of inflammatory cytokine production and LFA-1 expression) in previous studies.
  • polyamines that suppress inflammation which is important as a mechanism for the development of lifestyle-related diseases such as CVD, in particular spermine, is considered that polyamines that enter the body suppress inflammation and suppress the onset of CVD, This has been proved in epidemiological studies.
  • polyamine is a substance common to microorganisms, plants, animals, and humans, and humans, like mice, suppress lifestyle-related diseases such as arteriosclerosis, suppress the progression of aging, and extend lifespan. I understood.
  • FIG. 1 is a metabolic pathway of polyamines.
  • AdoMetsDC S-adenosylmethionine decarboxylase
  • ODC ornithine decarboxylase
  • FIG. 2 shows the relationship between S-adenosylmethionine and gene promoter region (CpG) methylation. Methylation of the promoter region of the gene controls gene expression. S-adenosylmethionine is the only substance that supplies methyl groups, and this increase in concentration promotes the progress of methylation of genes and the like. It has been found that LFA-1 promoter region is down-regulated by methylation.
  • FIG. 3 is a graph comparing the blood spermidine concentration of the group ingesting the low polyamine feed composition and the blood spermidine concentration of the group ingesting the high polyamine feed composition.
  • FIG. 4 shows the mouse blood spermine concentration increase data obtained in Example 3. In FIG. 4, the blood spermine concentration of the group ingesting the low polyamine feed composition is compared with the blood spermine concentration of the group ingesting the high polyamine feed composition.
  • FIG. 5 is a graph showing the cumulative survival rate of a group of mice fed with a high polyamine feed composition and the cumulative survival rate of a group of mice fed with a low polyamine feed composition.
  • FIG. 6A is a graph showing the blood concentration of spermine in a group of people who took natto every day
  • B is the graph showing the blood concentration of spermine in a group of people who did not take natto.
  • the blood spermine concentration was clearly increased after continuing the natto diet (After) compared to before the start of the experiment (Before).
  • FIG. 7 is a graph showing that polyamine synthesis decreases with age in mammals such as humans.
  • FIG. 8 shows data indicating that LFA-1 in peripheral blood mononuclear cells increases with increasing age.
  • FIG. 9 is data showing that an increase in spermine decreases LFA-1 in peripheral blood mononuclear cells.
  • FIG. 11 shows the mouse blood spermidine concentration increase data obtained in Example 2.
  • FIG. 12 is a photograph showing the difference in appearance between a mouse that continued to have a high polyamine diet and a mouse that had a low or normal polyamine diet. Obviously, the mice that ate a high polyamine concentration had good hair.
  • FIG. 12 is a photograph showing the difference in appearance between a mouse that continued to have a high polyamine diet and a mouse that had a low or normal polyamine diet. Obviously, the mice that ate a high polyamine
  • FIG. 13 shows a group of mice that ate a high polyamine diet and a group of mice that ate a diet with a low or normal polyamine concentration, when the follow-up test was performed in the same manner as in Example 5 and the survival times of the mice were compared. Data showing survival rate and extension of survival time.
  • FIG. 14B shows that in the low and normal polyamine-fed mice, kidney glomeruli (the organ that filters urine) is markedly cured (glomerulosclerosis), whereas in high-polyamine-fed mice, FIG. It is a photograph showing that the glomerulus is maintained as a young mouse as shown by A, the hardening is extremely mild, and the progression of aging and arteriosclerosis is not so much.
  • FIG. 14B shows that in the low and normal polyamine-fed mice, kidney glomeruli (the organ that filters urine) is markedly cured (glomerulosclerosis), whereas in high-polyamine-fed mice, FIG. It is a photograph showing that the glomerulus is maintained as
  • FIG. 15 is a photograph showing the expression level of SMP30 in the kidneys of mice of the low, normal and high polyamine diet groups (stained in black to dark gray in the photograph).
  • FIG. 16 is a photograph showing the expression level of SMP30 in the liver of mice of the low, normal and high polyamine diet groups (stained in black to dark gray in the photograph).
  • FIG. 18 is data showing the relationship between cardiovascular disease and cheese consumption.
  • FIG. 23 is data showing the actual relationship between polyamine intake and the life of a person (male).
  • FIG. 24 is data showing the actual relationship between polyamine intake and the life span of a person ( woman).

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Polymers & Plastics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Food Science & Technology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nutrition Science (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Zoology (AREA)
  • Epidemiology (AREA)
  • Animal Husbandry (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Mycology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Fodder In General (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)

Abstract

Disclosed are: a food composition; a feed composition for prolonging a life span of an animal; and a method for feeding an animal by using the feed composition. Specifically disclosed is a food composition or a feed composition for prolonging a life span of an animal, which comprises at least one compound selected from the group consisting of a polyamine represented by formula (1) and a pharmaceutically acceptable salt thereof. NH2-(CH2)m1-(NH)p1-(CH2)m2-(NH)p2-(CH2)m3-(NH)p3-(CH2)m4-(NH)p4- (CH2)m5-NH2 (1)

Description

食品組成物、該食品組成物を含む飼料組成物及び該飼料組成物を用いる動物の飼育方法Food composition, feed composition containing the food composition, and animal breeding method using the feed composition
　本発明は、食品組成物、動物の寿命を延長するための飼料組成物及び該飼料組成物を用いる動物の飼育方法に関するものである。さらに詳細に述べると、本発明は、特定のポリアミンを含む食品組成物、特定のポリアミンを含む、動物の寿命を延長するための飼料組成物、及び該飼料組成物を供与して動物の寿命を延長する飼育方法に関するものである。 The present invention relates to a food composition, a feed composition for extending the life of an animal, and an animal breeding method using the feed composition. More specifically, the present invention relates to a food composition containing a specific polyamine, a feed composition containing a specific polyamine for extending the life of an animal, and providing the feed composition to increase the life of the animal. It is about the breeding method to extend.
　従来から、人間や動物の老齢化を遅らせ、かつ寿命を延ばす化合物、薬剤、又は機能性食品などの研究が行われてきた。そして、例えば、ポリフェノールの含有量を増やした機能性食品やワインなどの飲料、EF-キナーゼの特異的な抑制により寿命を延ばす組成物（特許文献１）、及び特定の薬理学的な物質を含む老化を遅らせる組成物（特許文献３）などが開発されてきた。しかし、これらは老化を遅らせ、寿命を延ばす機能が不明瞭であり、さらに優れた老化遅延、寿命延長の機能を有する薬剤、又は食品の開発が望まれている。 Conventionally, research has been conducted on compounds, drugs, or functional foods that delay the aging of humans and animals and extend their lifespan. And, for example, a functional food or wine beverage with an increased polyphenol content, a composition that extends the life by specific inhibition of EF-kinase (Patent Document 1), and a specific pharmacological substance A composition for delaying aging (Patent Document 3) has been developed. However, these substances are unclear in their functions of delaying aging and prolonging life, and further development of drugs or foods having excellent functions of delaying aging and prolonging life is desired.
　ところで、動物細胞の表面には、様々な細胞膜分化抗原（Cluster of differentiation：以下、CDと呼ぶ）が発現しており、そのうちCD11aとCD18がLFA-1(leukocyte function associated antigen 1)を構成している。そして、炎症の初期の段階では、該LFA-1を表面に有するリンパ球、単球、マクロファージ、顆粒球等の免疫細胞が、リガンドであるICAM-1を発現している血管内皮細胞等に接着することにより活性化され、組織に炎症を生じさせる。この反応をきっかけに組織の炎症が始まると、様々な炎症を誘発するメディエーターの産生により、他の接着分子や機能的な細胞膜分化抗原分子の活性化が誘発され、炎症が増強される。このため、LFA-1の発現量を減少させるか、この接着分子に抗体や機能的な分子を結合させて接着分子の接着機能を低下させることにより、炎症の発生や進行を抑制することができる（非特許文献２，３及び４）。 By the way, various cell membrane differentiation antigens (Cluster of differentiation: CD) are expressed on the surface of animal cells, and CD11a and CD18 constitute LFA-1 (leukocyte function associated antigen 1). Yes. In the early stage of inflammation, immune cells such as lymphocytes, monocytes, macrophages and granulocytes having the LFA-1 on their surface adhere to vascular endothelial cells that express the ligand ICAM-1. Is activated and causes inflammation in the tissue. When tissue inflammation begins as a result of this reaction, the production of various mediators that induce inflammation induces activation of other adhesion molecules and functional cell membrane differentiation antigen molecules, thereby enhancing inflammation. For this reason, the occurrence and progression of inflammation can be suppressed by decreasing the expression level of LFA-1 or by reducing the adhesion function of the adhesion molecule by binding an antibody or a functional molecule to this adhesion molecule. (Non-Patent Documents 2, 3 and 4).
　本発明者らは、このような炎症の発生や進行の抑制について研究を行い、スペルミン等の特定のポリアミンがLFA-1の発現を減少させること、及び抗炎症作用があることを見出し（非特許文献１）、様々な炎症由来の疾患の予防、又は進行を抑制する、該ポリアミンを主成分とするLFA-1抑制剤を開発した（特許文献２）。本発明者らは、さらに研究を行った結果、年齢が高くなるほど免疫細胞表面のLFA-1が増え、炎症が起きやすくなること、加齢に伴いポリアミンの合成能力が低下し、若い個体と比較し好ましい血中のポリアミン濃度が低くなることを見出した。そして加齢に伴うLFA-1の増加により、血管の炎症に起因する動脈硬化、心臓疾患、自己免疫性関節炎、糖尿病性網膜症などが進行し易くなるので、LFA-1の増加を抑制するポリアミンを必要量食餌から摂取させることにより、動物の健康を維持し、かつ寿命を延ばす可能性があると考えた。 The present inventors have studied the suppression of the occurrence and progression of such inflammation, and found that specific polyamines such as spermine reduce the expression of LFA-1 and have an anti-inflammatory effect (non-patented). Reference 1), an LFA-1 inhibitor based on the polyamine was developed to prevent or prevent the progression of various inflammation-derived diseases (Patent Document 2). As a result of further research, the present inventors have found that LFA-1 on the surface of immune cells increases and inflammation tends to occur as age increases, and the ability to synthesize polyamines decreases with age, compared with young individuals It was found that the preferable polyamine concentration in the blood is lowered. Polyamine that suppresses the increase in LFA-1 because the increase in LFA-1 with aging facilitates the progression of arteriosclerosis, heart disease, autoimmune arthritis, diabetic retinopathy, etc. caused by vascular inflammation It was thought that taking the necessary amount of food from the diet could maintain the health of the animal and prolong its lifespan.
特表2003-508347Special table 2003-508347 国際公開公報WO2004/073701International Publication WO2004 / 073701 特表2007-513201Special table 2007-513201
　本発明は、加齢等に伴うLFA-1の増加に起因する炎症、及び関連疾患を予防、及び軽減するのに有効な機能性食品組成物、動物の寿命を延長するための飼料組成物並びに該飼料組成物を用いる動物の飼育方法を提供することを目的とする。さらに詳細に述べると、本発明は、特定のポリアミンを含む、加齢等に伴うLFA-1の増加に起因する炎症、及び関連疾患を予防、及び軽減するのに有効な機能性食品組成物、特定のポリアミンを含む、動物の寿命を延長するための飼料組成物、及び該飼料組成物を供与して動物の寿命を延長する飼育方法を提供することを目的とする。 The present invention relates to a functional food composition effective for preventing and reducing inflammation caused by an increase in LFA-1 accompanying aging and the like, and related diseases, a feed composition for extending the life of an animal, and It aims at providing the breeding method of the animal using this feed composition. More specifically, the present invention relates to a functional food composition that contains a specific polyamine and is effective for preventing and reducing inflammation caused by an increase in LFA-1 accompanying aging and the like, and related diseases, It aims at providing the feed composition for extending the life of an animal containing a specific polyamine, and the breeding method which extends the life of an animal by providing this feed composition.
　本件発明者らは、加齢に伴うLFA-1の増加に起因する炎症、及び関連疾患とポリアミンの関係を研究する過程で、該LFA-1の増加を抑制するポリアミンを食餌から摂取させることにより、動物の健康を維持し、かつ寿命を延ばす可能性があると考え、そのようなポリアミンの効果について研究を行った。その結果、該LFA-1の増加を抑制するポリアミンを食餌から摂取させることにより、動物の寿命を延ばすことができるという知見を得て、本発明を完成した。 In the course of studying inflammation caused by an increase in LFA-1 with aging and the relationship between related diseases and polyamines, the present inventors have ingested a polyamine that suppresses the increase in LFA-1 from the diet. Considering the potential for maintaining animal health and prolonging life, we studied the effects of such polyamines. As a result, the inventors have obtained the knowledge that the life span of animals can be extended by ingesting polyamines that suppress the increase in LFA-1 from the diet, thereby completing the present invention.
　これを詳細に述べると、図１に示す様に、免疫細胞内のスペルミンおよびスペルミジンの濃度上昇が生じると、スペルミン合成酵素であるSアデノシルメチオニン脱炭酸酵素（S-adenosylmethionine decarboxylase (AdoMet DC)）とオルニチン脱炭酸酵素（Ornithine decarboxylase (ODC)）の活性が低下し、結果としてSアデノシルメチオニン（S-adenosylmethionine）が過剰になる。ところが、図２に示す様に、Sアデノシルメチオニンは生体内にメチル基を供給する物質であり、この濃度上昇は遺伝子のメチル化の進行を促進することになる。LFA-1の発現は遺伝子のプロモーター領域（CpG）のメチル化（Methylation）により蛋白量の発現が低下する事が判っている。それ以外の遺伝子においても、Sアデノシルメチオニン脱炭酸酵素の活性が抑制されてSアデノシルメチオニンが過剰になると、遺伝子の一部でメチル化の進行が見られる。遺伝子のメチル化の変化は老化や老化に伴う様々な生活習慣病と呼ばれる疾患の発症に密接な関係のあることが示唆されている。LFA-1においても、加齢とともにそのプロモーター領域のメチル化異常が生じ，結果としてLFA-1の発現が増強していると考えられる。ポリアミンの持続的な経口摂取によってLFA-1の発現が抑制されることは、老化や老化に伴う疾患と密接に関係している他の遺伝子の発現にも影響を与えている可能性が高い。このような観点からも、ポリアミンの摂取により動物の健康を維持し、老化や老化に伴う疾患の発症及び進行を抑制し、かつ寿命を延ばす可能性があると考えたのである。 In detail, as shown in FIG. 1, when the concentration of spermine and spermidine in immune cells increases, S-adenosylmethionine decarboxylase (AdoMet DC), a spermine synthase. And ornithine decarboxylase (ODC) activity decreases, resulting in an excess of S-adenosylmethionine. However, as shown in FIG. 2, S-adenosylmethionine is a substance that supplies a methyl group into the living body, and this increase in concentration promotes the progression of gene methylation. The expression of LFA-1 is known to decrease in protein expression due to methylation of the promoter region (CpG) of the gene. In other genes as well, when the activity of S-adenosylmethionine decarboxylase is suppressed and S-adenosylmethionine becomes excessive, methylation progresses in part of the gene. It has been suggested that changes in gene methylation are closely related to aging and the onset of various lifestyle-related diseases associated with aging. LFA-1 also appears to have abnormal methylation of its promoter region with aging, resulting in increased expression of LFA-1. Suppressing the expression of LFA-1 by continuous ingestion of polyamines is likely to affect the expression of other genes closely related to aging and diseases associated with aging. From this point of view, he thought that the intake of polyamines may maintain the health of animals, suppress the onset and progression of diseases associated with aging and aging, and prolong lifespan.
　したがって、本発明は、下記式(1)のポリアミン、及びその医薬として許容し得る塩からなる群から選ばれる少なくとも１の化合物を含む、食品組成物を提供する。
 
　NH2-(CH2)m1-(NH)p1-(CH2)m2-(NH)p2-(CH2)m3-
　　　　　　(NH)p3-(CH2)m4-(NH)p4-(CH2)m5-NH2    …(1)
 
　該式中、m1～m5はそれぞれ独立に０～７の整数であって、そのうち少なくとも１つは０よりも大きく、m1＋m2＋m3＋m4＋m5の和は、２以上かつ１８未満であり、かつp1, p2,
p3及びp4は、それぞれ独立に０又は１である。 Accordingly, the present invention provides a food composition comprising at least one compound selected from the group consisting of a polyamine of the following formula (1) and a pharmaceutically acceptable salt thereof.

NH 2- (CH 2 ) m1- (NH) p1- (CH 2 ) m2- (NH) p2- (CH 2 ) m3-
(NH) p3- (CH 2 ) m4- (NH) p4- (CH 2 ) m5 -NH 2 … (1)

In the formula, m1 to m5 are each independently an integer of 0 to 7, at least one of which is greater than 0, and the sum of m1 + m2 + m3 + m4 + m5 is 2 or more and less than 18, and p1, p2,
p3 and p4 are each independently 0 or 1.
　さらに、本発明は、前記食品組成物からなる、動物の寿命を延ばすための飼料組成物を提供する。
　さらに本発明は、１日の供与単位に、動物の体重１Kgあたり式(1)のポリアミン及びその医薬として許容し得る塩からなる群から選ばれる少なくとも１種の化合物0.01～1000mg、好ましくは0.01～100mg含まれている、前記飼料組成物を提供する。 Furthermore, this invention provides the feed composition for extending the lifetime of an animal which consists of said food composition.
Furthermore, the present invention provides at least one compound selected from the group consisting of a polyamine of the formula (1) and a pharmaceutically acceptable salt thereof per kg body weight of an animal in a daily dosage unit of 0.01 to 1000 mg, preferably 0.01 to The feed composition comprising 100 mg is provided.
　さらに本発明は、動物に、その体重１Kgあたり式(1)のポリアミン及びその医薬として許容し得る塩からなる群から選ばれる少なくとも１種の化合物0.01～1000mg、好ましくは0.01～100mgが投与されるよう、前記飼料組成物を供給する、動物の寿命を延長する飼育方法を提供する。
　さらに本発明は、動物に、その体重１Kgあたり式(1)のポリアミン及びその医薬として許容し得る塩からなる群から選ばれる少なくとも１種の化合物0.01～1000mg、好ましくは0.01～100mgを投与する、動物の寿命を延長する飼育方法を提供する。 In the present invention, the animal is administered 0.01 to 1000 mg, preferably 0.01 to 100 mg, of at least one compound selected from the group consisting of the polyamine of the formula (1) and its pharmaceutically acceptable salt per kg body weight. Thus, there is provided a breeding method for extending the life of an animal, which supplies the feed composition.
Furthermore, the present invention administers to an animal 0.01 to 1000 mg, preferably 0.01 to 100 mg of at least one compound selected from the group consisting of the polyamine of formula (1) and its pharmaceutically acceptable salt per kg body weight. Provide a breeding method to extend the life of an animal.
（定義）
　本明細書中で用いる用語を下記のように定義する。
　用語「ポリアミン」とは、同一分子内に２個以上のアミノ基、及び炭素原子数２～７個を有する直鎖、又は分枝鎖のアルキレン部分２以上を含む化合物をいう。
　用語「医薬として許容し得る塩」とは、医薬として用いることができる、無機酸又は有機酸の無毒性酸付加塩をいう。
　用語「動物」とは、本発明の飼料組成物を供与する対象となる哺乳類のような温血動物を意味する。例えば、犬、猫、ラット、ハツカネズミ、馬、牛、羊、及び人などである。 (Definition)
The terms used in this specification are defined as follows.
The term “polyamine” refers to a compound containing two or more amino groups and two or more linear or branched alkylene moieties having 2 to 7 carbon atoms in the same molecule.
The term “pharmaceutically acceptable salts” refers to non-toxic acid addition salts of inorganic or organic acids that can be used as pharmaceuticals.
The term “animal” means a warm-blooded animal, such as a mammal, to which the feed composition of the present invention is to be provided. For example, dogs, cats, rats, mice, horses, cows, sheep, and people.
　用語「CD11a」は、別名として、LFA-1 α-chain、gp180/95、αL Integrin等と呼ばれているが、本明細書、及び請求の範囲においては、これらの名称を統一してCD11aと呼ぶ。
　用語「CD18」は、別名として、LFA-1 β-chain、Integrin β2等と呼ばれているが、本明細書、及び請求の範囲においては、これらの名称を統一してCD18と呼ぶ。
　用語「１日の供与単位」とは、１日分の飼料として与える飼料組成物、又は１日分の飼料に添加する飼料組成物の量をいう。該添加する飼料組成物の場合、粉剤、液剤、錠剤などの形態で提供することができる。 The term “CD11a” is called as LFA-1 α-chain, gp180 / 95, αL Integrin, etc. as aliases, but in this specification and claims, these names are unified to CD11a. Call.
The term “CD18” is referred to as LFA-1 β-chain, Integrin β2, etc. as aliases, but in the present specification and claims, these names are collectively referred to as CD18.
The term “daily feeding unit” refers to the amount of feed composition given as a daily feed or added to a daily feed. In the case of the feed composition to be added, it can be provided in the form of a powder, liquid, tablet or the like.
　本発明の飼料組成物を供与することにより、犬、猫などの愛玩動物、動物園等で飼育されている猿、鹿、象などの動物、水族館等で飼育されているイルカ、トド、ラッコ、シャチなどの海洋動物及び犬、馬等の使役動物の健康を維持し、その寿命を延ばす効果が得られる。また、人間に機能性食品として供与することにより、その健康維持、及び寿命の延長という効果が期待できる。 By providing the feed composition of the present invention, pets such as dogs and cats, animals such as monkeys, deer and elephants bred in zoos, dolphins, sea lions, sea otters and killer whales bred in aquariums and the like It is possible to maintain the health of marine animals such as dogs and horses such as horses, and to prolong their life. In addition, by providing humans with functional foods, the effects of maintaining their health and extending their life can be expected.
　本発明で用いるポリアミン化合物の多くは、生物体内に普遍的に存在する生体アミンであって、生物体からの抽出により製造することができる。また、その製造方法は、Beilsteins Handbuch Der Organischen Chemieなどの文献に開示されている。また、メルクインデックス第9版やMethod in Molecular Biology (Vol. 79, Polyamine Protocols, Edited by: D. Morgan, Humana Press Inc., Totowa, NJ) などにも、本発明で用いるポリアミン化合物の情報が記載されている。したがって、当業者であれば、これらの情報に基づき本発明のポリアミンを製造、又は入手できる。 Most of the polyamine compounds used in the present invention are biogenic amines that exist universally in living organisms, and can be produced by extraction from living organisms. The production method is disclosed in documents such as BeilsteinssteinHandbuch Der Organischen Chemie. Information on polyamine compounds used in the present invention is also described in the Merck Index 9th edition and Method in Molecular Biology (Vol. 79, Polyamine Protocols, Edited by: D. Morgan, Humana Press Inc., Totowa, NJ) Has been. Therefore, those skilled in the art can produce or obtain the polyamine of the present invention based on these information.
　本発明で用いるポリアミンは、下記式(1)のポリアミンが好ましい。
 
　NH2-(CH2)m1-(NH)p1-(CH2)m2-(NH)p2-(CH2)m3-
　　　　　　　　(NH)p3-(CH2)m4-(NH)p4-(CH2)m5-NH2  …(1)
　
　該式中、m1～m5はそれぞれ独立に０～７の整数であって、そのうち少なくとも１つは０よりも大きく、m1＋m2＋m3＋m4＋m5の和は、２以上かつ１８未満であり、かつp1, p2,
p3及びp4は、それぞれ独立に０又は１である。
　また、該式(1)中において、m1～m5がそれぞれ独立に０～５の整数であって、m1＋m2＋m3＋m4＋m5の和２以上かつ１７未満とすることができる。 The polyamine used in the present invention is preferably a polyamine represented by the following formula (1).

NH 2- (CH 2 ) m1- (NH) p1- (CH 2 ) m2- (NH) p2- (CH 2 ) m3-
(NH) p3- (CH 2 ) m4- (NH) p4- (CH 2 ) m5 -NH 2 … (1)

In the formula, m1 to m5 are each independently an integer of 0 to 7, at least one of which is greater than 0, and the sum of m1 + m2 + m3 + m4 + m5 is 2 or more and less than 18, and p1, p2,
p3 and p4 are each independently 0 or 1.
In the formula (1), m1 to m5 are each independently an integer of 0 to 5, and the sum of m1 + m2 + m3 + m4 + m5 is 2 or more and less than 17.
　さらに該式(1)中、m1＋m2＋m3＋m4＋m5の和が、４以上かつ１６未満とすることができる。
　さらに該式(1)中において、m1が２～７の整数、かつm2,m3, m4及びm5が０であり、p1，p2,p3及びp4がそれぞれ０とすることができる。
　さらに該式(1)中において、m1が２～７の整数、m2が２～７の整数、かつm3, m4及びm5が０であり、p1が１で、p2, p3及びp4がそれぞれ０とすることができる。
　さらに該式(1)中において、m1が３～５の整数、m2が２～５の整数、かつm3, m4及びm5が０であり、p1が１で、p2, p3及びp4がそれぞれ０とすることができる。 Further, in the formula (1), the sum of m1 + m2 + m3 + m4 + m5 can be 4 or more and less than 16.
Further, in the formula (1), m1 is an integer of 2 to 7, m2, m3, m4 and m5 are 0, and p1, p2, p3 and p4 can each be 0.
Further, in the formula (1), m1 is an integer of 2 to 7, m2 is an integer of 2 to 7, m3, m4 and m5 are 0, p1 is 1, and p2, p3 and p4 are 0 and 0, respectively. can do.
Further, in the formula (1), m1 is an integer of 3 to 5, m2 is an integer of 2 to 5, m3, m4 and m5 are 0, p1 is 1, p2, p3 and p4 are 0 and 0, respectively. can do.
　さらに該式(1)中において、m1が２～７の整数、m2及びm3が２～７の整数、m4及びm5が０であり、p1及びp2が１で、p3及びp4がそれぞれ０とすることができる。
　さらに該式(1)中において、m1が３～５の整数、m2及びm3が２～５の整数、かつm4及びm5が０であり、p1及びp2が１で、p3及びp4がそれぞれ０とすることができる。
　さらに該式(1)中において、m1、m2、m3及びm4が２～７の整数で、m5が０であり、p1～p3が１であり、かつp4が０とすることができる。
　さらに該式(1)中において、m1が３～５の整数、m2, m3及びm4が２～５の整数、かつm5が０であり、p1～p3が１であり、かつp4が０とすることができる。 Further, in the formula (1), m1 is an integer of 2 to 7, m2 and m3 are integers of 2 to 7, m4 and m5 are 0, p1 and p2 are 1, and p3 and p4 are 0, respectively. be able to.
Further, in the formula (1), m1 is an integer of 3 to 5, m2 and m3 are integers of 2 to 5, m4 and m5 are 0, p1 and p2 are 1, and p3 and p4 are 0 and 0, respectively. can do.
Further, in the formula (1), m1, m2, m3 and m4 are integers of 2 to 7, m5 is 0, p1 to p3 are 1, and p4 can be 0.
Further, in the formula (1), m1 is an integer of 3 to 5, m2, m3 and m4 are integers of 2 to 5, m5 is 0, p1 to p3 is 1, and p4 is 0. be able to.
　前記式(1)のポリアミンは、ジアミン、トリアミン、テトラアミン、ペンタアミン、及びヘキサアミンとすることができ、本発明ではこれらを単独で、又は組み合わせて使用することができる。次に前記ポリアミンの具体的な例を挙げる。 The polyamine of the formula (1) can be diamine, triamine, tetraamine, pentaamine, and hexaamine, and in the present invention, these can be used alone or in combination. Next, specific examples of the polyamine will be given.
　本発明で用いるジアミンの例を挙げると、下記のものがある。
プトレスシン（Putrescine）
　　NH2(CH2)4NH2　1,4-ブタンジアミン　(1,4-butanediamine)
カダベリン（Cadaverine）
　　NH2(CH2)5NH2　1,5-ペンタンジアミン　(1,5-pentanediamine)
エチレンジアミン（Ethylenediamine）
　　NH2(CH2)2NH2　1,2-エタンジアミン　(1,2-etanediamine)
トリメチレンジアミン（Trimethylenediamine）
　　NH2(CH2)3NH2　1,3-プロパンジアミン　(1,3-propanediamine)
ヘキサメチレンジアミン（Hexamethylenediamine）
　　NH2(CH2)6NH2
　　1,6-ヘキサンジアミン　(1,6-hexanediamine)
　これらジアミンで好ましいのは、プトレッシンである。 Examples of diamines used in the present invention include the following.
Putrescine
NH 2 (CH 2 ) 4 NH 2 1,4-butanediamine
Cadaverine
NH 2 (CH 2 ) 5 NH 2 1,5-pentanediamine
Ethylenediamine
NH 2 (CH 2 ) 2 NH 2 1,2-etanediamine
Trimethylenediamine
NH 2 (CH 2 ) 3 NH 2 1,3-propanediamine
Hexamethylenediamine
NH 2 (CH 2 ) 6 NH 2
1,6-hexanediamine
Preferred among these diamines is putrescine.
　本発明で用いるトリアミンの例を挙げると、下記のものがある。
カルジン（ノルスペルミジン）(Norspermidine)
　　NH2(CH2)3NH(CH2)3NH2　
　　3,3'-イミノビスプロピルアミン　(3,3'-iminobispropylamine)
                 
[Biochem Biophys. Res. Commun. 63. 69(1975)]  
スペルミジン (Spermidine) 
　　NH2(CH2)3NH(CH2)4NH2
　　Ｎ-アミノブチル-1,3-ジアミノプロパン
　　(N-aminobutyl-1,3-diaminopropane)
　　　　　　　　　　[Beil. 4 (2) 704]　               
ホモスペルミジン (Homospermidine)　            
　　NH2(CH2)4NH(CH2)4NH2　
　　4,4'-イミノビスブチルアミン　
(4,4'-iminobisbutylamine)
アミノプロピルカダベリン (Aminopropylcadaverine)
　　NH2(CH2)3NH(CH2)5NH2
　　Ｎ-アミノペンチル-1,3-ジアミノプロパン
　　
(N-aminopentyl-1,3-diaminopropane)
　これらトリアミンで好ましいのは、スペルミジンである。 Examples of triamines used in the present invention include the following.
Cardin (Norspermidine)
NH 2 (CH 2 ) 3 NH (CH 2 ) 3 NH 2
3,3'-iminobispropylamine

[Biochem Biophys. Res. Commun. 63. 69 (1975)]
Spermidine
NH 2 (CH 2 ) 3 NH (CH 2 ) 4 NH 2
N-aminobutyl-1,3-diaminopropane
[Beil. 4 (2) 704]
Homospermidine
NH 2 (CH 2 ) 4 NH (CH 2 ) 4 NH 2
4,4'-Iminobisbutylamine
(4,4'-iminobisbutylamine)
Aminopropylcadaverine
NH 2 (CH 2 ) 3 NH (CH 2 ) 5 NH 2
N-aminopentyl-1,3-diaminopropane
(N-aminopentyl-1,3-diaminopropane)
Of these triamines, spermidine is preferred.
　本発明で用いるテトラアミンの例を挙げると、下記のものがある。
テルミン（ノルスペルミン）　　
　　NH2(CH2)3NH(CH2)3NH(CH2)3NH2
　　4,8-ジアザウンデカン-1,11-ジアミン
　　(4,8-diazaundecane-1,11-diamine)
スペルミン (Spermine)　
　　NH2(CH2)3NH(CH2)4NH(CH2)3NH2
　　4,9-ジアザドデカン-1,12-ジアミン
　(4,9-diazadodecane-1,12-diamine)
　　[Beil. 4 (2) 704, メルクインデックス9.8515]
テルモスペルミン
　　NH2(CH2)3NH(CH2)3NH(CH2)4NH2
　　4,8-ジアザドデカン-1,12-ジアミン
　(4,8-diazadodecane-1,12-diamine)
カナバルミン　
　　NH2(CH2)4NH(CH2)3NH(CH2)4NH2
　　5,9-ジアザトリデカン-1,13-ジアミン
　(5,9-diazatridecane-1,13-diamine)
アミノペンチルノルスペルミジン
　　NH2(CH2)3NH(CH2)3NH(CH2)5NH2
　　4,8-ジアザトリデカン-1,13-ジアミン
　(4,8-diazatridecane-1,13-diamine) Examples of the tetraamine used in the present invention include the following.
Theremin (Norspermine)
NH 2 (CH 2 ) 3 NH (CH 2 ) 3 NH (CH 2 ) 3 NH 2
4,8-diazaundecane-1,11-diamine
Spermine
NH 2 (CH 2 ) 3 NH (CH 2 ) 4 NH (CH 2 ) 3 NH 2
4,9-diazadodecane-1,12-diamine
[Beil. 4 (2) 704, Merck Index 9.8515]
Terumospermine NH 2 (CH 2 ) 3 NH (CH 2 ) 3 NH (CH 2 ) 4 NH 2
4,8-diazadodecane-1,12-diamine
Canabalmin
NH 2 (CH 2 ) 4 NH (CH 2 ) 3 NH (CH 2 ) 4 NH 2
5,9-diazatridecane-1,13-diamine
Aminopentylnorspermidine NH 2 (CH 2 ) 3 NH (CH 2 ) 3 NH (CH 2 ) 5 NH 2
4,8-diazatridecane-1,13-diamine
N,N’-ビス（アミノプロピル）カダベリン
　　NH2(CH2)3NH(CH2)5NH(CH2)3NH2
　　4,10-ジアザトリデカン-1,13-ジアミン 
　　(4,10-diazatridecane-1,13-diamine)
アミノプロピルホモスペルミン (Aminopropylhomospermine)
　　NH2(CH2)3NH(CH2)4NH(CH2)4NH2   
　　4,9-ジアザトリデカン-1,13-ジアミン
　(4,9-diazatridecane-1,13-diamine)
カナバルミン (Canavalmine) 
　　NH2(CH2)4NH(CH2)3NH(CH2)4NH2   
　　5,9-ジアザトリデカン-1,13-ジアミン
　(5,9-diazatridecane-1,13-diamine)
ホモスペルミン (Homospermine)
　　NH2(CH2)4NH(CH2)4NH(CH2)4NH2
　　5,10-ジアザテトラデカン-1,14-ジアミン
　　(5,10-diazatetradecane-1,14-diamine)
　　これらテトラアミンで好ましいのは、テルミン、スペルミン、ホモスペルミン、テルモスペルミン、アミノペンチルノルスペルミジン、及びN,N’-ビス（アミノプロピル）カダベリンであり、特に好ましいのはスペルミンである。 N, N'-Bis (aminopropyl) cadaverine NH 2 (CH 2 ) 3 NH (CH 2 ) 5 NH (CH 2 ) 3 NH 2
4,10-diazatridecane-1,13-diamine
(4,10-diazatridecane-1,13-diamine)
Aminopropylhomospermine
NH 2 (CH 2 ) 3 NH (CH 2 ) 4 NH (CH 2 ) 4 NH 2
4,9-diazatridecane-1,13-diamine
Canavalmine
NH 2 (CH 2 ) 4 NH (CH 2 ) 3 NH (CH 2 ) 4 NH 2
5,9-diazatridecane-1,13-diamine
Homospermine
NH 2 (CH 2 ) 4 NH (CH 2 ) 4 NH (CH 2 ) 4 NH 2
5,10-diazatetradecane-1,14-diamine
Preferred among these tetraamines are theremin, spermine, homospermine, thermospermine, aminopentylnorspermidine, and N, N′-bis (aminopropyl) cadaverine, and spermine is particularly preferred.
　本発明で用いるペンタアミンの例を挙げると、下記のものがある。
カルドペンタミン　(Caldopentamine)　　　
　　NH2(CH2)3NH(CH2)3NH(CH2)3NH(CH2)3NH2
　　4,8,12-トリアザペンタデカン-1,15-ジアミン
　　(4,8,12-triazapentadecane-1,15-diamine)
ホモカルドペンタミン  (Homocaldopentamine)
　　NH2(CH2)3NH(CH2)3NH(CH2)3NH(CH2)4NH2
　　4,8,12-トリアザヘキサデカン-1,16-ジアミン
　　(4,8,12-triazahexadecane-1,16-diamine)
アミノプロピルカナバルミン　(Aminopropylcanavalmine) 
　　NH2(CH2)3NH(CH2)4NH(CH2)3NH(CH2)4NH2
　　4,9,13-トリアザヘプタデカン-1,17-ジアミン
　　(4,9,13-triazaheptadecane-1,17-diamine)
ビス（アミノプロピル）ホモスペルミン
　　(Bis(aminopropyl)homospermidine)
　　NH2(CH2)3NH(CH2)4NH(CH2)4NH(CH2)4NH2
　　4,9,14-トリアザオクタデカン-1,18-ジアミン
　　(4,9,14-triazaoctadecane-1,18-diamine)
ビス（アミノプロピル）ノルスペルミン
　　(Bis(aminobutyl)norspermidine)
　　NH2(CH2)4NH(CH2)3NH(CH2)3NH(CH2)4NH2
　　5,9,13-トリアザヘプタデカン-1,17-ジアミン
　　(5,9,13-triazaheptadecane-1,17-diamine) Examples of pentaamine used in the present invention include the following.
Caldopentamine
NH 2 (CH 2 ) 3 NH (CH 2 ) 3 NH (CH 2 ) 3 NH (CH 2 ) 3 NH 2
4,8,12-triazapentadecane-1,15-diamine
Homocaldopentamine
NH 2 (CH 2 ) 3 NH (CH 2 ) 3 NH (CH 2 ) 3 NH (CH 2 ) 4 NH 2
4,8,12-triazahexadecane-1,16-diamine
Aminopropylcanavalmine
NH 2 (CH 2 ) 3 NH (CH 2 ) 4 NH (CH 2 ) 3 NH (CH 2 ) 4 NH 2
4,9,13-triazaheptadecane-1,17-diamine
Bis (aminopropyl) homospermidine
NH 2 (CH 2 ) 3 NH (CH 2 ) 4 NH (CH 2 ) 4 NH (CH 2 ) 4 NH 2
4,9,14-triazaoctadecane-1,18-diamine
Bis (aminopropyl) norspermidine
NH 2 (CH 2 ) 4 NH (CH 2 ) 3 NH (CH 2 ) 3 NH (CH 2 ) 4 NH 2
5,9,13-triazaheptadecane-1,17-diamine
アミノブチルカナバルミン (Aminobutylcanavalmine)
　　NH2(CH2)4NH(CH2)3NH(CH2)4NH(CH2)4NH2
　　5,9,14-トリアザオクタデカン-1,18-ジアミン
　　(5,9,14-triazaoctadecane-1,18-diamine)
アミノプロピルホモスペルミン (Aminopropylhomospermine)
　　NH2(CH2)3NH(CH2)4NH(CH2)4NH(CH2)4NH2
　　4,9,14-トリアザオクタデカン-1,18-ジアミン
　　(4,9,14-triazaoctadecane-1,18-diamine)
ホモペンタミン (Homopentamine)
　　NH2(CH2)4NH(CH2)4NH(CH2)3NH(CH2)4NH2
　　5,10,14-トリアザオクタデカン-1,18-ジアミン
　　(5,10,14-triazaoctadecane-1,18-diamine)
　これらペンタアミンで好ましいのは、カルドペンタミン及びホモカルドペンタミンである。 Aminobutylcanavalmine
NH 2 (CH 2 ) 4 NH (CH 2 ) 3 NH (CH 2 ) 4 NH (CH 2 ) 4 NH 2
5,9,14-triazaoctadecane-1,18-diamine
Aminopropylhomospermine
NH 2 (CH 2 ) 3 NH (CH 2 ) 4 NH (CH 2 ) 4 NH (CH 2 ) 4 NH 2
4,9,14-triazaoctadecane-1,18-diamine
Homopentamine
NH 2 (CH 2 ) 4 NH (CH 2 ) 4 NH (CH 2 ) 3 NH (CH 2 ) 4 NH 2
5,10,14-triazaoctadecane-1,18-diamine
Preferred among these pentaamines are cardopentamine and homocardopentamine.
　本発明で用いるヘキサアミンの例を挙げると、下記のものがある。
カルドヘキサミン  (Caldohexamine)
　　NH2(CH2)3NH(CH2)3NH(CH2)3NH(CH2)3NH(CH2)3NH2
　　4,8,12,16-テトラアザノナデカン-1,19-ジアミン
　　(4,8,12,16-tetraazanonadecane-1,19-diamine)
ホモカルドヘキサミン (Homocaldohexamine)
　　NH2(CH2)3NH(CH2)3NH(CH2)3NH(CH2)3NH(CH2)4NH2
　　4,8,12,16-テトラアザアイコサン-1,20-ジアミン
　　(4,8,12,16-tetraazaicosane-1,20-diamine)
セルモヘキサミン (Thermohexamine)
　　NH2(CH2)3NH(CH2)3NH(CH2)3NH(CH2)4NH(CH2)3NH2
　　4,8,12,17-テトラアザアイコサン-1,20-ジアミン
　　(4,8,12,17-tetraazaicosane-1,20-diamine)
ホモセルモヘキサミン (Homethermohexamine)
　　NH2(CH2)3NH(CH2)3NH(CH2)4NH(CH2)3NH(CH2)3NH2
　　4,8,13,17-テトラアザアイコサン-1,20-ジアミン
　　(4,8,13,17-tetraazaicosane-1,20-diamine)
　これらヘキサアミンで好ましいのは、カルドヘキサミン及びホモカルドヘキサミンである。 Examples of hexaamine used in the present invention include the following.
Caldohexamine
NH 2 (CH 2 ) 3 NH (CH 2 ) 3 NH (CH 2 ) 3 NH (CH 2 ) 3 NH (CH 2 ) 3 NH 2
4,8,12,16-tetraazanonadecane-1,19-diamine
Homocaldohexamine
NH 2 (CH 2 ) 3 NH (CH 2 ) 3 NH (CH 2 ) 3 NH (CH 2 ) 3 NH (CH 2 ) 4 NH 2
4,8,12,16-tetraazaicosane-1,20-diamine
Thermohexamine
NH 2 (CH 2 ) 3 NH (CH 2 ) 3 NH (CH 2 ) 3 NH (CH 2 ) 4 NH (CH 2 ) 3 NH 2
4,8,12,17-tetraazaicosane-1,20-diamine
Homosermohexamine
NH 2 (CH 2 ) 3 NH (CH 2 ) 3 NH (CH 2 ) 4 NH (CH 2 ) 3 NH (CH 2 ) 3 NH 2
4,8,13,17-tetraazaicosane-1,20-diamine
Preferred among these hexaamines are cardohexamine and homocardohexamine.
　本発明では、前記ポリアミンを、医薬として許容し得る塩の形態で用いることができる。該塩は、有機酸又は無機酸の付加塩類であって、例えば、塩酸、フッ化水素酸、硫酸、硝酸、リン酸などの無機酸付加塩、及び例えば、スルホン酸、メタンスルホン酸、スルファミン酸、酒石酸、フマル酸、臭化水素酸、グリコール酸、クエン酸、マレイン酸、コハク酸、酢酸、安息香酸、アスコルビン酸、p-トルエンスルホン酸、ベンゼンスルホン酸、ナフタリンスルホン酸、プロピオン酸、乳酸、ピルビン酸、シュウ酸、ステアリン酸、ケイ皮酸、アスパラギン酸、サリチル酸、グルコン酸などの有機酸付加塩である。該塩は、遊離の塩基のにおいがないので特に塩酸付加塩類が好ましい。該酸付加塩類は、本発明の技術分野における常法で、遊離の塩基形態のポリアミンと、適当な酸との接触により調製することができる。 In the present invention, the polyamine can be used in the form of a pharmaceutically acceptable salt. The salt is an addition salt of an organic acid or an inorganic acid, and includes, for example, inorganic acid addition salts such as hydrochloric acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, and, for example, sulfonic acid, methanesulfonic acid, sulfamic acid , Tartaric acid, fumaric acid, hydrobromic acid, glycolic acid, citric acid, maleic acid, succinic acid, acetic acid, benzoic acid, ascorbic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, propionic acid, lactic acid, Organic acid addition salts such as pyruvic acid, oxalic acid, stearic acid, cinnamic acid, aspartic acid, salicylic acid and gluconic acid. Since the salt has no free base odor, hydrochloric acid addition salts are particularly preferred. The acid addition salts can be prepared by contacting the free basic form polyamine with a suitable acid in a conventional manner in the technical field of the present invention.
（供与量）
　本発明の飼料組成物の投与量は、対象動物の種類、性別、年齢、体重に合わせて適宜変えることになるが、通常、哺乳動物では一日当り、ポリアミンとして、0.01～1000mg/Kg体重、0.01～400mg/Kg体重、0.01～100mg/Kg体重、0.05～100mg/Kg体重、0.05～40mg/kg体重、さらに0.05～4mg/kg体重とすることができる。 (Donation amount)
The dose of the feed composition of the present invention is appropriately changed according to the type, sex, age, and body weight of the target animal. Usually, in mammals, 0.01 to 1000 mg / kg body weight, 0.01 mg of polyamine per day is used. -400 mg / Kg body weight, 0.01-100 mg / Kg body weight, 0.05-100 mg / Kg body weight, 0.05-40 mg / kg body weight, and further 0.05-4 mg / kg body weight.
　なお本発明は、動物に、その体重１Kgあたり、前記式(1)のポリアミン及びその医薬として許容し得る塩からなる群から選ばれる少なくとも１の化合物を一日当り、ポリアミンとして、0.01～1000mg/Kg体重、0.01～400mg/Kg体重、0.01～100mg/Kg体重、0.05～100mg/Kg体重、0.05～40mg/kg体重、さらに0.05～4mg/kg体重を投与することを含む、動物の寿命を延長する飼育方法を提供する。この場合、通常の飼料に含まれるポリアミン等と、本発明の飼料組成物により供与されるポリアミン等との合計量が前記供与量となればよい。 In the present invention, 0.01 to 1000 mg / kg of polyamine per day as the polyamine of at least one compound selected from the group consisting of the polyamine of the formula (1) and a pharmaceutically acceptable salt thereof per 1 kg body weight of the present invention. Prolong the life of animals, including administering body weight, 0.01-400 mg / Kg body weight, 0.01-100 mg / Kg body weight, 0.05-100 mg / Kg body weight, 0.05-40 mg / kg body weight, and further 0.05-4 mg / kg body weight Provide breeding methods. In this case, the total amount of the polyamine and the like contained in the normal feed and the polyamine and the like provided by the feed composition of the present invention may be the above-mentioned supply amount.
（供与形態と使用方法）
　本発明の食料組成物、及び飼料組成物の形態は、対象動物の特性に合わせて適宜選択することができる。例えば、液体、半流動体、又は固形とすることができる。液体飼料組成物は、動物の飼料に混入、又は振りかけて使用することができる。半流動体の飼料組成物は、そのまま単体で、又は他の流動性、半練り製品飼料に加えて使用することができる。また、固形飼料組成物は、粉末状又は一定の大きさに切ったペレットなどペットフードの形態として利用することができる。
　また、本発明の食料組成物、及び飼料組成物のポリアミン含有量は、一回の投与単位当たり、ポリアミンとして、0.0025～100mg/kg体重、好ましくは0.005～40mg/kg体重、さらに好ましくは0.01～4mg/kg体重である。 (Form of donation and usage)
The form of the food composition and the feed composition of the present invention can be appropriately selected according to the characteristics of the target animal. For example, it can be liquid, semi-fluid, or solid. The liquid feed composition can be used by mixing or sprinkling with animal feed. The semi-liquid feed composition can be used alone or in addition to other fluid, semi-kneaded product feeds. In addition, the solid feed composition can be used as a pet food form such as a powder or a pellet cut into a certain size.
In addition, the polyamine content of the food composition and the feed composition of the present invention is 0.0025 to 100 mg / kg body weight, preferably 0.005 to 40 mg / kg body weight, more preferably 0.01 to as polyamine per dosage unit. 4 mg / kg body weight.
　なお、本発明の飼料組成物を単体で供与する場合、様々な粒状の固形形態で製造することができる。例えば、本発明の飼料組成物がドッグフードである場合、肉と野菜を含むベース飼料に、所定量のポリアミンを添加し、寒天を加えて凝固させることができる。該ベース飼料の肉は、牛肉、馬肉、鶏肉、魚肉等で、これらの肉を単独で、又は複数種を混合して使用する。該ベース飼料の野菜は、人参、キャベツ、コーン、トマト等であって、これらの野菜を単独で、又は複数種を混合して使用する。さらに、該ベース飼料には、肉と野菜に加えて、チーズ、パスタ、鳥がらスープ、ビーフコンソメ等を添加することもできる。通常、ベース飼料をミンチの状態に粉砕し、次いでポリアミンと水と寒天を加え、加熱、成型後冷却、固化する。 In addition, when supplying the feed composition of this invention alone, it can manufacture with various granular solid forms. For example, when the feed composition of the present invention is a dog food, a predetermined amount of polyamine can be added to a base feed containing meat and vegetables, and agar can be added and coagulated. The meat of the base feed is beef, horse meat, chicken meat, fish meat, etc., and these meats are used alone or in combination. The base feed vegetables are carrots, cabbage, corn, tomatoes, etc., and these vegetables are used alone or in combination. Furthermore, in addition to meat and vegetables, cheese, pasta, fried chicken soup, beef consomme and the like can be added to the base feed. Usually, the base feed is pulverized into a minced state, and then polyamine, water and agar are added, heated, molded, cooled and solidified.
　なお、本発明の飼料組成物には有効成分として前記ポリアミン又はその医薬として許容し得る塩、又はそれら組み合わせを単独で、又はその他の所望の栄養補助剤、薬剤と組み合わせて使用することができる。該栄養補助剤の例を挙げると、ビタミンＣ、ビタミンＥ、ニンニク、複合ビタミンＢ等の各種ビタミン剤、ビール酵母、亜麻仁油、魚油、醸造酢、タンパク質濃縮物、乳製品、ミネラル剤などがある。また、該薬剤には、食欲増進剤、抗細菌剤、消化酵素、抗感染薬、抗真菌剤、抗炎症薬、鎮痛剤、代謝作用薬、殺寄生虫薬、その他の医薬品がある。 In the feed composition of the present invention, the polyamine or a pharmaceutically acceptable salt thereof or a combination thereof can be used alone or in combination with other desired nutritional supplements and drugs as active ingredients. Examples of the nutritional supplements include various vitamins such as vitamin C, vitamin E, garlic, and complex vitamin B, brewer's yeast, linseed oil, fish oil, brewed vinegar, protein concentrate, dairy products, and mineral agents. . Examples of the drug include an appetite enhancer, an antibacterial agent, a digestive enzyme, an anti-infective agent, an antifungal agent, an anti-inflammatory agent, an analgesic agent, a metabolic agent, a parasiticide agent, and other pharmaceutical agents.
（供与時期）
　本発明の飼料組成物は、動物個体が加齢によりポリアミンを合成、及び維持する能力が衰え、血管等に炎症が生じ易くなる前に供与し始めるのが好ましい。例えば、ネズミ等の齧歯類では生後４～１０週以降、猫や犬等の動物では生後４～８ヶ月以降、馬、牛、象などの大型草食動物では生後６ヶ月～２年以降、ヒトでは生後８～１８年以降が好ましい。
　また、本発明の飼料組成物の供与期間は、供与開始から少なくとも３ヶ月、好ましくは６ヶ月、さらに好ましくは１２ヶ月であり、また必要ならば生存中継続的に供与してもよい。 (Grant time)
It is preferable that the feed composition of the present invention starts to be fed before the animal individual's ability to synthesize and maintain polyamines with aging and the blood vessels and the like are prone to inflammation. For example, rodents such as mice are 4 to 10 weeks old, animals such as cats and dogs are 4 to 8 months old, and large herbivores such as horses, cows, and elephants are 6 months to 2 years old Then, 8-18 years after birth is preferable.
Further, the feed composition of the present invention is fed for at least 3 months, preferably 6 months, more preferably 12 months from the start of feeding, and if necessary, the feed composition may be continuously fed throughout the life.
　また、ポリアミンの延命効果を発揮する有効量は動物の種類、年齢などに応じて異なるが、１日当たりの必要量に対応する本発明の飼料組成物は、１日１回まとめて与えてもよいし、各飼料供給時に分けて与えてもよい。 Moreover, although the effective amount which exhibits the life extension effect of a polyamine changes with kinds, age, etc. of animals, the feed composition of this invention corresponding to the required amount per day may be given once a day. However, they may be given separately at the time of each feed supply.
　次に実施例に基づき、本発明をさらに詳細に説明する。 Next, the present invention will be described in more detail based on examples.
　本実施例では特に断らない限り、割合％とは重量％（w/w%）を意味する。
（実施例１）飼料組成物の製造　
　まず、基本となる飼料組成物を調製した。以下、低ポリアミン飼料組成物という。該飼料組成物の組成は次のとおりである。
　水分　　　　　　　７．６％
　タンパク質　　　２６．４％
　脂質　　　　　　１０．２％
　繊維　　　　　　　２．５％
　灰分　　　　　　　６．０％
　無窒素抽出物　　４７．３％
　熱量　　　　　　３９７ Kcal/100g
　該飼料組成物の調製に用いた原料は、ミルクカゼイン、白身魚肉、酵母、小麦胚芽、豚脂、小麦フスマ、脱脂米糠、アルファルファ粗挽き粉、小麦粗挽き粉、トウモロコシ、ミロ、ビタミン混合物、及びミネラル混合物である。これらの原料を上記組成となるよう配合し、適量の水分とともに混合し、ペレット状に成型した。 In this embodiment, unless otherwise specified, the ratio% means weight% (w / w%).
(Example 1) Production of feed composition
First, a basic feed composition was prepared. Hereinafter, it is referred to as a low polyamine feed composition. The composition of the feed composition is as follows.
Moisture 7.6%
Protein 26.4%
Lipid 10.2%
Fiber 2.5%
Ash content 6.0%
Nitrogen-free extract 47.3%
Calorie 397 Kcal / 100g
Raw materials used for the preparation of the feed composition are milk casein, white fish meat, yeast, wheat germ, pork fat, wheat bran, defatted rice bran, alfalfa coarse flour, wheat coarse flour, corn, milo, vitamin mixture, and It is a mineral mixture. These raw materials were blended so as to have the above composition, mixed with an appropriate amount of water, and molded into pellets.
　次に、合成スペルミン（商品名：スペルミン、和光純薬工業株式会社）、スペルミジン（商品名：スペルミジン、シグマアルドリッチ）及びプトレスシン（商品名：プトレスシン、和光純薬工業株式会社）を用いて、高ポリアミン飼料組成物を調製した。該ポリアミンの添加量は、各飼料組成物毎にスペルミン０．０１５％、スペルミジン０．０６％、及びプトレスシン０．０１５％とした。該ポリアミンを添加した以外は、前記低ポリアミン飼料組成物と同様に調製した。 Next, synthetic polyspermine (trade name: spermine, Wako Pure Chemical Industries, Ltd.), spermidine (trade name: spermidine, Sigma Aldrich) and putrescine (trade name: putrescine, Wako Pure Chemical Industries, Ltd.) A feed composition was prepared. The amount of polyamine added was 0.015% spermine, 0.06% spermidine, and 0.015% putrescine for each feed composition. It was prepared in the same manner as the low polyamine feed composition except that the polyamine was added.
（実施例２）実施例１の飼料組成物使用時の血中ポリアミン濃度測定
　２４週齢のマウス（Jc1:ICRマウス、オス）を８匹ずつ２群に分け、一群に実施例１の低ポリアミン飼料組成物を与え、他の群に実施例１で調製した、スペルミジン含有ポリアミン飼料組成物を投与し、２６週後のスペルミジン血中濃度を比較した。この場合、マウスの体重は３０～７０gであり、一日当たり約３～１０gの飼料を消費するので、前記スペルミジンの摂取量はマウス１匹当たり約２０～２００mg/kg/日である。図３に示すように、低ポリアミン飼料組成物を摂取した群の血中スペルミジン濃度は約３２nmol/mlであるが、高ポリアミン飼料組成物を摂取した群の血中スペルミジン濃度は約５０nmol/mlである。したがって、本発明の飼料組成物を摂取することにより、血中ポリアミン濃度が高くなることが判る。 (Example 2) Measurement of blood polyamine concentration when using the feed composition of Example 1 24-week-old mice (Jc1: ICR mouse, male) were divided into 2 groups of 8 mice, and the low polyamine of Example 1 was divided into one group. The spermidine-containing polyamine feed composition prepared in Example 1 was administered to other groups, and the blood concentrations of spermidine after 26 weeks were compared. In this case, the body weight of the mouse is 30 to 70 g, and about 3 to 10 g of food is consumed per day. Therefore, the intake of spermidine is about 20 to 200 mg / kg / day per mouse. As shown in FIG. 3, the blood spermidine concentration of the group ingesting the low polyamine feed composition is about 32 nmol / ml, while the blood spermidine concentration of the group ingesting the high polyamine feed composition is about 50 nmol / ml. is there. Therefore, it is understood that the blood polyamine concentration is increased by ingesting the feed composition of the present invention.
（実施例３）実施例１の飼料組成物使用時の血中ポリアミン濃度測定
　２４週齢のマウス（Jc1:ICRマウス、オス）を９匹ずつ２群に分け、一群に実施例１の低ポリアミン飼料組成物を与え、他の群に実施例１で調製した、スペルミン含有ポリアミン飼料組成物を投与し、２６週後のスペルミン血中濃度を比較した。この場合、マウスの体重は３０～７０gであり、一日当たり約３～１０gの飼料を消費するので、前記スペルミンの摂取量はマウス１匹当たり約５～５０mg/kgである。図４に示すように、低ポリアミン飼料組成物を摂取した群の血中スペルミジン濃度は約５nmol/mlであるが、高ポリアミン飼料組成物を摂取した群の血中スペルミン濃度は約１０nmol/mlである。したがって、本発明の飼料組成物を摂取することにより、血中ポリアミン濃度が高くなることが判る。 (Example 3) Measurement of blood polyamine concentration when using the feed composition of Example 1 24-week-old mice (Jc1: ICR mouse, male) were divided into 2 groups of 9 mice, and the low polyamine of Example 1 was divided into 1 group. The feed composition was given, and the spermine-containing polyamine feed composition prepared in Example 1 was administered to the other groups, and the spermine blood concentrations after 26 weeks were compared. In this case, the body weight of the mouse is 30 to 70 g, and about 3 to 10 g of feed is consumed per day. Therefore, the intake of the spermine is about 5 to 50 mg / kg per mouse. As shown in FIG. 4, the blood spermidine concentration of the group ingesting the low polyamine feed composition is about 5 nmol / ml, while the blood spermine concentration of the group ingesting the high polyamine feed composition is about 10 nmol / ml. is there. Therefore, it is understood that the blood polyamine concentration is increased by ingesting the feed composition of the present invention.
（実施例４）本発明の高ポリアミン含有飼料組成物の効果の検討（生存率）
　２４週齢のマウス（Jc1:ICRマウス、オス）を９匹ずつ２群に分け、一群に実施例１の低ポリアミン飼料組成物を与え、他の群に実施例１で調製した、スペルミン含有ポリアミン飼料組成物を投与し、８０週齢まで累積生存率を比較した。マウスは各ゲージに４～６匹を入れ、温度および湿度調整が可能で、フィルターを通した空気を送付する装置のついた密閉した飼育器で飼育した。全ての実験に供した動物は１つの飼育器で飼育し、水はすべての動物に同一の物を投与した。また、飼育器の空気は全体に拡散する構造であり、実験に供した動物は同じ空気で呼吸を行っていたことになる。 (Example 4) Examination of effect of high polyamine-containing feed composition of the present invention (survival rate)
24 week-old mice (Jc1: ICR mice, male) were divided into 2 groups of 9 mice, one group was given the low polyamine feed composition of Example 1, and the other group was prepared in Example 1 with spermine-containing polyamines. The feed composition was administered and the cumulative survival rate was compared up to 80 weeks of age. Mice were housed in a closed incubator with 4-6 mice in each gauge, temperature and humidity controllable and equipped with a device that sends air through a filter. Animals used in all experiments were kept in one incubator, and the same water was administered to all animals. In addition, the air in the incubator has a structure that diffuses throughout, and the animals used in the experiment were breathing with the same air.
　この場合、マウスの体重は３０～７０gであり、一日当たり約３～１０gの飼料を消費するので、前記スペルミンの摂取量はマウス１匹当たり約５～５０mg/kgである。また、前記スペルミジンの摂取量はマウス１匹当たり約２０～２００mg/kgである。 In this case, the body weight of the mouse is 30 to 70 g, and about 3 to 10 g of feed is consumed per day. Therefore, the intake of the spermine is about 5 to 50 mg / kg per mouse. The intake of spermidine is about 20 to 200 mg / kg per mouse.
　マウスの生存は２日に１度確認した。対表観察および解剖によって死因を特定した。生存率はKaplan-Meier法によって解析し、各群間の生存率の有意差の検定はLogrank(Mantel-Cox)法で行った。図５に示すように、４０週齢を過ぎるころから、高ポリアミン飼料組成物摂取群の累積生存率は、低ポリアミン飼料組成物摂取群の累積生存率より明らかに高くなる。８０週齢になると、低ポリアミン飼料組成物摂取群の累積生存率約０．６に対して、高ポリアミン飼料組成物摂取群の累積生存率は０．８を越えており、高ポリアミン飼料組成物を摂取した群のマウスは明らかに寿命が延びている（Logrank(Mantel-Cox)検定にてp=0.003）。 The survival of the mice was confirmed once every 2 days. Cause of death was identified by paired observation and dissection. Survival rate was analyzed by Kaplan-Meier method, and the significant difference in survival rate between each group was tested by Logrank (Mantel-Cox) method. As shown in FIG. 5, after about 40 weeks of age, the cumulative survival rate of the high polyamine feed composition intake group is clearly higher than the cumulative survival rate of the low polyamine feed composition intake group. At the age of 80 weeks, the cumulative survival rate of the high polyamine feed composition intake group exceeds 0.8, while the cumulative survival rate of the low polyamine feed composition intake group is about 0.6. The mice in the group ingesting the lipase clearly have a longer life (p = 0.003 by Logrank (Mantel-Cox) test).
（実施例５）本発明の高ポリアミン含有飼料組成物の効果の検討（状態）
　２４週齢から本発明の飼料組成物の供与をマウス（Jc1:ICRマウス、オス）開始し、生後８０週齢で観察を行った。実験動物１１０匹中、低ポリアミン食を供与したマウスは６６匹であったが、生後８０週齢で生存していたのは３７匹であった。一方、高ポリアミン食を供与したマウスは４４匹であったが、生後８０週齢で生存していたのは３７匹であった。生後８０週齢の時点で生存していた高ポリアミン食を供与したマウスでは、生存した３７匹中２１匹が、毛並みが良好で肉付きがよく運動も活発であった。しかし、低ポリアミン供与群のマウス３７匹中では、毛並みが良好で肉付きがよく運動も活発なマウスは１２匹しか存在せず、毛並みが悪いものが多かった。 (Example 5) Examination of effect of feed composition of high polyamine content of the present invention (state)
Mice (Jc1: ICR mouse, male) started feeding the feed composition of the present invention from 24 weeks of age, and observation was made at 80 weeks of age. Of the 110 experimental animals, 66 mice were fed a low polyamine diet, but 37 were alive at 80 weeks of age. On the other hand, 44 mice were fed a high polyamine diet, but 37 were alive at 80 weeks of age. Of the mice that were fed a high polyamine diet that had survived at the age of 80 weeks of age, 21 of the 37 surviving mice had good fur, fleshiness, and active exercise. However, among the 37 mice in the low polyamine donating group, there were only 12 mice with good fur, fleshy and active movement, and many had poor fur.
（実施例６）ポリアミンの毒性
　追加実験により、スペルミン０.０４５％（餌１０kg内に４.５g混入）、スペルミジン０.１１５％（餌１０kg内に１１.５g混入）及びプトレスシン０.０４５％（餌１０kg内に４.５g混入）を含有する飼料組成物を継続的に供与してマウスを飼育した。ここで使用した飼料組成物は、ポリアミンの量を除き実施例１で製造したものと同じである。該実験開始から８ヶ月（３３週間経過）経過後も飼育中のマウスに特に変化はなく毒性は見られなかった。 (Example 6) Toxicity of polyamines According to additional experiments, 0.045% spermine (contained 4.5 g in 10 kg of food), 0.115% spermidine (contained 11.5 g in 10 kg of bait) and 0.045% of putrescine ( Mice were reared with a continuous feed composition containing 4.5 g in 10 kg of feed. The feed composition used here is the same as that produced in Example 1 except for the amount of polyamine. Even after 8 months (33 weeks have passed) since the start of the experiment, no changes were observed in the bred mice and no toxicity was observed.
（参考例１）ポリアミン高含有食品の摂取による血中ポリアミン濃度の上昇
　霊長類であるヒトを対象に、ポリアミン高含有食品の摂取による血中ポリアミン濃度の上昇を確認した。通常、納豆にはスペルミンとスペルミジンなどのポリアミンが１００gあたりおおよそ１０～１００mg含まれておりポリアミン高含有食品である。該納豆４５～５０g入り１パック以上を毎日摂取する群（成人１０人）と、納豆を摂取しない群（成人7人）に分け、実験開始２ヶ月後にスペルミンの血中濃度を測定した。その結果、図６のＡに示すように納豆を毎日摂取した群はスペルミンの血中濃度が明らかに上昇したのに対し、納豆を摂取しない群ではスペルミンの血中濃度に変動はなかった。したがって、ヒトを含む霊長類でも、本発明の高ポリアミン飼料組成物を摂取することにより、血中のポリアミン濃度が上昇することが判る。 (Reference Example 1) Increase in blood polyamine concentration due to ingestion of food containing high polyamine The increase in blood polyamine concentration due to ingestion of food containing high polyamine was confirmed in humans who are primates. Usually, natto contains about 10 to 100 mg of polyamines such as spermine and spermidine per 100 g, and is a high polyamine-containing food. The blood concentration of spermine was measured 2 months after the start of the experiment, divided into a group (10 adults) who ingested 1 or more packs containing 45-50 g of natto every day and a group (7 adults) who did not take natto. As a result, as shown in FIG. 6A, the blood concentration of spermine was clearly increased in the group ingesting natto every day, whereas the blood concentration of spermine was not changed in the group not ingesting natto. Therefore, it can be seen that even in primates including humans, the blood polyamine concentration is increased by ingesting the high polyamine feed composition of the present invention.
（考察）
（加齢によるポリアミンの合成の低下とLFA-1の増加）
　図７に示すように、哺乳動物、例えばヒトでは加齢とともにポリアミンの合成が低下する(Das Rらの論文: Das R. & Kanungo MS. Exp Gerontol 17:95-103(1982))。
　そして、図８に示すように、高齢者ほど末梢血単核球のLFA-1が増える。図８のデータはボランティアで参加した人の血液を採取して、末梢血単核球と呼ばれるリンパ球や単核球などの免疫細胞の表面に存在するLFA-1（＝CD11a及びCD１８）の発現を調べたものであって、年齢が高くなるほど発現が強くなることが示されている。このLFA-1は炎症を誘発するために重要な細胞膜タンパク質であり、この発現の増強が炎症を誘発する。したがって、動物では加齢とともにポリアミンの合成が低下するので、リンパ球や単核球などの免疫細胞の発現が増強され、これらの細胞が司る慢性炎症が起きやすくなる。そして、その事が生活習慣病の原因であると考えられている。すなわち、動脈硬化などの多くの生活習慣病が炎症で誘発されることが判ってきたからである。 (Discussion)
(Aging decreases polyamine synthesis and increases LFA-1)
As shown in FIG. 7, the synthesis of polyamines decreases with age in mammals such as humans (Das R et al .: Das R. & Kanungo MS. Exp Gerontol 17: 95-103 (1982)).
And as shown in FIG. 8, LFA-1 of a peripheral blood mononuclear cell increases as an elderly person. The data in FIG. 8 shows the expression of LFA-1 (= CD11a and CD18) present on the surface of immune cells such as lymphocytes and mononuclear cells called peripheral blood mononuclear cells by collecting blood from volunteer volunteers. It has been shown that the expression increases with age. This LFA-1 is an important cell membrane protein for inducing inflammation, and this enhanced expression induces inflammation. Therefore, since the synthesis of polyamines decreases with age in animals, the expression of immune cells such as lymphocytes and mononuclear cells is enhanced, and chronic inflammation governed by these cells tends to occur. And that is thought to be the cause of lifestyle-related diseases. That is, it has been found that many lifestyle-related diseases such as arteriosclerosis are induced by inflammation.
（ポリアミンの摂取量増加とその効果）
　図９に示すように、スペルミンは末梢血単核球のLFA-1を減少させる。上記と同じ血液で、血液中のポリアミン濃度を測定して、LFA-1の発現との関係から、ポリアミン（スペルミン）濃度依存的にLFA-1の発現が抑制（LFA-1が減る）される事を発見した。生活習慣病の進行の原因が炎症である事を考慮すると、血液中（血液細胞を含めた全血中）のポリアミン濃度を上昇させることができれば、生活習慣病の予防効果が期待できるという知見を得た。
さらに人の免疫細胞を取りだし、実際にポリアミン（スペルミンとスペルミジン）と培養するとLFA-1(=CD11aおよびCD18)の発現だけが低下することが判った（図10参照）。図10のデータを得るため、ポリアミンとともに培養した細胞における接着分子の平均蛍光強度(MIF)の変化を測定した。
　また、従来の研究ではポリアミン（スペルミンとスペルミジン）は炎症性サイトカインの産生を抑制することが判っている。ポリアミン（スペルミンとスペルミジン）は年齢とともに、体内での合成が低下し、刺激によっても合成が亢進しにくい（図７参照）。しかし、同時にポリアミンは分解される事なく消化管から吸収され、体内に広く分布する事が知られている。また、ポリアミンは微生物、植物、動物に共通の物質であり、我々人はこれらの生物からポリアミンを摂取することが出来る。 (Increased polyamine intake and its effects)
As shown in FIG. 9, spermine decreases LFA-1 in peripheral blood mononuclear cells. In the same blood as above, the polyamine concentration in the blood is measured, and the expression of LFA-1 is suppressed (LFA-1 is decreased) depending on the concentration of polyamine (spermine) due to the relationship with the expression of LFA-1. I found a thing. Considering that the cause of the progression of lifestyle-related diseases is inflammation, the knowledge that the prevention effect of lifestyle-related diseases can be expected if the polyamine concentration in the blood (whole blood including blood cells) can be increased. Obtained.
Furthermore, when human immune cells were taken out and cultured with polyamines (spermine and spermidine), it was found that only the expression of LFA-1 (= CD11a and CD18) decreased (see FIG. 10). In order to obtain the data of FIG. 10, changes in the mean fluorescence intensity (MIF) of adhesion molecules in cells cultured with polyamines were measured.
Previous studies have also shown that polyamines (spermine and spermidine) suppress the production of inflammatory cytokines. The synthesis of polyamines (spermine and spermidine) decreases with age, and the synthesis is less likely to be enhanced by stimulation (see FIG. 7). However, at the same time, polyamines are known to be absorbed from the digestive tract without being decomposed and distributed widely in the body. Polyamine is a substance common to microorganisms, plants, and animals, and we can ingest polyamine from these organisms.
（ポリアミンの摂取量と血中濃度の増加）
　図11に、実施例２で得られたマウス血中スペルミジン濃度上昇のデータを示す。また、図12に実施例３で得られたマウス血中スペルミン濃度上昇のデータを示す。実施例１で調製した餌を投与した結果、投与２６週目になり、ポリアミンを多量に含んだ高ポリアミン餌を食べたマウスの血中ポリアミン（スペルミジンおよびスペルミン）濃度が上昇した。しかし、ポリアミン濃度が普通の餌や低いポリアミン濃度の餌を食べたマウスでは、血中ポリアミン濃度は上昇しなかった。
　また図６に示すように、人でも、高ポリアミン食（高ポリアミン食である納豆を１日１‐２パックを食べた場合）、２ヶ月ほどして血中のスペルミン濃度が上昇した。
　ポリアミン濃度の上昇のパターンはマウスと人とでは異なっているが、いずれにしてもポリアミン（プトレスシン、スペルミジン、スペルミンの３種類のポリアミン）の濃度の高い食品を一定期間摂取すると血中ポリアミン濃度が上昇することがわかった。したがって、本発明の食品組成物又は飼料組成物を一定期間摂取することで血中ポリアミン濃度が上昇することが判る。 (Increased polyamine intake and blood levels)
FIG. 11 shows the mouse blood spermidine concentration increase data obtained in Example 2. In addition, FIG. 12 shows the data on the increase in mouse blood spermine concentration obtained in Example 3. As a result of administration of the diet prepared in Example 1, the concentration of polyamines (spermidine and spermine) in the blood of mice fed a high polyamine diet containing a large amount of polyamine increased at 26 weeks after administration. However, blood polyamine levels did not increase in mice that ate normal or low polyamine levels.
In addition, as shown in FIG. 6, even in humans, the spermine concentration in the blood increased in about two months even when a human had a high polyamine diet (when natto as a high polyamine diet was eaten 1-2 packs a day).
The pattern of increase in polyamine levels is different between mice and humans, but in any case, foods with high levels of polyamines (putrescine, spermidine, and spermine) will increase blood polyamine levels for a certain period of time. I found out that Therefore, it can be seen that the blood polyamine concentration increases by taking the food composition or feed composition of the present invention for a certain period of time.
　実施例５で説明したように、ポリアミン濃度の高い食餌を続けたマウスと、低もしくは普通のポリアミン濃度の餌を食べたマウスでは、８０週齢の様子が明らかに異なった。すなわち、高ポリアミン濃度を食べたマウスでは毛並みがよく、元気で活動的であったが、低もしくは普通ポリアミン濃度の餌を食べたマウスの毛並みは不良で、活動性も低下していた。図12は８０週齢マウスの外観的相違を示す写真である。明らかに高ポリアミン濃度を食べたマウスでは毛並みがよいことが判る。 As described in Example 5, the state of 80-week-olds was clearly different between mice that continued to have a high polyamine diet and mice that had a low or normal polyamine diet. In other words, the mice that ate high polyamine concentrations had good fur and were healthy and active, but the mice that ate low or normal polyamine concentrations had poor fur and decreased activity. FIG. 12 is a photograph showing the difference in appearance of 80-week-old mice. Obviously, the mice that ate a high polyamine concentration had good hair.
　さらに、実施例５と同じ方法で追試を行いマウスの生存期間を比較すると、図13に示すように、高ポリアミン餌を食べたマウスの集団は、低もしくは普通ポリアミン濃度の餌を食べたマウスの集団より、明らかに生存率が高く、生存期間が延長することがわかった（３群間の比較でも、高ポリアミン群と普通ポリアミン群および高ポリアミン群と低ポリアミン群の２群間の比較でもp値が0.05以下であり有意の差を認めた）。また、低ポリアミン群と普通ポリアミン群の間には有意差がなかった。図13のデータはKaplan-Meierによる検定で、３群間ではp=0.011, 高と普通ではp=0.003, 高と低ではp=0.032であり、有意の差をもって高ポリアミン餌(c)が長生きであることが判った。
　実施例５を継続し、８８週でマウスの腎臓を取り出し、各臓器の組織を検討した。ところ、図14のBに示すように、低および普通ポリアミン餌のマウスでは、腎臓の糸球体（尿を濾過する器官）の硬化（糸球体硬化）が著明であった。該糸球体硬化は老化に伴う変化としてはもっとも特徴的な変化の一つであり、動脈硬化などの生活習慣病の進行が原因である。すなわち、低および普通ポリアミン餌群のマウスでは糸球体硬化が進行しており、動脈硬化や老化がより進行していることが判る。これに対し、高ポリアミン餌を食べたマウスでは、図14のAで示すように該糸球体が若年マウスのように保たれて、硬化が極軽度であり、老化や動脈硬化の進行があまりない事を示している。（若年マウス（２０週齢）の腎臓の組織像と比較すると明らかである。）。 Further, when the follow-up test was performed in the same manner as in Example 5 and the survival times of the mice were compared, as shown in FIG. 13, the population of mice that ate the high polyamine diet showed that It was found that the survival rate was clearly higher than that of the group, and the survival time was prolonged (in comparison between the three groups, the comparison between the high polyamine group and the normal polyamine group, and the high polyamine group and the low polyamine group between the two groups). The value was 0.05 or less, and a significant difference was recognized). There was no significant difference between the low polyamine group and the normal polyamine group. The data in Fig. 13 is a test by Kaplan-Meier, p = 0.011, high and normal p = 0.003, high and low p = 0.032 between the three groups, high polyamine bait (c) lives long with significant difference It turned out that.
Example 5 was continued, and the kidneys of the mice were removed at 88 weeks, and the tissues of each organ were examined. However, as shown in FIG. 14B, in the low and normal polyamine-fed mice, hardening of the kidney glomeruli (organ that filters urine) (glomerulosclerosis) was prominent. The glomerulosclerosis is one of the most characteristic changes as a result of aging, and is caused by the progression of lifestyle-related diseases such as arteriosclerosis. That is, it can be seen that glomerulosclerosis is progressing in the low and normal polyamine-fed mice, and that arteriosclerosis and aging are further progressing. On the other hand, in mice that ate a high polyamine diet, the glomeruli were kept as young mice, as shown in FIG. 14A, and the cure was extremely mild, with little progression of aging and arteriosclerosis. Shows things. (It is clear when compared with the histology of the kidneys of young mice (20 weeks of age)).
　さらに腎臓をsenescence marker protein 30（SMP30）の抗体を用いて免疫染色した。該SMP30は加齢とともに組織中から減少するタンパク質であり、他のホルモンの影響等をうけず、酸化ストレスに対する組織の防御機能を有する。このタンパク質の減少は、生体の酸化ストレスからの防御機能を低下させ、老化の進行をさらに早める。図15に示すように、実施例５で得た、高ポリアミン餌群のマウスの腎臓のSMP30の発現量（写真で黒乃至濃灰色に染色されている）は高く、高ポリアミン餌を食べたマウスでは多くのSMP30が存在する事が判った。一方、低又は普通ポリアミン餌群マウスの腎臓のSMP30の量は低下（色が薄い）していた。比較で示した若年マウスでは、当然SMP30の発現は高度である。 Further, the kidney was immunostained with an antibody of senescence marker protein 30 (SMP30). The SMP30 is a protein that decreases from the tissue with age, and is not affected by other hormones and has a function of protecting the tissue against oxidative stress. This decrease in protein lowers the defense function against oxidative stress in the body and further accelerates aging. As shown in FIG. 15, the amount of expression of SMP30 (stained in black to dark gray in the photograph) in the kidneys of the mice of the high polyamine diet group obtained in Example 5 was high, and the mice that ate the high polyamine diet Then we found that there are many SMP30. On the other hand, the amount of SMP30 in the kidneys of low or normal polyamine-fed mice decreased (light color). Of course, the expression of SMP30 is high in the young mice shown in the comparison.
　また、該SMP30は主に腎臓と肝臓に多く存在するので、さらに肝臓をSMP30の抗体を用いて免疫染色した。図16に示すように、腎臓と同様に、高ポリアミン餌群のマウスの肝臓のSMP30の発現量は高く（写真で濃い色に染色されている）、高ポリアミン餌を食べたマウスでは多くのSMP30が存在する事が判った。一方、低又は普通ポリアミン餌群マウスの肝臓のSMP30の量は低下していた（色が薄い）。比較で示した若年マウスでは、当然SMP30の発現は高度である。 In addition, since the SMP30 is mainly present in the kidney and liver, the liver was further immunostained using an SMP30 antibody. As shown in FIG. 16, like the kidney, the expression level of SMP30 in the liver of mice with a high polyamine diet group is high (stained in a dark color in the photograph), and many SMP30 in mice that ate a high polyamine diet. Was found to exist. On the other hand, the amount of SMP30 in the liver of low or normal polyamine-fed mice was decreased (light color). Of course, the expression of SMP30 is high in the young mice shown in the comparison.
　これらのことから、高ポリアミン食はマウスの老化に伴う重要臓器の組織学的な変化を抑制し、毛並みを若々しく、活動性を保った。すなわち老化や、その典型的な変化である糸球体硬化を防いで、寿命を延長させることが判る。該マウスの病理学的な差で明らかにした様に、高ポリアミン食、すなわち本発明の食品組成物及び飼料組成物は動脈硬化などの生活習慣病や老化を抑制し、生活習慣病の原因である酸化ストレスに対する防御機能（SMP30）を保つことが出来ることは明かである。 From these facts, the high polyamine diet suppressed the histological changes of important organs accompanying aging of mice, and kept the youthful and active. That is, it can be seen that aging and glomerular hardening, which is a typical change thereof, are prevented and the life is extended. As revealed by the pathological differences of the mice, the high polyamine diet, that is, the food composition and feed composition of the present invention suppresses lifestyle-related diseases such as arteriosclerosis and aging, and causes lifestyle-related diseases. It is clear that a protective function against certain oxidative stress (SMP30) can be maintained.
（公開データに基づく、人におけるポリアミンの摂取量増加とその効果の考察）
　次に、人でも高ポリアミン食が、加齢等に伴うLFA-1の増加に起因する炎症、及び関連疾患、すなわち老化を防ぐ、及び軽減するのに有効か否かを、統計資料を用いて検討した。人の老化の典型的な発病の形態は動脈硬化による疾患である、そこで心臓血管疾患（cardiovascular disease = CVD）の発症頻度を指標にした。該動脈硬化はコレステロールの血管壁への沈着で生じるが、その発病には炎症が重要な働きをする。すなわち、沈着したコレステロールに免疫細胞（末梢血単核球など）が作用し、炎症を起こす事によって動脈硬化が進行するのである。この心臓血管疾患は、心筋梗塞や脳梗塞といった心臓血管疾患を引き起こすが、先進工業国とくに西欧諸国における死因の第一位であり、この疾患の克服は寿命を延長させることにつながると考えられている。したがって、強力な抗炎症作用（炎症性サイトカイン産生抑制、LFA-1発現抑制）を有するポリアミン、特にスペルミンが動脈硬化を抑制していることを示す証拠があるかどうかに焦点をあてて検討した。 (Consideration of increase in polyamine intake and its effects based on public data)
Next, using statistical data to determine whether a high polyamine diet is effective in preventing and reducing inflammation caused by an increase in LFA-1 associated with aging, etc., and related diseases, that is, aging investigated. The typical pathogenesis of aging in humans is a disease caused by arteriosclerosis. Therefore, the incidence of cardiovascular disease (CVD) was used as an index. The arteriosclerosis is caused by the deposition of cholesterol on the blood vessel wall, and inflammation plays an important role in its pathogenesis. That is, immune cells (peripheral blood mononuclear cells, etc.) act on the deposited cholesterol, and inflammation is caused to advance arteriosclerosis. Although this cardiovascular disease causes cardiovascular diseases such as myocardial infarction and cerebral infarction, it is the leading cause of death in industrialized countries, especially Western countries, and it is thought that overcoming this disease will lead to a longer life span. Yes. Therefore, we focused on whether there is evidence that polyamines, particularly spermine, that have strong anti-inflammatory effects (suppression of inflammatory cytokine production and LFA-1 expression) suppress arteriosclerosis.
　まず、WHO（World Health Organization）ホームページの統計情報システム(Statistical Information System (WHOSIS) (http://www.who.int/whosis/en/))　から心臓血管疾患の訂正死亡率（２００２年）及び男女の寿命（life expectancy、２０００年）のデータを、国連食糧農業機構の統計部(FAOSTAT)のデータベース（http://www.fao.org/economic/en/）から２００２年の食料消費量データのなかのCrops  primary equvalentおよびLivestock and Fish primary equivalentに関するデータを用いた。また、各食品中のポリアミン濃度は、下記３つの論文に記載されている濃度の平均値を用いた。
1)  Polyamine contents in current
foods: a basis for polyamine reduced diet and a study of its long term observance and tolerance in prostate carcinoma patients. Cipolla BG, Havouis R, Moulinoux JP. Amino Acids. 33: 203-212, 2007.　
2) Polyamines in food-implications for growth and health. Bardocz S, Duguid TJ, Brown DS, Grant G, Pusztai A, White A, Ralph A. J.Nutr.Biochem. 4: 66-71, 1993.
3) Nishibori N, Fujihara S, Akatuki T. Amounts of polyamines in foods in Japan and intake by Japanese. Food Chemistry 100: 491-497, 2007. First, the WHO (World Health Organization) homepage's Statistical Information System (WHOSIS) (http://www.who.int/whosis/en/)) is used to correct cardiovascular disease mortality (2002) and Data on life expectancy (2000) for men and women from the United Nations Food and Agriculture Organization's Statistics Department (FAOSTAT) database (http://www.fao.org/economic/en/) Among them, data on Crops primary equvalent and Livestock and Fish primary equivalent were used. Moreover, the average value of the density | concentration described in the following three papers was used for the polyamine density | concentration in each foodstuff.
1) Polyamine contents in current
foods: a basis for polyamine reduced diet and a study of its long term observance and tolerance in prostate carcinoma patients.Cipolla BG, Havouis R, Moulinoux JP. Amino Acids. 33: 203-212, 2007.
2) Polyamines in food-implications for growth and health.Bardocz S, Duguid TJ, Brown DS, Grant G, Pusztai A, White A, Ralph A. J. Nutr. Biochem. 4: 66-71, 1993.
3) Nishibori N, Fujihara S, Akatuki T. Amounts of polyamines in foods in Japan and intake by Japanese.Food Chemistry 100: 491-497, 2007.
　対象とした国は、ロシアを含むヨーロッパ諸国およびアメリカ合衆国、カナダ、オーストラリアとニュージーランド（アルバニア、アルメニア、オーストラリア、オーストリア、アゼルバイジャン、ベラルーシ、ベルギー、ボスニア及びヘルツェゴビナ、ブルガリア、カナダ、クロアチア、シプラス、チェコ共和国、デンマーク、エストニア、フィンランド、フランス、ジョージア、ドイツ、ギリシア、ハンガリー、アイスランド、アイルランド、イスラエル、イタリア、カザフスタン、ラトビア、リトアニア、マルタ、ニュージーランド、ノルウェイ、ポーランド、ポトルトガル、ルーマニア、ロシア連邦、スロバキア、スロベニア、スペイン、スウェーデン、タジキスタン、マケドニアの前ユーゴスラビア共和国、トルコ、トルクメニスタン、ウクライナ、英国、アメリカ合衆国、ウズベキスタン）の４９カ国であり、文化、人種構成、食文化、宗教的な背景の比較的類似した国家を対象にした。
　調査した食品は動物性脂肪、水産動物、水産物、牛肉、バター、ギー、頭足動物、チーズ、クリーム、甲殻類、深海魚、卵、 動物性脂肪（未加工）、淡水魚、蜂蜜、海魚（他）、肉（他）、全乳、ミルク調製バター(ミルクを転換した乳製品を伴う全乳)、軟体動物 (他)、マトン及びヤギ肉、食用内臓肉、豚肉、鶏肉、 乳清、リンゴ、バナナ、レモン及びライム、柑橘類 (他)、パイナップル、グレープ、オレンジ及びマンダリン、フルーツ類（他）、pulses (other), 樹木性ナッツ、地上性ナッツ、シリアル（シリアル（他）、大麦、オーツ麦、ライ麦、小麦、ライス (ミルドeq))、ジャガイモ、トウモロコシ、オニオン、トマト、野菜（他）、刺激物、油料穀物、砂糖、コーヒー、ビール、ワイン、アルコール性飲料の全食品である。 The target countries are European countries including Russia and the United States, Canada, Australia and New Zealand (Albania, Armenia, Australia, Austria, Azerbaijan, Belarus, Belgium, Bosnia and Herzegovina, Bulgaria, Canada, Croatia, Siplus, Czech Republic, Denmark , Estonia, Finland, France, Georgia, Germany, Greece, Hungary, Iceland, Ireland, Israel, Italy, Kazakhstan, Latvia, Lithuania, Malta, New Zealand, Norway, Poland, Pottgart, Romania, Russian Federation, Slovakia, Slovenia, Spain , Sweden, Tajikistan, Macedonia, Yugoslavia, Turkey, Turkmenis Emissions, Ukraine, United Kingdom, United States of America, is the 49 countries of Uzbekistan), and cultural, racial makeup, food culture, a relatively similar national religious background in the subject.
The investigated foods are animal fats, aquatic animals, marine products, beef, butter, ghee, cephalopods, cheese, cream, crustaceans, deep sea fish, eggs, animal fat (raw), freshwater fish, honey, sea fish (others) ), Meat (other), whole milk, milk preparation butter (whole milk with dairy products converted from milk), mollusks (other), mutton and goat meat, edible internal organs, pork, chicken, whey, apples, Banana, lemon and lime, citrus (other), pineapple, grape, orange and mandarin, fruit (other), pulses (other), tree nut, ground nut, cereal (cereal (other), barley, oat, Rye, wheat, rice (mild eq)), potatoes, corn, onions, tomatoes, vegetables (others), stimulants, oil grains, sugar, coffee, beer, wine, alcoholic beverages.
　これらの国々では、心臓血管疾患（CVD）訂正死亡率と男女の寿命が極めて強い負の相関（男性は相関係数＝-0.950, p<0.0001：女性は相関係数＝-0.942, p<0.0001）を示しており、CVDは死因としてきわめて重要であり、CVDの発症抑制は寿命延長をもたらすことが容易に推測できる（図なし）（CVD event＝訂正心臓血管疾患の年間発症数）。 In these countries, the negative correlation between cardiovascular disease (CVD) corrected mortality and male and female longevity (correlation coefficient = -0.950, p <0.0001 for men: correlation coefficient = -0.942, p <0.0001 for women) ), And CVD is extremely important as a cause of death, and it can be easily inferred that suppression of the onset of CVD results in prolonged lifespan (not shown) (CVD event = number of annual onset of corrected cardiovascular disease).
　これまでの疫学調査でも報告されているとおり、ミルク消費量(全乳)とCVDの発症数の関連は弱いが、消費量の多い国のほうがCVDの発症数も多い傾向がみとめられた（相関係数＝+3.80, p=0.0066）（図17参照）。
　一方、心臓血管疾患とチーズ消費量との関係をみると、乳製品のなかでもポリアミンを比較的多く含むチーズとCVDの発症数は強い負の相関（相関係数＝-0.797, p<0.0001）を示した（図18参照）。
　この統計を用いると、これまで指摘されてきたことと同じ傾向があることが判った。しかし、FAOSTATの数値は、各国家間で消費できる状態にある数値であり、実際にすべての食品が摂食されているわけではない。しかし、この各食品の量やその中に含まれる各種成分の比は国家内で必要とされている食品の比率を確実に反映していると考える事ができる。そこで、次に食品や成分などの比を用いて検討することとした。
　まず、CVD発症数とミルク全製品消費量（バターを除くミルク製品）に占めるチーズ消費量の比を比較すると、両者は強い負の相関（相関係数＝-0.774,
p<0.0001）を示した（図19参照）。この事は、同じミルクを原料とするチーズにはCVDを抑制する物質が含まれている可能性を示唆する。
　一方、既に動脈硬化などの生活習慣病に予防的に作用していることが科学的に明らかにされている、不飽和脂肪酸を多く含む魚食の影響を見るために、魚食の量と動脈硬化を進行させる飽和脂肪酸を多く含む動物の肉食量の比率とCVDの関係を検討した。この結果、心臓血管疾患と魚食／肉食比の間には、弱い負の相関（相関係数＝-0.365, p=0.0095）があることが示された。これは、これまで指摘されてきたように、魚類に多く含まれる多価不飽和脂肪酸(PUFA)がCVDを抑制する可能性をサポートするデータである。 As reported in previous epidemiological studies, the relationship between milk consumption (whole milk) and the incidence of CVD is weak, but countries with higher consumption tended to have a higher incidence of CVD. Number of relationships = + 3.80, p = 0.0066) (see FIG. 17).
On the other hand, looking at the relationship between cardiovascular disease and cheese consumption, there is a strong negative correlation between the incidence of CVD and cheese containing relatively high polyamines in dairy products (correlation coefficient = -0.797, p <0.0001) (See FIG. 18).
Using this statistic, it was found that there was the same tendency as previously indicated. However, FAOSTAT values are values that can be consumed between countries, and not all foods are actually consumed. However, it can be considered that the amount of each food and the ratio of various components contained therein surely reflect the ratio of food required in the country. Therefore, it was decided to consider using the ratio of food and ingredients.
First, when comparing the ratio of the incidence of CVD and the ratio of cheese consumption to the total milk consumption (milk products excluding butter), they showed a strong negative correlation (correlation coefficient = -0.774,
p <0.0001) (see FIG. 19). This suggests that the cheese made from the same milk may contain substances that suppress CVD.
On the other hand, in order to see the effects of fish foods rich in unsaturated fatty acids, which have been scientifically clarified to have a preventive action on lifestyle-related diseases such as arteriosclerosis, the amount of fish food and arteries We investigated the relationship between the ratio of carnivorous amount of animals rich in saturated fatty acids that promote hardening and CVD. As a result, it was shown that there is a weak negative correlation (correlation coefficient = −0.365, p = 0.0095) between the cardiovascular disease and the fish / meat ratio. This is data that supports the possibility that polyunsaturated fatty acids (PUFA) contained in a large amount of fish suppress CVD as pointed out so far.
　さらに、近年になって動脈硬化などの生活習慣病に予防的に作用していることの証明が困難になってきたポリフェノールとの関係を見るために、全アルコール飲料にしめるワインの消費量の比とCVDの関係を検討した。しかし、ワイン消費量／全アルコール飲料消費量とCVD発症数には関係がなかった（相関係数＝-0.086, p=0.5588）。 In addition, in order to see the relationship with polyphenols that have proved difficult to prove that they have a preventive effect on lifestyle-related diseases such as arteriosclerosis in recent years, The relationship of CVD was examined. However, there was no relationship between wine consumption / total alcohol consumption and the number of CVD cases (correlation coefficient = -0.086, p = 0.5588).
　次に、食品中に含まれるポリアミン量とCVDの関係を検討する。
まず、摂取カロリーあたりの総ポリアミン摂取量とCVD発症数の関係を検討した。総ポリアミン摂取量とは、食品および飲料中に含まれるプトレスシン、スペルミジン、及びスペルミンの量（全て分子量＝molで計算）である。図20に示されているように、両者の間には負の相関を認めた（相関係数＝-0.560, p<0.0001）。すなわち、摂取カロリーあたりに含まれるポリアミン量の多い国家ほど心臓血管疾患による死亡率が低いということである。
次に、これまでの検討で抗炎症作用（炎症性サイトカイン産生抑制、LFA-1発現抑制作用）がもっとも強力であったスペルミンの摂取量と総カロリーの関係を検討した。その結果、摂取総カロリーにおけるスペルミン摂取量の比とCVDの発症数は強い負の相関（相関係数＝ -0.717, p<0.0001）を認めた(図21参照)。すなわち、総カロリーあたりのポリアミン、特にスペルミンの割合が多い食品を食べている対象国の国民ほど、心臓血管疾患が少ないことが判る。
　ポリアミンは大半が細胞内に存在し、とくにタンパク質などと一緒に存在する。そこで、タンパク質摂取量あたりのポリアミン量とCVD発症数を比較すると、やはり両者の間には負の相関を認めた（相関係数＝-0.670, p<0.0001）(図22参照)。すなわち、同じタンパク質でもスペルミンが多く含まれている食品を食べている国民の方がCVDの発症率が低いことが判る。
　これらの検討結果は、本発明者が行った試験管レベルでの研究によるポリアミンの抗炎症抑制作用、及びマウスへの高ポリアミン食投与実験による動脈硬化などの老化の進行抑制の実験結果とよく一致する。すなわち、LFA-1の増加に起因する炎症、及び関連疾患、すなわちCVDの発症は炎症により進行する。そして食品中のポリアミンは体内にそのまま吸収されるが、先の統計的なデータでも実際に人で高ポリアミン食の継続で血中のポリアミン濃度が上昇した。すなわち、CVDなどの生活習慣病の発症の機序として重要な炎症を抑制するポリアミン、特にスペルミンを摂取することで、体内に入ったポリアミンが炎症を抑制しCVDの発症を抑制すると考えられるが、そのことが疫学調査上でも証明されたことになる。 Next, we will examine the relationship between the amount of polyamine contained in food and CVD.
First, the relationship between total polyamine intake per calorie intake and the number of CVD episodes was examined. The total polyamine intake is the amount of putrescine, spermidine, and spermine contained in foods and beverages (all calculated with molecular weight = mol). As shown in FIG. 20, a negative correlation was recognized between the two (correlation coefficient = −0.560, p <0.0001). In other words, a country with a higher amount of polyamines per calorie intake has a lower mortality from cardiovascular disease.
Next, we examined the relationship between spermine intake and total calories, which had the strongest anti-inflammatory effects (inhibition of inflammatory cytokine production and LFA-1 expression) in previous studies. As a result, a strong negative correlation (correlation coefficient = -0.717, p <0.0001) was found between the ratio of spermine intake to the total calorie intake and the number of CVD episodes (see Fig. 21). That is, it can be seen that the nationality of the target country that eats food with a high proportion of polyamines per calorie, especially spermine, has fewer cardiovascular diseases.
Polyamines are mostly present in cells, especially with proteins. Therefore, when comparing the amount of polyamine per protein intake and the number of CVD episodes, a negative correlation was found between the two (correlation coefficient = 0.670, p <0.0001) (see FIG. 22). In other words, people who eat foods that contain the same protein but are rich in spermine have a lower incidence of CVD.
The results of these studies are in good agreement with the experimental results of the anti-inflammation action of polyamines by in vitro studies conducted by the present inventor and the suppression of the progression of aging such as arteriosclerosis in mice administered with a high polyamine diet. To do. That is, inflammation due to an increase in LFA-1 and the onset of related diseases, that is, CVD proceeds by inflammation. Polyamines in foods are absorbed directly into the body, but the previous statistical data also showed that the concentration of polyamines in the blood increased with the continued high polyamine diet. In other words, polyamines that suppress inflammation, which is important as a mechanism for the development of lifestyle-related diseases such as CVD, in particular spermine, is considered that polyamines that enter the body suppress inflammation and suppress the onset of CVD, This has been proved in epidemiological studies.
　そして、実際にポリアミンの摂取量と人の寿命の関係を検討すると、男性寿命では、摂取総カロリーあたりのポリアミン摂取量の多い国民ほど寿命が長く（相関係数＝0.658, p<0.0001）(図23参照)、また、女性寿命でも、摂取総カロリーあたりのポリアミン摂取量の多い国民ほど寿命が長い（相関係数＝0.553, p<0.0001）ことがわかった(図24参照)。
　したがって、ポリアミンは微生物、植物、動物や人の共通の物質であり、人でも、マウスと同様に動脈硬化などの生活習慣病を抑制し、老化の進行を抑制し、寿命を延長していることがわかった。 When we actually examine the relationship between polyamine intake and human life expectancy, the life expectancy of males with longer polyamine intake per total calorie intake is longer (correlation coefficient = 0.658, p <0.0001). 23) In addition, it was found that the life expectancy of women with a higher polyamine intake per total calorie intake was longer (correlation coefficient = 0.553, p <0.0001).
Therefore, polyamine is a substance common to microorganisms, plants, animals, and humans, and humans, like mice, suppress lifestyle-related diseases such as arteriosclerosis, suppress the progression of aging, and extend lifespan. I understood.
図１は、ポリアミンの代謝経路である。高ポリアミン食によって細胞内スペルミンとスペルミジン濃度が増加すると、Sアデノシルメチオニン脱炭酸酵素（S-adenosylmethioninedecarboxylase(AdoMet DC)）とオルニチン脱炭酸酵素（Ornithinedecarboxylase(ODC)）の活性が低下する。FIG. 1 is a metabolic pathway of polyamines. When intracellular spermine and spermidine concentrations are increased by a high polyamine diet, the activities of S-adenosylmethionine decarboxylase (AdoMetsDC) and ornithine decarboxylase (ODC) decrease. 図２は、Sアデノシルメチオニン（S-adenosylmethionine）と遺伝子のプロモーター領域（CpG）のメチル化（Methylation）との関係を示す。遺伝子のプロモーター領域のメチル化は遺伝子発現を制御している。Sアデノシルメチオニンはメチル基を供給する唯一の物質であり、この濃度上昇は遺伝子等のメチル化の進行を促進することになる。LFA-1のプロモーター領域はメチル化によって発現が低下する事が判っている。FIG. 2 shows the relationship between S-adenosylmethionine and gene promoter region (CpG) methylation. Methylation of the promoter region of the gene controls gene expression. S-adenosylmethionine is the only substance that supplies methyl groups, and this increase in concentration promotes the progress of methylation of genes and the like. It has been found that LFA-1 promoter region is down-regulated by methylation. 図３は、低ポリアミン飼料組成物を摂取した群の血中スペルミジン濃度と、高ポリアミン飼料組成物を摂取した群の血中スペルミジン濃度とを比較したグラフである。FIG. 3 is a graph comparing the blood spermidine concentration of the group ingesting the low polyamine feed composition and the blood spermidine concentration of the group ingesting the high polyamine feed composition. 図４は、実施例３で得られたマウス血中スペルミン濃度上昇のデータを示す。図４では、低ポリアミン飼料組成物を摂取した群の血中スペルミン濃度と、高ポリアミン飼料組成物を摂取した群の血中スペルミン濃度とを比較している。FIG. 4 shows the mouse blood spermine concentration increase data obtained in Example 3. In FIG. 4, the blood spermine concentration of the group ingesting the low polyamine feed composition is compared with the blood spermine concentration of the group ingesting the high polyamine feed composition. 図５は、高ポリアミン飼料組成物摂取マウス群の累積生存率と、低ポリアミン飼料組成物摂取マウス群の累積生存率を示すグラフである。FIG. 5 is a graph showing the cumulative survival rate of a group of mice fed with a high polyamine feed composition and the cumulative survival rate of a group of mice fed with a low polyamine feed composition. 図６のＡは納豆を毎日摂取したヒトの群のスペルミン血中濃度を示し、Ｂは納豆を摂取しないヒトの群のスペルミンの血中濃度を示すグラフである。Ａの納豆を毎日摂取した群では実験開始前（Before）と比較すると納豆食を継続した後（After）では明らかに血中スペルミン濃度が上昇している。しかし、Bの納豆を食べなかった群では、実験前（Before）と実験後（After）の間に変化を認めなかった。FIG. 6A is a graph showing the blood concentration of spermine in a group of people who took natto every day, and B is the graph showing the blood concentration of spermine in a group of people who did not take natto. In the group that ingested natto A every day, the blood spermine concentration was clearly increased after continuing the natto diet (After) compared to before the start of the experiment (Before). However, in the group that did not eat B natto, there was no change between before and after the experiment. 図７は、哺乳動物、例えばヒトでは加齢とともにポリアミンの合成が低下することを示すグラフである。FIG. 7 is a graph showing that polyamine synthesis decreases with age in mammals such as humans. 図８は、高齢者ほど末梢血単核球のLFA-1が増えることを示すデータである。FIG. 8 shows data indicating that LFA-1 in peripheral blood mononuclear cells increases with increasing age. 図９は、スペルミンの増加が末梢血単核球のLFA-1を減少させることを示すデータである。FIG. 9 is data showing that an increase in spermine decreases LFA-1 in peripheral blood mononuclear cells. 図10は、人の免疫細胞を取りだし、実際にポリアミン（スペルミンとスペルミジン）と培養するとLFA-1(=CD11aおよびCD18)の発現だけが低下することを示すデータのデータである。図10のデータを得るため、ポリアミンとともに培養した細胞における接着分子のMFIの変化を平均蛍光強度を測定した。FIG. 10 is data data showing that when human immune cells are taken out and cultured with polyamines (spermine and spermidine), only the expression of LFA-1 (= CD11a and CD18) decreases. In order to obtain the data of FIG. 10, the average fluorescence intensity was measured for the change in MFI of adhesion molecules in cells cultured with polyamine. 図11は、実施例２で得られたマウス血中スペルミジン濃度上昇のデータを示す。FIG. 11 shows the mouse blood spermidine concentration increase data obtained in Example 2. 図12は、ポリアミン濃度の高い食餌を続けたマウスと、低もしくは普通のポリアミン濃度の餌を食べたマウスにおける外観的相違を示す写真である。明らかに高ポリアミン濃度を食べたマウスでは毛並みがよいことが判る。FIG. 12 is a photograph showing the difference in appearance between a mouse that continued to have a high polyamine diet and a mouse that had a low or normal polyamine diet. Obviously, the mice that ate a high polyamine concentration had good hair. 図13は、実施例５と同じ方法で追試を行いマウスの生存期間を比較した場合における、高ポリアミン餌を食べたマウスの集団、低もしくは普通ポリアミン濃度の餌を食べたマウスの集団毎の、生存率と、生存期間の延長を示すデータである。FIG. 13 shows a group of mice that ate a high polyamine diet and a group of mice that ate a diet with a low or normal polyamine concentration, when the follow-up test was performed in the same manner as in Example 5 and the survival times of the mice were compared. Data showing survival rate and extension of survival time. 図14のBは、低および普通ポリアミン餌のマウスでは、腎臓の糸球体（尿を濾過する器官）の硬化（糸球体硬化）が著明であり、一方、高ポリアミン餌のマウスでは図14のAで示すように該糸球体が若年マウスのように保たれて、硬化が極軽度であり、老化や動脈硬化の進行があまりない事を示す、写真である。FIG. 14B shows that in the low and normal polyamine-fed mice, kidney glomeruli (the organ that filters urine) is markedly cured (glomerulosclerosis), whereas in high-polyamine-fed mice, FIG. It is a photograph showing that the glomerulus is maintained as a young mouse as shown by A, the hardening is extremely mild, and the progression of aging and arteriosclerosis is not so much. 図15は、低、普通及び高ポリアミン餌群のマウスの腎臓のSMP30の発現量を示す写真である（写真で黒乃至濃灰色に染色されている）。FIG. 15 is a photograph showing the expression level of SMP30 in the kidneys of mice of the low, normal and high polyamine diet groups (stained in black to dark gray in the photograph). 図16は、低、普通及び高ポリアミン餌群のマウスの肝臓のSMP30の発現量を示す写真である（写真で黒乃至濃灰色に染色されている）。FIG. 16 is a photograph showing the expression level of SMP30 in the liver of mice of the low, normal and high polyamine diet groups (stained in black to dark gray in the photograph). 図17は、ミルク消費量(全乳)とCVDの発症数の関連を示すデータである。その関連は弱いが、消費量の多い国のほうがCVDの発症数も多い傾向がみとめられる（相関係数＝+3.80, p=0.0066）。FIG. 17 is data showing the relationship between milk consumption (whole milk) and the number of CVD episodes. Although the relationship is weak, countries with higher consumption tend to have a higher incidence of CVD (correlation coefficient = +3.80, = 0p = 0.0063). 図18は、心臓血管疾患とチーズ消費量との関係を示すデータである。乳製品のなかでもポリアミンを比較的多く含むチーズとCVDの発症数は強い負の相関（相関係数＝-0.797, p<0.0001）を示している。FIG. 18 is data showing the relationship between cardiovascular disease and cheese consumption. Among dairy products, cheeses with relatively high polyamines and the incidence of CVD show a strong negative correlation (correlation coefficient = -0.797, p <0.0001). 図19は、まず、CVD発症数とミルク全製品消費量（バターを除くミルク製品）に占めるチーズ消費量の比を比較するデータを示す。両者は強い負の相関（相関係数＝-0.774, p<0.0001）を示し、この事は、同じミルクを原料とするチーズにはCVDを抑制する物質が含まれている可能性を示唆する。FIG. 19 shows data comparing the ratio of cheese consumption to the total number of CVD episodes and total milk product consumption (milk products excluding butter). Both show a strong negative correlation (correlation coefficient = -0.774, p <0.0001), which suggests that cheese made from the same milk may contain substances that suppress CVD. 図20は、摂取総カロリーにおけるポリアミン摂取量の比とCVDの発症数の関係を示すデータである。両者には強い負の相関（相関係数＝ -0.560, p<0.0001）が認められる。FIG. 20 is data showing the relationship between the ratio of polyamine intake in the total calorie intake and the number of CVD episodes. Both have a strong negative correlation (correlation coefficient = -0.560, p <0.0001). 図21は摂取総カロリーにおけるスペルミン摂取量の比とCVDの発症数の関係を示すデータである。両者には強い負の相関（相関係数＝-717, p<0.0001）が認められる。FIG. 21 is data showing the relationship between the ratio of spermine intake to the total calorie intake and the number of CVD episodes. Both have a strong negative correlation (correlation coefficient = -717, <p <0.0001). 図22は、タンパク質摂取量あたりのポリアミン量とCVD発症数を比較したデータである。やはり両者の間には負の相関を認めた（相関係数＝-0.670, p<0.0001）。すなわち、同じ蛋白質でもスペルミンが多く含まれている食品を食べている国民の方がCVDの発症数が少ないことが判る。FIG. 22 shows data comparing the amount of polyamine per protein intake and the number of CVD episodes. After all, a negative correlation was recognized between the two (correlation coefficient = 0.670, p <0.0001). In other words, people who eat foods that contain the same protein but high in spermine are found to have fewer CVD cases. 図23は、実際にポリアミンの摂取量と人（男）の寿命の関係を示すデータである。FIG. 23 is data showing the actual relationship between polyamine intake and the life of a person (male). 図24は、実際にポリアミンの摂取量と人（女）の寿命の関係を示すデータである。FIG. 24 is data showing the actual relationship between polyamine intake and the life span of a person (woman).

Claims (26)

  1. 　下記式(1)のポリアミン、及びその医薬として許容し得る塩からなる群から選ばれる少なくとも１の化合物を含む、食品組成物：
     
    　NH2-(CH2)m1-(NH)p1-(CH2)m2-(NH)p2-(CH2)m3-
    　　　　　　(NH)p3-(CH2)m4-(NH)p4-(CH2)m5-NH2    …(1)
     
    （式中、m1～m5はそれぞれ独立に０～７の整数であって、そのうち少なくとも１つは０よりも大きく、m1＋m2＋m3＋m4＋m5の和は、２以上かつ１８未満であり、かつp1, p2,
    p3及びp4は、それぞれ独立に０又は１である。）。     A food composition comprising at least one compound selected from the group consisting of a polyamine of the following formula (1) and a pharmaceutically acceptable salt thereof:

    NH 2- (CH 2 ) m1- (NH) p1- (CH 2 ) m2- (NH) p2- (CH 2 ) m3-
    (NH) p3- (CH 2 ) m4- (NH) p4- (CH 2 ) m5 -NH 2 … (1)

    (Wherein m1 to m5 are each independently an integer of 0 to 7, at least one of which is greater than 0, and the sum of m1 + m2 + m3 + m4 + m5 is 2 or more and less than 18, and p1, p2,
    p3 and p4 are each independently 0 or 1. ).
  2. 　式(1)中において、m1～m5がそれぞれ独立に０～５の整数であって、m1＋m2＋m3＋m4＋m5の和が２以上かつ１７未満である、請求項１記載の食品組成物。 The food composition according to claim 1, wherein in formula (1), m1 to m5 are each independently an integer of 0 to 5, and the sum of m1 + m2 + m3 + m4 + m5 is 2 or more and less than 17.
  3. 　式(1)中、m1＋m2＋m3＋m4＋m5の和が、４以上かつ１６未満である、請求項２記載の食品組成物。 The food composition according to claim 2, wherein in formula (1), the sum of m1 + m2 + m3 + m4 + m5 is 4 or more and less than 16.
  4. 　式(1)中において、m1が２～７の整数、かつm2,m3, m4及びm5が０であり、p1，p2, p3及びp4がそれぞれ０である、請求項１記載の食品組成物。 The food composition according to claim 1, wherein in formula (1), m1 is an integer of 2 to 7, m2, m3, m4 and m5 are 0, and p1, p2, p3 and p4 are each 0.
  5. 　式(1)中において、m1が３～５の整数、かつm2,m3, m4及びm5が０であり、p1，p2, p3及びp4がそれぞれ０である、請求項１記載の食品組成物。 The food composition according to claim 1, wherein, in formula (1), m1 is an integer of 3 to 5, m2, m3, m4 and m5 are 0, and p1, p2, p3 and p4 are each 0.
  6. 　式(1)中において、m1が２～７の整数、m2が２～７の整数、かつm3, m4及びm5が０であり、p1が１で、p2, p3及びp4がそれぞれ０である、請求項１記載の食品組成物。 In the formula (1), m1 is an integer of 2 to 7, m2 is an integer of 2 to 7, and m3, m4 and m5 are 0, p1 is 1, and p2, p3 and p4 are each 0. The food composition according to claim 1.
  7. 　式(1)中において、m1が３～５の整数、m2が２～５の整数、かつm3, m4及びm5が０であり、p1が１で、p2, p3及びp4がそれぞれ０である、請求項１記載の食品組成物。 In the formula (1), m1 is an integer of 3 to 5, m2 is an integer of 2 to 5, and m3, m4 and m5 are 0, p1 is 1, and p2, p3 and p4 are each 0. The food composition according to claim 1.
  8. 　式(1)中において、m1が２～７の整数、m2及びm3が２～７の整数、m4及びm5が０であり、p1及びp2が１で、p3及びp4がそれぞれ０である、請求項１記載の食品組成物。 In the formula (1), m1 is an integer of 2 to 7, m2 and m3 are integers of 2 to 7, m4 and m5 are 0, p1 and p2 are 1, and p3 and p4 are 0, respectively. Item 10. A food composition according to Item 1.
  9. 　式(1)中において、m1が３～５の整数、m2及びm3が２～５の整数、かつm4及びm5が０であり、p1及びp2が１で、p3及びp4がそれぞれ０である、請求項１記載の食品組成物。 In the formula (1), m1 is an integer of 3 to 5, m2 and m3 are integers of 2 to 5, m4 and m5 are 0, p1 and p2 are 1, and p3 and p4 are 0, respectively. The food composition according to claim 1.
  10. 　式(1)中において、m1、m2、m3及びm4が２～７の整数で、m5が０であり、p1～p3が１であり、かつp4が０である、請求項１記載の食品組成物。 The food composition according to claim 1, wherein m1, m2, m3, and m4 are integers of 2 to 7, m5 is 0, p1 to p3 is 1, and p4 is 0 in formula (1). object.
  11. 　式(1)中において、m1が３～５の整数、m2, m3及びm4が２～５の整数、かつm5が０であり、p1～p3が１であり、かつp4が０である、請求項１記載の食品組成物。 In the formula (1), m1 is an integer of 3 to 5, m2, m3 and m4 are integers of 2 to 5, m5 is 0, p1 to p3 is 1, and p4 is 0. Item 10. A food composition according to Item 1.
  12. 　前記ポリアミンが、3,3’－イミノビスプロピルアミン、Ｎ－アミノブチル－1,3－ジアミノプロパン、4,4'－イミノビスブチルアミン、及びＮ－アミノペンチル－1,3－ジアミノプロパンからなる群から選ばれたものである、請求項１記載の食品組成物。 The group consisting of 3,3′-iminobispropylamine, N-aminobutyl-1,3-diaminopropane, 4,4′-iminobisbutylamine, and N-aminopentyl-1,3-diaminopropane; The food composition according to claim 1, which is selected from.
  13. 　前記ポリアミンが、4,8-ジアザウンデカン-1,11-ジアミン、4,9-ジアザドデカン-1,12-ジアミン、4,8-ジアザドデカン-1,12-ジアミン、5,9-ジアザトリデカン-1,13-ジアミン、4,8-ジアザトリデカン-1,13-ジアミン、4,10-ジアザトリデカン-1,13-ジアミン、4,9-ジアザトリデカン-1,13-ジアミン、5,9-ジアザトリデカン-1,13-ジアミン、及び5,9-ジアザテトラデカン-1,14-ジアミンからなる群から選ばれたものである、請求項１記載の食品組成物。 The polyamine is 4,8-diazaundecane-1,11-diamine, 4,9-diazadodecane-1,12-diamine, 4,8-diazadodecane-1,12-diamine, 5,9-diazatridecane-1, 13-diamine, 4,8-diazatridecane-1,13-diamine, 4,10-diazatridecane-1,13-diamine, 4,9-diazatridecane-1,13-diamine, 5,9-diazatridecane-1,13- The food composition according to claim 1, wherein the food composition is selected from the group consisting of diamine and 5,9-diazatetradecane-1,14-diamine.
  14. 　前記ポリアミンが、4,8,12-トリアザペンタデカン-1,15-ジアミン、4,8,12-トリアザヘキサデカン-1,16-ジアミン、4,9,13-トリアザヘプタデカン-1,17-ジアミン、4,9,14-トリアザオクタデカン-1,18-ジアミン、5,9,13-トリアザヘプタデカン-1,17-ジアミン、5,9,14-トリアザオクタデカン-1,18-ジアミン、4,9,14-トリアザオクタデカン-1,18-ジアミン、5,10,14-トリアザオクタデカン-1,18-ジアミンからなる群から選ばれたものである、請求項１記載の食品組成物。 The polyamine is 4,8,12-triazapentadecane-1,15-diamine, 4,8,12-triazahexadecane-1,16-diamine, 4,9,13-triazaheptadecane-1,17 -Diamine, 4,9,14-triazaoctadecane-1,18-diamine, 5,9,13-triazaheptadecane-1,17-diamine, 5,9,14-triazaoctadecane-1,18- The food according to claim 1, wherein the food is selected from the group consisting of diamine, 4,9,14-triazaoctadecane-1,18-diamine, and 5,10,14-triazaoctadecane-1,18-diamine. Composition.
  15. 　前記ポリアミンが、4,8,12,16-テトラアザノナデカン-1,19-ジアミン、4,8,12,16-テトラアザアイコサン-1,20-ジアミン、4,8,12,17-テトラアザアイコサン-1,20-ジアミン、及び4,8,13,17-テトラアザアイコサン-1,20-ジアミンからなる群から選ばれたものである、請求項１記載の食品組成物。 The polyamine is 4,8,12,16-tetraazanonadecane-1,19-diamine, 4,8,12,16-tetraazaeicosane-1,20-diamine, 4,8,12,17-tetra The food composition according to claim 1, which is selected from the group consisting of azaicosane-1,20-diamine and 4,8,13,17-tetraazaeicosan-1,20-diamine.
  16. 　請求項１～１５のいずれか１項記載の食品組成物からなる、動物の寿命を延長するための飼料組成物。 A feed composition for extending the life of an animal, comprising the food composition according to any one of claims 1 to 15.
  17. 　前記動物が、哺乳類である、請求項１６記載の飼料組成物。 The feed composition according to claim 16, wherein the animal is a mammal.
  18. 　前記動物が、犬、猫、ラット、ハツカネズミ、馬、牛、羊、及び人からなる群から選ばれたものである、請求項１７記載の飼料組成物。 The feed composition according to claim 17, wherein the animal is selected from the group consisting of dogs, cats, rats, mice, horses, cows, sheep, and humans.
  19. 　１日の供与単位に、前記動物の体重１Kgあたり式(1)のポリアミン0.01～1000mgが含まれている、請求項１６～１８のいずれか１項記載の飼料組成物。 The feed composition according to any one of claims 16 to 18, wherein the daily dosage unit contains 0.01 to 1000 mg of polyamine of formula (1) per kg body weight of the animal.
  20. 　１日の供与単位に、前記動物の体重１Kgあたり式(1)のポリアミン0.05～400mgが含まれている、請求項１６～１８のいずれか１項記載の飼料組成物。 The feed composition according to any one of claims 16 to 18, wherein the daily unit contains 0.05 to 400 mg of the polyamine of the formula (1) per kg body weight of the animal.
  21. 　１日の供与単位に、前記動物の体重１Kgあたり式(1)のポリアミン0.05～100mgが含まれている、請求項１６～１８のいずれか１項記載の飼料組成物。 The feed composition according to any one of claims 16 to 18, wherein the daily dosage unit contains 0.05 to 100 mg of polyamine of formula (1) per kg body weight of the animal.
  22. 　動物に、その体重１Kgあたり下記式(1)のポリアミン及びその医薬として許容し得る塩からなる群から選ばれる少なくとも１の化合物0.01～1000mgを投与できるよう、請求項１６～２１のいずれか１項記載の飼料組成物を供与する、動物の寿命を延長する飼育方法：
    　NH2-(CH2)m1-(NH)p1-(CH2)m2-(NH)p2-(CH2)m3-
    　　　　　　(NH)p3-(CH2)m4-(NH)p4-(CH2)m5-NH2    …(1)
    （式中、m1～m5はそれぞれ独立に０～７の整数であって、そのうち少なくとも１つは０よりも大きく、m1＋m2＋m3＋m4＋m5の和は、２以上かつ１８未満であり、かつp1, p2, p3及びp4は、それぞれ独立に０又は１である。）。     The animal of any one of claims 16 to 21, so that the animal can be administered 0.01 to 1000 mg of at least one compound selected from the group consisting of a polyamine of the following formula (1) and a pharmaceutically acceptable salt per kg of the body weight. Breeding methods for extending the lifespan of animals, providing the described feed composition:
    NH 2- (CH 2 ) m1- (NH) p1- (CH 2 ) m2- (NH) p2- (CH 2 ) m3-
    (NH) p3- (CH 2 ) m4- (NH) p4- (CH 2 ) m5 -NH 2 … (1)
    (Wherein m1 to m5 are each independently an integer of 0 to 7, at least one of which is greater than 0, and the sum of m1 + m2 + m3 + m4 + m5 is 2 or more and less than 18, and p1, p2, p3 and p4 is independently 0 or 1.)
  23. 　動物に、その体重１Kgあたり式(1)のポリアミン及びその医薬として許容し得る塩からなる群から選ばれる少なくとも１の化合物0.05～400mgを投与する、請求項２２記載の飼育方法。 The breeding method according to claim 22, wherein the animal is administered with 0.05 to 400 mg of at least one compound selected from the group consisting of the polyamine of formula (1) and its pharmaceutically acceptable salt per kg of its body weight.
  24. 　動物に、その体重１Kgあたり式(1)のポリアミン及びその医薬として許容し得る塩からなる群から選ばれる少なくとも１の化合物0.05～100mgを投与する、請求項２２記載の飼育方法。 The breeding method according to claim 22, wherein the animal is administered with 0.05 to 100 mg of at least one compound selected from the group consisting of the polyamine of formula (1) and its pharmaceutically acceptable salt per kg body weight.
  25. 　前記動物が、犬、猫、ラット、ハツカネズミ、馬、牛、羊、及び人からなる群から選ばれたものである、請求項２２～２５のいずれか１項記載の飼育方法。 The breeding method according to any one of claims 22 to 25, wherein the animal is selected from the group consisting of dogs, cats, rats, mice, horses, cows, sheep, and humans.
  26. 　動物に、その体重１Kgあたり、下記式(1)のポリアミン、及びその医薬として許容し得る塩からなる群から選ばれる少なくとも１の化合物0.01～1000mgを投与することを含む、動物の寿命を延長する飼育方法：
    　NH2-(CH2)m1-(NH)p1-(CH2)m2-(NH)p2-(CH2)m3-
    　　　　　　(NH)p3-(CH2)m4-(NH)p4-(CH2)m5-NH2    …(1)
    （式中、m1～m5はそれぞれ独立に０～７の整数であって、そのうち少なくとも１つは０よりも大きく、m1＋m2＋m3＋m4＋m5の和は、２以上かつ１８未満であり、かつp1, p2, p3及びp4は、それぞれ独立に０又は１である。）。     Prolonging the lifespan of the animal, comprising administering to the animal 0.01 to 1000 mg of at least one compound selected from the group consisting of a polyamine of the following formula (1) and a pharmaceutically acceptable salt thereof per kg body weight: Breeding method:
    NH 2- (CH 2 ) m1- (NH) p1- (CH 2 ) m2- (NH) p2- (CH 2 ) m3-
    (NH) p3- (CH 2 ) m4- (NH) p4- (CH 2 ) m5 -NH 2 … (1)
    (Wherein m1 to m5 are each independently an integer of 0 to 7, at least one of which is greater than 0, and the sum of m1 + m2 + m3 + m4 + m5 is 2 or more and less than 18, and p1, p2, p3 and p4 is independently 0 or 1.)
PCT/JP2009/000223 2008-01-23 2009-01-22 Food composition, feed composition comprising the food composition, and method for feeding animal by using the feed composition WO2009093454A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2009550472A JPWO2009093454A1 (en) 2008-01-23 2009-01-22 Food composition, feed composition containing the food composition, and animal breeding method using the feed composition

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2008-012180 2008-01-23
JP2008012180 2008-01-23

Publications (1)

Publication Number Publication Date
WO2009093454A1 true WO2009093454A1 (en) 2009-07-30

Family

ID=40900964

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2009/000223 WO2009093454A1 (en) 2008-01-23 2009-01-22 Food composition, feed composition comprising the food composition, and method for feeding animal by using the feed composition

Country Status (2)

Country Link
JP (1) JPWO2009093454A1 (en)
WO (1) WO2009093454A1 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010081204A3 (en) * 2009-01-14 2011-04-14 Katholieke Universiteit Leuven Polyamine activators ( s permine, s permidine) of the autophagic pathway
JP2014080408A (en) * 2012-10-18 2014-05-08 Combi Corp Composition including polyamine as active ingredient for promoting tissue regeneration
JP2015081252A (en) * 2013-10-24 2015-04-27 学校法人関西学院 Growth promoter for animals and plants
JP2016117772A (en) * 2016-03-25 2016-06-30 コンビ株式会社 Composition including polyamine as active ingredient for promoting tissue regeneration
JP2016138082A (en) * 2015-01-26 2016-08-04 小川　和宏 Anti-fatigue drug and anti-fatigue food

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004073701A1 (en) * 2003-02-19 2004-09-02 Kuniyasu Soda Lfa-1 inhibitors and use thereof
JP2007291027A (en) * 2006-04-26 2007-11-08 Toyobo Co Ltd Method for preparing polyamine composition from plant
WO2007148739A1 (en) * 2006-06-22 2007-12-27 Toyo Boseki Kabushiki Kaisha Cell activator, anti-aging agent and extracellular matrix production promoter derived from plant
JP2008156330A (en) * 2006-04-26 2008-07-10 Toyobo Co Ltd Activating agent and anti-aging agent

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004073701A1 (en) * 2003-02-19 2004-09-02 Kuniyasu Soda Lfa-1 inhibitors and use thereof
JP2007291027A (en) * 2006-04-26 2007-11-08 Toyobo Co Ltd Method for preparing polyamine composition from plant
JP2008156330A (en) * 2006-04-26 2008-07-10 Toyobo Co Ltd Activating agent and anti-aging agent
WO2007148739A1 (en) * 2006-06-22 2007-12-27 Toyo Boseki Kabushiki Kaisha Cell activator, anti-aging agent and extracellular matrix production promoter derived from plant

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KUNIYASU HAYATA: "Anti-Aging no Honmei= Ko-Polyamine-shoku", NEW FOOD INDUSTRY, vol. 49, no. 2, 2007, pages 1 - 14 *
KUNIYASU HAYATA: "Anti-Aging-shoku Polyamine ni yoru Anti-Aging Natto nado no Hakko Shokuhin ni Taryo ni Fukumareru Busshitsu", SHOKU NO KAGAKU, 2006, pages 20 - 28 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010081204A3 (en) * 2009-01-14 2011-04-14 Katholieke Universiteit Leuven Polyamine activators ( s permine, s permidine) of the autophagic pathway
JP2014080408A (en) * 2012-10-18 2014-05-08 Combi Corp Composition including polyamine as active ingredient for promoting tissue regeneration
JP2015081252A (en) * 2013-10-24 2015-04-27 学校法人関西学院 Growth promoter for animals and plants
JP2016138082A (en) * 2015-01-26 2016-08-04 小川　和宏 Anti-fatigue drug and anti-fatigue food
JP2016117772A (en) * 2016-03-25 2016-06-30 コンビ株式会社 Composition including polyamine as active ingredient for promoting tissue regeneration

Also Published As

Publication number Publication date
JPWO2009093454A1 (en) 2011-05-26

Similar Documents

Publication Publication Date Title
O'Dea Traditional diet and food preferences of Australian Aboriginal hunter-gatherers
NO861673L (en) PROCEDURE FOR PROCESSING A FOOD OR ANIMAL FOOD.
WO2009093454A1 (en) Food composition, feed composition comprising the food composition, and method for feeding animal by using the feed composition
WO2003086100A1 (en) Dietary methods for canine performance enhancement
JP2011528556A (en) Methods for improving the quality of life of older animals
Neog et al. The distribution, economic aspects, nutritional, and therapeutic potential of Swamp Eel Monopterus Cuchia: A Review
Wolf Rodent diet aids and the fallacy of caloric restriction
JP2011502516A (en) Drugs aimed at improving carcass performance in finishing pigs
US20220362287A1 (en) Foods to promote better health and/or to maintain homeostais and method of production thereof
El-Speiy et al. Effect of feed restriction on productive performance, carcass yield, blood pictures and relative organ weights of growing rabbits.
JP2011037811A (en) Fat-decreasing composition
Kurbah et al. Variation of biochemical composition in relation to reproductive cycle of Mud Eel (Monopterus cuchia) under the agro climatic conditions of Meghalaya, India
Rembiałkowska et al. Organic food quality and impact on human health
WO2022203684A1 (en) Foods to promote better health and/or to maintain homeostais and method of production thereof
Biobaku et al. Evaluation of chevon characteristics to assess xylazine and ascorbic acid efficacy in rendering welfare to bucks subjected to long road transportation and stocking stress
KR100531695B1 (en) A method for raising an aquatic and land organism using methyl sulfonyl methane as an agent for enhancing water quality
CN108902478A (en) A kind of composite feed additive and its application for improving Pelteobagrus fulvidraco immunity
WO2018206573A1 (en) Composition comprising stilbenes suitable for enhancing aquaculture productivity
RU2774770C1 (en) Method for increasing weight gain with simultaneous prevention of oxidative stress in broiler chickens
Odutayo et al. Influence of cinnamon (Cinnamomum cassia) powder as additive on jejenal histomophometry, growth performance, haemato-biochemical indices, carcass traits and breast meat lipid profile of broiler chickens
JP2001122717A (en) Antiparasitic and antimicrobial agent for fishes
JP2018019602A (en) Method for improving meat quality of edible animals such as cattle, pigs, horses, deer, whales, and chickens
Noureddine et al. Effects of water stress on zootechnical physiological and blood parameters of Ouled Djellal ewes in Algeria
Iwegbu et al. Effect of Carica papaya Aqueous Leaf Extract on Growth Performance and Blood Characteristics of Weaner Rabbits
Araba et al. Performance, carcass characteristics and meat quality of Timahdite-breed lambs finished on pasture or on hay and concentrate

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09703768

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2009550472

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09703768

Country of ref document: EP

Kind code of ref document: A1