Axonal degenerations with aging and their rescue by genetic and nutritional manipulations

我们对加速衰老小鼠、SAMP10和klotho突变小鼠以及易卒中的自发性高血压大鼠（SHRSP）的中枢神经系统（CNS）中的神经元，特别是其轴突进行了生化和形态学分析，发现这些轴突表现出随着细胞器如神经丝（NF）、溶酶体和线粒体的积累而扩大的退行性轮廓。由于认为红葡萄酒的多酚对预防动脉硬化相关疾病有效，因此我们将红葡萄酒与其他酒精、日本清酒和稀释乙醇（乙醇浓度相同，14%，在所有情况下）进行了比较。与对照组（水剂量）相比，观察到细胞损伤，如NF和脂褐质颗粒增加，与老年动物中观察到的相似，但红葡萄酒的变化最轻微。姜黄还显示出抑制酒精引起的细胞损伤的外观。因此，这两种多酚似乎都能有效预防或延缓由衰老或与年龄相关的疾病引起的细胞损伤。我们将分析酚是否单独具有延长这些动物寿命的强大作用。klotho突变小鼠不确定它们是否因为寿命太短（2个月）而表现出衰老相关的疾病，但klotho基因的过表达显示出显着的长寿。我们还集中分析了这些小鼠CNS神经元和神经胶质细胞性质的变化，发现在这些细胞中表达的蛋白质在生物化学上在老年动物中增加，表达增加，而那些随着年龄的增长而减少的蛋白质则减少，并且在形态学上，NF和溶酶体显着增加，而突触相关的轮廓减少。结果表明，klotho突变小鼠是研究人类衰老的理想动物模型。

We analyzed biochemically and morphologically neurons, especially their axons, in the central nervous system (CNS) of senescence-accelerated mice, SAMP10 and klotho mutant mice, and stroke-prone spontaneously hypertensive rats (SHRSP), and found that these axons showed degenerative profiles expanded with accumulation of cell organells such as neurofilaments (NFs), lysosomes and mitochondria. Since the polyphenol of red wine is considered to be effective to prevent arteriosclerosis-associated diseases, we administrated the red wine in comparison with other alcohols, Japanese sake and diluted ethanol (concentration of ethanol was the same, 14%, in all cases). Compared to the control (water dosage), the cellular damages, such as increases of NFs and lipofuscin granules, which were similar to those seen in aged animals, were observed, but the mildest in the alteration with the red wine. Turmeric also showed inhibition of the appearance of cellular damages by alcohols. Therefore, both polyphonols appear to be effective for preventing or delaying cellular damages caused by aging or age-related disorders. We are going to analyze whether pholyphenols alone have such powerful effects to extend the lifespan of these animals. The klotho mutant mice were not sure whether they showed senescence-associated disorders because of their too short lifespan (2 months), but the overexpression of klotho gene showed significant extended longevity. We also concentrated on analyzing alterations in nature of CNS neurons and glial cells of these mice, and found that in them biochemically the proteins expressed in these cells, which increase in aged animals, increased in expression, while those decreasing with aging were reduced, and morphologically, NFs and lysosomes increased significantly, while synapse-associated profiles decreased. The results indicate that klotho mutant mice are useful as well as convenient animal model for the human aging.