PROCEEDINGS Retrospective on nine years of the Anti-Aging Health Check-ups in Tokai University Hospital: From establishment to future

Yasuhiro Nishizaki1, 2, 3 Chizumi Yamada1 Noriaki Kishimoto1 Hirokazu Shiozawa2 Asami Takeda1 Tamae Ogata1 Emiko Kuroda1 Akira Kubo1 Ichiro Kuwahira4 Naoaki Ishii3, 5

1Health Screening Center, Tokai University Tokyo Hospital 2Digestive and Liver Disease Center, Tokai University Tokyo Hospital 3Life Care Center, Graduate School of Medicine, Tokai University 4Department of Pulmonary Medicine, Tokai University Tokyo Hospital 5Department of Molecular Life Science, Tokai University School of Medicine

ABSTRACT In June 2006, Tokai University launched the Check-up System at the Tokyo Hospital with the aim of assessing age- related changes and various factors that influence their progression, and following up with medical intervention. Prior to launching this Anti-Aging Health Check-up System, we conducted a questionnaire survey of individuals who had received general health check-ups at our hospital. More than 90% of the respondents knew about anti-aging medicine and were interested in it. The tests carried out as part of our anti-aging health check-ups are broadly divided into those that indi- cate the present degree of aging and those that focus on factors that contribute to aging. Our Anti-Aging Health Check- up System includes more than 70 examination items and provides various unique services. As of March 2015, approximately 1,640 individuals had received the anti-aging health check-up, and 75.4% of these were repeat recipients. The average age is currently 63.7 years for males and 61.7 for females. The gender ratio is 54% male compared to 46% female. Of the total number of recipients, 57% also received a general health check-up at the same time. By age group, individuals in their 60s account for the largest proportion with one-third of the total, and more than 80% of all those tested are aged 50 to 70. Some individuals have finished their 9th check-up, and many of them have kept aging-related markers steady or actually improved them. The rationale of the Anti-Aging Health Check-up System, which assumes advancing age to be the biggest risk factor for disease and aims to identify signs and intervene at an early stage, is considered an appropriate step in the right direction in terms of primary prevention. However, it may not always be possible to clearly convey its importance due to its complex nature. To properly develop this aspect, it should always be based on evidence with the target of extending life expectancy; it should be judged objectively, without ignoring conflicting evidence, while sufficient information should be provided and options offered to those receiving the check-ups. In view of the super-aging society, we hope that this kind of health assess- ment and guidance method will take root and flourish. (HEP. 2015; 42: 465-470.)

Key words NASH, NAFLD, Metabolic syndrome, Life style related diseases

however, national growth had carried into an age of plenty. 1. Introduction Now, the disease structure is the complete reverse; currently In Japan, changing the emphasis of healthcare from “treat- measures to combat overnutrition are required. Meanwhile, the ment” to “prevention” has been highlighted as a government government has been promoting preventive medicine to control policy. As the national population shrinks and the problems of rising medical costs associated with population aging. low birth rate and population aging become increasingly serious, Since 2008, specific health check-ups have been implemented it is now more important than ever for people to age healthily – for relevant risk groups such as people who could be affected by in other words, to extend their healthy life expectancy. Anti-aging metabolic syndrome. Japan’s population started shrinking in is thought to a key approach to this end. Immediately after WW 2004, and is predicted to fall below 100 million by 2050. This II, the focus of Japan’s healthcare policy was on the need to decrease in population will cause a decline in national power, as combat malnutrition and improve sanitation. Six decades later, by that time, one in every three Japanese citizens will be aged 65 or over. It will therefore be important to ensure that people are Received: May 8, 2015 healthy enough, even in old age, to make a full contribution to Corresponding author: Yasuhiro NISHIZAKI, M.D., Ph.D. the labor force without relying on public healthcare spending. Professor/Assistant Senior Executive director Preventive medicine is divided into primary, secondary and 1Address; Tokai University Tokyo Hospital tertiary prevention, depending on the stage of intervention. The 1-2-5 , -ku, Tokyo 153-0065, Japan TEL: +81-3-3370-2321, FAX: +81-3-5354-5366 medical examinations and general health check-ups now widely E-mail: [email protected] practiced under government guidance correspond to secondary

HEP Vol.42, No.4, 2015 (465) 31 prevention aimed at early discovery and treatment. This mainly system is to assess age-related changes and various factors that consists of recognizing and treating diseases that already exist. influence their progression, and to follow this up with medical By contrast, the aim of primary prevention is to improve lifestyle intervention1). habits and environments and promote health through proactive 2. Questionnaire before the launch of the Anti-Aging nutrition, exercise, recuperation, etc., before symptoms or posi- Health Check-up System tive test results appear. Tertiary prevention includes rehabilitation and prevention of recurrence after a disease has been contracted. Before launching Anti-Aging Health Check-up System, we The field of anti-aging medicine assumes aging to be a basic conducted a questionnaire survey of individuals who had received cause of disease, and blocks it by starting medical intervention general health check-ups. When asked if they knew about anti- before the disease occurs, thus providing a form of primary pre- aging medicine and if they were interested in it, more than 90% vention. In June 2006, Tokai University launched the Anti-Aging of the respondents replied in the affirmative (Fig. 1). Again, more Health Check-up System at the Tokyo Hospital. The aim of the than 85% responded that they would like to receive an anti-aging

Question: Have you heard and had an interest in the “anti-aging”?

（Number of answer／％） a) Yes, I know well and am already controlling my health for the purpose of anti-aging. （25/4.8％） b) Yes. I have heard of it and am thinking of controlling my health for anti-aging in future. （175/33.9％） c) I have never heard of it but am interested. （278/53.9％）

d) I have never heard of it and am not interested. （30/5.8％）

e) I have heard of it but am not interested. （8/1.6％） 0 50 100 150 200 250 300 （Number of subject）

Interest

Yes No chi-square p value = 0.0191 Yes 200 8 Odd ratio = 2.70 knowledge No 278 30 Yates’ correction (-)

Fig. 1 Knowledge and interest to the anti-aging medicine

Question : Would you want to receive guidance on improving your health if you could know the difference between your actual age and physical age through anti-aging health check- ups?

(Number of answers/%)

a) I am interested and want to receive. (248/48.1%)

b) I am interested but don’t want to receive. (194/37.6%)

c) I am not interested and don’t want to receive. (40/7.8%)

d) I am not interested but can’t decide. (27/5.2%)

e) I don’t think there is any benefit for me. (7/1.3%)

0 50 100 150 200 250 300 (Number of subjects) Fig. 2 Interest in receiving anti-aging health check-up

32 (466) HEP Vol.42, No.4, 2015 Nishizaki et al.: Fatal Fatty Liver NASH Degree of Aging Aging risk factor Degree of Aging Aging risk factor Muscle (motor) Immunity

Muscle (motor) Immunity

Blood Metabolism Bone oxidative stress vessel and AGEs* Blood Metabolism Bone oxidative stress vessel and AGEs*

Hormone Brain and Life style Stress Neoron Hormone Brain and Life style Stress Neoron

* AGEs : Advanced Glycation End products Fig. 3 Categories of items in anti-aging health check-up* AGEs : Advanced Glycation End products

Table 1 Examination Items in Anti-aging health check-up (male advance course)

oxidization and serum lipids and alteriosre- Immunological General Body composition Degree of Arteriosclerosis anti-oxidization Serum hormones losis related items tests check-up items analysis balance Carotid arterial echogram Total cholesterol 8OHdG Growth hormone Natural Killer WBC Body fat ratio Iitima Media Thickness (IGF-1) nuclear (White corpus- (Somatomedin C) (Natural Killer cles count) nuclear activity) Max thickness Low Density Lipoprotein LPO Thyroid hormone IL-6 RBC Muscular distribution of Carotid artery Cholesterol (LDL-C) (Lipid peroxide) (FT4) (High sensitivity (Red corpuscles Interleukin) count) ABIR High Density Lipoprotein Iso plus tongue Adrenal cortex Hb BMI (Blood-pressure ratio of Cholesterol-2 (HDL2) generation hormone (Amount of right upper arm & right ankle) speed (Cortisol) hemoglobin) ABIL High Density Lipoprotein Free testosterone Ht W/H ratio (Blood-pressure ratio of Cholesterol-3 (HDL3) (Isolation) (Hematocrit) left upper arm & left ankle) RBPWV Triglyceride (TG) STAS DHEA-s PLT Bone mass (RB Pulse wave sound wave (Dehydroepiandros- (The number of velocity) terone sulfate) blood platelets) RAPWV Free fatty acid (FFA) Vitamin A Ferritin Body measurement (RA Pulse wave sound wave (Waist measurement) velocity) LAPWV Lpa Vitamin C GOT Balanced function (LAPulse wave sound wave (Lipoprotein-a) (Center-of-gravity velocity) gitation) ASI RLP-C Vitamin E GPT Back strength (Arterial stiffness index) (Remnant style liboprotein) Inspection of of the fundus Adiponectin β-Carotene γGT Grip ICAM-1 All PAI-1 Vitamin B12 LDH Oxygen saturation (Plasminogen) Platelet activation Fibrinogen Folic acid Blood suger Bone density (DXA) (dual energy x-ray bsorptiometric scan) All homocysteine HbA1c (Fixed quantity Amino acid) High sensitivity CRP CPR (C Peptide) HDL-C CRE Cysteine C Uric acid (UA) Fe Ca Alterations of Amino Acid pepsinogen (PG) 《LA》pepsinogen The pillory antigen in stools

HEP Vol.42, No.4, 2015 (467) 33 health check-up or were interested in the anti-aging health check- received the check-up, and 75.4% of these were repeat recipients. up system (Fig. 2). As for the content expected of the system, Around 95% consented to the research, with the data collected respondents (1) wanted to know their level of arteriosclerosis, (2) being strictly stored and managed as well as being used for wanted to know if they were naturally predisposed to stroke or analysis. Few are smokers, about 70% exercise regularly, and heart attacks, (3) wanted to know about exercise therapy, and (4) about 60% use supplements. wanted to receive guidance on health maintenance and fitness2). We accumulated and analyzed the data, then reflected the To reflect these results, we included various services in our Anti- results in the interview and intervention. Our evaluation of the Aging Health Check-up System besides the actual check-ups data for individuals who received the check-up once, by gender themselves. A good example is the 30-minute consultation with a and age, revealed a strong correlation with advancing age in the doctor, designed to enhance health levels through two-way arteriosclerosis markers baPWV and IMT (increase), sex hor- exchange with the patient. This is very beneficial for obtaining mones (DHEA-S, testosterone, estradiol (decrease), free fatty guidance on diet and exercise from a specialist, taking into acids (increase) and cystatin C (increase), IGF-1 (decrease), sys- account not only the check-up results but also past medical his- tolic blood pressure (increase), and body fat percentage (increase). tory, history of present illness, types of medication taken, and so This research was very useful in that we were able to confirm, in on. Also, the “anti-aging lunch” we provide includes more than the same group of Japanese individuals, factors strongly corre- 35 ingredients consisting mainly of anti-oxidant foods. It contains lated with advancing age, as well as surrogate markers for its less than 5 g of salt as a low-salt diet, and is provided together effects. This enabled us to give guidance based on aging-related with recipes and an explanation of nutrients. Besides this, indi- physiological changes3). vidual exercise guidance is available upon request1). We recognized early on that there were conspicuously abnor- mal values in “kakurehiman,” which means the same as normal 3. Indicators tested in the Anti-Aging Health Check- weight obesity (NWO), whereby BMI is within the normal range up System yet the body fat percentage is high. We reported that the number Examination items in the Anti-Aging Health Check-up System of individuals categorized under NWO tended to increase with are broadly divided into those that show the present degree of age among both men and women, and that various factors associ- aging and factors that contribute to aging. These correspond to ated with lifestyle-related diseases in this group had deteriorated “aging” and “aging risk factors” as defined by the Japanese to the same level as in obese individuals (Fig. 4, 5)4). Based on Society of Anti-Aging Medicine (Fig. 3). The former category this supporting evidence, we are promoting exercise regimes that comprises indicators such as arteriosclerosis, in which changes increase protein intake and boost muscle volume, or at least do due to aging are clear, while the latter is concerned with indica- not decrease them, in our health guidance under the Anti-Aging tors like HDL cholesterol, which are clearly influenced on that Health Check-up System. “aging” but fluctuate irrespective of aging. Items in the former We are very interested in knowing whether age-related changes category reveal changes with time, and do not change greatly improve as a result of guidance under the Anti-Aging Health when the same person is tested under the same conditions, while Check-up System. In the results aggregated on a pilot basis soon the latter tends to reflect the person’s recent lifestyle. The Anti- after the launch of the system, a comparison of the rate of change Aging Health Check-up System assesses the degree of aging in in just 25 individuals before and after they underwent this hospi- terms of Arterial sclerosis, hormones, body composition, lung function, visual function, hearing function, bones, nerves, etc., and aging risk factors in terms of blood lipids, oxidative stress （H（igHhig）h） NormNormal al and scavengers, mental and physical stress, and other general WeightWeight Fatt y Fatt y indicators. Examination items included in the Anti-Aging Health MaleMale Female Female ObesityObesity ObesitObesity y Check-up System at Tokai University Tokyo Hospital are shown 2525 30 30 3) in the table (Table 1) . att y att y Mild f Mild f % % 4. Actual use and findings of the Anti-Aging Health 2020 25 25 Check-up System skinnyskinny ControlControl AthAthletelete typetype The average age of individuals tested under the Anti-Aging Normal Normal Body fat Body fat Health Check-up System is 63.7 years for males and 61.7 for 1515 20 20 females. The gender ratio is 54% male compared to 46% female. fa t fa t Of the total, 57% also receive a general health check-up at the （ （ ） ） Low Low same time, while some options for tumor marker, upper and LowLow lower endoscopy, or pulmonary helical CT scans, or seek broadly PoorPoor NormalNormal ObesObesity ity holistic tests within a short period of time. By age group, indi- 18.518.5 25 25 30 30 viduals in their 60s account for the largest proportion with one- BMIBMI［ Weight［ Weight (kg) (kg) ÷ ÷HeightHeight (m) (m)2 ］2 ］ third of the total, and more than 80% of all those tested are aged Fig. 4 Body compositions evaluated by BMI and Body fat rate 50 to 70. As of March 2015, more than 1,640 individuals had in our study

34 (468) HEP Vol.42, No.4, 2015 Nishizaki et al.: Fatal Fatty Liver NASH

(mm/sec) 2500 right left ＊ P >0.05 vs control N.S. Not significant NOW vs Obesity

＊ ＊ N.S. N.S. 2000 ＊ ＊ ＊ ＊ ＊

1500

1000 Control NWO Obesity Control NWO Obesity

Male Female NOW: Normal Weight Obesity Fig. 5 PWV worsened in NOW group as same level as real obesity

＊ P＜0.05 101 Rt Lt 100 98.8 98.7 ±0.05 98.6 ±0.08 99 ±0.07 98.6 97.7 97.7 ±0.06 98.4 97.4 ±0.07 ±0.09 98 ±0.06 ±0.07 98.0 ±0.08 97.4 96.3 97 ±0.07 97.2 ±0.07 ±0.08 96 95.9 ±0.07

% basal change (%) % basal change 95 94.2 ±0.06 94

93 1st 2nd 3rd 4th 5th 6th 7th 8th

n=136 n=74 n=48 n=31 n=21 n=11 n=5 Male Male Male Male Male Male Male Female Female Female Female Female Female Female Fig. 6 ABI tended to improve in repeated recipient tal’s Anti-Aging Health Check-up System showed that PWV with the target of extending life expectancy; it should be judged (which clearly rises with age) tended to be suppressed after guid- objectively, without ignoring conflicting evidence, while suffi- ance, while there was no change in the rise in DHEA, which cient information should be provided and options offered to those clearly decrease with age. These and other changes were recog- receiving the check-ups. nized after just one year5). Some individuals have finished their As issues for the future, it may be necessary to formulate new 9th check-up, and many of them have kept aging-related markers health (aging) indicators and biomarkers that also take into steady or actually improved them6) (Fig. 6). account genetic testing, etc., to create an academic system of health guidance, and to globalize health-related medical care. In 5. Problems with the Anti-Aging Health Check-up view of the super-aging society, we hope that this kind of health System and future issues assessment and guidance method will take root and flourish. The rationale of the Anti-Aging Health Check-up System, which assumes advancing age to be the biggest risk factor for The authors state that they have no Conflict of Interest (COI). disease and aims to identify signs and intervene at an early stage, is considered an appropriate step in the right direction in terms of REFERENCES primary prevention. However, it may not always be possible to clearly convey its importance due to its complex nature. To prop- 1) Nishizaki Y, Kubo A, Kuwahira I, Kuroda E, Nigou N, Motegi S, erly develop this aspect, it should always be based on evidence et al. Anti-aging health check-up system: For the prevention of

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