Mechanisms Underlying Brain Aging Under Normal and Pathological Conditions / 神经科学通报·英文版

Aging is a major risk factor for many human diseases, including cognitive impairment, which affects a large population of the elderly. In the past few decades, our understanding of the molecular and cellular mechanisms underlying the changes associated with aging and age-related diseases has expanded greatly, shedding light on the potential role of these changes in cognitive impairment. In this article, we review recent advances in understanding of the mechanisms underlying brain aging under normal and pathological conditions, compare their similarities and differences, discuss the causative and adaptive mechanisms of brain aging, and finally attempt to find some rules to guide us on how to promote healthy aging and prevent age-related diseases.

Aging

Aging is initiated based on genetic and environmental factors that operate from the time of birth of organisms. Aging induces physiological phenomena such as reduction of cell counts, deterioration of tissue proteins, tissue atrophy, a decrease of the metabolic rate, reduction of body fluids, and calcium metabolism abnormalities, with final progression onto pathological aging. Despite the efforts from many researchers, the progression and the mechanisms of aging are not clearly understood yet. Therefore, the authors would like to introduce several theories which have gained attentions among the published theories up to date; genetic program theory, wear-and-tear theory, telomere theory, endocrine theory, DNA damage hypothesis, error catastrophe theory, the rate of living theory, mitochondrial theory, and free radical theory. Although there have been many studies that have tried to prevent aging and prolong life, here we introduce a couple of theories which have been proven more or less; food, exercise, and diet restriction.

Effect of Ethanol on Short-term Memory in Rats:A Mechanism of Alcoholic Dementia

Chronic and excessive alcohol consumption produces a subtle brain damage, which induces such organic mental disorders as delayed mental processes, abstract thinking impairment, and disturbances in learning and recent memory loss. These phenomena had been known to be caused by malnutrition. However, recent researches showed that it could be caused by mild brain lesions by direct neurotoxic effect of alcohol on the prefrontal cortex, or its related subcortical structures. This study was tried to evaluate the effect of alcohol on the short-term memory function, to compare with the histological changes, and to find out responses to the agonists and antagonists of possibly related neurotransmitters. For experiment 1, 10 aged male Sprague-Dawley rats weighed about 400-500 gm were used. 45 younger adult male Sprague-Dawley rats weighed about 200-300 gm were used for experiment 2 and 3. Therefore, 55 rats were totally used. In experiment 1, T-maze test with 10 nomal aged rats were done first, and then it was divided into 5 atropine-administered group and 5 control group. For the atropine-administered group, T-maze test was repeated on every 30, 60, 120 minute after the atropine injection. After the completion, of behavioral tests, the rats were sacrificed by the intracardiac perfusion with phosphate buffered 10% formaldehyde solution, and the brain specimen was stained with hematoxylin-eosin to count cells in the prefrontal cortex and the hippocampus. In experiment 2, T-maze test with 10 normal younger adult rats were done first, and then it was dividied into five 14% (v/v) ethanol administered group and 5 control group raised with tap water. T-maze test was repeated on every week for a month. After the completion of behavioral tests on the 4th week, histology was done by the same procedure. In experiment 3, T-maze test with 35 normal younger adult rats were done first, and then it was divided into seven groups with five rats each other. 14% (v/v) ethanol was administered ad libitum. In addition, normal saline, fluoxetine, bromocriptine, bethacholine, nimodipine, clonidine, and ketamine were intramuscularly injected on every other day. T-maze test was repeated on every week for a month. After the completion of behavioral tests on the 4th week, histology was done by the same procedure. 1) The reaction time of T-maze test was more delayed on 120 minutes after atropine injection in atropine-administered rats than those in normal aged rats without statistical significance. 2) The reaction time of T-maze test was more delayed in ethanol-treated rats, especially most prominent on the 3rd week, than those in normal younger adult rats without statistical significance. However, cell numbers in the CA1, CA3, dentate gyrus and the prefrontal cortex were significantly reduced in ethanol-treated rats on histology (p<0.05). 3) The reaction time of T-maze test was more shortened in fluoxetine and ketamine-treated rats on the 1st week without statistical significance. It was rather shortened in fluoxetine, ketamine, bromocriptine and nimodipine-treated rats without statistical significance on the 2nd week. On the 3rd week, the reaction time of T-maze test was shortened in every drug-treated rats. It returned to be delayed in all but fluoxetine, clonidine and bethacholine-treated rats on the 4th week without statistical significance. However, cell numbers in the CA1 were significantly increased in bromocriptine-treated rats (p<0.05) and in bethacholine-treated rats (p<0.01). In the CA3 and the dentate gyrus, cell numbers in bethacholine and clonidine-treated rats were significantly increased (p<0.05 respectively). In the prefrontal cortex, cell numbers in bethacholine-treated rats were significantly increased (p<0.005) on histology. 4) While there were no significant difference on the reaction time of T-maze test between ethanol-treated group, normal aged group and atropine-treated group, cell numbers in the prefrontal cortex were significantly different between those of normal aged group and atropine-treated group (p<0.05). Cell numbers in the prefrontal cortex of ethanol-treated group were signifncantly correlated with those of atropine-treated group (r=0.977, p<0.001), and of normal aged group (r=0.448, p<0.05). In conclusion, we should not neglect the risk of memory loss even in the subclinical cases, because neuronal cells in the prefrontal cortex and the hippocampus were significantly reduced on histology, while ethanol-induced short-term memory loss was not functionally significant. The drug responses in this experiments showed that the mechanism of alcohol-induced short-term memory loss might be mainly related with cholinergic system. Otherwise, adrenergic or dopaminergic mechanisms could be involved. Furthermore, we could not exclude the possiblity that pathological aging process might be exerted as an important mechanism underlying alcoholic dementia.