Enpp1 is an anti-aging factor that regulates Klotho under phosphate overload conditions

Ryuichi Watanabe, Nobuyuki Fujita, Yuiko Sato, Tami Kobayashi, Mayu Morita, Takatsugu Oike, Kana Miyamoto, Makoto Kuro-o, Toshimi Michigami, Seiji Fukumoto, Takashi Tsuji, Yoshiaki Toyama, Masaya Nakamura, Morio Matsumoto, Takeshi Miyamoto

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Abstract

Control of phosphate metabolism is crucial to regulate aging in mammals. Klotho is a well-known anti-aging factor that regulates phosphate metabolism: mice mutant or deficient in Klotho exhibit phenotypes resembling human aging. Here we show that ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) is required for Klotho expression under phosphate overload conditions. Loss-of-function Enpp1ttw/ttw mice under phosphate overload conditions exhibited phenotypes resembling human aging and Klotho mutants, such as short life span, arteriosclerosis and osteoporosis, with elevated serum 1,25(OH)2D3 levels. Enpp1ttw/ttw mice also exhibited significantly reduced renal Klotho expression under phosphate overload conditions, and aging phenotypes in these mice were rescued by Klotho overexpression, a low vitamin D diet or vitamin D receptor knockout. These findings indicate that Enpp1 plays a crucial role in regulating aging via Klotho expression under phosphate overload conditions.

Original languageEnglish
Article number7786
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - 2017 Dec 1

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Watanabe, R., Fujita, N., Sato, Y., Kobayashi, T., Morita, M., Oike, T., Miyamoto, K., Kuro-o, M., Michigami, T., Fukumoto, S., Tsuji, T., Toyama, Y., Nakamura, M., Matsumoto, M., & Miyamoto, T. (2017). Enpp1 is an anti-aging factor that regulates Klotho under phosphate overload conditions. Scientific Reports, 7(1), [7786]. https://doi.org/10.1038/s41598-017-07341-2