【Special Feature: The Future of Preventive Medicine】 Hiroshi Itoh: Metabolic Dominoes and "Mibyo" Medicine—Creating Conviviality

In 2003, I coined the term "Metabolic Dominoes" (Figure 1) to describe the sequence where changes in lifestyle (diet, exercise, sleep, etc.) lead to weight gain (especially visceral fat accumulation), followed by increased blood pressure, high postprandial blood glucose, and dyslipidemia (increased triglycerides, decreased HDL cholesterol) occurring in the same person at roughly the same time. This results in metabolic syndrome, which leads to diabetes, arteriosclerosis, and chronic kidney disease, eventually progressing to stroke, myocardial infarction, and renal dialysis. In today's super-aging society, heart failure and dementia are particularly major issues, and sarcopenia—a loss of muscle strength and mass—as well as cancers (colorectal, pancreatic, uterine, etc.) are also complications. While the world was ravaged by the COVID-19 pandemic, with 7 million deaths as of September 2023, deaths from metabolic domino diseases (known as "non-communicable diseases") account for 70% of the 57 million annual deaths worldwide.

My mentor, Dr. Hiroo Imura (former President of Kyoto University and former President of the Japan Academy), advocated "preemptive medicine" in 2011. This is medical care that identifies the upstream flow of these dominoes when a disease is still in its budding stage and intervenes early. Recently, attention has turned even further upstream to addressing the so-called "Mibyo" (pre-symptomatic) stage, or "Mibyo medicine." In 625 AD, the famous Tang Dynasty physician Sun Simiao stated that a doctor who treats a disease after it has occurred is of the lowest rank, a doctor who treats a disease when it is about to occur (preemptive medicine) is of middle rank, and a doctor who treats a disease before it occurs (Mibyo medicine) is of the highest rank.

Mibyo is a vague definition referring to a period when one is not clearly ill, yet not entirely healthy; the Ministry of Health, Labour and Welfare also treats it as a gray zone that is neither white nor black. It is a concept of a pathological state with a certain breadth, and its interpretation varies from person to person. Because of this, it is a state where responses tailored to the individual can be expected. Mibyo measures vary from person to person: some want to be full of vitality, fun, and happiness in both body and mind; others want to maintain a physical and mental state that allows them to continue working; some want to prevent abnormal checkup data from turning into a disease (the typical realm of Mibyo); and still others want to prevent a disease from recurring once they have already fallen ill.

Kazuyuki Aihara, Special University Professor at the University of Tokyo, states that both health and disease states are extremely stable in terms of the biological energy state. When transitioning from health to disease, the energy level temporarily rises, becoming unstable and capable of tipping in either direction; this is the Mibyo state. I believe that the "fluctuations" of the biological state at this time are important. Even with test values from health checkups, the values first begin to vary before the average value exceeds the normal range and is judged as abnormal. In renal dialysis patients at the furthest downstream of the metabolic dominoes, it has been reported that serum albumin, a nutritional indicator, gradually decreases during the progression toward death, but the range of fluctuation first increases even within the normal range. Furthermore, including our own reports, it is known that not only the absolute values of blood pressure and blood glucose but also the fluctuations within a single day, or the variations in values during hospital visits, themselves become risks for cardiovascular disease. I believe that in the flow of dominoes, there is a time when the biological state fluctuates greatly before organ damage occurs, and that is the appropriate time for Mibyo intervention (Figure 2).

Why do "fluctuations" occur? When following the test data of people who live long and healthy lives, it is surprising to see that there is almost no deviation. To realize a body that does not deviate—biological homeostasis—it is important to maintain a constant rhythm and periodic vibration through the work of feedback mechanisms between various substances with antagonistic effects. My specialty is hormones, and the more than 100 types of hormones have rhythmic secretions throughout the day, which creates biological robustness. "Fluctuations" can be understood as a manifestation of "rhythm disturbance" in the living organism due to the dysfunction of this feedback.

Professor Kazuhiro Sakurada of the Department of Extended Intelligence Medicine at the Keio University School of Medicine notes that while medicine has traditionally sought to clarify causal relationships and elucidate pathology from those networks, current medical statistics attempts to position an individual's biological state space vector on the coordinate axes of multi-dimensional biological state measurements, regardless of causal relationships. Together with them, we hope to elucidate the "fluctuations" in the transition of biological vectors from health to disease.

I maintain that living is "the use of genes" ("The Secret of 'Super Longevity'" by Hiroshi Itoh, Shodensha Shinsho). The use of genes refers to the creation of gene copies (replication) and the translation of genes to create biological functional substances (transcription/translation). In either case, the double-stranded genes, DNA, unravel, and at that time, DNA damage occurs due to external influences such as ultraviolet rays and the action of reactive oxygen species generated within cells. The organism lives while repairing this, but in the process, chemical modifications occur to the genes and the proteins that regulate their functions, changing how the genes work. This is called an epigenomic change ("epi" meaning above, "genome" meaning gene; referring to changes related to how genes work rather than the genes themselves).

Unrepaired genetic damage and epigenomic changes steadily accumulate, becoming the driving force for aging and metabolic dominoes. Therefore, by grasping the degree of genetic damage and epigenomic change, we can know the "story" of how that person has lived and understand how genetically old they are ("epigenetic age"). Epigenetic age can be calculated by analyzing the genes of blood cells, and we intend to detect genetic damage and epigenomic changes at the Mibyo stage before organ damage occurs (Figure 2). The kidney is the pacemaker organ for various organs in the body, and its aging reflects the aging of the entire body. The waste filtration function of the kidney usually decreases by about 0.5% to 1% per year, but a decrease exceeding 2% will cause "chronic kidney disease" in the future and becomes a risk for the onset of many diseases. Our preliminary results showed that patients with chronic kidney disease have a higher epigenetic age (are genetically older) than healthy individuals.

Recently, with the rapid development of digital technology, various wearable devices and IoT equipment have been developed, making it possible to continuously record 24-hour biological logs—namely, blood pressure, blood glucose fluctuations, heart rate, presence of arrhythmia, sleep patterns, step counts, exercise volume, exercise posture, and dietary content and timing. As a result of this "visualization" of one's own health status, a health literacy of "managing one's own health by oneself" is fostered. It has often been observed that simply wearing a wearable device leads to spontaneous changes in dietary and exercise behavior, even without guidance from experts such as doctors. Treatment support apps for smoking cessation, hypertension, and insomnia, which have become covered by insurance, are an extension of this. In collaboration with Oishi Kenko Inc., we developed the app "Tabetime." Furthermore, we are proposing the "We are Not Alone Project," which aims for further spontaneous behavioral changes based on a sense of camaraderie. In this project, users share their own dietary behavior data and, while ensuring individual privacy, view each other's data to realize a "realization" of differences between themselves and others and "mutual encouragement."

It is expected that interacting with one's own avatar, constructed from one's own measurement data using ChatGPT (generative AI), which is currently expected to be applied in all fields, will also progress. We are entering an era where the future trajectories of individuals can be predicted with high accuracy through AI analysis of vast amounts of data obtained from wearable devices and the like. At the 117th Annual Meeting of the Japanese Society of Internal Medicine in 2020, I gave a lecture titled "Medical Sciences Creating a Centenarian Society in the With-Corona Era," and cited three keywords for modern medical sciences: Health Diversity, Health Sharing, and Precision Health (individualized precision healthcare). From now on, I believe our awareness will shift from "my health" to "our health" through AI and DX (Digital Transformation).

Ryugen Matsunami, the abbot of the experimental temple Hodo-ji in Kyoto, states that Mahayana Buddhism has two fundamental thoughts: "Yogacara" (consciousness-only) and "Madhyamaka philosophy" (the concept of "Ku" or emptiness). Everything exists only through individual perception, and the "self" is defined only through relationships with all "others" who are not the "self." These relationships constantly change spatially and temporally and have infinite possibilities. The totality of this is "Ku," and "Shiki Soku Ze Ku" (Form is Emptiness) means that actual "Shiki" (form/reality) is created from "Ku." Conversely, "Ku Soku Ze Shiki" (Emptiness is Form) means that because reality exists, possibilities can be inferred. This Buddhist philosophy connects to modern AI and big data science. In modern medical sciences, "Ku" is exactly the "cloud." Future medical care will involve efforts to predict an individual's unique future ("Shiki") from the analysis of vast amounts of human data ("Ku") regarding various metabolic domino pathologies generated not only from individual habits but also within relationships with others.

Until now, the various pathologies of metabolic dominoes and non-communicable diseases have been called "lifestyle diseases." However, currently, disturbances in lifestyle habits are often treated as a matter of self-responsibility, and because the individual's life is deemed "sloppy," it is left to individual awareness and effort. This problem is called "stigma" and has become a major medical issue. However, it is becoming recognized that the reason a person was forced to adopt such lifestyle habits lies in the social environment surrounding them—upbringing, education, housing, workplace, etc. Analysis of factors related to dementia suppression in Europe and the US has pointed to improvements in educational background in addition to smoking cessation and blood pressure optimization. It is also known that elderly people living in designated cities have a lower incidence of dementia than those living in rural areas. This is estimated to be because people in cities walk more without using cars due to the development of transportation systems like subways, and have better access to parks.

"Global warming" is the most important issue among the targets of the 17 SDGs (Sustainable Development Goals). We are conducting studies to monitor the housing environment in which patients live—namely, room temperature, humidity, noise, and illuminance—by attaching various sensors to their homes and correlating these indicators with the patients' biological states.

Future-oriented preventive medicine aims to make healthy people even healthier. Hints for this can be found in Japan's super-aging society. The Center for Supercentenarian Medical Research at the Keio University School of Medicine conducted a survey on what diseases people aged 100 and older (centenarians), whose numbers currently exceed 90,000 in Japan and continue to increase, suffer from. While centenarians often suffer from diseases such as hypertension, cataracts, and fractures, it is noteworthy that they only suffer from such diseases after passing the age of 85, and until then, they have not had any significant illnesses. This is called "compression of morbidity" (diseases are pushed into the final period of life). The reality is living "thick and long" rather than "thin and long."

A further characteristic is the low prevalence of diabetes. Only a few percent of them suffer from it. In the general population, it is about 10%, and if the pre-diabetic group is included, it is about 20%. This tells us that nutrition and energy metabolism—so-called metabolism—are extremely important for determining lifespan.

Our energy source is a substance called ATP (adenosine triphosphate), which is produced by the power of oxygen in organelles called "mitochondria" existing inside cells, primarily using nutrients such as sugar and fat as raw materials. When mitochondrial function declines, ATP production decreases, oxygen is not used properly, and it becomes "reactive oxygen species" that have high chemical reactivity and damage cells, leading to aging and organ damage. The falling of the metabolic dominoes is exactly the decline of mitochondria. Diabetes occurs due to a disorder of energy metabolism, but it is no exaggeration to say it is a disease of the mitochondria. Therefore, keeping mitochondria healthy is the secret to health and longevity. And one of the key substances for that is sirtuin.

It has been shown that calorie restriction (reducing intake to 70-80% of normal) extends lifespan even in monkeys, and reduces diabetes, cardiovascular disease, cancer, and dementia—extending the so-called healthy life expectancy. Sirtuins are involved in the fact that this "eating until 80% full" brings longevity. Sirtuins are enzymes activated by NAD (nicotinamide adenine dinucleotide), which is made from vitamin B3 (niacin), and they have the effect of energizing mitochondria and regulating epigenomic changes. As metabolic dominoes progress, it has become clear that NMN (nicotinamide mononucleotide), a precursor substance for NAD, decreases in various organs, leading to the progression of aging. We have clarified the significance of NMN in kidney aging and chronic kidney disease, which are the keys to systemic aging. Currently, NMN is attracting feverish attention in the field of anti-aging. As a preemptive medicine for metabolic dominoes and a measure against Mibyo, we were the first in the world to orally administer NMN to humans in 2016, reporting that NMN is sufficiently absorbed by the body and acts safely. Since then, the effects of administration have been verified at various facilities, and effects on sarcopenia and dementia are also expected.

Until now, medical care has involved clarifying the causes of each disease and developing drugs to specifically remove those causes. However, in a super-aging society, aging exists at the foundation of many of these diseases, serving as their mother. Therefore, it tends to become a game of whack-a-mole where even if one disease is suppressed, another occurs. A mode of medical care that intervenes in aging itself from an early stage is important, and NMN has the potential to be one such intervention.

Currently, there are two trends in anti-aging methods. One is the method of removing aged cells (Senolysis: "seno" meaning old, "lysis" meaning to erase), and the other is the method of stimulating precursor cells (stem cells) that create new cells. The former involves finding markers for senescent cells and removing them based on those markers, or disabling the mechanisms by which senescent cells try to survive. This is currently the hottest field, but I believe that no matter how many aged cells are killed, "rejuvenation" will not go well unless young new cells are produced. NMN therapy falls into the category of the latter approach.

David Sinclair, in his book "LIFESPAN: Why We Age—and Why We Don't Have To," states that aging is a disease. While we have previously accepted aging as something inevitable and passive, he presents the idea that aging can be cured.

The number of people living past 100 will increase in the future, but there are only about 150 people in Japan who have passed 110 (supercentenarians), and that number is not increasing. This fact indicates that the lifespan limit for humans as a current form of life is around 110 years. I have had the opportunity to meet supercentenarians, and what left a deep impression was that they seemed "happy." Even I, talking to them, felt happy. I maintain that there is a "happiness lifespan" as another dimension of lifespan in addition to average lifespan (biological lifespan) and healthy life expectancy ("Happiness Lifespan" by Hiroshi Itoh, Asahi Shinsho). Health and happiness are close but not the same; some people feel unhappy even if they are healthy, while others can feel happiness even more deeply despite suffering from a major illness. Ultimately, our purpose in living is to live happily, and looking at supercentenarians, I feel that if you feel happy, you will naturally live long and be able to fulfill your natural lifespan.

I believe that Mibyo measures—rather than the idea that happiness waits beyond the state of not being ill—can be naturally achieved by aiming for happiness itself.

Currently, happiness and well-being are attracting attention. I believe that happiness lies in the "between." In Japanese, the word for human is written as "between people" (人間), and only then does one become human-like; even in English, it is "human being" (where "be" can imply a state of being among). Happiness, too, is "well-being" in English—a "good between." Professor Takashi Maeno of the Keio University Graduate School of System Design and Management is a master of "happiness studies" and has identified four factors of happiness. The second factor is the "Thank you!" factor (the factor of connection and gratitude). Through contact with people, the secretion of oxytocin, a hormone that increases feelings of bonding (commitment), increases.

My image of well-being is a society where "conviviality" is realized. "Convivial" comes from "con" (together) and "vivere" (to live), which literally translates to "symbiosis," but "vivere" has nuances of liveliness and cheerfulness, carrying connotations of (people being) jovial, (events being) lively, and (atmospheres being) cozy. Conviviality is a state where one meets others who are different from oneself and shares the same place and time while respecting each other's spontaneity ("Convivial Technology" by Hisato Ogata, BNN).

I believe that the creation of "conviviality" will be the foundation of Mibyo medicine, and the realization of Mibyo medicine will require a wide-angle understanding and respect for every single human being.