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

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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.