会社案内 【notice】 2023 Year 3 From April, in addition to sales as test materials, PHB started wholesale. Please contact us if you are interested. ​ 株式会社 ビヨンドサイエンス 英語名 ／ Beyond Science Ltd. ​ 所在地／ 東京都 八王子市三崎町 ／Tokyo, Japan ​​代表取締役／ 佐藤千晶 ／Chiaki Satoh 設立年月日／ 2019 年 5 月 30 日 資本金 ／ 633万円 ~~~Email address~~~ beyondscience(AT)polyhydroxyphb.com 送信の際は (AT) を＠に変えてください ​ 主な目的／ ＊ ペットサプリメント、 ヘルシーペットフード、 療法食等の原材料の研究開発 ＊血中のケトン体を低濃度で持続的に増加させる食品 の研究開発 ​＊加工食品の製造販売 ケトバイオティクスの理念 Public Relations Office 【お知らせ２ 】 2023年11 月 ポリヒドロキシ酪酸のペットサプリメント【ラクケト】での​ク ラウドファンディングの募集期間が終了致しました。 ​おかげ様で希望額を上回るご支援を賜りました。​ 本当にありがとうございました。 クラウドファンディング/ Campfire さん​でのページはこちら⇩ https://camp-fire.jp/projects/view/700012?utm_campaign=cp_po_share_c_msg_mypage_projects_show 【お知らせ ３】 2023 年 11 月武内製薬さんのホームページにインタビュー記事を掲載して頂きました。こちらです⇩ https://takeuchi-md.jp/?p=1414&preview=1&_ppp=5e5a99d2fe Break room chocolate pudding recipe PROFILEページ

​Carbohydrate restriction and ketone bodies There are two things you can do to keep your ketones consistently high: 1) Fasting 2) Limit carbohydrates The physiological basis for these two to increase ketone body concentrations is It's all about not inducing blood sugar spikes. Why would suppressing blood sugar spikes lead to a constant increase in ketone body levels? For this you need to understand the hormone "insulin". Insulin secretion is induced by a blood sugar spike, causing a phenomenon called an insulin spike. When an insulin spike occurs, all the enzymes that synthesize ketone bodies are suppressed, and all the ketone body synthesis systems are shut out. normal diet (about60 % carbohydrates), ketone bodies are unlikely to increase. sugar if possible30-40% If you eat a diet that is suppressed to0.2~0.3 I think it goes up to about millimoles. Also, it is said that you can expect various effects of ketone bodies to some extent.

beyond science High Purity-PHB About (polyhydroxybutyric acid) The PHB provided by Beyond Science is the highest level in the world. ​ PHB is now produced in many countries around the world. However, there are a limited number of companies and countries that can produce high-quality and highly safe PHB that can be used in pet food. PHB handled by Beyond Science , Produced in the world's top-level PHB laboratory. ​～ History of high-purity PHB ~ Invention [Delivering ketone bodies to intestinal bacteria] ketobiotics is a rough definition of About six years ago, a Japanese researcher, Mr. S, who was researching ketone bodies, discovered it and named it as a new prebiotic. Mr. S said, ``This will surely be useful for mammals. ’ thought. Already then, ``it is only possible with very pure PHB. I was secretly aware of that. but, PHB is "safe enough for mammals to eat and has little off-taste" companies that deal with couldn't find it no matter how much I searched. At that time, the manufacturing technology/know-how itself There were several research institutes and companies that had Unfortunately, it was far from practical for practical use. First, high-purity PHB was too expensive. In addition, unfortunately, the place with equipment that can mass-produce enough to be released as a product domestically there wasn't one. However, Mr. S did not give up, and next Of overseas I kept looking, turning to the institutes and laboratories. and finally Researching high-purity PHB there is Institute with researchers I immediately contacted him and visited him without delay. When I met him, Mr. G was surprisingly a very friendly person despite being in a high position as a researcher. At the same time, however, Mr. S quickly discovered that he was very intelligent and an outstanding researcher. When I talked to Mr. G himself, the developer, "The hidden potential of high-purity PHB" for ​As expected I had already noticed. It didn't take long for the two to come to terms. the hidden potential talk about for a while They say they didn't run out. ​ in this way Thanks to the miraculous exchanges between these researchers, it is now possible to release high-quality PHBs into the world. Research (world-class laboratories) the Research to realize "high-purity PHB" is Mr. G I went to study abroad in Europe and went there with my friends for more than 10 years. Laboratory after returning to Japan To Together with a group of bright young people, it has been studied for many more years and continues to this day. Manufacture (equipment with advanced technology) The PHB handled by Beyond Science is Specially manufactured in high-tech equipment commissioned by Mr. G's lab. Thorough hygiene control and high In equipment with technology, specially manufactured It is a thing. ​ 《 Photo of highly purified PHB 》 Texture unimaginable with conventional PHB detail. Conventionally, the powder is coarser and has a lot of miscellaneous tastes, In terms of safety, There were various problems for mammals to eat. Only natural products can be refined to this extent thanks to advanced research and advanced technology. ​, and special equipment It is because of 《 ISO9001取得 》 国際標準化機構 (ISO) による品質マネジメントシステム に関する規格の認証を得た設備で製造しています。 シェア

​What is a ketone donor? To better understand ketone donors, let us first define the concept of "degree of polymerization (N)". "Degree of polymerization" refers to how many ketone bodies (or equivalents) are contained in the molecule, That's what it means. ​ N=1 means ketone body (3R-hydroxybutyric acid) itself. Ketone bodies alone are strong acids (like acetic acid), so sodium salts of ketone bodies are used. ​It has too much of a peculiar flavor to eat. Therefore, free ketone bodies are rarely used, A compound obtained by neutralizing ketone bodies with sodium hydroxide may be used. ​ Next is the ketone ester (N=2), which is an ester of a ketone body and an alcohol. The beauty of this is that it is hydrolyzed by mammalian digestive enzymes. In other words, when ketone esters are eaten, they are immediately hydrolyzed in the small intestine, and ketone bodies can be rapidly increased. It is used in certain places such as among athletes (mostly in the research stage), but it is characterized by a unique taste (flavor like glue). ​ In contrast, PHB / polyhydroxybutyric acid (N > 1000) is not hydrolyzed by mammalian enzymes, but is hydrolyzed by intestinal bacterial enzymes. In this case, it is conceivable that a constant ketone body concentration will persist. Although it has not yet been approved for humans, it is expected to be used to maintain the health of pets and industrial animals. ​Classification of ketone donors The criteria for classifying ketone donors is how many ketone bodies are released. It is indicated by the value of the degree of polymerization N. ​ Ketone bodies release 1 ketone body itself. →→ N=1 A ketone ester is one ketone body and one equivalent. →→ N=2 Oxidized in the body to ketone bodies. PHB is a polymer in which 1000 or more ketone bodies are ester-bonded. →→ N>1000 It is broken down by intestinal bacteria and gradually released into ketone bodies. It allows you to maintain a constant ketone body concentration. "Ketone Donor 1: Ketone Body Salt" Ketone bodies (chemical formula 1), also called 3-beta-hydroxybutyrate, are organic acids and one of the most important energy substrates. Since ketone bodies are weak acids as weak as acetic acid, they are usually used as sodium or arginine salts. These salts readily ionize in aqueous solutions. Ketone bodies mostly exist as ions in the weakly alkaline environment of the small intestine and are readily and rapidly absorbed into the body via specific monocarboxylic acid transporters. However, eating ketone bodies by themselves is not a good idea. A single ketone body is a strong acid, and it is impossible to eat several tens of grams of it as it is because of its strong stimulation. Ketone salts (eg, sodium salts) can be eaten up to tens of grams, but sodium loading becomes a problem. In general, ketone bodies are very hydrophilic and are very difficult to precipitate, requiring know-how to precipitate salts, and high-purity products are said to be expensive. "Ketone Body Absorption Mechanism" In order to increase blood ketone body concentration, ketone bodies themselves may be orally administered. In this case, since the ketone body itself is acidic, a sodium salt or the like of the ketone body is used. Ketone body salts become free acids in the acidic environment of the stomach and are transported into the body by a specific transporter (monocarboxylic acid transporter) in the epithelium of the small intestine. To increase. ​ "Ketone Donor 2: Ketone Ester" The formal name of the ketone ester (chemical formula 2) is 3-hydroxybutyl-3-hydroxybutyrate, which is a synthetic compound in which the ketone body of an organic acid having a carboxylic acid and an alcohol are ester-bonded. Since this ester bond is rapidly decomposed by esterase in the small intestine, the ketone body ionizes and exists in the form of an anion in the small intestine, which is in a weakly alkaline environment. Like ketone bodies, it is readily absorbed by the body via specific monocarboxylic acid transporters. Also, the ester-bonded alcohol is oxidized to a carboxylic acid and converted to a ketone body. Since the sodium salt of ketone bodies poses a problem of sodium loading, arginine salts and the like have been devised, but there are problems such as further increase in cost. To solve this problem, ketone esters were devised. A ketone ester is a form of an ester bond between a ketone body and 1,3-butanediol. It is broken down by digestive enzymes in the small intestine to produce ketone bodies. Ketone bodies are absorbed by specific transporters in the small intestinal epithelium and exert various health functions. "Absorption Mechanism of Ketone Esters" Mammals also have enzymes that hydrolyze the ester bond of ketone esters, and they can rapidly (within minutes) produce ketone bodies in high concentrations. Ketone esters are broken down by digestive enzymes in the small intestine to produce ketone bodies. Ketone bodies are absorbed by a specific transporter (monocarboxylic acid transporter) in the small intestinal epithelium, rapidly increasing the concentration of ketone bodies. Like ketone body salts, ketone esters also have an immediate effect, increasing the blood ketone body concentration to several mM in several minutes. "Ketone donor 3:PHB" PHBs (Polyhydroxybutyrate) is a compound in which a ketone body is polymerized by an ester bond (average degree of polymerization: about 2000), and this ester bond cannot be hydrolyzed by mammalian esterases.PHBs can be hydrolyzed by only some intestinal bacteria, which makes it behave differently than other ketone donors. In addition, whereas ketone bodies and ketone esters are highly hydrophilic,PHBs One of the characteristics is that the hydrophilicity is extremely low. "PHB absorption mechanism" PHB is decomposed into ketone bodies by the lipase of intestinal bacteria in the large intestine, absorbed from the large intestine epithelium of animals, and has the effect of contributing to the maintenance of ketone body concentration. シェア

chocolate pudding recipe Ally of carbohydrate restriction Low sugar sweets chocolate pudding RECIPE * 1 can of coconut milk (400g) *A little less than 1g of powdered agar (around 0.8g) (For gelatin, 6 g → Soak in water and mix at the end.) * Sweetener 25g → Lakanto or coconut sugar (8 g for stevia) ＊Black cocoa 25g ***Add a little whiskey, rum, etc. for flavor. ​ ~Precautions during cooking: Be sure to stay by your side so that it doesn't boil over~ ​ ① Pour coconut milk into a small pan, sprinkle agar powder, Cook over medium-low heat, stirring occasionally. (Stay close so it doesn't squirt!) Add sweetener halfway through. ② When it boils, turn off the heat and strain the cocoa. (Miso strainer is convenient!) Let it rest for about 2 minutes on the lowest heat, stirring occasionally. ③ Turn off the heat and leave it for about 10 minutes. (To prevent burns...) → Transfer to a bowl while straining. ​ How to make ① How to make ② ​ ④ Divide into 5-6 cups before it cools down. ⑤ After it cools further, chill it in the refrigerator for about an hour. ​ (Make a bamboo skewer between the cup and the pudding and then put it on the plate.) ​ *** If you use 35 g of cocoa, it's more like a chocolate pudding. It will make a rich chocolate mousse. ＊＊＊＊ *** Substitute 13 g of matcha for a rich matcha mousse instead of cocoa. Topped with sweet red bean paste. . . ＊＊＊＊ ​ Coconut milk is the source of MCT oil, Because it contains a large amount of medium-chain fatty acids, it can easily be used as an energy source, and can also be expected to increase ketone bodies. On top of that, as long as it contains minerals such as potassium and magnesium, as well as vitamin E and vitamin C! _cc781905-5cde-3194-bb 3b-136bad5cf58d_ just at once Please don't eat too much! ONE POINT Take a break! for the time of bittersweet

腸内細菌叢と脳の関係 幸せホルモンとして知られるセロトニンは以下のように合成されます。 トリプトファン→①→水酸化トリプトファン→②→セロトニン トリプトファンは腸内で蛋白質が加水分解して生成しますが、これが小腸上皮から吸収されて、その上皮細胞が水酸化して水酸化トリプトファンを作るとされています。すなわち幸せホルモンは腸内で水酸化トリプトファンが生成することが前提となります。トリプトファン水酸化は腸内環境の影響を受けやすく、強いストレスがかかると腸内環境が悪化し、水酸化トリプトファンの生成量が十分ではなくなります。従って腸内環境が悪化すると脳で十分な量の幸せホルモンが生産できないことになります。さらに糞便移植（FMT）で腸内細菌を移植するとうつ病が改善されるという報告があり、この仮説はかなりの支持を得ています。 文献 O'Mahony SM, Clarke G, Borre YE, Dinan TG, Cryan JF. Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav Brain Res. 2015 Jan 15;277:32-48. Roth W, Zadeh K, Vekariya R, Ge Y, Mohamadzadeh M. Tryptophan Metabolism and Gut-Brain Homeostasis. Int J Mol Sci. 2021 Mar 15;22(6):2973. Jenkins TA, Nguyen JC, Polglaze KE, Bertrand PP. Influence of Tryptophan and Serotonin on Mood and Cognition with a Possible Role of the Gut-Brain Axis. Nutrients. 2016 Jan 20;8(1):56.

【お問合せフォーム】 メッセージを送信いただければ、折り返しご連絡いたします。 メールアドレス（必須項目） お名前／苗字のみお願いいたします。（必須項目）） お問合せ内容／簡単にご記入ください（必須項目） 送信 お問合わせフォームへご記入頂き、ありがとうございました。 後ほどメールにてご連絡させていただきます。 しばらくお待ちいただけますとありがたく存じます。

安全性試験 ペットフード安全性検査 合格 PHB（ポリヒドロキシ酪酸） 安全性試験の結果 急性毒性・亜急性毒性検査 所見なし（合格） ポリヒドリキシ酪酸 2%混合ペレット飼料： ラットへの試食による 単回経口投与毒性試験【急性毒性試験】 試験結果 死亡はみられず、最小致死量は雌雄ともに5000 mg/kgを上回ると推定された。 雌雄ともにいずれ にも一般状態の異常はみられなかった。 雌雄ともに被験物質投与による体重への影響はみられなかった。 ​ ※本試験は以 下のガイドラインに準拠して実施した。 • 「動物の愛護及び管理に関する法律」 • 「実験動物の飼養及び保管並びに苦痛の軽減に関する基準」 • 「動物実験の適正な実施に向けたガイドライン」 ​※ 本試験は動物実験委員会（IACUC）の承認を受けて実施した​。 ポリヒドリキシ酪酸 2%混合ペレット飼料： ラットへの試食による 4 週間混餌投与毒性試験【亜急性毒性試験】 試験結果 一般状態 一般状態の異常はみられなかった。 体重 体重への影響はみられなかった。 摂餌量 摂餌量への影響はみられなかった。 尿検査（摂水量測定含む） 被験物質投与による影響はみられなかった。 血液学検査 被験物質投与による影響はみられなかった。 血液化学検査 被験物質投与による影響はみられなかった。 器官重量 被験物質投与による影響はみられなかった。 病理組織学検査 被験物質投与に起因する変化はみられなかった。 小核試験 被験物質投与群のPCE2000個中に占めるMNPCEの出現頻度は3 ± 2であった。こ の値は対照群の値に 統計学的に有意な増加を示さなかった。 本試験条件下では 被験物質の染色体異常誘発能は陰性と判定した。 PHB( ポリヒドロキシ酪酸 ) 安定性試験 （加速試験） ​の 結果

Diverse effects of ketogenic and ketogenic diets first, Ketone bodies that are naturally present in the body what kind of work does it have? In recent years, researchers have reported various effects. In papers and patents on the Ketogenic diet Emerging physiology of ketone bodies As The main ones are: (1) (2) Suppression of oxidative stress (3) (4) (5) (6) Suppression of inflammatory response (7) improving kidney function ​ and so on. ​ ** However, most of these papers are data obtained from mice, ​other animals and I don't know yet if it applies to humans. ** Clarified in patents and papers on the ketogenic diet The main physiological functions of ketone bodies are as follows. (1) Decrease in blood sugar level (2) Suppression of oxidative stress (3) anticancer effect (4) Protective effect on nerve cells (inhibition of epileptic seizures, etc.) (5) Reduction of blood fatty acids (6) suppression of inflammatory response (7) improvement of kidney function ​ ​ "Blood sugar level spike suppression effect" ​ Diabetes is chronically high blood glucose levels caused by excessive glucose in the blood. If left untreated, arteriosclerosis progresses and blood vessels become more susceptible to damage. My blood sugar fluctuates all the time and I was diagnosed with diabetes. It is not uncommon for postprandial blood glucose levels to be 140 mg/dL or higher, even in people who do not. This rise in blood sugar level for about 1 to 2 hours after eating before falling into a state of constant high blood sugar level is called "blood sugar level spike". Controlling "blood sugar level spikes," in which blood sugar levels rise sharply in a short period of time after meals, is the basis of dietary habits to prevent diabetes. Ketone bodies are It is known to strongly suppress blood sugar level spikes. That is, ketone bodies are known to activate their receptor HCAR2 and promote the uptake of glucose into tissues (eg, skeletal muscles of the arms and legs). “Acquisition of resistance to oxidative stress (active oxygen)” Cell survival depends on mitochondrial energy metabolism, but at the same time, it is thought that it is endangered by reactive oxygen species generated from this. Almost all cells have enzymes that remove active oxygen by themselves. Their expression is regulated at the gene level. One such regulation that occurs at the gene level is histone acetylation. When histones are acetylated, enzymes that scavenge active oxygen are produced more and more, and resistance to oxidative stress can be acquired. The presence of ketone bodies at this time promotes acetylation and can further enhance resistance to active oxygen. A group from the University of Tokyo School of Medicine clarified the mechanism (published in 2013 / US scientific journal Science), and found that ketone bodies bind to histone deacetylase and inhibit it (release the inhibition of histone acetylation). rice field. "Protection of nerve cells" Direct administration of ketone bodies to cultured rat hippocampal cells reduced cell death caused by addition of amyloid-β, and similarly, in cultured midbrain cells, it prevented cell destruction by free radicals produced by Parkinson's disease (PK) causative agents. understood. Ketone bodies have the effect of activating gene expression by inhibiting histone deacetylase, a nuclear protein that binds to DNA and regulates gene expression. Ketone bodies act as regulators of gene expression and induce a group of enzymes that remove active oxygen. Ketone bodies thus protect nerve cells. The ketogenic diet may be one of the mechanisms by which neurodegenerative diseases associated with oxidative stress such as Parkinson's disease and Alzheimer's disease are effective. “Neural cell membrane stabilization effect” Ketone bodies have the effect of stabilizing the membrane potential of nerve cells and suppressing abnormal excitation. Ketone bodies activate ATP-dependent potassium channels, lower membrane potential, and suppress neuronal abnormal excitation. This is the molecular mechanism by which the ketogenic diet suppresses epileptic seizures. However, the membrane potential stabilizing effect of ketone bodies on nerve cells requires an increase in concentration to at least the mM order, and a thorough ketogenic diet is required. It has been known for more than 100 years that the ketogenic diet is highly effective against intractable epilepsy, but the reason why it is not widely used in clinical practice is that this thorough ketogenic diet is necessary. There is a cause. However, since ketone bodies have the function of maintaining a wide variety of brain functions normally, a ketogenic diet that can increase ketone bodies to the mM order is effective in preventing or treating various neurodegenerative diseases. It is believed that there is. "Cancer suppression effect" Ketone bodies suppress the growth of cancer cells and have the effect of regressing cancer. Cancer cells use only glycolysis to proliferate (Warburg effect). In other words, even if mitochondria exist in cancer cells, they are hardly utilized, and most of the energy substrates they need use glycolysis. mitochond Cancer cells are known to undergo apoptosis or stop growing under conditions where ketone bodies and other organic acids, which can act directly on the rear, predominate. In addition to acting as an energy substrate for ketone bodies, it has been suggested that ketone bodies may inhibit cancer cell growth through activation of the HCAR2 receptor, inhibiting the growth of many types of cancer cells. reported to do. "Adjuvant action" Of particular interest in the cancer-suppressing action of ketone bodies are gliomas. Gliomas are characterized by the following two characteristics. One is that radiotherapy is possible due to its low invasiveness. The other is that most anticancer drugs cannot pass through the blood-brain barrier, so they have little effect on gliomas. On the other hand, ketone bodies are highly transmissible to the brain, and 20-30% of ketone bodies are translocated to the brain. In this sense, the combination of radiotherapy and ketone bodies is a combination with high clinical expectations. Against this background, cancer adjuvant action has attracted attention as a prominent action of the ketogenic diet. We found that irradiation of mouse gliomas significantly improved mouse survival, but radiation plus a ketogenic diet improved mouse survival even more. The effect of ketone bodies on inhibiting the growth of cancer cells is not limited to gliomas, but is observed in many cancer cells, so this report is noteworthy in terms of the effective use of ketone bodies as food in the medical science field. It can be said that the ketogenic diet is effective as a means for significantly enhancing the therapeutic effects of 1) chemotherapy, 2) radiation therapy and 3) surgical therapy, which are the most basic therapies for cancer. Focusing on this adjuvant action, clinical trials for cancer treatment are being conducted in various countries. ​ ​​ " Neutral fat lowering effect" ​ When a healthy person follows a ketogenic diet, the concentration of ketone bodies in the blood increases. It activates mitochondrial metabolism throughout the body (especially in skeletal muscle). Therefore, in skeletal muscle, the function shifts in the direction of producing energy (by decomposing fat). The amount of triglycerides taken up from the blood by skeletal muscles is increased, and blood glycerol (triglycerides) is significantly reduced. metabolism like this The shift in is an energy shift to permanently eliminate obesity. Conceivable. "Anti-inflammatory action" Ketone bodies suppress chronic inflammation. That is, ketone bodies It suppresses the function of the protein NLRP3, which is a component of the protein complex necessary to continuously promote sexual inflammation, and suppresses chronic inflammation. In addition, ketone bodies have the ability to activate HCAR2, a receptor for some organic acids, suppress various inflammatory reactions, and consequently suppress cancer. From these basic studies, it can be easily inferred that ketone bodies have inhibitory effects on pathological conditions involving inflammatory reactions such as ulcerative colitis, colon cancer, rheumatism, arteriosclerosis, and obesity. ​ “Renal function improving effect” A group at Shiga University of Medical Science has revealed that ketone bodies activate autophagy and suppress diabetic nephropathy. (Published in July 2020 / American scientific journal Cell Metabolism) ​ In experiments with mice, administration of a ketone body precursor (1,3-butanediol: 1,3-BD) ameliorated the increase in serum cystatin C and tissue damage, which indicate increased renal dysfunction in a diabetes model. Feeding a substance (butanediol *1) that converts to ketone bodies in the liver decreases the protein cystatin C in the blood, which indicates a decline in renal function. Therefore, it can be expected to improve the symptoms of diabetic nephropathy in humans as well. ​ *For citation sources, please refer to the references below. *1 / Explain butanediol. 1,3-butanediol (a ketone body precursor) is oxidized in the liver to produce 3-hydroxybutyrate (a ketone body), which enters the systemic circulation. Physiological functions of ketone esters "Lipolysis by ketone ester diet" David Veech et al. tested mice on synthetic keto 60% of their regular diet carbohydrates. (2012) observed the effects of feeding mice on a ketone ester diet replaced with amine esters. The effect of the ketone ester diet on mice is remarkable, blood ketone body concentration increases 5-3 times compared to the ketone diet, and the mitochondria of brown adipose tissue develop and show a clear internal structure after 1 month of breeding. become. In other words, it was shown that ketone esters increase the concentration of ketone bodies, induce the decomposition of visceral fat, and markedly suppress obesity. Increased uncoupling proteins that promote mitochondrial thermogenesis and accelerated breakdown of intracellular lipids. Uncoupling proteins also increase in subcutaneous adipose tissue, contributing to fat loss. “Anti-dementia effect of ketone ester diet” David Veech and colleagues found that feeding mice with Alzheimer's disease a ketone ester diet improved cognitive function. Amyloid-β and phosphorylated tau protein, which are said to be involved in neuronal degeneration, are reduced. Although it is an animal experiment, since ketone bodies improve cognitive behavioral lesions in Alzheimer's disease A, ketone bodies are expected to have similar effects in Alzheimer's disease in humans. “Improving endurance with a ketone ester diet” A study of ketone esters by Kieren Clark et al. It can be said that it is the biggest breakthrough in several years. Drinking Ketone Ester Beverages Therefore, it was reported that the athlete's endurance and record were significantly improved. Historically, carb-loading has been used before endurance training for athletes. Although it was normal to ingest carbohydrates, this actually lowered the record, Only the ketone ester intake group showed significant improvement in recording. Moreover, this effect is immediate Effective and detectable tens of minutes after ingestion. In addition, intake of ketone esters Therefore, it was also found that the decomposition of visceral fat is rapidly promoted. until then ketones There have been many reports that the functions of the body have an immediate effect on the brain, but this report Thus, it was shown for the first time that athletes' endurance also improved rapidly. ​ References [Prior art documents] [Patent document] [Patent document 1] JP 2018-166481 [Patent document 2] JP 2018-000073 [Patent Document 3] JP 2017-071644 [Patent Document 4] JP 2018-138549 [Patent Document 5] Special table 2015-514104 [Patent Document 6] W2005/021013 [Patent Document 7] WO2019035486A1 [Patent Document 8] JP 2010-168595 [Patent Document 9] JP 2012-72148 [Patent Document 10] W2008/120778 [Non-Patent Literature] Nakatani T, Yasuda K, Ozawa K, Tobe T. Changes in blood glucose levels in relation to blood ketone body ratio following hypertonic glucose infusion in 70% hepatectomized rabbits. Eur Surg Res. 1984;16(5):303-311. doi : 10.1159/000128423 [Non-Patent Literature] Shimazu T, Hirschey MD, Newman J, et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. 2013;339(6116):211-214. doi:10.1126/science.1227166 [Non-Patent Literature] Tomita I, Kume S, Sugahara S, et al. SGLT2 Inhibition Mediates Protection from Diabetic Kidney Disease by Promoting Ketone Body-Induced mTORC1 Inhibition [published online ahead of print, 2020 Jul 19]. Cell Metab. 2020;S1550-4131(20 )30358-2. doi:10.1016/j.cmet.2020.06.020 [Non-Patent Literature] Fery F, Bourdoux P, Christophe J, Balasse EO. Hormonal and metabolic changes induced by an isocaloric isoproteinic ketogenic diet in healthy subjects. Diabete Metab. 1982;8(4):299-305. [Non-Patent Document 1] Evidence that supports the prescription of low-carbohydrate high-fat diets: a narrative review. Noakes TD, Windt J. Br J Sports Med. 2017 Jan;51(2):133-139. [Non-Patent Document 2] Nutritional Ketosis for Weight Management and Reversal of Metabolic Syndrome. Gershuni VM, Yan SL, Medici V. Curr Nutr Rep. 2018 Sep;7(3):97-106. [Non-Patent Document 3] Analysis of energy restriction and physical activity on brain function: the role of ketone body and brain-derived neurotrophic factor. Park CH, Kwak YS. J Exerc Rehabil. 2017 Aug 29;13(4):378- 380. [Non-Patent Document 4] How Can a Ketogenic Diet Improve Motor Function? Veyrat-Durebex C, Reynier P, Procaccio V, Hergesheimer R, Corcia P, Andres CR, Blasco H. Front Mol Neurosci. 2018 Jan 26;11:15. [Non-Patent Document 5] Role of Ketogenic Diets in Neurodegenerative Diseases (Alzheimer's Disease and Parkinson's Disease). Włodarek D. Nutrients. 2019 Jan 15;11(1). [Non-Patent Document 6] The ketogenic diet as a potential treatment and prevention strategy for Alzheimer's disease. Broom GM, Shaw IC, Rucklidge JJ. Nutrition. [Non-Patent Document 7] Ketogenic dietary therapies for epilepsy and beyond. deCampo DM, Kossoff EH. Curr Opin Clin Nutr Metab Care. 2019 Apr 24. [Non-Patent Document 8] 2-Deoxyglucose and Beta-Hydroxybutyrate: Metabolic Agents for Seizure Control. Rho JM, Shao LR, Stafstrom CE. Front Cell Neurosci. 2019 Apr 30;13:172. [Non-Patent Document 9] Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer's disease: a randomized, double-blind, placebo-controlled, multicenter trial. Henderson ST, Vogel JL, Barr LJ, Garvin F, Jones JJ, Costantini LC. Nutr Metab (Lond). 2009 Aug 10;6:31. [Non-Patent Document 10] Medical foods for Alzheimer's disease. Shah RC. Drugs Aging. 2011 Jun 1;28(6):421-8. [Non-Patent Document 11] Potential Synergies of β-Hydroxybutyrate and Butyrate on the Modulation of Metabolism, Inflammation, Cognition, and General Health. Cavaleri F, Bashar E. J Nutr Metab. 2018 Apr 1. [Non-Patent Document 12] β-Hydroxybutyrate: A Signaling Metabolite. Newman JC, Verdin E. Annu Rev Nutr. 2017 Aug 21;37:51-76. [Non-Patent Document 13] Biomarkers, ketone bodies, and the prevention of Alzheimer's disease. VanItallie TB. Metabolism. 2015 Mar;64(3 Suppl 1):S51-7. [Non-Patent Document 14] Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, Le Moan N, Grueter CA, Lim H, Saunders LR, Stevens RD, Newgard CB, Farese RV Jr, de Cabo R, Ulrich S, Akassoglou K, Verdin E. Science. 2013 Jan 11;339(6116):211-4. [Non-Patent Document 15] Epilepsy treatment. Targeting LDH enzymes with a stiripentol analog to treat epilepsy. Sada N, Lee S, Katsu T, Otsuki T, Inoue T. Science. 2015 Mar 20;347(6228):1362-7. [Non-Patent Document 16] Ketone Bodies as Anti-Seizure Agents. Simeone TA, Simeone KA, Rho JM. Neurochem Res. 2017 Jul;42(7):2011-2018 [Non-Patent Document 17] Tumor Metabolism, the Ketogenic Diet and βHydroxybutyrate: Novel Approaches to Adjuvant Brain Tumor Therapy. Woolf EC, Syed N, Scheck AC. Front Mol Neurosci. 2016 Nov 16;9:122. [Non-Patent Document 18] The influence of ketogenic therapy on the 5 R's of radiobiology. Klement RJ. Int J Radiat Biol. 2019 Apr;95(4):394-407. [Non-Patent Document 19] The ketogenic diet is an effective adjuvant to radiation therapy for the treatment of malignant glioma. Abdelwahab MG, Fenton KE, Preul MC, Rho JM, Lynch A, Stafford P, Scheck AC. PLoS One. 2012;7 (5): e36197. [Non-Patent Document 20] Tumor Metabolism, the Ketogenic Diet and β-Hydroxybutyrate: Novel Approaches to AdjuvantBrain Tumor Therapy. Woolf EC, Syed N, Scheck AC. Front Mol Neurosci. 2016 Nov 16;9:122. [Non-Patent Document 21] The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, D'Agostino D, Planavsky N, Lupfer C, Kanneganti TD, Kang S, Horvath TL, Fahmy TM, Crawford PA, Biragyn A, Alnemri E, Dixit VD. Nat Med. 2015 Mar;21(3):263-9. [Non-Patent Document 22] The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages. Rahman M, Muhammad S, Khan MA, Chen H, Ridder DA, Müller-Fielitz H, Pokorná B, Vollbrandt T, Stölting I, Nadrowitz R 2014 May 21;5:3944. [Non-Patent Document 23] Ketone esters increase brown fat in mice and overcome insulin resistance in other tissues in the rat. Veech RL. Ann NY Acad Sci. 2013 Oct;1302:42-48. [Non-Patent Document 24] A ketone ester diet exhibits anxiolytic and cognition-sparing properties, and lessens amyloid and tau pathologies in a mouse model of Alzheimer's disease. Kashiwaya Y, Bergman C, Lee JH, Wan R, King MT, Mughal MR, Okun E, Clarke K, Mattson MP, Veech RL. Neurobiol Aging. 2013 Jun;34(6):1530-9. [Non-Patent Document 25] Nutritional Ketosis Alters Fuel Preference and Adverse Endurance Performance in Athletes. Cox PJ, Kirk T, Ashmore T, Willerton K, Evans R, Smith A, Murray AJ, Stubbs B, West J, McLure SW, King MT , Dodd MS, Holloway C, Neubauer S, Drawer S, Veech RL, Griffin JL, Clarke K. Cell Metab. 2016 Aug 9;24(2):256-68. [Non-Patent Document 26] Mitochondrial biogenesis and increased uncoupling protein 1 in brown adipose tissue of mice fed a ketone ester diet. Srivastava S, Kashiwaya Y, King MT, Baxa U, Tam J, Niu G, Chen X, Clarke K, Veech RL. FASEB J. 2012 Jun;26(6):2351-62. [Non-Patent Document 27] Ketone Bodies and Exercise Performance: The Next Magic Bullet or Merely Hype? Pinckaers PJ, Churchward-Venne TA, Bailey D, van Loon LJ. Sports Med. 2017 Mar;47(3):383-391. [Non-Patent Document 28] Ketone body metabolism and cardiovascular disease. Cotter DG, Schugar RC, Crawford PA. Am J Physiol Heart Circ Physiol. 2013 Apr 15;304(8):H1060-76. [Non-Patent Document 29] Ketoacids? Good medicine? Cahill GF Jr, Veech RL. Trans Am Clin Climatol Assoc. 2003;114:149-6. [Non-Patent Document 30] Ketone bodies, potential therapeutic uses. Veech RL, Chance B, Kashiwaya Y, Lardy HA, Cahill GF Jr. IUBMB Life. 2001 Apr;51(4):241-7. [Non-Patent Document 31] On the Metabolism of Exogenous Ketones in Humans. Stubbs BJ, Cox PJ, Evans RD, Santer P, Miller JJ, Faull OK, Magor-Elliott S, Hiyama S, Stirling M, Clarke K. Front Physiol. 2017 Oct 30;8:848. [Non-Patent Document 32] A Ketone Ester Drink Lowers Human Ghrelin and Appetite. Stubbs BJ, Cox PJ, Evans RD, Cyranka M, Clarke K, de Wet H. Obesity (Silver Spring). 2018 Feb;26(2):269 -273

Mechanism of “longevity bacteria” Why does butyric acid provide longevity? This is because when the concentration of butyric acid increases in the large intestine, it changes the entire mammalian immune system. In other words, a butyric acid-dominant intestinal environment has a great positive effect on the whole body. An increase in butyric acid concentration in the large intestine affects the immune system of mammals. This Peyer's patch differs greatly in structure and function from other colonic epithelia. 1) It can pass butyric acid in the large intestine. 2) Concentrated antigen-presenting cells (macrophages) and immunocompetent cells (T cells) These two points. This allows colonic butyrate to directly impact macrophage and T-cell function. So what are the implications? This is what promotes the differentiation of regulatory T cells. Due to the presence of Peyer's patches, increased butyrate concentrations result in an increased number of regulatory T cells. These regulatory T cells have the effect of suppressing excessive immune responses in mammals and restoring them to a normal state. For example, Philippe Langella's group found that Faecalibacterium prausnitzii cultured and reintroduced into the gut of mice with ulcerative colitis and Crohn's disease ameliorated these conditions. This effect has been shown to be mediated by an increase in regulatory T cells. Many immune disorders involve excessive activation of helper T cells. Regulatory T cells suppress this abnormal activation. It is said that this suppresses excessive immunity and improves the disease condition. Longevity village and butyric acid bacteria Mr. Metchnikoff researched longevity villages, extracted their common eating habits, and found that they ate yogurt almost every day. was over 100 years ago. Since then, many scholars have speculated that gut bacteria may be the key to healthy longevity. Analysis using the latest technology such as the microbiome has revealed that butyric acid bacteria are also very important for maintaining a healthy intestinal environment. The microbiome revealed that Faecalibacterium prausnitzii, one of the butyric bacteria, was greatly reduced in patients with Crohn's disease. ​Butyric acid bacteria and Treg cells ​acetic acid, lactic acid, propionic acid The ideal environment in the intestine is slightly acidic. In order to maintain weak acidity, it is necessary to produce acidic substances (lower fatty acids) from intestinal bacteria, and there are mainly 4 types of lower fatty acids. That is, acetic acid (carbon number C=2), lactic acid (C=3), propionic acid (C=3), butyric acid (C=4). A ketone body is a hydroxylated carbon at the 3-position of butyric acid. Many intestinal bacteria have the ability to produce these lower fatty acids, but which lower fatty acids are preferentially produced and released outside the bacterial body is determined by the type of intestinal bacteria. Intestinal bacteria that predominantly produce acetic acid, lactic acid, propionic acid, and butyric acid are called acetic acid bacteria, lactic acid bacteria, propionic acid bacteria, and butyric acid bacteria, respectively. Butyric acid bacteria are “longevity bacteria” This pioneering work was followed by a series of reports on the health benefits of butyric acid bacteria. At the 22nd Annual Meeting of the Society of Enterobacteriology held in 2018, it was reported that ``a large amount of butyric acid bacteria was detected when analyzing the intestinal bacteria of elderly people living in areas with many longevity''. It was reported that there was a difference when comparing the intestinal microflora of Kyoto City (control) residents and Kyotango City residents (there are significantly more long-lived people). (From research by Dr. Yuji Naito, Kyoto Prefectural University of Medicine) In other words, residents of Kyotango City have significantly more butyric acid bacteria such as Rosebria and Lactococcus. Based on this report, it was proposed to call butyric acid bacteria "longevity bacteria". In other words, creating a butyric acid-dominant intestinal environment may be one of the basics of anti-aging. ​ [reference paper] Naito Y, Takagi T, Inoue R, Kashiwagi S, Mizushima K, Tsuchiya S, Itoh Y, Okuda K, Tsujimoto Y, Adachi A, Maruyama N, Oda Y, Matoba S. Gut microbiota differences in elderly subjects between rural city Kyoto and urban city Kyoto: an age-gender-matched study. J Clin Biochem Nutr. 2019 Sep;65(2):125-131.