[Special Feature: The Future of Preventive Medicine] Masaru Mimura: The Importance of Preventive Medicine and Mental Health—Aging with a Healthy Mind

“No health without mental health.” This was the proposal in a 2007 Lancet paper by Prince et al.*1. Among Japan's five major diseases (diabetes, mental illness, malignant tumors, cerebrovascular disease, and ischemic heart disease), the prevalence of mental illness ranks second only to diabetes. In terms of the burden of disease measured by Disability-Adjusted Life Years (DALY), depression ranked second globally in fiscal 2020, following ischemic heart disease. Mental health is truly a critical issue when considering human health.

The WHO Constitution adopted in 1947 defines "health" as "a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity." For a person to be healthy, it means that in addition to physical health, their mind is fulfilled, cognitive functions are maintained, and they have appropriate social connections. October 10th was World Mental Health Day, with events held around the globe. Here, I would like to reflect once again on the importance of mental health in preventive medicine.

The Keio University Center for Preventive Medicine, which is newly expanding and relocating to Azabudai Hills, has the slogan "Medicine that walks alongside each individual's life." Its basic philosophies are "to play a role in extending healthy life expectancy," "to develop and practice highly personalized health management programs," and "to create new value in preventive medicine." Mental health is indispensable to all of these concepts.

People do not necessarily remain in a desirable physical, mental, or social state forever. Naturally, the core mission of the Center for Preventive Medicine is the early detection and treatment of physical diseases, but some people may feel anxious when an abnormality is found during a health checkup. Mental distress can also occur if a proper diagnosis or treatment is not reached, or if symptoms persist even after treatment. The key in such situations is resilience. In Japanese, it is translated as "resistance to disease" or "stress resistance." It is certain that even after going through similar adversity, stress, or traumatic experiences, some people fall into poor mental health while others do not; some have high stress resistance and others low. This is one of the concepts born from a positive way of living (positive psychology and positive psychiatry*2). To use an analogy, the dent created when you press a rubber ball with your finger is stress, and the way it swells back up to bounce back is the image of resilience. The ultimate mission of mental health support at the Center for Preventive Medicine is to walk alongside each health checkup recipient and enhance the resilience of the client and their family.

The Center for Preventive Medicine plans to promote research on preventive medicine aimed at creating a "city where people of all generations can live healthily and vibrantly," in collaboration with the preceding "Hills Joint Research Laboratory for Future Preventive Medicine and Wellness" (hereafter, Future Preventive Medicine Laboratory) (Project Professor Taishiro Kishimoto). In particular, we are developing an app to predict mental health status by collecting and analyzing health data regarding daily activities and mental states (perceived stress scales, life satisfaction scales, sleepiness, etc.) using healthcare devices such as wearables. Based on this information, we intend to implement new preventive medicine and wellness services in society while providing advice on lifestyle habits such as diet, exercise, and sleep.

The Center for Preventive Medicine considers support for three major generations excluding early childhood: adolescence to young adulthood, middle age, and old age. Adolescence to young adulthood generally refers to ages 15 to 39, also known as the AYA generation, but I will omit that here due to space constraints. Below, I will briefly introduce my plans for middle age and old age.

Middle Age (Business Person Generation)

These are the working generations, roughly in their 40s to 60s. They play core roles in companies and are the primary targets for health checkups and physical health management at the Center for Preventive Medicine.

On the other hand, this is an age group that often experiences mental health issues such as adjustment disorders, depression, bipolar disorder, and anxiety disorders, triggered by stress stemming from work or family issues. While stress checks are mandatory at many companies, the current reality is that they struggle with the discovery of and response to high-stress individuals. I have served as the Director of the Keio University Keio Center for Stress Research (CSR). At the core of our activities, the Keio Employee Assistance Program (KEAP), we have developed multidisciplinary industrial mental health services under the slogan "Work exists within wellness," collaborating with certified public psychologists, industrial physicians from various companies, and health management staff. For the business people who are clients of the Center for Preventive Medicine, we must balance job satisfaction with economic growth.

The accuracy of early diagnosis and treatment techniques for depression is improving every year. Regarding diagnosis, a project led by Project Professor Kishimoto of the aforementioned Future Preventive Medicine Laboratory—which uses machine learning for wearable devices, digital phenotypes, brain MRI findings, EEG, and body movements—has made it possible to diagnose depression with very high accuracy (Figure 1). Regarding treatment, we are also developing a smartphone AI support app under the "International Brain" project to predict in a tailor-made fashion which of the four treatment techniques currently insurance-approved for depression will be most effective for a specific individual.

While the diagnosis and treatment of depression have made rapid progress in recent years, challenges remain in terms of improving subjective satisfaction, such as the quality of life (QOL) and well-being of those affected. We need services that monitor various factors leading to a decline in QOL and well-being and provide feedback on lifestyle behaviors such as diet, exercise, and sleep as solutions to prevent them. We anticipate that this initiative will make it possible to enhance individual resilience. Furthermore, under the guidance of Professor Mitsuhiro Sado of the Health Management Center and Senior Lecturer Toshiaki Kikuchi of the Department of Neuropsychiatry, we are striving to widely disseminate and promote cognitive behavioral therapy. Mindfulness-based cognitive therapy for healthy individuals can increase life satisfaction, fulfillment, and positive emotions, and we believe it can contribute to improving the well-being of clients at the Center for Preventive Medicine*3 (Figure 2).

Old Age (Silver Generation)

This assumes those roughly 70 years of age and older. In this age group, depression and depressive states are not uncommon, but even more problematic are dementia and Mild Cognitive Impairment (MCI), which can be considered its precursor. MCI refers to a stage where a person is independent in daily life and has no trouble managing personal affairs alone, but memory impairment (amnesia) is observed in cognitive function tests.

Alzheimer's disease, which accounts for more than half of dementia cases, is a disease hallmarked by the accumulation of abnormal proteins called amyloid in the brain. Surprisingly, today, one in six to seven "healthy" people (those without memory impairment) aged 65 and older already has amyloid accumulated in their brain (called preclinical Alzheimer's disease), and those individuals are extremely likely to develop Alzheimer's disease 10 to 20 years later. In Japan, where the super-aging society is progressing, the total number of people with dementia and MCI combined is at least 10 million by even the most conservative estimates, and we must deal with this "era of 10 million people with dementia" that will progress further in the future.

Lecanemab, an anti-amyloid antibody drug, was approved in Japan this year, and I believe various other disease-modifying drugs for Alzheimer's disease will be brought to market in the future. While the current target for anti-amyloid antibody drugs is MCI to mild Alzheimer's disease, there is a possibility that this will expand to preclinical Alzheimer's disease in the future. In other words, an era is approaching where we can predict future dementia risk at an ultra-early stage before memory loss occurs, intervene with treatment from that stage, and suppress the progression to dementia. The Center for Preventive Medicine plans to open a Forgetfulness Consultation Clinic (tentative) to assess the presence of amyloid accumulation through blood biomarkers and brain MRI, and if positive results are suspected, link them to Positron Emission Tomography (PET) scans at Keio Hospital to label amyloid and tau (Figure 3).

On the other hand, guidance on lifestyle habits to prevent dementia or MCI (prevention) or to reduce risk is modest but has solid evidence. This time, our project "Development of a Tailor-made Behavioral Change Program Based on Future Cognitive Function Prediction," to be deployed at the Center for Preventive Medicine, was selected by the Japan Agency for Medical Research and Development (AMED). Here, we will incorporate a cognitive function simulation app into smartphones to increase adherence to behavioral changes regarding diet and exercise habits based on the prediction of cognitive reserve several years later. Additionally, sleep is important for dementia prevention, and we plan to provide guidance on sleep depth, sleep quality, and lifestyle rhythms using wearable devices such as the Apple Watch and the Insomnograf from S’UIMIN Inc., founded by Professor Masashi Yanagisawa of the University of Tsukuba.

In all lifestyle habits, "aging" and "frailty" are key important concepts. Brain age can be predicted to some extent through simple cognitive function tests performed on smartphones and machine learning analysis of brain MRI. In recent years, the idea that aging itself is a disease has also emerged*4, and I would like to consider the theme of how to face aging together with Project Professor Hiroshi Itoh. Regarding frailty, while collaborating with Professor Kazuki Sato of Sports Medicine on physical frailty, it is important to reduce the risks of cognitive frailty and social frailty (social isolation). It is well known that MCI is likely to coexist with physical frailty, and it is required to find common factors such as lifestyle-related diseases, nutritional disorders, hormonal abnormalities, and depression early and intervene with appropriate prevention. Even as disease-modifying drugs for dementia come into clinical use, I am convinced that we should aim for a society that can reduce dementia risk by combining these preventive factors in a multifaceted and multi-domain manner.

Above, I have described the importance of mental health in preventive medicine as I envision it upon the relocation of the Keio University Center for Preventive Medicine to Azabudai Hills. Keeping "No health without mental health" in mind once again, I hope to contribute even slightly to improving the resilience of the clients of the Center for Preventive Medicine, their families, those in related companies, and the faculty and staff of Keio University.