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

doi:10.1038/s41598-017-07341-2

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 Enpp1^ttw/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. Enpp1^ttw/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 language	English (US)
Article number	7786
Journal	Scientific reports
Volume	7
Issue number	1
DOIs	https://doi.org/10.1038/s41598-017-07341-2
State	Published - Dec 1 2017

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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), Article 7786. https://doi.org/10.1038/s41598-017-07341-2

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title = "Enpp1 is an anti-aging factor that regulates Klotho under phosphate overload conditions",

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.",

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

note = "Funding Information: T. Miyamoto was supported by a grant-in-aid for Scientific Research in Japan and a grant from the Japan Agency for Medical Research and Development. Y. Sato and K. Miyamoto were supported by a grant-in-aid for Scientific Research in Japan. This study was supported in part by a grant-in-aid for Scientific Research, a grant from the Translational Research Network Program. Publisher Copyright: {\textcopyright} 2017, The Author(s).",

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doi = "10.1038/s41598-017-07341-2",

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AU - Watanabe, Ryuichi

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AU - Sato, Yuiko

AU - Kobayashi, Tami

AU - Morita, Mayu

AU - Oike, Takatsugu

AU - Miyamoto, Kana

AU - Kuro-o, Makoto

AU - Michigami, Toshimi

AU - Fukumoto, Seiji

AU - Tsuji, Takashi

AU - Toyama, Yoshiaki

AU - Nakamura, Masaya

AU - Matsumoto, Morio

AU - Miyamoto, Takeshi

N1 - Funding Information: T. Miyamoto was supported by a grant-in-aid for Scientific Research in Japan and a grant from the Japan Agency for Medical Research and Development. Y. Sato and K. Miyamoto were supported by a grant-in-aid for Scientific Research in Japan. This study was supported in part by a grant-in-aid for Scientific Research, a grant from the Translational Research Network Program. Publisher Copyright: © 2017, The Author(s).

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

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

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