[Feature: The Future of Preventive Medicine] Hiroshi Itoh: Metabolic Domino and "Mibyo" Medicine—Creating Conviviality

2023/11/06

In 2003, I coined the term "Metabolic Domino" (Figure 1) to describe the sequence where changes in lifestyle (diet, exercise, sleep, etc.) lead to weight gain (especially visceral fat accumulation), followed by high blood pressure, high postprandial blood glucose, and dyslipidemia (increased triglycerides, decreased HDL cholesterol) occurring in the same person at roughly the same time, resulting in metabolic syndrome. This subsequently 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, often accompanied by cancer (colorectal, pancreatic, uterine, etc.) and sarcopenia, where muscle strength and mass decrease. 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 domino flow upstream, at the stage where the disease is still budding, and intervenes early. Recently, attention has shifted even further upstream to "Mibyo medicine," which addresses the so-called "Mibyo" (pre-symptomatic) stage. In 625 AD, the famous Tang Dynasty physician Sun Simiao stated that a doctor who treats a disease after it has developed 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 has a vague definition: 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 range, and its interpretation varies from person to person. Consequently, it is a state where personalized responses can be expected. Mibyo measures vary from person to person: some want to be full of vitality and happiness, some want to maintain a mind and body capable of continuing work, some want to prevent abnormal health check data from turning into disease (the typical realm of Mibyo), and some want to prevent recurrence even after becoming 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 body's 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 the "fluctuations" in the biological state at this time are important. Even with health check data, before an average value exceeds the normal range and is judged abnormal, the values first begin to vary. In renal dialysis patients at the bottom of the metabolic domino, serum albumin (a nutritional indicator) gradually decreases toward death, but it has been reported that 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 their fluctuations within a day, or the variability of values during hospital visits, themselves become risks for cardiovascular disease. I believe that in the domino flow, 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).

How do "fluctuations" arise? When following the test data of people who live long and healthy lives, it is surprising how little deviation there is. To realize a body that does not deviate—homeostasis—it is important to maintain a constant rhythm and periodic vibration through the feedback mechanisms of 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 seen as a manifestation of "rhythm disturbance" in the body due to the failure of this feedback.

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

I believe that living is "the use of genes" (The Secret of "Super Longevity," Hiroshi Itoh, Shodensha Shinsho). Using genes refers to making gene copies (replication) and translating genes to create biological functional substances (transcription/translation). In either case, the double-stranded DNA unravels, 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" means above, "genome" means gene; it refers to changes in how genes work rather than the genes themselves).

Unrepaired DNA damage and epigenomic changes steadily accumulate, becoming the driving force for aging and the metabolic domino. Therefore, by grasping the degree of DNA 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 in blood cells, and we intend to detect DNA 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 kidney's waste filtration function 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 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—blood pressure, blood glucose fluctuations, heart rate, presence of arrhythmia, sleep patterns, step counts, exercise volume, exercise posture, and dietary content and timing. The results are then fed back to the users themselves. By "visualizing" one's health status in this way, a health literacy of "managing one's own health" is fostered. It has often been observed that simply wearing a wearable device leads to spontaneous changes in diet and exercise behavior even without professional guidance. 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 change based on a sense of camaraderie by having users share their own dietary behavior data and view each other's data while ensuring privacy, thereby realizing "awareness" of differences and "mutual encouragement."

It is expected that interacting with one's own avatar, constructed from one's 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 "Medicine to Create a Centenarian Society in the With-Corona Era," where I cited three keywords for modern medicine: Health Diversity, Health Sharing, and Precision Health. From now on, through AI and DX (Digital Transformation), I believe our consciousness will shift from "my health" to "our health."

Ryugen Matsunami, the abbot of the experimental temple Hodo-ji in Kyoto, states that Mahayana Buddhism has two fundamental philosophies: "Yuisiki" (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. This relationship constantly changes spatially and temporally and has infinite possibilities. The totality of this is "Ku," and "Shiki Soku Ze Ku" (Form is Emptiness) means that actual "form" (Shiki) is created from "emptiness" (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 medicine, "Ku" is exactly the "cloud." Future medical efforts will involve predicting an individual's unique future ("Shiki") from the analysis of vast amounts of human data ("Ku") regarding various metabolic domino pathologies generated within relationships with others, not just individual habits.

Until now, metabolic domino pathologies and non-communicable diseases have been called "lifestyle-related diseases." However, currently, lifestyle disturbances are often treated as a matter of self-responsibility, left to individual awareness and effort as if the individual's life is simply "sloppy." This issue is called "stigma" and has become a major medical challenge. However, it is increasingly recognized that the reason a person is forced into such a lifestyle 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 ordinance-designated cities have a lower incidence of dementia than those living in rural areas. This is estimated to be because urban dwellers 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 17 Sustainable Development Goals (SDGs). We are conducting studies to monitor the housing environment in which patients live—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 now 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 succumb to these diseases after passing the age of 85; until then, they have not suffered from any significant illnesses. This is called "compression of morbidity" (disease is compressed 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 are affected. In the general population, it is about 10%, and if the pre-diabetic group is included, it reaches about 20%. This tells us that nutrition and energy metabolism—so-called metabolism—are extremely important in determining lifespan.

Our energy source is a substance called ATP (adenosine triphosphate), which is produced by the power of oxygen using nutrients like sugar and fat as raw materials in organelles called "mitochondria" inside cells. When mitochondrial function declines, ATP production decreases, oxygen is not used properly, and it becomes "reactive oxygen species" that are highly chemically reactive and damage cells, leading to aging and organ damage. The falling of the metabolic dominoes is exactly the decline of mitochondria. Diabetes is caused by 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 healthy 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 and reduces diabetes, cardiovascular disease, cancer, and dementia—extending the so-called healthy life expectancy—even in monkeys. Sirtuins are involved in this "eating until 80% full" bringing about longevity. Sirtuins are enzymes activated by NAD (nicotinamide adenine dinucleotide), which is made from vitamin B3 (niacin); they energize mitochondria and regulate epigenomic changes. It has become clear that as the metabolic domino progresses, 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 preemptive medicine for the metabolic domino and as a Mibyo measure, 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 focused on 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 medicine 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" means old, "lysis" means 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 latter category of 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 treated.

The number of people living past 100 will increase, 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 biological entities in their current form is around 110. I have had the opportunity to meet supercentenarians, and what was impressive was that they looked "happy." Even I, talking to them, felt happy. I believe there is another dimension of lifespan called "happiness lifespan" in addition to average lifespan (biological lifespan) and healthy life expectancy ("Happiness Lifespan," 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 more deeply even if they suffer from a serious 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 fulfill your natural lifespan.

I do not believe that happiness waits at the end of Mibyo measures—the state of not becoming ill—but rather that by aiming for happiness itself, Mibyo can be achieved naturally.

Currently, happiness and well-being are attracting attention. I believe happiness lies in the "between" (aida). 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" ("be" can imply being in the middle). Happiness in English is also "well-being," 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). Contact with people increases the secretion of oxytocin, a hormone that enhances feelings of bonding (commitment).

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 being jovial (people), lively (events), or cozy (atmosphere). 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," 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 human being.