Neurons in the Klotho Mutant Mouse Show Biochemical and Morphological Characteristics Resembling Age-Related Disorders

AbstractThe klotho gene is considered to regulate the lifespan of animals including humans. The klotho mutant mouse, which has a defective klotho gene, shows many age-related disorders and has a short lifespan, around 2 months old; the overexpression of this gene in the normal wild-type mouse extends lifespan significantly. In klotho mutant mice, various organs/tissues have been analyzed extensively, especially with regard to the problem in ion homeostasis. However, the central nervous system (CNS) of this mutant mouse has not attracted as much attention, probably due to its protection from peripheral circumstances. Although it is suggested that some neurons in the CNS of klotho mice are degenerative, no distinct evidence has yet emerged. There are alterations in neurofilaments and microtubules with their constituent or associated proteins, and significant differences in the distribution and expression of these structures and proteins between wildtype and mutant CNS. The expression of antiapoptotic and proapoptotic proteins were significantly changed in klotho mutant mice compared with wild-type mice. Lysosomes, lysosome-like profiles and synapse-related structures with their respective associated proteins were also altered in the mutant mice. Neuronal degeneration was evident in some restricted regions of the CNS, such as in the hippocampus. Gliofilaments in astrocytes and GFAP were drastically altered in density and expression, respectively. These alterations in klotho mutant mouse CNS are similar to those in aged animals or humans, despite some differences between them, probably because of very early death of the mutant mice, which indicate that the mutant mice would be a valuable genetic model for multiple analyses on the aging of the CNS including the autonomic nervous system. Prevention of neurodegeneration in the mutant mice with nutritional manipulation using antioxidants such as polyphenols is also discussed