Elucidation of novel NAD synthesis pathway to develop anti-aging strategy

• Project/Area Number: 18K17921
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• 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): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: NAD代謝 / 老化 / NAD / 代謝

Outline of Final Research Achievements

Nicotiniamide adenine dinucleotide (NAD) levels in the body decline with age, while replenishment of NAD is expected to slow or reverse aging processes. In this study, we aimed to elucidate the metabolism of Nicotinamide riboside (NR) which is the effective precursor for NAD repletion. We found that NR is digested into Nicotinamide by CD157, then converted into NR by gut microbiota.

Academic Significance and Societal Importance of the Research Achievements

NADは生命維持に必須であるビタミンB3であり、その体内量を維持することが老化関連疾患の予防・治療に有効であると考えられている。NAD補充方法の中でも前駆体の経口投与は最も簡便であり、効果的なNAD前駆体の探索が行われている。本研究ではNAD補充効率が良いと期待されるNRの消化管内での動態を明らかにした。これらの結果は肥満や糖尿病などの老化関連疾患に対する介入方法を確立する上で重要な知見となる。

Research Products

• [Journal Article] Simultaneous Measurement of Amino Acid Enantiomers in Aged Mouse Brain Samples by LC/MS/MS Combined with Derivatization Using Nα-(5-Fluoro-2,4-dinitrophenyl)-l-leucinamide (l-FDLA) (2021)
  • Author(s): Yamamoto Taiji、Yaku Keisuke、Nakagawa Takashi
  • Journal Title: Metabolites Volume: 11 Issue: 1 Pages: 57-57
  • DOI: 10.3390/metabo11010057
  • Peer Reviewed / Open Access
• [Journal Article] NAD+ Metabolism Regulates Preadipocyte Differentiation by Enhancing α-Ketoglutarate-Mediated Histone H3K9 Demethylation at the PPARγ Promoter (2020)
  • Author(s): Okabe Keisuke、Nawaz Allah、Nishida Yasuhiro、Yaku Keisuke、Usui Isao、Tobe Kazuyuki、Nakagawa Takashi
  • Journal Title: Frontiers in Cell and Developmental Biology Volume: 8 Pages: 586179-586179
  • DOI: 10.3389/fcell.2020.586179
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Deletion of the GAPDH gene contributes to genome stability in Saccharomyces cerevisiae (2020)
  • Author(s): Hanasaki Miki、Yaku Keisuke、Yamauchi Motohiro、Nakagawa Takashi、Masumoto Hiroshi
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 21146-21146
  • DOI: 10.1038/s41598-020-78302-5
  • NAID: 120006980741
  • Peer Reviewed / Open Access
• [Journal Article] The microRNAs miR-302b and miR-372 regulate mitochondrial metabolism via the SLC25A12 transporter, which controls MAVS-mediated antiviral innate immunity. (2020)
  • Author(s): Yasukawa K, Kinoshita D, Yaku K, Nakagawa T, Koshiba T.
  • Journal Title: J Biol Chem. Volume: 295(2) Issue: 2 Pages: 444-457
  • DOI: 10.1074/jbc.ra119.010511
  • Peer Reviewed / Open Access
• [Journal Article] Implications of altered NAD metabolism in metabolic disorders. (2019)
  • Author(s): Okabe K, Yaku K, Tobe K, Nakagawa T.
  • Journal Title: J Biomed Sci. Volume: 26(1) Issue: 1 Pages: 34-34
  • DOI: 10.1186/s12929-019-0527-8
  • Open Access
• [Journal Article] Implications of NAD metabolism in pathophysiology and therapeutics for neurodegenerative diseases. (2019)
  • Author(s): Hikosaka K, Yaku K, Okabe K, Nakagawa T.
  • Journal Title: Nutr Neurosci. Volume: - Issue: 5 Pages: 1-17
  • DOI: 10.1080/1028415x.2019.1637504
  • Peer Reviewed
• [Journal Article] Metabolism and biochemical properties of nicotinamide adenine dinucleotide (NAD) analogs, nicotinamide guanine dinucleotide (NGD) and nicotinamide hypoxanthine dinucleotide (NHD). (2019)
  • Author(s): Yaku K, Okabe K, Gulshan M, Takatsu K, Okamoto H, Nakagawa T.
  • Journal Title: Sci Rep. Volume: 9(1) Issue: 1 Pages: 13102-13102
  • DOI: 10.1038/s41598-019-49547-6
  • Peer Reviewed / Open Access
• [Journal Article] NAD metabolism: Implications in aging and longevity (2018)
  • Author(s): Yaku Keisuke、Okabe Keisuke、Nakagawa Takashi
  • Journal Title: Ageing Research Reviews Volume: 47 Pages: 1-17
  • DOI: 10.1016/j.arr.2018.05.006
  • Peer Reviewed
• [Journal Article] Overexpression of Nmnat3 efficiently increases NAD and NGD levels and ameliorates age-associated insulin resistance (2018)
  • Author(s): Gulshan Maryam、Yaku Keisuke、Okabe Keisuke、Mahmood Arshad、Sasaki Tsutomu、Yamamoto Masashi、Hikosaka Keisuke、Usui Isao、Kitamura Tadahiro、Tobe Kazuyuki、Nakagawa Takashi
  • Journal Title: Aging Cell Volume: 17 Issue: 4
  • DOI: 10.1111/acel.12798
  • Peer Reviewed / Open Access
• [Journal Article] Deletion of PHGDH in adipocytes improves glucose intolerance in diet-induced obese mice (2018)
  • Author(s): Okabe Keisuke、Usui Isao、Yaku Keisuke、Hirabayashi Yoshio、Tobe Kazuyuki、Nakagawa Takashi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 504 Issue: 1 Pages: 309-314
  • DOI: 10.1016/j.bbrc.2018.08.180
  • Peer Reviewed / Open Access
• [Journal Article] Neuronal SIRT1 regulates macronutrient-based diet selection through FGF21 and oxytocin signalling in mice (2018)
  • Author(s): Matsui Sho、Sasaki Tsutomu、Kohno Daisuke、Yaku Keisuke、Inutsuka Ayumu、Yokota-Hashimoto Hiromi、Kikuchi Osamu、Suga Takayoshi、Kobayashi Masaki、Yamanaka Akihiro、Harada Akihiro、Nakagawa Takashi、Onaka Tatsushi、Kitamura Tadahiro
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 1-17
  • DOI: 10.1038/s41467-018-07033-z
  • Peer Reviewed / Open Access
• [Journal Article] NAD Metabolism in Cancer Therapeutics (2018)
  • Author(s): Yaku Keisuke、Okabe Keisuke、Hikosaka Keisuke、Nakagawa Takashi
  • Journal Title: Frontiers in Oncology Volume: 8 Pages: 622-622
  • DOI: 10.3389/fonc.2018.00622
  • Peer Reviewed / Open Access
• [Presentation] 腸管恒常性維持におけるNAD代謝の役割 (2021)
  • Author(s): 夜久 圭介、中川 崇
  • Organizer: 第94回日本薬理学会年会
• [Presentation] NAD代謝による腸管恒常性維持機構の解明 (2020)
  • Author(s): 夜久 圭介、中川 崇
  • Organizer: 第93回日本薬理学会年会
• [Presentation] 新規NAD合成経路の解析 (2019)
  • Author(s): 夜久 圭介、中川 崇
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] 新規NAD合成経路の発見と抗老化戦略に与える影響について (2018)
  • Author(s): 夜久圭介，中川 崇
  • Organizer: 第91回日本生化学会大会
• [Presentation] 新規NADアナログNGDの機能解析 (2018)
  • Author(s): 夜久圭介，中川 崇
  • Organizer: 第41回日本分子生物学会大会
• [Presentation] 新規NAD代謝経路による抗老化機構 (2018)
  • Author(s): 中川 崇，夜久圭介
  • Organizer: 第41回日本分子生物学会大会