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Morbidity of Tokyo-Area Centenarians and Its Relationship to Functional Status

¹ Division of Geriatric Medicine, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
² Tokyo Metropolitan Institute of Gerontology, Japan.
³ Health Care Center, Shoko Chukin Bank, Tokyo, Japan.
⁴ Tohoku Bunka Gakuen University, Miyagi, Japan.

Address correspondence to Michiyo Takayama, MD, Division of Geriatric Medicine, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582 Japan. E-mail: michiyo{at}sc.itc.keio.ac.jp

	Abstract

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Background. Research in Western countries has shown most centenarians to be survivors with multiple comorbidities. However, Japanese centenarians' morbidity and its relationship to functional status has yet to be elucidated. The aim of this study is to clarify the association of morbidity with the physical and cognitive function of centenarians. We examined Tokyo-area centenarians to determine their kinds of morbidity profiles and how such morbidity related to their functional status.

Methods. We studied 302 centenarians living in Tokyo (101.2 ± 1.8 years; 65 men, 237 women), and assessed their physical status, morbidity, and use of medication. Activities of daily living and cognitive function were also assessed using the Barthel Index and the Clinical Dementia Rating.

Results. More than 95% of the centenarians had chronic diseases. Both the physical and cognitive functions were significantly higher in men. The present and previous illnesses most frequently included hypertension, heart disease, stroke, fractures, and cataracts. Fractures were observed significantly more frequently in women. Diabetes mellitus was uncommon. The physical and cognitive function of centenarians with a history of stroke or fracture were particularly poor, whereas those centenarians with hypertension tended to show a high level of physical and cognitive function.

Conclusions. Almost all centenarians had chronic diseases. Stroke and fracture were correlated with poorer function; therefore, we hypothesize that prevention of stroke and fracture might improve functional status in the oldest-old.

At present, more than 25,000 centenarians live in Japan (13); as the number of such centenarians is increasing rapidly, there are now various phenotypes of centenarians that can be observed—namely, most centenarians seem to be frail (physically dependent or have low cognitive function), but there is a small number of centenarian individuals with excellent physical and cognitive functions (14). Advanced medical technology, socioeconomic growth, and improvement of social welfare may have in combination contributed to such a phenomenon. A chronological study of Okinawan centenarians has shown the levels of the activities of daily living (ADL) to have declined markedly during the 20-year period from the 1970s to the 1990s and that the decline in physical activities was clearly observed in institutionalized persons (15), thus suggesting that medical intervention and adequate care might allow survival with exceptional longevity even in less genetically robust individuals. The National Institute on Aging (NIA) Advisory Panel on Exceptional Longevity concluded that it is of great importance to understand the factors that contribute to an exceptional "health span" (survival without disease or disability) (16). However, the relationship between disease and disability among exceptionally old people has been unclear. From this point of view, we examined the physical status and morbidities of Japanese centenarians living in the Tokyo metropolitan area. We assessed what kinds of morbidity they experienced, and how such morbidity related to their functional status.

	METHODS

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Overview of Study and Participants
The data analyzed herein were collected as part of the Tokyo Centenarian Study, initiated in 1992 (17); the sampling methodology has been described in detail elsewhere (14,18). In summary, we collected centenarians (100 years old and older) and candidates for becoming centenarians (persons who were assumed to turn 100 years old by March 31, 2002) during the sampling period (between July 2000 and May 2002). To obtain residential information on persons for recruitment, we collected name, birth date, gender, and address of people who were older than 97 years from the basic residential register at the administrative institution of each of 23 wards of the Tokyo metropolitan area, in which all residents (about 8 million) were listed. The total number of persons identified was 1194, and we sent all of them a letter asking them to participate in our study. As a result, we recruited 513 centenarians (43% of the invitees). Among 681 centenarians who did not participate in this study, 100 died before recruitment, and 46 had a different address from what we were given. There was no difference in gender distribution or mean age between the 513 centenarians who agreed to participate and the 535 who did not (p =.209, p =.449, respectively).

First, we mailed the 513 centenarians a questionnaire about their residence, family members, smoking and alcohol habits, physical activities, medical history (past and present illness), and current medications. Second, we asked them to participate in a home survey, during which our visiting survey team (including a geriatrician, a psychologist, and a practical nurse) examined their physical status, ADL, and cognitive function. A total of 304 centenarians (25% of invitees, age 100–108 years, mean age 101.1 ± 1.7 years; 65 men, 239 women) agreed to participate in our visiting survey. The male-to-female ratio in our participant group was 1:3.6, which was not significantly different from the ratio in the total centenarian population in this area (1:3.8).

Prior to participation, written informed consent was obtained either from the centenarians or their proxies. This study was approved by the Ethics Committee of Keio University School of Medicine.

Data Collection
All of 304 centenarians were examined by our visiting survey team consisted of three specialists; a geriatrician, an experienced psychologist, and a practical nurse. Before visiting, we reviewed questionnaire replies regarding social background, smoking and alcohol habits, physical activities, medical history (past and present illness) and current medications. These questionnaires were answered by centenarians with the help of their proxies or caregivers. There were 10 centenarians (6 men, 4 women) who had answered the questionnaires by themselves. If there were any inappropriate answers in the questionnaires, we asked the participants or their proxies to confirm these answers; however, we could not get answers about medical history from two women because of their refusal, so we excluded these two women from this study. The resulting 302 total centenarians (65 men, 237 women) were finally enrolled in this study. Regarding specific questions about medical history, we made a list of common diseases as a matter of convenience, and also asked about any operations they underwent. A part of the questionnaire used in this study is given in Appendix I.

We chose the following diseases because they are known to be major age-related diseases or life-threatening diseases: hypertension, heart disease, cerebrovascular disease, pulmonary tuberculosis, respiratory disease, renal disease, type 2 diabetes mellitus (T2DM), Parkinson's disease, and malignant disease. We also included diseases that commonly influence the centenarians' quality-of-life (QOL) (gastrointestinal disease, collagen disease, fractures, and cataracts). The classification of diseases was based on the International Classification of Diseases, 10th Revision (ICD-10) (19) as follows: hypertension (I10), heart disease (I20–I22, I25, I48, I50, Z95.0), cerebrovascular disease (I60–I63), gastrointestinal disease (K21, K25–K27, K29, K59), pulmonary tuberculosis (A15, A16), respiratory disease (J18, J43–J45), renal disease (N05, N18, N19), T2DM (E11), collagen disease (M05, M06, M30–M35), Parkinson's disease (G20), malignant disease (C00–C97), fractures (M80), and cataracts (H25).

In Japan, it is prohibited to review personal medical records. As a result, the prevalence and onset of these diseases were obtained from personal interviews and medical examinations (a general examination, measurement of blood pressure in arm, an electrocardiogram, and blood test) by a geriatrician. Also, a geriatrician and a nurse checked all prescription or pill containers. ADL and cognitive function were assessed by a psychologist using the Barthel Index (20) and the Clinical Dementia Rating (CDR) (21). The diagnostic criteria used in this study are given in Appendix II.

Statistics
Statistical analyses were conducted using the SPSS 13.0J software package (SPSS, Chicago, IL). The variables are presented as the mean ± standard deviation. Comparisons between two groups were analyzed by using the Mann–Whitney U test. The chi square test was used to compare categorical data. A p value of <.05 was considered to indicate statistical significance, and two-sided tests were applied.

	RESULTS

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Characteristics of Centenarians
The characteristics of the centenarians are shown in Table 1. No significant differences were seen between participants and nonparticipants in the visit phase as to gender, living situation, smoking and alcohol habits, educational background, and work experience, although significant differences concerning age and residence were noted between these two groups. Among participants, approximately 80% were women and 20% were men. The Barthel Index was significantly higher in men than in women (overall, 44.2 ± 34.9; men, 59.2 ± 34.9; women, 40.1 ± 33.8; p <.01), and the CDR score was significantly lower in men than in women (overall, 1.72 ± 1.63; men, 1.06 ± 1.46; women, 1.90 ± 1.63; p <.01). About 70% of centenarians were living at home, and 30% at a nursing home or a long-term-care hospital. Among centenarians living at home, eight lived by themselves, two lived with their spouses, and nearly all others lived with their families (i.e., sons, daughters, and grandchildren). Chronic illness was present in 294 centenarians (97.4%). About two-thirds of the centenarians regularly took medication ranging from 1 to 12 different medicines (mean; 5.0 ± 2.6).

	DISCUSSION

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As in previous studies (3–9), the prevalence of cardiovascular diseases such as hypertension, heart disease, and cerebrovascular disease was high. Notably, the prevalence of T2DM was very low. According to a nationwide survey of the prevalence of circulatory disease in Japanese adults (30 years) in 2000 (22), the prevalence of T2DM was 2.6% in persons in their 30s, 6.3% in their 40s, 11.6% in their 50s, 15.3% in their 60s, and 14.7% in elderly persons (70 years). In our present study, only 6.0% of centenarians had T2DM, a percentage that was lower than that of individuals in their 40s. It is well-known that the prevalence of diabetes is higher in Finland than in other countries. The Finnish Centenarians Study (8) revealed that the prevalence of T2DM in Finnish centenarians was 10%. Although that percentage seems to be higher than that of our participants, it was lower than that in 65- to 85-year-old people living in Finland. Moreover, our result was comparable to those in previous reports from the Italian Multicenter Study on Centenarians (23) (4.9% of 602 centenarians, lower than that of 65- to 84-year-old elderly persons) and from the New England Centenarian Study (4% of 424 centenarians) (3). Our result was also in accordance with those from a previous report by Paolisso and colleagues (24), which demonstrated a better preservation of glucose tolerance and insulin action in centenarians compared to elderly persons older than 75 years. In addition, Barzilai and colleagues (25) recently demonstrated that larger high-density lipoprotein and low-density lipoprotein particle sizes were associated with a lower prevalence of hypertension, cardiovascular disease, metabolic syndrome, and longevity. This accumulating evidence suggests that a protective phenotype exists against metabolic syndrome that may be very important for survival to an advanced age.

Regarding hypertension (under treatment or 140/90 mmHg), a nationwide survey indicated the prevalence of hypertension in 5.3% of persons in their 30s, and it increased gradually with age to 11.0% in persons in their 40s, 23.4% in their 50s, 33.0% in their 60s, and 45.4% in elderly persons ( 70 years old) (22). Our present study revealed a relatively high prevalence (63.6%) compared with the findings of a nationwide survey. Even if we used the moderate hypertension criteria (26), 160/90 mmHg, the prevalence of hypertension would have been 49.0%. It seems that the prevalence of hypertension grows higher even in exceptionally old persons.

The nationwide survey also showed the prevalence of cerebrovascular disease to be <1.0% in Japanese young adults, 1.7% in persons in their 50s, 4.1% in their 60s, and 8.9% in elderly persons (70 years old) (22). In comparison with this survey, the prevalence of cerebrovascular disease in centenarians in our study was high. Recently, an Okinawan centenarian study revealed the lifetime prevalence for stroke to be 11.0%; moreover, about two-thirds of such strokes had occurred at 90 years of age (27). The New England Centenarian Study (3) showed the prevalence of stroke in U.S. centenarians to be 14% in men and 15% in women. Our results presented in this study therefore appear compatible with the above findings.

Another remarkable finding about the morbidity profile was that no lung cancers were observed in our study. An autopsy report of Japanese centenarians demonstrated that cancers were observed in 16 of 42 cases (38%) and that the total number of cancer lesions was 22 (most [82%] were subclinical). The most frequent cancer was colon cancer (eight foci), and urinary bladder cancer was the next most prevalent (three foci). Lung cancer, stomach cancer, and malignant lymphoma were observed in the same order (two foci) (28). A recent American study about the prevalence of cancer in nonagenarians and centenarians reported that centenarians and nonagenarians had a lower lifetime prevalence of lung cancer than was shown in data from the National Cancer Institute (29). The Finnish Centenarians Study showed that only one participant had lung cancer despite the fact that the prevalence of cancer increased steadily with age (8). Our results were in agreement with these findings, and centenarians might thus have a relatively lower incidence of cancer, especially lung cancer.

Associations Between Morbidity and Functional Status
To determine how morbidity was related to function, we assessed the impact of the prevalence of six age-related diseases on centenarians' ADL and cognitive function. Our findings demonstrated stroke and fracture to be associated with a decline in physical activity and in cognitive function. These two illnesses are widely recognized to be major reasons for elderly persons to be bedridden; as a result, these findings are considered to be reasonable. However, caution is needed to consider fractures as a marker of lower levels of physical and cognitive function because frail elderly persons are more prone to suffer a fracture. The causality of fracture and functional decline could not be evaluated because the design of our study was cross-sectional. Regarding gender differences, levels of both physical and mental function were higher in men than in women as shown in Table 1, and the higher incidence of fracture in women may have affected their decline in functional status.

It is interesting that our data indicated that centenarians with prevalent hypertension (including those under treatment) maintained better physical and cognitive function than did participants with relatively low blood pressure levels. Moreover, when we used moderate hypertension criteria (160/90 mmHg) (26), the beneficial effects of hypertension on ADL and cognition remained (Barthel Index, 36.9 ± 34.5 vs 51.8 ± 33.8, p <.01; CDR score, 2.00 ± 1.65 vs 1.42 ± 1.57, p <.01, in absent vs prevalent hypertension, respectively). We reviewed a previous report about the beneficial-appearing relationships between centenarians' high blood pressure and functional independence (30). According to this report, centenarians who were physically independent showed significantly higher systolic blood pressure, better cognitive function, and lower prevalence of stroke in comparison to centenarians who required physical assistance. A Finnish study (8) also showed that mentally independent and completely independent (healthy) centenarians had higher systolic blood pressure than did centenarians who were moderately or severely demented or physically ill. Based on these observations, we hypothesize that mild to moderate hypertension (140–160/80–90 mmHg) might have a favorable effect (or at least not have a harmful effect) on the functional status of centenarians. However, because of the cross-sectional design of our study, we could not rule out the alternative explanation for the association between high blood pressure and better function in centenarians. For example, it might be possible that hypertensive persons with poor physical and cognitive function tended not to survive until the age of 100. Longitudinal observation is needed to address this issue.

There are large-scale controlled clinical trials of antihypertensive therapy (the Systolic Hypertension in the Elderly Program [SHEP] and the Systolic Hypertension in Europe study [Syst-Eur]) in older patients with isolated systolic hypertension (ISH), defined as systolic blood pressure of 160–219 mmHg with a diastolic blood pressure <90 or <95 mmHg. These trials have demonstrated a decrease in clinical events such as stroke, myocardial infarction, and heart failure in elderly persons older than 65 years who undergo antihypertensive treatment (31,32). Although it is difficult to compare our study with these trials because the study design was different, there are several important factors of interest. In our study, participants who were defined as ISH were few (only 38; 12.5%), and the mean blood pressure was lower than that in SHEP (31) or Syst-Eur (32); that is, 152.1 ± 20.0/80.0 ± 13.4 mmHg in centenarians with hypertension, and 118.9 ± 11.8/70.1 ± 8.8 mmHg in centenarians without hypertension. Among the oldest-old enrolled in our study, those with a greater risk for cardiovascular events might have already been selected due to differential survival. Further study is required as to whether one should treat or not and which level should be the target blood pressure if treatment is chosen in the oldest-old (such as centenarians).

The prevalence of heart disease, T2DM, and cancer was not associated with our centenarians' physical activities and cognitive function. Almost all cancers reported in this study had been cured surgically, except for a minority component of slow-growing, nonlife-threatening cancers such as prostate and nonmelanoma skin cancers. If a cancer is treated effectively, the harmful effects on physical activities and cognitive function in late life can thus be minimized.

Study Limitations
There were several limitations to this study. It is important to note that population studies of extremely old people may sometimes be affected by a selection bias, because relatively healthy people tend to be selected. The participation rate of this study was 43% in the mailing survey and 25% for the visiting survey. This participation rate was lower than rates reported in other centenarian studies (3–5,7,8). According to our prior study of Tokyo-area centenarians, the participation rate was 43%, which was the same as in the present mailing survey (17). To confirm medical condition and physical status, we had to limit the centenarians to only those participating in the visiting survey; this resulted in a lower participation rate. Recently, Selim and colleagues (33) reported a mailing survey of 273 centenarians from veteran enrollees with a 37% response rate. They reported that the prevalence of dementia and the mortality rate were higher in the nonrespondents than in the respondents, and they considered these differences as plausible explanations for the low response rate. Although we did not find significant differences in gender and age distribution between participants and nonparticipants in our study, we could not get data on morbidity or physical function of nonparticipants. Thus we cannot exclude the possibility that we had sampled relatively healthier centenarians, so our results should be cautiously compared with other centenarian studies with high participation rates.

There is another difficult problem in centenarian studies—namely, how to obtain accurate medical histories of the participants. In Japan, the morbidity registry system is not well established, and because of legal restrictions it is very difficult to review official medical records. Moreover, it is uncommon that extremely old people get high-level clinical examinations, so underlying pathological conditions tend to be underdiagnosed. To obtain more accurate information about medical histories, we visited centenarians directly and assessed their physical conditions by a trained geriatric physician, took blood samples, asked not only centenarians but their proxies or caregivers about detailed health conditions, and investigated all medications thoroughly. As a result, we considered the medical information from our participants to be reliable. However, it cannot be ruled out that some underdiagnosed diseases could have been missed.

Conclusion
In investigating the medical conditions, ADL, and cognitive function even among a select group of Tokyo-area centenarians, we found several distinctive characteristics. More than 95% of Tokyo-area centenarians had chronic disease, and >60% took at least one medication regularly. The levels of physical and cognitive function in men were higher than in women. The prevalence of cardiovascular diseases, such as hypertension, heart disease, and cerebrovascular disease was high, whereas T2DM was infrequently observed. The prevalence of stroke and fracture was related to poor physical and cognitive function; in contrast, hypertension was associated with higher functional status. Prevention of stroke and fracture may improve the QOL, and mild-to-moderate hypertension may have a favorable effect on functional status in the oldest-old. Further prospective studies are needed to elucidate how morbidity affects function in exceptionally old persons, including octogenarians and nonagenarians. It would be helpful to use performance-based measures of physical function, such as muscle strength, and tests of walking and balance to define the healthy aging phenotype more precisely than defining it based on disease prevalence alone (34).

	APPENDIX I. QUESTIONNAIRE ABOUT PAST AND PRESENT ILLNESS

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In this section, we would like to ask you about past and present illnesses, especially age-related diseases listed below. Please read the following questions and circle the number (1. Yes or 2. No). If yes, please write down the age of onset of the disease if you remember. Moreover, if you are under treatment, please check in the boxes.

• I. Have you ever been diagnosed with hypertension?
  
• 1. Yes / ( ) years. Under treatment?
  
• 2. No
  
• II. Have you ever been diagnosed with one or more of the following: congestive heart failure, angina pectoris, myocardial infarction, arrhythmia, valvular heart disease, and/or pacemaker implantation?
  
• 1. Yes / ( ) years. Under treatment?
  
• 2. No
  
• III. Have you ever been diagnosed with one or more of the following: cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, and/or subdural hematoma?
  
• 1. Yes / ( ) years. Under treatment?
  
• 2. No
  
• IV. Have you ever been diagnosed with one or more of the following: gastritis, peptic ulcer, gastroesophageal reflux disease, irritable colon, and/or constipation?
  
• 1. Yes / ( ) years. Under treatment?
  
• 2. No
  
• V. Have you ever been diagnosed with pulmonary tuberculosis?
  
• 1. Yes / ( ) years. Under treatment?
  
• 2. No
  
• VI. Have you ever been diagnosed with one or more of the following: pneumonia, bronchial asthma, and/or chronic obstructive pulmonary disease?
  
• 1. Yes / ( ) years. Under treatment?
  
• 2. No
  
• VII. Have you ever been diagnosed with chronic renal disease or chronic renal dysfunction?
  
• 1. Yes / ( ) years. Under treatment?
  
• 2. No
  
• VIII. Have you ever been diagnosed with type 2 diabetes mellitus?
  
• 1. Yes / ( ) years. Under treatment?
  
• 2. No
  
• IX. Have you ever been diagnosed with collagen disease?
  
• 1. Yes / ( ) years. Under treatment?
  
• 2. No
  
• X. Have you ever been diagnosed with Parkinson's disease?
  
• 1. Yes / ( ) years. Under treatment?
  
• 2. No
  
• XI. Have you ever been diagnosed with any cancer?
  
• 1. Yes / ( ) years. Under treatment?
  
• 2. No
  
• If yes, what kind of cancer? Please write precisely.
  
• ( )
  
• XII. Have you ever had any fractures?
  
• 1. Yes / ( ) years. Under treatment?
  
• 2. No
  
• If yes, which bone did you break?
  
• ( )
  
• How did you treat your fractures?
  
• ( )
  
• XIII. Have you ever been diagnosed with cataracts that affected your visual acuity a great deal?
  
• 1. Yes / ( ) years. Under treatment?
  
• 2. No
  

QUESTIONNAIRE ABOUT SURGICAL OPERATION
In this section, we would like to ask you about surgical operations. Please circle the number (1. Yes or 2. No). If yes, please write down what kinds of operations and your age at the time of the operation (if you remember).

• I. Have you ever had any surgical operations?
  
• 1. Yes
  
• What kind of operation? ( )
  
• ( ) years
  
• 2. No
  

QUESTIONNAIRE ABOUT MEDICATION
In this section, we would like to find out about any medicines, vitamins, nutritional supplements, and/or herbal medicines you have taken regularly. Please circle the number (1. Yes or 2. No). If yes, please write down what kinds of medicines you have taken.

• I. Have you regularly taken any medicines that were prescribed by a doctor?
  
• 1. Yes
  
• What kinds of medicines? ( )
  
• No
  

	APPENDIX II. THE DIAGNOSTIC CRITERIA USED IN THIS STUDY

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The classifications of diseases are based on the International Classification of Diseases, 10th revision (ICD-10) (19).

All diagnoses are included under treatment or past histories.

The definitions of diseases used in this study are as follows:

Hypertension (I10): if diagnosed by a physician. We also regarded participants with blood pressure 140/- or -/90 mmHg as hypertensive, in accordance with the guidelines of the Japanese Society of Hypertension (26). We included all centenarians even if they had normal blood pressure during examination because of treatment. Blood pressure was measured two times at the arm in the supine position with a mercury sphygmomanometer, and the lower blood pressure was used.

Heart disease (I20–I22, I25, I48, I50, Z95.0): if a physician had diagnosed one or more of the following: congestive heart failure, angina pectoris, myocardial infarction, arrhythmia, valvular heart disease, and/or pacemaker implantation. The diagnosis of congestive heart failure was considered actual if the centenarian was under treatment or if specific signs were found on physical examination, such as S₃ or S₄ gallop, elevated jugular venous pressure, pulmonary rales, and/or dependent edema. Pathological findings on electrocardiogram were noted for the diagnosis of angina pectoris, myocardial infarction, arrhythmia, and pacemaker implantation; Minnesota Code 1-1, 1-2, and 1-3 for the diagnosis of myocardial infarction, Minnesota Code 4-1, 4-2, 4-3, and 4-4 for ischemia, Minnesota Code 8-3-1 and 8-3-2 for atrial fibrillation and flutter, and Minnesota Code 6-8 for pacemaker implantation.

Specific medications taken by centenarians were also noted for diagnosis: aspirin, warfarin, nitrates, coronary vasodilators, beta-blockers, angiotensin-converting enzyme inhibitors, calcium channel blockers and antiarrhythmic agents.

Cerebrovascular disease (I60–I63): if a physician had diagnosed one or more of the following: cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, and/or subdural hematoma. Focal neurological signs found on neurological examination were also considered valid.

Gastrointestinal disease (K21, K25–K27, K29, K59): if a physician had diagnosed one or more of the following: gastritis, peptic ulcer, gastroesophageal reflux disease, and/or constipation. Specific medications taken by centenarians were also noted for diagnosis: H₂-recepter antagonists, proton pump inhibitors, other antacids, and laxatives.

Pulmonary tuberculosis (A15, A16): if diagnosed by a physician.

Other respiratory disease (J18, J43–J45): if a physician had diagnosed one or more of the following: pneumonia, bronchial asthma, and/or chronic obstructive pulmonary disease. Specific medications taken by centenarians were also noted for diagnosis: inhaled steroids, long-acting beta-agonist bronchodilators, theophylline, and anticholinergic agents.

Renal disease (N05, N18, N19): if a physician had diagnosed any type of glomerulonephritis or chronic renal failure. We also regarded participants with serum creatinine 1.5 mg/dL as having chronic renal failure.

Type 2 diabetes mellitus (E11): if diagnosed by a physician. We also regarded participants with postprandial plasma glucose 200 mg/dL or hemoglobin A1c 7.0% as diabetic. Hemoglobin A1c was measured by an isoelectric focusing method with a normal range of 4.3%–5.8%. Specific medications taken by centenarians were also noted for diagnosis: sulfonylureas and alfa-glucosidase inhibitors.

Collagen disease (M05, M06, M30–M35): if a physician had diagnosed any type of collagen disease (e.g., rheumatic arthritis, systemic lupus erythematosus, and/or dermatomyositis). Collagen disease is identified as a specific intractable disease that is eligible for medical benefits by the Ministry of Health, Labor and Welfare.

Parkinson's disease (G20): if diagnosed by a physician. Parkinson's disease is identified as a specific intractable disease that is eligible for medical benefits by the Ministry of Health, Labor and Welfare.

Malignant disease (C00–C97): if diagnosed by a physician.

Fracture (M80): if diagnosed by a physician.

Cataract (H25): if a physician had diagnosed corneal opacification that either substantially interfered with visual function or necessitated treatment.

	Acknowledgments

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This work was supported by a grant for a multidisciplinary study of centenarians and its international comparison (principal investigator, Nobuyoshi Hirose) sponsored by the Ministry of Health, Labor and Welfare of the Japanese Government, and partly by a grant sponsored by the Keio Health Counseling Center, Tokyo, Japan.

We sincerely appreciate the assistance of the centenarians, their families, and caregivers. This study could not have been conducted without their cooperation. We also thank Kanoko Konishi, Junko Akiyama, and Yoshiko Kanno for their cooperation and Yukiko Abe for her assistance.

	Footnotes

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Decision Editor: Luigi Ferrucci, MD, PhD

Received October 7, 2005

Accepted October 11, 2006

	References

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