Elucidating the role of NAD metabolism in amino acids uptake for the prevention of sarcopenia

• Project/Area Number: 21K11593
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 59040:Nutrition science and health science-related
• Research Institution: University of Toyama
• Principal Investigator: Yaku Keisuke 富山大学, 学術研究部医学系, 助教 (70761865)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: NAD代謝 / サルコペニア / 老化 / NAD / 腸管機能

Outline of Research at the Start

ニコチンアミドアデニンジヌクレオチド（NAD）は生体に必須の補酵素であり、また体内のNAD量は老化によって減少することから、老化研究における重要な因子とされている。
本研究は、老化に伴うNAD代謝の変化が腸管でのアミノ酸吸収能低下を介してサルコペニア発症に関わっているという仮説の検証を目的としている。また、NAD代謝を介したアミノ酸吸収制御機構を標的としたサルコペニアの新たな予防・治療法の開発を目指す。

Outline of Final Research Achievements

In this study, we investigated the effect of NAD supplementation on the improvement of muscle function, aiming at the prevention and treatment of sarcopenia. Furthermore, we analyzed the pathway through which NAD precursors are utilized for NAD synthesis in muscle. We found that NAD precursors improved muscle function in mice whose muscle NAD levels are decreased. Additionally, the efficiency of NAD repletion was greater with intravenous administration than that with oral administration. Furthermore, we found that the microbiota is associated with NAD metabolism in both oral and intravenous administration of NAD precursors.

Academic Significance and Societal Importance of the Research Achievements

NRやNMNを用いたNAD補充は抗老化分野で世界的に注目されており、これらを用いた臨床試験が盛んに行われている。また、これらのサプリメントはサプリメントとして一般的にも用いられている。本研究では、NAD代謝の新たな側面として、NRとNMNがいずれも腸内細菌の影響を受けること、また投与経路によって利用効率の差が認められることを明らかにした。これらの知見はNAD代謝を標的とした健康増進において非常に重要な知見である。

Research Products

• [Journal Article] Deletion of Nmnat1 in Skeletal Muscle Leads to the Reduction of NAD⁺ Levels but Has No Impact on Skeletal Muscle Morphology and Fiber Types (2023)
  • Author(s): Karim M, Iqbal T, Nawaz A, Yaku K, Nakagawa T.
  • Journal Title: Journal of Nutritional Science and Vitaminology Volume: 69 Issue: 3 Pages: 184-189
  • DOI: 10.3177/jnsv.69.184
  • ISSN: 0301-4800, 1881-7742
  • Year and Date: 2023-06-30
  • Peer Reviewed
• [Journal Article] NAD+ Precursors in Human Health and Disease: Current Status and Future Prospects (2023)
  • Author(s): Yaku K, Nakagawa T.
  • Journal Title: Antioxidants & Redox Signaling Volume: 39 Issue: 16-18 Pages: 1133-1149
  • DOI: 10.1089/ars.2023.0354
  • Peer Reviewed
• [Journal Article] Adipocyte NMNAT1 expression is essential for nuclear NAD+ biosynthesis but dispensable for regulating thermogenesis and whole-body energy metabolism (2023)
  • Author(s): Yamaguchi Shintaro、Kojima Daiki、Iqbal Tooba、Kosugi Shotaro、Franczyk Michael P.、Qi Nathan、Sasaki Yo、Yaku Keisuke、Kaneko Kenji、Kinouchi Kenichiro、Itoh Hiroshi、Hayashi Kaori、Nakagawa Takashi、Yoshino Jun
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 674 Pages: 162-169
  • DOI: 10.1016/j.bbrc.2023.07.007
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Regional contributions of D-serine to Alzheimer’s disease pathology in male AppNL－G－F/NL－G－F mice. (2023)
  • Author(s): Ni Xiance、Inoue Ran、Wu Yi、Yoshida Tomoyuki、Yaku Keisuke、Nakagawa Takashi、Saito Takashi、Saido Takaomi C.、Takao Keizo、Mori Hisashi
  • Journal Title: Frontiers in Aging Neuroscience Volume: 15 Pages: 1211067-1211067
  • DOI: 10.3389/fnagi.2023.1211067
  • Peer Reviewed / Open Access
• [Journal Article] Niacin restriction with NAMPT-inhibition is synthetic lethal to neuroendocrine carcinoma. (2023)
  • Author(s): Nomura M, Ohuchi M, Sakamoto Y, Kudo K, Yaku K, Soga T, Sugiura Y, Morita M, Hayashi K, Miyahara S, Sato T, Yamashita Y, Ito S, Kikuchi N, Sato I, Saito R, Yaegashi N, Fukuhara T, Yamada H, Shima H, Nakayama KI, Hirao A, Kawasaki K, Arai Y, Akamatsu S, Tanuma S, Sato T, Nakagawa T and Tanuma N.
  • Journal Title: Nature Communications. Volume: 14(1) Issue: 1 Pages: 8095-8095
  • DOI: 10.1038/s41467-023-43630-3
  • Peer Reviewed / Open Access
• [Journal Article] Blood levels of nicotinic acid negatively correlate with hearing ability in healthy older men (2023)
  • Author(s): Nakagawa-Nagahama Yoshiko、Igarashi Masaki、Miura Masaomi、Kashiwabara Kosuke、Yaku Keisuke、Fukamizu Yuichiro、Sato Toshiya、Sakurai Takanobu、Nakagawa Takashi、Kadowaki Takashi、Yamauchi Toshimasa
  • Journal Title: BMC Geriatrics Volume: 23 Issue: 1 Pages: 97-97
  • DOI: 10.1186/s12877-023-03796-3
  • Peer Reviewed / Open Access
• [Journal Article] Oral Administration of Nicotinamide Mononucleotide Is Safe and Efficiently Increases Blood Nicotinamide Adenine Dinucleotide Levels in Healthy Subjects (2022)
  • Author(s): Okabe Keisuke、Yaku Keisuke、Uchida Yoshiaki、Fukamizu Yuichiro、Sato Toshiya、Sakurai Takanobu、Tobe Kazuyuki、Nakagawa Takashi
  • Journal Title: Frontiers in Nutrition Volume: 9 Pages: 868640-868640
  • DOI: 10.3389/fnut.2022.868640
  • Peer Reviewed / Open Access
• [Journal Article] Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men (2022)
  • Author(s): Igarashi Masaki、Nakagawa-Nagahama Yoshiko、Miura Masaomi、Kashiwabara Kosuke、Yaku Keisuke、Sawada Mika、Sekine Rie、Fukamizu Yuichiro、Sato Toshiya、Sakurai Takanobu、Sato Jiro、Ino Kenji、Kubota Naoto、Nakagawa Takashi、Kadowaki Takashi、Yamauchi Toshimasa
  • Journal Title: npj Aging Volume: 8 Issue: 1 Pages: 5-5
  • DOI: 10.1038/s41514-022-00084-z
  • Peer Reviewed / Open Access
• [Journal Article] Loss of hepatic Nmnat1 has no impact on diet-induced fatty liver disease (2022)
  • Author(s): Iqbal Tooba、Nawaz Allah、Karim Mariam、Yaku Keisuke、Hikosaka Keisuke、Matsumoto Michihiro、Nakagawa Takashi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 636 Pages: 89-95
  • DOI: 10.1016/j.bbrc.2022.10.072
  • Peer Reviewed
• [Journal Article] Nmnat3 deficiency in hemolytic anemia exacerbates malaria infection (2022)
  • Author(s): Mahmood Arshad、Yaku Keisuke、Hikosaka Keisuke、Gulshan Maryam、Inoue Shin-ichi、Kobayashi Fumie、Nakagawa Takashi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 637 Pages: 58-65
  • DOI: 10.1016/j.bbrc.2022.11.003
  • Peer Reviewed
• [Journal Article] Food odor perception promotes systemic lipid utilization (2022)
  • Author(s): Tsuneki Hiroshi, Sugiyama Masanori, Ito Toshihiro, Sato Kiyofumi, Matsuda Hiroki, Onishi Kengo, Yubune Koharu, Matsuoka Yukina, Nagai Sanaka, Yamagishi Towa, Maeda Takahiro, Honda Kosuke, Okekawa Akira, Watanabe Shiro, Yaku Keisuke, et al.
  • Journal Title: Nature Metabolism Volume: 4 Issue: 11 Pages: 1514-1531
  • DOI: 10.1038/s42255-022-00673-y
  • Peer Reviewed / Open Access
• [Journal Article] BST1 regulates nicotinamide riboside metabolism via its glycohydrolase and base-exchange activities. (2021)
  • Author(s): Yaku K, Palikhe S, Izumi H, Yoshida T, Hikosaka K, Hayat F, Karim M, Iqbal T, Nitta Y, Sato A, Migaud ME, Ishihara K, Mori H, Nakagawa T
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 6767-6767
  • DOI: 10.1038/s41467-021-27080-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Nicotinamide riboside とnicotinamide mononucleotide の代謝動態の解析 (2023)
  • Author(s): 夜久 圭介、Palikhe Sailesh、Iqbal Tooba、中川 崇
  • Organizer: 第77回日本栄養・食糧学会大会
• [Presentation] NAD の再合成を抑制すると細胞死を誘導できる (2023)
  • Author(s): 新田 康人、彦坂 圭介、内田 仁司、夜久 圭介、中川 崇
  • Organizer: 日本生化学会北陸支部 第 41 回大会
• [Presentation] NAD+前駆体の体内利用にはNaprtが重要である (2023)
  • Author(s): 夜久 圭介、Palikhe Sailesh、Iqbal Tooba、中川 崇
  • Organizer: 第74回日本薬理学会北部会
• [Presentation] A combination of oxidative stress-induced DNA damage and NAD+ synthesis Inhibition induces synthetic lethality in cancer cells (2023)
  • Author(s): Nitta Y, Yamamoto M, Yaku K, Uchida H, Hayashi H, Nakagawa T
  • Organizer: 日本トリプトファン研究会 第42回学術集会
• [Presentation] 酸化ストレスとNAD+合成阻害の組み合わせが癌細胞の合成致死を誘導する (2023)
  • Author(s): 新田 康人、彦坂 圭介、夜久 圭介、中川 崇
  • Organizer: 第97回日本薬理学会年会
• [Presentation] NAD+前駆体の生体内での利用経路の解析 (2022)
  • Author(s): 夜久圭介, Sailesh Palikhe, 中川崇
  • Organizer: 第16回トランスポーター研究会
  • Invited
• [Presentation] CD38の阻害は筋再生を促進する (2022)
  • Author(s): 夜久圭介, Nawaz Allah, 中川崇
  • Organizer: 第73回日本薬理学会北部会
• [Presentation] Nicotinamide mononucleotideの体内動態の解析 (2022)
  • Author(s): 夜久圭介, Sailesh Palikhe, 中川崇
  • Organizer: 第95回日本生化学会大会
• [Presentation] Inhibition of CD38 promotes muscle regeneration (2022)
  • Author(s): 夜久圭介, Nawaz Allah, 中川崇
  • Organizer: 第96回日本薬理学会年会
• [Presentation] CD38は骨格筋損傷における治療標的である (2022)
  • Author(s): 夜久圭介, Nawaz Allah, 中川崇
  • Organizer: 日本トリプトファン研究会第41回学術集会
• [Presentation] NAD 代謝における腸内細菌の役割について (2021)
  • Author(s): 飴井千佳乃、佐伯玲奈、夜久圭介、中川 崇
  • Organizer: 日本生化学会北陸支部 第39回大会
• [Presentation] 高脂肪食誘導性肥満に対する NAD 前駆体の併用効果 (2021)
  • Author(s): 佐伯玲奈、飴井千佳乃、夜久圭介、中川 崇
  • Organizer: 日本生化学会北陸支部 第39回大会
• [Presentation] Nicotinamide riboside generates NAD+ through the Preiss Handler pathway during oral administration (2021)
  • Author(s): Sailesh Palikhe、Keisuke Yaku、Takashi Nakagawa
  • Organizer: 第94回日本生化学会大会
• [Presentation] NAD前駆体ニコチン酸のNAD増加効果に対する老化の影響 (2021)
  • Author(s): 西岡 文音 、夜久 圭介、中川 崇
  • Organizer: 第44回日本分子生物学会年会
• [Book] 生物の寿命延長 (2022)
  • Author(s): 南野 徹
  • Total Pages: 460
  • Publisher: エヌ・ティー・エス
  • ISBN: 9784860437732