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

我们对衰老加速小鼠、SAMP10和klotho突变小鼠以及卒中易感自发性高血压大鼠(SHRSP)的中枢神经系统(CNS)中的神经元，特别是轴突进行了生化和形态分析，发现这些轴突呈现变性的轮廓，随着神经丝蛋白(NFs)、溶酶体和线粒体等细胞器的积累而扩大。由于红酒中的多酚被认为对预防动脉硬化相关疾病有效，我们将红酒与其他酒精、日本清酒和稀释乙醇(乙醇浓度相同，均为14%)进行比较。与对照组(加水组)相比，红酒对细胞的损伤与老年动物相似，如神经纤维和脂褐素颗粒增多，但红酒的影响较轻。姜黄对酒精引起的细胞损伤也有抑制作用。因此，这两种多酚似乎都能有效地预防或延缓衰老或年龄相关疾病造成的细胞损伤。我们将分析单靠酚类是否有如此强大的作用来延长这些动物的寿命。Klotho突变小鼠不确定它们是否因为寿命太短(2个月)而出现衰老相关疾病，但klotho基因的过度表达显示出显著的延长寿命。我们还集中分析了这些小鼠中枢神经系统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化上增加，随着年龄的增加而增加，而随着年龄的增加而减少，形态上，神经纤维和溶酶体显著增加，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一种有效的、方便的动物模型。

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.