It is widely known that the aging is processed by complex mechanisms. These mechanisms include two main theories, program theory and error catastrophy theory. Other theories are mutation theory, free radical theory, cross-linkage theory, autoimmune theory and so on. However, at present, there is no established theory to account for the all phenomenon accompanying in aging. In this paper, the complex mechanism in aging is outlined, and some progeroid syndromes as a model of normal aging are also introduced including the results of our recent studies. In normal aging, the life span of fibroblast reduces and the incidence of spontaneous mutation rate increases in in vitro study. In Werner syndrome, the incidence of spontaneous mutation rate of lymphocyte or fibroblast was about ten times higher than that in normal elderly. This was mainly caused by the large deletion of gene which was studied using Southern blot analysis. This may be associated with the mechanism of aging in Werner syndrome. SV-40 transformed fibroblasts from Cockayne syndrome was highly sensitive to UV irradiation. This high sensitivity was partially recovered by the introduction of cDNA of ribonucleotide reductase which is a rate limiting enzyme of deoxyribonucleotide synthesis. This may suggest that the regulatory deficit of the initiation of DNA replication may be related to the aging in Cockayne synerome. The mechanism of aging in progeria was more complex than that in Werner syndrome or Cockayne syndrome. We have a case of aged progeria of 45 years old who had a severe systemic arteriosclerosis with calcification and cardiovascular diseases. It is suggested that aging is caused by the multi-mechanisms including the abnormalities in the DNA replication.
The authors studied age-related changes in brain volume and cerebral blood flow in neurologically normal subjects with and without risk factors for cerebral arteriosclerosis (hypertension, diabetes mellitus, ischemic heart disease, hyperlipidemia). Using computed tomography brain volume index (BVI; 100%×braun volume/cranial cavity volume) was calculated as an indicator of brain atrophy. Using xenon-133 inhalation method, initial slopw index (ISI) was calculated as an indicator of mean regional cerebral blood flow. The ISI was further corrected for brain atrophy and called cISI (cISI=ISI×BVI). In the subjecs with risk factors (7 men and 25 women), the BVI declined with age (BVI=105.8-0.181×age, r=0.601, p<0.001). While the ISI did not decline with age, the cISI declined with age (cISI=72.1-0.350×age, r=0.350, p<0.05) and was related to the BVI (BVI=87.2+0.137×cISI, r=0.454, p<0.01) in those subjects. In the subjects without risk factors (30 men and 27 women), the BVI declined with age (BVI=105.0-0.178×age, r=0.700, p<0.001). Both the ISI and cISI did not decline with age and the cISI was not related to the BVI.
We studied age-related changes in peripheral and central sensory conduction times, using short latency somatosensory evoked potensials in 50 healthy volunteers aged between 26 and 84 years. The subjects were divided into three groups according to their age; young group consisted of 17 subjects (26-36 years), middleaged group, of 12 subjects (40-58 years), and aged group, of 21 subjects (61-84 years). Somatosensory evoked potentials following stimulation of the median nerve were recorded from the electrodes on the neck (N13) and the scalp (N19). Those following stimulation of the posterior tibial nerve were recorded from the 12th thoracic spine (N20) and scalp (P40). Peripheral conduction times were estimated by N13 and N20, while central conduction times, by CCT1 (N19-N13) and CCT2 (P40-N20). N13, N19, N20 and P40 significantly prolonged as the heights of the subjects increased; whereas CCT1 and CCT2 were not correlated with the heights of the subjects. Thus N13, N19, N20 and P40 corrected for the standard height (160cm) were used in the present study. N13 and N20 increased with age. On the other hand, N19, CCT1, P40 and CCT2 remained unchanged between young and middle-aged groups, but increased significantly in the aged group, compared to those of the other two groups. These results indicate that the effect of aging on sensory conductions differ between the central and peripheral sensory systems.
In order to investigate various influences to serum levels of apoproteins in healthy adults, we applied box-plots which are fundamental methods of exploratory data analysis and robust regression analysis. Serum concentrations of apoprotein A-I, A-II, B, C-II, C-III and E were measured by a single radial immunodiffusion method. The subjects consist of 179 males and 60 females aged 30-69 who are the staff and the retirees of Hiroshima University. The following results were obtained: 1. The levels of apoprotein A-II (aged 40-49), B (aged 30-39), C-II (aged 40-49) and C-III (aged 30-39, 40-49) in male were significantly higher than those in female. 2. It was observed that the levels of apoprotein-B, C-II and C-III in male, and A-II, B and E in female elevated with age. 3. Drinkers had higher levels of apoprotein A-I, A-II and C-III than non-drinkers in male. 4. Cigarette smokers had higher levels of apoprotein C-II and C-III than non-smokers in male. 5. Overweight adults had higher levels of apoprotein A-II, B, C-II, C-III and E in male and apoprotein-E in female than adults who are not overweight.
The relationship of common carotid blood flow volume to aging and dementia was studied using a new ultrasonic Doppler blood flow-meter which enables the measurement of carotid blood flow volume under monitoring of the diameter of the common carotid artery on the B-mode image. Prior to studies in clinical cases the reliability of this equipment was examined using canine carotid artery. A positive linear correlation of y=0.92x+8.6 (r=0.78, n=45, p<0.01) was obtained between the blood flow volumes determined by electromagnetic flow-meter (x) and ultrasonic flow-meter (y). As clinical studies mean blood flow volume, velocity and vessel diameters of both common carotid arteries were measured in 5 young controls in the 20's (mean 25.4 years) and 30 elders ranging from 71 to 98 years in age who presented points less than 7 in Hackinski's Ischemic Socre. Also the mean systemic blood pressure and cerebrovascular resistance were measured. The mean blood flow volume and velocity of both common carotid arteries were 7.77±0.31ml/sec, 8.47±0.75ml/sec, 18.77±0.23cm/sec, 22.24±2.24cm/sec, in the 20's; 4.46±1.77ml/sec, 4.43±1.51ml/sec, 9.25±2.35 cm/sec, 9.04±4.00cm/sec in the 70's; 4.12±1.25 ml/sec 3.92±0.98ml/sec, 9.19±2.27cm/sec, 8.96±1.72cm/sec in the 80's and 3.62±0.26ml/sec, 3.67± 0.12ml/sec, 8.46±2.31cm/sec, 7.41±0.86cm/sec in the 90's showing significant difference (p<0.01) between the 20's and all eldery groups above 70 years old. The mean diameter of the common carotid artery showed increase in the elderly groups compared with the 20's although without significance. Cerebrovascular resistance showed increase in accordance with aging presenting significant difference between the 20's and elderly groups above 70 years in age (5.27±0.20mmHg/ml/sec vs 9.62±1.91mmHg/ml/sec, 11.93±3.10mmHg/ ml/sec, 12.97±1.73mmHg/ml/sec, p<0.01 for each). Considering factors other than aging, Hasegawa's dementia scale test was performed in 21 subjects and a positive linear correlation of y=0.21x+4.86 (r=0.72, p<0.01) was obtained between scores of Hasagawa's dementia scale (x) and the sum of both common carotid arterial blood flow volumes (y).
Effects of age on the progress of brain atrophy were studied in 30 men and 40 women without any neurologic disturbances, ranging in age from 36 to 88 years (mean, 64.2 years). Brain volume index (BVI; brain volume/cranial cavity volume×100%) for each subject was serially measured 3-6 times (mean, 3.2 times) during 12 to 92 months (mean, 39.0 months) using computed tomography. The BVI decreased proportionally to the square of age (BVI=-0.003x age2+0.2x age+93, r=0.71, p<0.001). Increase in BVI per year was calculated using the method of least squares and called annual brain atrophy (ABA) as an indicator of the progress in brain atrophy. The ABA increased proportionally to increasing age (ABA=0.014x age -0.46, r=0.44, p<0.001). Both of the BVI and ABA were not significantly different between two groups with and without risk factors for cerebral arteriosclerosis.
The response of lymphocytes from healthy controls (N=28, 41-67 years, female) and Alzheimer's disease patients (N=11, 50-64 years, female) to phytohemagglutinin (PHA-P) has been measured according to MTT-assay, by which the activities of dehydrogenases in mitochondria could be estimated. A linear age-related decrease in reactivity to PHA-P was found both for healthy controls (r=-0.496, α<0.01), and for Alzheimer's disease patients (r=-0.603, α<0.05). The regression equations are: Y=-0.0146X+1.461 (healthy controls) Y=-0.0150X+1.437 (Alzheimer's disease patients) where, X and Y designate the age of individuals and absorbance, respectively.