Functional alteration of granulocytes, NK cells, and natural killer T cells in centenarians.

The immune system in centenarians was characterized as elevated levels in the proportion and number of granulocytes, NK cells, and extrathymic T cells (including NKT cells) in the peripheral blood. Conventional T cells, abundant in youth, were decreased in proportion and number. In addition to this numerical change in centenarians, the function was significantly altered in comparison with that in middle-aged subjects. The phagocytic function and cytokine production of granulocytes in centenarians increased whereas the production of superoxides from granulocytes decreased. This tendency was almost the same in both healthy and unhealthy centenarians. IFN gamma production by NK and extrathymic T cells in centenarians seemed to be augmented and resulted in an elevated level of serum IFN gamma. Possibly due to the effect of this endogenous IFN gamma, the proportion of CD64(+) (Fc gamma RI) cells among granulocytes was elevated. The expansion of CD64 antigens on granulocytes is known to be regulated by IFN gamma and to be associated with their induction of phagocytosis. These results suggest that the immune system of centenarians is not merely impaired, but altered in terms of the number and functions of granulocytes, NK cells, NKT cells.

[Serum globulin levels and activities of daily living in centenarians].

Serum globulin levels in 101 centenarians (77 women, 24 men) were analyzed by zonal electrophoresis and immunoglobulin assays. Six subjects showed an M band in electrophoretograms. Five M bands were immunoglobulin G (IgG) type and one was IgA. One subject was suspected to suffer from IgG-type multiple myeloma, and the others were thought to have essential (benign) monoclonal gammopathy. The relationship between serum globulin levels and activities of daily living (ADL) was studied in remaining 95 subjects. There were 21 rank-J (free-living), 25 rank-A (unable to go outside without help), 23 rank-B (bedridden but able to sit on the bed), and 26 rank-C (completely bedridden) centenarians. The mean serum alpha 1-, alpha 2-, and beta-globulin level in the rank-J centenarians was at the upper limit of the normal adult range. The mean alpha 1-globulin levels in rank-B (3.3 +/- 0.4%) and C (3.4 +/- 0.5%) subjects were significantly higher than those in rank-J (2.9 +/- 0.3%) centenarians. The mean serum gamma-globulin level of rank-J centenarians (16.9 +/- 3.7%) was within the normal range. The mean gamma-globulin levels in rank-B (21.0 +/- 2.7%) and C (22.8 +/- 4.9%) subjects were significantly higher than that in rank-J centenarians. The mean immunoglobulin G concentrations in rank-B (1.620 +/- 304 mg/dl) and C (1.720 +/- 392 mg/dl) subjects were significantly higher than those in rank-J centenarians (1.320 +/- 361 mg/dl) and in normal adults (1.150 +/- 235 mg/dl). IgA concentrations in all centenarians were higher than in normal controls. There was no significant difference in IgA or IgM concentration between rank-J subjects and those in other ranks. Serum globulin levels measured with electrophoresis, and the immunoglobulin concentrations, can be valuable indicators of the ability to perform activities of daily living, and may be useful predictors of subclinical diseases or morbidity in centenarians.

[Okinawa Longevity Study. Molecular genetic analysis of HLA genes in the very old].

We analyzed HLA class II genes of Okinawan centenarians using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to identify primary genetic factors in the major histo-compatibility complex (MHC) region associated with human longevity. Gene frequencies of centenarians were compared with those of normal adults of the same ethnicity who were selected in the same vicinity as the centenarians. The following differences were identified in the HLA-DQB1 and DQA1 genes: the frequencies of DQB1*0503, DQA1*0101 (04) and DQA1*05 were increased in the centenarians, whereas those of DQA1*0102, DQA1*0103 and DQB1*0604 were decreased. Similarly, for the DRB1 gene, the frequencies of DRB1*0101, DRB1*1201 and DRB1*1401 were increased in the centenarians, whereas those of DRB1*0403 and DRB1*1302 were decreased. These data suggest that several alleles of the HLA-DRB1 and/or HLA-DQ genes are involved in human longevity.

[Serum albumin level and activities of daily living in centenarians].

The relationship between serum albumin level and activities of daily living was studied in 95 centenarians. There were 73 women (12 rank J: free-living, 18 rank A: unable to go outside without help, 20 rank B: bedridden but able to sit on the bed, 23 rank C: completely bedridden) and 22 men (9 rank J, 7 rank A, 6 rank B or C). The serum albumin level (mean +/- S.D. 4.0 +/- 0.4 g/dl) of the rank J women was at the lower limit of normal for young adults. The albumin levels of rank A, rank B, and rank C were 3.7 +/- 0.4 g/dl, 3.5 +/- 0.3 g/dl, and 3.4 +/- 0.4 g/dl, respectively. The levels of rank B and rank C women were significantly lower than that of rank J women. The albumin level of rank J men (3.9 +/- 0.3 g/dl) was lower than that of young adults. The albumin level of ranks B and C men (3.1 +/- 0.3 g/dl) was significantly lower than that of rank J men. The A/G ratio or albumin fraction (%) measured by serum electrophoresis was similar to that of the serum albumin level of centenarians of both sexes. There were no significant differences in the serum protein level or in the peripheral hemoglobin level between rank J centenarians and those of other ranks, for both sexes. The serum albumin level is a valuable indicator of the ability to perform activities of daily living and may be a useful prognostic index in centenarians.

Molecular genetic studies on DNA polymorphism of the HLA class II genes associated with human longevity.

Okinawan Japanese are well known for their longevity; the population rate of centenarians in Okinawa is about 3.8 times higher than that of the whole Japan, where the average life expectancies both among men and among women are the highest in the world. In this study, we analyzed HLA class II alleles of Okinawan centenarians by the polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) method for the purpose of clarifying the presence of primary genetic factors in the major histocompatibility complex (MHC) region associated with human longevity. DRB1*1401, DQB1*0503, DQA1*0101=0104 and DQA1*05 were significantly increased in the centenarians. The significant increase of HLA-DQB1*0503 and/or DQA1*0101=0104 in the centenarians can be explained by a linkage disequilibrium with DRB1*1401, or vice versa. Further, the tendency was observed toward increase with respect to DRB1*0101 and DRB1*1201. These data suggest that several alleles of the HLA-DRB1 and/or HLA-DQ genes are involved in human longevity.

[A study of bone density and lifestyles of high school girls].

To obtain basic data on the bone density of high school girls, the bone density of the right heel was measured in principle and their lifestyles were surveyed. The subjects were 142 girls (15-18 years, mean +/- SD = 16.5 +/- 0.8 years old) of a high school in Nagano Prefecture, who accepted our visiting bone health check. Bone density was measured with an 'Achilles' ultrasound bone-densitometer (Lunar Co.) and a self-registered questionnaire on their lifestyles was also employed in this study. The main results were as follows: 1. There were no significant correlations between Stiffness and, age, grade, bone fracture, family history, and regularity of menstruation. However, Stiffness significantly correlated to the age of menophania (r = -0.191, p = 0.002) 2. High school girls who belonged to a sports club had significantly higher bone density than other girls. Those who did-exercises which consist mainly of jumping, had significantly higher bone density than others who participated in running sports or did no exercise. There were also significant differences in the frequency of exercise and the duration of exercise. Moreover, those who had a regular exercise history had higher bone density than those who had no regular exercise history, and the mean Stiffness of the group that did exercises daily was higher than for those who did not. 3. There were no significant correlations between Stiffness and food intakes. There also were no significant difference for Stiffness concerning intake of calcium-containing food groups. Regarding the cause of weight loss of more than 2 kg/month, the mean Stiffness of the group with intense exercise was significantly higher than those in the no-weigh loss group and the group that had reduced dietary intake. 4. Regarding the relationships between bone density and the lifestyles of high school girls, a delayed age of menophania had a significantly decreasing effect on Stiffness, whereas three variables of regular exercise habits at present, body weight, and exercise histories had significantly increasing effects on Stiffness in multiple regression analysis. 5. It is considered that there may be other important factors in the relationship between bone density and lifestyle of adolescent females who are in a developmental state. Therefore, the measurement of bone density and its assessment need consideration from points of view which are different from those for middle-aged and the elderly people.

[Longitudinal and comprehensive follow-up study of the oldest man in Japan].

The oldest man in Japan reached the age of 112 years in October 1996. As an Okinawan centenarians, he had been followed closely for the previous 12 years. One sister, 8 years younger, was alive at the start of the study; all other family members were killed in the Okinawan War, 1945. The man did agricultural work until age 85, after which he continued to be physically active and to pay close attention to his health. Results of medical examinations, including blood tests, remained within the normal limits, with a few exceptions. Some abnormalities were found on the electrocardiogram; the red blood cell count and the hemoglobin and hematocrit values decreased relatively slowly. His intake of nutrients was relatively well-balanced, and at the age of 100 his intake energy was 1361 kilocalories per day, which is close to the value recommended for centenarians. His personality was categorized as "Type A", but the pattern was typical of that seen in other Okinawan centenarians. He was able to perform almost activities of daily living until the age of 108. At that time he was admitted to the hospital and his ability to perform those activities decreased sharply. His scores on the revised version of the Hasegawa dementia scale was within the normal range when he was 106 years old, but 3 years later it was in the "dementia" range. The rapidity of the decreases in his mental status and in his ability to perform activities of daily living that occurred when he was admitted to the hospital indicate that, if circumstances permit, elderly men may benefit from living at home with their families. Close attention to diet and exercise from youth through senescence may also contribute to health and longevity.

Energy and nutrient intakes of Okinawan centenarians.

Energy and nutrient requirements of younger people have been well studied, unlike that of centenarians. The average life span of the Japanese is the longest in the world, and the population of the very aged is rapidly growing. In addition, the average life span of Okinawan people is the longest in all of Japan. Their food habits also differ from other parts of Japan. To obtain basic dietary information, we surveyed 21 centenarians in Okinawa (17 women and 4 men). The dietary survey was done by one 24 h recall method, as was done for centenarians living throughout Japan (3). The energy intake of the Okinawan centenarians living at home was about 1,100 kcal/day for both sexes, which was similar to that of centenarians throughout Japan. Energy, some nutrient intakes and food consumption pattern (in terms of food groups) were different from those of the centenarians throughout Japan. We also measured their heights, weights, hematological values and activities of daily living (ADL). Comparison between the nutrient intakes and the recommended dietary allowances (RDAs) estimated for the centenarians showed that the estimated RDA of energy for the Okinawan centenarians might be less than their actual intakes.

[Family history and the frequency of human leukocyte antigen (HLA-DR) in centenarians].

There are a few reports that associate several loci of the human leukocyte antigen (HLA) with longevity, such as DR1 which is significantly frequent in the very old, especially in Okinawa centenarians. In contrast DR9 is decreased. This report investigates 87 healthy Okinawan centenarians and 148 healthy Okinawan controls examined since 1987 with HLA phenotyping and family history questionnaires. The mean age in centenarians was 101.6 years, and that of controls was 66.4. We inquired the age and the cause of death of the parents of the subjects. Subjects whose parent's deaths were by suicide, homicide, accident, war or due to war trauma, were excluded and only those resulting from illness or natural causes were included. The relation between age of death of parents and DR types were studied. Compared to controls, DR1 was significantly increased in the centenarians (p = 0.036, RR 4.239), and DR8 was decreased (p = 0.012, RR = 0.412). When the mean age of death of parents for each DR group and that of total was determined, the mean death age of those with DR9 was significantly lower than the mean of the total (p < 0.05). More over, when the frequency rate of the DR types were compared with the parents' death age, that of DR9 decreased as the age of death increased. It is suggested that some loci of HLA-DR relate to longevity and some genetic protection against immunorelated diseases contributes to long-lived lineage.

[Case of a hypertensive centenarian who was able to record 24-hr ambulatory blood pressure].

Our visiting health-check team has followed a 102 year-old centenarian male for 2 years. During this period his blood pressure (BP) was always normal and physically he was almost always in good condition. Physical examinations and blood tests revealed no remarkably abnormal findings. In March, a household BP measuring instrument indicated a rise in systolic BP to more than 190 mmHg. Consequently, his family physician administered a calcium channel blocking anti-hypertensive agent (Nifedipine: Adalat L; 20 mg/day). However, after taking the medicine he felt sick and stopped taking it. During our visit in June, his family requested us to carry out further examination, while continuing to record his BP. His physical and hematological data showed no abnormal findings. We tried to record his normal ambulatory BP during an entire day, first, without drugs, and then followed by medication (Nifedipine 10 mg/day). The results revealed a great gap of pre- and post-medication BP with a maximum of 100 mmHg during the day. We should therefore be much more careful in administering and hypertensive agents such as calcium channel blockers to the very elderly.

[Red blood cell parameters of healthy centenarians].

Since the number of centenarians is increasing rapidly in recent years, the establishment of normal ranges in red blood cell (RBC) parameters for healthy centenarians is necessary for diagnostic criteria of anemia. The subjects were 129 centenarians consisting of 27 men (17; healthy, 69; low ADL) and 102 women (33; healthy, 69; low ADL) after excluding centenarians with diseases affecting RBC parameters. The t test was used for statistical evaluation. The mean RBC count for healthy centenarian men was 403 +/- 54.7 x 10(4)/microliters; hemoglobin (Hb) level, 12.4 +/- 1.3 g/dl; hematocrit (Hct), 38.2 +/- 3.9%; MVC, 95.3 +/- 5.3 fl; MCH, 31.4 +/- 2.2 pg; and MCHC, 32.1 +/- 1.1%. Comparable results for healthy centenarian women were as follows: 375 +/- 43.9 x 10(4)/microliters, 11.6 +/- 1.2 g/dl, 36.3 +/- 3.6%, 97.1 +/- 5.3 fl, 31.0 +/- 2.3 pg, and 32.0 +/- 1.3%, respectively. The mean Hb for healthy centenarian women was significantly lower than that for healthy centenarian men. The mean RBC, Hb and hematocrit values for low ADL-centenarian men were lower than the comparable values for healthy centenarian men. Conversely, the mean MCV value for low ADL-centenarian men was higher than that for healthy centenarian men. There was no difference in any RBC parameter between healthy centenarian women and low ADL-centenarian women. In addition, there was no difference in any RBC parameter between centenarian women living in their own homes and those living in old-aged homes. This study demonstrated the normal ranges of RBC parameters for healthy centenarians, and lower RBC, Hb, and Hct values for low ADL-centenarian men.

[Chronological study concerning ADL among Okinawan centenarians].

Since 1976 medicobiological and sociological surveys have been carried out upon centenarians in Okinawa. Recently dementia and disability have increased among centenarians. In order to determine the statistical significance, ADL (Activities of Daily Living) scores among Okinawan centenarians were compared; 43 subjects were studied from the 1970's (1976-1980), 99 subjects from the 1980's (1986-1988), and 109 subjects from the 1990's (1992-1994). ADL scores of each centenarian were recorded by the same researchers at the University of the Ryukyus Hospital, based on observation and examination of the centenarians where they lived. Five categories of self sufficiency were defined; completely independent, independent but slow, independent with difficulty, partially dependent, and completely dependent. There were seven physical tasks scored; taking meals, bowel and bladder continence, ability to rise from a toilet, ability to stand, extent of general activities, ability to bathe, and ability to dress oneself. Their sensory functions (auditory acuity and eyesight) and cognitive abilities (comprehension and self-expression) were also scored. Declining rates of total ADL scores were more marked between the 1970's and the 1980's than between the 1980's and the early 1990's. It was also more remarkable in institutionalized centenarians than in centenarians living at home. Decline in physical activities was more distinct in institutionalized than in home-living centenarians. On the other hand, cognitive abilities declined more among centenarian living at home than among institutionalized centenarians. The population of centenarians has increased 23 times over the past 22 years in Okinawa. Human life span has been remarkably extended by advanced medical technology, physically easier life style, and improvement in overall social welfare.(ABSTRACT TRUNCATED AT 250 WORDS)

[The relationship between aortic pulse wave velocity and atherogenic index in centenarians].

It is considered that the atherogenic index (AI), calculated from cholesterol fraction levels, is biochemically acceptable but cannot completely express the degree of physiological development of individual arteriosclerotic changes in extremely elderly persons. The purpose of this study is to search for another form of the atherosclerotic index which is more reliable in terms of physiological aspects, and to clarify the relationship between aortic pulse wave velocity (PWV) and AI in centenarians. We have measured the PWV in 40 healthy centenarians (7 males and 33 females; age 100 to 105, average age 101.1) and 92 ordinary elderly people (45 males and 47 females; age 70 to 89, average age 75.8) in Okinawa, Japan. The conventional AI was calculated by the Fridewald Method. A statistically significant difference in the AI value was observed between centenarians (1.91), and controls (2.59, p < 0.0001). Higher levels of PWV in centenarians (10.15 m/sec), were recognized than in the controls (8.45 m/sec, p < 0.0001). However, no significant correlations were noticed between PWV and AI in centenarians (r = 0.0049) and in controls (r = 0.094). These results suggested that pathological findings in centenarians are produced mainly by physiological fibrotic changes of the arterial wall instead of pathological atherosclerotic changes.