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Differences between “prime aging” and “anti-aging”


Prime aging and intestinal microflora

Intestinal microflora

In the third essay, I would like to talk about intestinal flora.
Approximately 100 to 1000 trillion intestinal bacteria, which are roughly categorized into 50 to 1000 species, are alive in the intestine, forming intestinal flora. The large intestine, especially has a large number of intestinal bacteria, among the digestive tract organs. The intestinal flora remarkably varies among age groups or individuals. A fetus in the womb is kept in a sterile environment, and gets into contact with bacteria while going through the birth canal during the delivery. After 4 or 5 days from the birth, lactic acid bacilli and bifidobacteria begin to grow. After their middle ages, their numbers turn to decrease, and Clostridium perfringens instead increase. Clostridium perfringens are categorized into Proteus that spoil proteins to produce toxic substances such as ammonia, amines, phenols, and indole, which include carcinogens. Although most of them are broken down at the liver, they have systemic harmful effects when their synthesis exceeds the capacity of the liver.
Why are intestinal bacteria necessary for us? It is because they promote growth of Peyer’s patches and intestinal mucosal lymph nodes that promote activities and regulation of the complex immune mechanisms. In a sterile mice model, in fact, the lymphatic system, including Peyer’s patches and spleen, develops poorly, and the number of IgA- producing plasma cells and epithelial lymphocytes in the intestinal lamina propria are significantly reduced. In other words, intestinal bacteria can be regarded to play an important role in organizing the mucosal and systemic immune system. The mucous layer of the large intestine consists of inner layers and outer layer. The inner layer is organized in a stratified manner by the secreted mucin, while the outer layer is movable and has an expanded volume. Intestinal bacteria can reach the outer layers, but not the inner layer. Therefore, the mucous layer luminal surface maintains a variety of bacteria such as Bacteroides, Bifidobacterium, Streptococcus, Enterobacta, Clostridium, Lactobacillus, and Luminococcus. Dietary fiber encourages butyric- acid production, which is used as energy for epithelial cells that exerts anti-inflammatory effects mediated by stimulating T cells and suppressing NF-kB. Therefore, insufficient intake of dietary fiber leads to invasion of antigen through thinner mucus layer, which causes inflammation. In recent years, in order to further proceed studies of intestinal flora, analysis methods of bacterial genes have been developed, along with culturing methods of bacterium itself. These progresses of research methods have revealed the relationship between intestinal flora and diseases. It has been clearly shown that intestinal flora is involved in development of inflammatory bowel disease, obesity, diabetes, colon cancer, autism, and atherosclerosis, and other diseases.

Single-chain fatty acids (SCFA) produced by intestinal bacteria

Short-chain fatty acids (SCFA) produced by intestinal flora are raising concerns in recent years as one of the causes for lifestyle-related diseases. The SCFAs including propionic acids and butyric acids, are produced in various parts of the intestinal tracts. Free fatty acid receptor (free fatty acid receptor: FFAR), which is G protein-coupled receptors (G protein-coupled receptor: GPR) plays a role as a receptor for SCFA. GPR is known to be expressed at each organ in a human body, and exerts a wide variety of effects. For example, FFAR2 , FAR3, and GPR109A express in white adipose tissues to suppress lipolysis to enhance leptin secretion. As described above, materials generated from the intestine circulate systemically, and exert their effectiveness by binding to receptors. These activities are attracting greater attentions.

The relations between intestinal microflora and obesity

We would like to think about diseases that intestinal flora is involved in. Obesity is one of the examples. A study shows that obese mouse has a greater number of intestinal bacterium called Firmicutes and less Bacteroidetes. In addition, an experiment found that transplantation of stool obtained from an obese mouse into a healthy mouse resulted in its increased body fat, suggesting that stool of obese mouse contain microbe inducing obesity. Furthermore, it has been also demonstrated that obesity can be caused by changes in intestinal bacteria due to fatty diet. In a study, high-fat diet is given to RELM β-knockout mice that hardly gain weight even after fed with a high-fat diet, and its intestinal microflora was observed. The result showed that increase in Firmicutes and decrease in Bacteroidetes were found, compared to mouse fed with normal diet. It suggests that diabetic conditions may bring changes to the intestinal microflora. These alternations may be caused by changes of fat and dietary fiber intake.
There is a study comparing intestinal flora of European and African children, Firmicutes are abundant in intestinal microflora of European children, while more Bacteroidetes were found in these of African children. One of the causes of this phenomenon may be that diets of African children are low in fat and protein, and rich in dietary fiber. Among B acteroidetes, Prevotella, and Xylanibacter have enzymes that hydrolyze cellulose and xylan, which are abundant in dietary fiber. As a result of this hydrolysis process, SCFA is produced and the intestinal flora is activated. Another possible cause may be that when bile- secretion is enhanced to digest high- fat meals, cholic acid, the main component of bile, reduces the diversity of intestinal bacteria and instead increases Firmicutes. Cholic acid is converted to deoxycholic acid (DCA) by Clostridia, exerting its surface-activating effects that destroy other intestinal bacteria. It causes Firmicutes to be dominant in intestinal flora, and to increase the efficiency of energy absorption in the intestines. Analysis on the gene expression of intestinal bacteria in mouse reported the expression of genes that decompose polysaccharides and encourage their absorption in the intestines in intestinal flora of mice fed with high-fat diet. Additionally, SCFA produced by bacteria that belong to Bacteroidetes act on FFAR in adipocytes to reduce energy intake in adipocytes and prevent adipocyte hypertrophy. It also effects on FFAR in nerve cells, and is considered to regulate energy balance by promoting energy consumption through activation of the sympathetic nervous system.

Blood pressure regulation activities by intestinal bacteria

Intestinal bacteria are also considered to be involved in blood pressure regulation. Increased Firmicutes and decreased Bacteroidetes are observed in intestinal flora of hypertensive mice, similar to that in obese mice. In addition, continuous administration of angiotensin II to hypertensive mice raises the blood pressure, resulting in further increased gap of F/S ratio. Lactic acid bacteria, one of the intestinal bacteria, produces peptide, which is known to have a blood pressure lowering effect mediated by angiotensin II- inhibition effect. SCFA, including propionic acid and acetic acid, are also involved in blood pressure regulation as ligands for receptors in the renal arteries and juxtaglomerular cell cells.

The influence of intestinal flora on chronic kidney disease

In patients with chronic kidney disease, alternations of intestinal flora are observed. The reduced expression of proteins forming intestinal barrier is found in a mice with renal dysfunction. On the contrary, prebiotic treatment, in which intestinal bacteria are directly replenished in mice after nephrectomy, prolongs lifespan and reduces BUN. In the case of renal insufficiency, inflammatory symptoms are observed; creatinine, BUN, urinary protein is increased, accompanying the rise in the serum blood level of I S that is one of the uremic toxins absorbed from the intestinal tract, and cytokine IL-6, and endotoxin and CRP that are both toxic substances produced by intestinal microflora, are also elevated. Additionally, reduced Lactobacillus and increased Bacteroidetes are found in their intestinal flora.

Intestinal flora and inflammatory diseases

Inflammatory bowel disease (IBD) sometimes develops for young people. It has been regarded as an autoimmune disease in which inflammatory cells, mainly lymphocytes, attack the intestinal mucosa of the patient due to immune disorders, causing inflammation and ulcers. However, it is these days said that inflammatory bowel disease is a kind of intestinal bacterial infections, since enteritis do not develop in sterile mouse models. In fact, an acrozine- orange staining test shows that bacteria adhere and invade to the lesion mucosa of patients with ulcerative colitis. It means that the mucosal defense mechanism preventing the attachment and invasion of intestinal bacteria isn’t functioning in IBD patients. As a result, many intestinal bacteria invade and attach to the mucosa.

Intestinal flora for prime aging

As mentioned above, the conditions of intestinal flora are deeply involved in various diseases, and the whole intestinal flora itself has been increasingly regarded as one organ. Dr. Irya Mechnikov, a Russian Nobel Prize scholar, reported that the increase of toxic bacteria in the intestine accelerates aging and causes various diseases. It was found that people from the village known for its healthy longevity in Japan commonly possessed relatively lots of intestinal bacteria including Escherichia coli, Escherichia coli, and bifidobacteri that secrete one of the SCFAs, butyric acid. These bacteria are the “longevity bacteria” necessary for prime aging. We should eat root vegetables, beans, mushrooms, and seaweeds that are rich in dietary fiber. Healthy eating habits improve our intestinal environments, leading to the healthy longevity. Additionally, regular physical exercises help us strengthen the muscles of the lower body, improving the intestinal environment by promoting smooth defecation and by preventing constipation. Overeating and excessive consumption of cold foods lead to deteriorated gastrointestinal functions, poor digestion, and poor nutrient absorption. In this disturbed intestinal flora, corruption of food that inhibits nutrient absorption proceeds. In these cases, performing short fasting helps you to eliminate unwanted substances in the intestines. In performing short fasting, you stay in starvation for 16 hours a day to improve your health conditions by reducing inflammation, improving the intestinal environments, and by activating autophagy which promotes cell metabolism. This process is helpful in maintaining healthy cells. We are allowed to eat during the remaining 8 hours, however, food rich in fat and sugar, such as cakes and ice cream should be avoided. It should be also noted that we refrain from eating for 3 hours before going to bed. Fasting allows the blood flow and energy that was previously used in the gastrointestinal tract to be used in other organs and cells, which in turn activates brain activity and improves concentration and thinking ability. There are more and more business persons trying to improve performance by practicing fasting. Let’s improve the intestinal environment, rejuvenate cells, and activate the brain by practicing short fasting.


Midori Meshitsuka M.D.

Midori Meshitsuka M.D.
M Regenerative Clinic Director

2008 Graduated from Peking University Health Science Center (China)
2009 Obtained Chinese medical license
2014 Obtained Japanese medical license
2019 M Regenerative Clinic Director
Dr. Midori completed her internship at Harvard medical school Massachusetts General Hospital and Peking University Third Hospital. She then worked at the University of Tokyo Hospital, Tokyo Women’s medical University. In 2019 she joined her family practice, established M Regenerative Clinic as Director.

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