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The Progression of Aging in Klotho Mutant Mice Can Be Modified by Dietary Phosphorus and Zinc

Koji Morishita, Akio Shirai^*, Madoka Kubota, Yuji Katakura, Yo-ichi Nabeshima, Kazuhiko Takeshige^* and Toshikazu Kamiya¹

Tsukuba Research Laboratories, Kyowa Hakko Kogyo Company Limited, Tsukuba-shi, Ibaraki 305-0841, Japan; ^* Tokyo Research Laboratories, Kyowa Hakko Kogyo Company Limited, Machida-shi, Tokyo 194-8533, Japan; and Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan

¹To whom correspondence should be addressed. E-mail: tkamiya{at}kyowa.co.jp.

Reduction in klotho gene expression causes accelerated senescence in klotho mutant mice. We have now found two key substances, phosphorus and zinc, which affect the appearance of klotho phenotypes. Klotho mutant homozygotes fed nonpurified diet with a phosphorus concentration of 1.03 g/100 g showed typical klotho phenotypes. However, most of the klotho phenotypes no longer appeared in male homozygotes fed a 0.4 g/100 g phosphorus diet. These homozygotes were capable of spermatogenesis. In the kidneys of the rescued male homozygotes, klotho protein expression was clearly detected. On the other hand, female klotho mice required supplementation of 0.25 g/100 g zinc orotate to the 0.4 g/100 g phosphorus diet to be rescued. Unlike in the rescued male mice, klotho protein levels in the kidneys of the rescued females were quite low. Wild-type (C3H/He) mice fed 1.5 or 1.0 g/100 g phosphorus diets had lower klotho protein expression in the kidneys than those fed a 0.4 g/100 g phosphorus diet (Kruskal-Wallis test, P < 0.05). These results indicate that dietary phosphorus and zinc modulate the phenotypes of klotho mice, and that klotho expression in the kidneys is regulated not only in klotho mutant mice, but also in wild-type mice.

KEY WORDS: • klotho • phosphorus • zinc orotate • mice

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