Attempting to explain aging by a single factor was the weakness of most theories. G.A. Sacher proposed a synthetic theory named the longevity-assurance theory. Here, I propose a revised version of it. A comprehensive phylogenic tree based on molecular biology is available for organisms including bacteria, plants, protozoa, fungi, insects and vertebrates. Combining this tree with classical data, we conclude that land plants evolved from immortal, gigantic plants to perenials and then annuals, i. e., from the giant to the miniature. In animals, too, the number of present-day species exponentially increases with decreasing body length except for very small insects. Organisms of smaller size usually have shorter lifespans and earlier maturations, resulting in more success in the reproduction. Annual plants and insects are genetically programmed to die shortly after production of offspring. Genes for programmed death or division arrest are senescence genes. They were acquired by annual plants and insects to assure successful production of offspring. However, mammals evolved toward the opposite direction from small ancestral animals to larger ones of various sizes. There is an empirical rule that mammalian species of greater body-weight have longer lifespans and lower values of specific metabolic-rate (cal/g/day). These results support the explanation that metabolisms themselves produce senescence-accelerating toxins, presumably free radicals. Most primates have two-fold longer lifespans than most other mammals when compared at comparable specific metabolic-rates. This indicates that primates have specifically advanced longevity-assurance mechanisms. In fact, cultured human fibroblasts are unbelievably resistant to malignant transformation whereas cultured rodent fibroblasts are easily transformed. When cultured in vitro, human fibroblasts always stop the DNA synthesis after a limited number of cell division; they nerver produce immortal clones. Around the time of entering senescence, fibroblasts begin to produce DNA-synthesis-inhibiting proteins. Most human tumor cell-lines are defective at genes that produce inhibiting proteins. Thus, senescence genes work for anti-tumor mechanisms. Even if a single aged cell becomes immortal within the body, it will be a potential cause of tumorigenesis or autoimmune disease. Absolute altruism is the rule for the behavior of individual cells in the animal body. Evidence is avilable that various types of cells frequently die by activating senescence genes for the maintenence of the whole-body's function. Thus, senescence genes are involved in altruistic suicide of cells to assure longevity of the host. In Drosophila melangogaster, senescence genes to inhibit post-larval DNA synthesis are mapped at more than 20 loci. One of them has recently been cloned and identified as a gene coding for a cell-membrane adhesion protein. Cloning of senescence genes is opening up an exciting new field in gerontology.

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The change of haemodynamics and cardiac function due to aging in essential hypertension were studied in 1668 patients of nontreated and compensated essential hypertension. The haemodynamic measurements were performed by polygraphic analysis used of Welzer-Boeger's and Blumberger-Holldack's methods before the antihypertensive therapy. These subjects were classified for haemodynamic characteristic type of hypertension (W, W+E′, E′, M types etc.). In W type hypertensives (hyper-resistant hypertension), there were many cases in younger group and a little in elderly age group. The persentage of E′ (hyper-volume elasticity coefficient type) and W+W′ type (mixed resistant type) were increased with aging, however, N (normal type), M (high output type) and M+E′ type (mixed high output type) were noted with no relation of aging. In aging change of blood pressure and heart rate, increase of systolic pressure and pulse pressure, and decrease of diastolic pressure and heart rate were observed. On haemodynamics, with aging, increase of cardiac output and volume elasticity coefficient, and decrease of total peripheral resistance were demonstrated and also increase of cardiac function indices (ET/PEP, DP/ICT, SV/ET) among elderly age group were revealed. In W type hypertensives, diastolic hypertension was noted, moreover, decrease of cardiac output, increase of total peripheral resistance and lowering of cardiac function were shown among elderly age group, though tendency of increasing cardiac output, decreasing total peripheral resistance and increasing cardiac function were observed with aging in other haemodynamic characteristic types. In elderly age group of essential hypertension, the cardiac function was relatively kept well and the afterload was not so significant. On the other hand, in younger and middle age groups, the increased afterload and the lowered cardiac function were revealed, and then the afterload reduction therapy due to vasodilator was required clinically.

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CT findings of demented patients with CVD (49 cases) and without CVD (51 cases) were compared with those of healthy age matched volunteers with CVD (29 cases) and without CVD (110 cases). The results were as follows. 1) About 20% of healthy volunteers had CVD (silent stroke) and these cases should never be regarded as real healthy aged peoples. 2) In aged healthy peoples, size of lateral ventricles, sulci and Sylvian fissure were increased with aging. The degree of PVL and size of third ventricle were not increased with age. 3) Incidence of PVL was closely related with presence of CVD. In demented patients without CVD, however, PVL increased with aging. 4) In dementia the size of lateral ventricle, sulci, Sylvian fissure and third ventricle showed no correlation with aging. In general, enlargement of the lateral ventricle and Sylvian fissure were more prominent in demented peoples without CVD. 5) Atrophy in the medial temporal lobe were observed most frequently in demented peoples without CVD aged 50 to 59 years. In demented patients over 60, no difference was observed in finding of the area between those with and without CVD.

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The aim of this study was to identify problems encountered in using the diagnostic criteria based on oral glucose tolerance test (OGTT) levels recommended by the Japan Diabetic Society (JDS-recommended levels) in evaluating OGTT data for elderly patients of diabetes mellitus. We analysed a total of 451 cases (144 male and 307 female), all inmates of the Yokufukai Home for the Aged who had underwent a 50-gram OGTT while alive. All of them were subjected to autopsy upon decease, with respect to vital prognosis and autoptic findings. They were divided into the following four groups by category of glucose tolerance: normal, borderline, diabetic (DM₁ and DM₂). Of those patients aged less than 75 and not less than 60 at the time of the OGTT, the diabetic group with fasting plasma glucose levels in excess of 140mg/dl (DM₂ group) is found to be the poorest in vital prognosis, giving the highest incidence of myocardial infarction, advanced cerebral atherosclerosis and cerebral infarction occuring individually or in combination. While the diabetic group with fasting plasma glucose levels below 140mg/dl (DM₁ group) is similar to the borderline group in prognosis and in incidence of any of the three types of atherosclerotic lesions, falling in between the normal group and the DM₂ group. Of those patients aged not less than 75 at the time of the OGTT, the four glucose tolerance groups show no significant differences between them in vital prognosis and in incidence of any of the three types of atheroscleotic lesions. These results indicate that, considerling the effect of glucose intolerance on the vital prognosis and cardiovascular lesions, it is clinically practical to set the diagnostic criteria for diabetes by specifying a minimum fasting plasma glucose level of 140mg/dl for aged patients. While the diabetic groups below the 140mg/dl level should be treated simillarly to the borderline group. Our results also suggest that glucose intolerance in patients in their mid seventies and above does not significantly affect their vital prognosis or the development of their atherosclerotic lesions.

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Pseudomonas aeruginosa bacteremia remains an important cause of multiple organ failure (MOF) and mortality in the eldery. In order to characterize clinical and laboratory features, we reviewed retrospectively the manifestation of the Pseudomonas bacteremia in 35 patients (20 males, 15 females). The average age was 72.7 years old, and all patients were hospitalized. MOF occurrd in 17 cases (48.6%) and none survived. Acute respiratory failure (ARF) was observed in 12 cases (34%) and all of these cases developed MOF. On the contrary, only one fifths of patients without ARF developed MOF. While neoplasms and puolmonary disorders were the frequent underlying diseases in the MOF group (53%, 47%), the non-MOF group was frequently associated with urinary and nervous system abnormalities and neoplasms. The respiratory tract was the most frequent part of entry of bacteria in the MOF group (47%), and urinary tract in the non-MOF group (50%). The most notable laboratory finding was the presence of coagulation disorders. Five (14%) of all cases developed DIC, and four of them showed ARF. We conclude that Pseudomonas aeruginosa bacteremia in the elderly was often responsible for the development of MOF with high mortality.

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Hemodynamic effects of upright posture, isometric exercise and norepinephrine infusion were investigated before and after subligual administratin of calcium antagonist nifedipine 10mg in elderly hypertensives and normotensives, aged 65 to 85 years. Hypertensives (n=12) responded to upright posture (60° head-up tilt) with increase in systolic blood pressure, diastolic blood pressure, heart rate, total peripheral resistance and decrease in cardiac output. Nifedipine decreased blood pressure and total peripheral resistance and increased heart rate and cardiac output. Hemodynamic responses to upright posture were not different before or after administration of nifedipine. Plasma norepinephrine levels were significantly higher during upright posture than at supine position. Hypertensives (n=10) responded to isometric exercise (weight susteining isometric exercise) with increase in blood pressure, heart rate, cardiac output and total peripheral resistance. Although nifedipine reduced the absolute values of blood pressure, the rates of hemodynamic responses to isometric exercise were unchanged before or after administration of nifedipine. Plamsa norepinephrine levels were significantl highery during isometric exercise than at rest. Normotensives (n=7) responded intravenous norepinephrine infusion of 0.2μg/kg/min with increase in blood pressure and total peripheral resistance and decrease in heart rate and cardiac output. After administration of nifedipine, norenephrine slightly elevated blood pressure and total peripheral resistance and did not change heart rate or cardiac output. The rates of blood pressure and total peripheral resistance rises in response to norepinephrine were significantly lower after administraiton of nifedipine than before administration. Nifedipine did not suppress the increase in vascular resistance during upright posture or isometric exercise. However, the drug inhibited the increase in vascular resistance to the infused norepinephrine. The sympathetic effects are mediated predominantly via postjunctional alpha-1-adrenoceptors and postjunctional alpha-2-adrenoceptors are preferentially stimulated by circulating norepinephrine because of their extrajunctional location. The discrepancy in response to endogenous sympathetic stimulation by physical exercise and intravenously infused norepinephrine might be due to the fact that postjunctional alpha-2-rather than postjunctional alpha-1-adrenoceptor-mediated vasoconstriction is suppressed by calcium antagonist. In conclusion, calcium antagonist had no adverse hemodynamic effects during upright posture or isometric exercising in elderly patients with hypertension. Calcium antagonist may dominantly inhibit the effects of intravenously administered norepinephrine rather than those of norepinephrine released from sympathetic nerve ending.

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