KEIO RESEARCHERS INFORMATION SYSTEM

Career 【 Display / hide 】

Career 【 Display / hide 】

• 1999.04

  -

  2005.03

  Keio university school of medicine

• 2009.04

  -

  2013.03

  Keio university school of medicine

• 2014.10

  -

  2017.03

  Washington university school of medicine

Academic Background 【 Display / hide 】

Academic Background 【 Display / hide 】

• 2005.03

  慶應義塾大学, 医学部

  Graduated

• 2013.03

  慶應義塾大学, 医学研究科大学院博士課程

  Graduated

Academic Degrees 【 Display / hide 】

Academic Degrees 【 Display / hide 】

• 医学博士, 慶應義塾大学, 2013.03

Licenses and Qualifications 【 Display / hide 】

Licenses and Qualifications 【 Display / hide 】

• 日本内科学会総合内科専門医・指導医, 2008

• 日本腎臓学会専門医・指導医, 2013

• 日本内分泌学会専門医, 2017

• 日本透析医学会専門医

• 日本糖尿病学会専門医, 2023.12

Research Areas 【 Display / hide 】

Research Areas 【 Display / hide 】

• Life Science / Metabolism and endocrinology (予防医学、老年医学、インスリン抵抗性、NAD合成系)

Papers 【 Display / hide 】

Papers 【 Display / hide 】

• Vascular Endothelial NAMPT-Mediated NAD+ Biosynthesis Regulates Angiogenesis and Cardiometabolic Functions in Male Mice

  Shotaro Kosugi, Shintaro Yamaguchi, Ken Nishioka, Taichi Nagahisa, Yasuhiro Watanabe, Daiki Kojima, Kenji Kaneko, Ryunosuke Mitsuno, Ran Nakamichi, Yoshinaga Kawano, Kenichiro Kinouchi, Koichiro Homma, Takeshi Kanda, Junichiro Irie, Kazutoshi Miyashita, Toshiaki Monkawa, Jun Yoshino, Hiroshi Itoh, Kaori Hayashi

  Aging Cell .  2025.11

  Joint Work, Corresponding author, Accepted

• Safety and efficacy of long-term nicotinamide mononucleotide supplementation on metabolism, sleep, and nicotinamide adenine dinucleotide biosynthesis in healthy, middle-aged Japanese men

  Yamaguchi, S., Irie, J., Mitsuishi, M., Uchino, Y., Nakaya, H., Takemura, R., Inagaki, E., Kosugi, S., Okano, H., Yasui, M., Tsubota, K., Hayashi, K., Yoshino, J. and Itoh, H.

  Endocr J 71 ( 2 ) 153 - 169 2024

  Lead author, Corresponding author,  ISSN  09188959

  　View Summary

  Obesity and aging are major risk factors for several life-threatening diseases. Accumulating evidence from both rodents and humans suggests that the levels of nicotinamide adenine dinucleotide (NAD(+)), a regulator of many biological processes, declines in multiple organs and tissues with aging and obesity. Administration of an NAD(+) intermediate, nicotinamide mononucleotide (NMN), replenishes intracellular NAD(+) levels and mitigates aging- and obesity-associated derangements in animal models. In this human clinical study, we aimed to investigate the safety and effects of 8-week oral administration of NMN on biochemical, metabolic, ophthalmologic, and sleep quality parameters as well as on chronological alterations in NAD(+) content in peripheral tissues. An 8-week, single-center, single-arm, open-label clinical trial was conducted. Eleven healthy, middle-aged Japanese men received two 125-mg NMN capsules once daily before breakfast. The 8-week NMN supplementation regimen was well-tolerated; NAD(+) levels in peripheral blood mononuclear cells increased over the course of NMN administration. In participants with insulin oversecretion after oral glucose loading, NMN modestly attenuated postprandial hyperinsulinemia, a risk factor for coronary artery disease (n = 3). In conclusion, NMN overall safely and effectively boosted NAD(+) biosynthesis in healthy, middle-aged Japanese men, showing its potential for alleviating postprandial hyperinsulinemia.

  • Access to Document (DOI)

• Adipose tissue NAD+ biosynthesis is required for regulating adaptive thermogenesis and whole-body energy homeostasis in mice.

  Yamaguchi S, Franczyk MP, Chondronikola M, Qi N, Gunawardana SC, Stromsdorfer KL, Porter LC, Wozniak DF, Sasaki Y, Rensing N, Wong M, Piston DW, Klein S, Yoshino J.

  Proc Natl Acad Sci U S A. (Proceedings of the National Academy of Sciences of the United States of America)  116 ( 47 ) 23822 - 23828 2019.11

  Research paper (scientific journal), Joint Work, Lead author, Accepted,  ISSN  00278424

  　View Summary

  Nicotinamide adenine dinucleotide (NAD(+)) is a critical coenzyme for cellular energy metabolism. The aim of the present study was to determine the importance of brown and white adipose tissue (BAT and WAT) NAD(+) metabolism in regulating whole-body thermogenesis and energy metabolism. Accordingly, we generated and analyzed adipocyte-specific nicotinamide phosphoribosyltransferase (Nampt) knockout (ANKO) and brown adipocyte-specific Nampt knockout (BANKO) mice because NAMPT is the rate-limiting NAD(+) biosynthetic enzyme. We found ANKO mice, which lack NAMPT in both BAT and WAT, had impaired gene programs involved in thermogenesis and mitochondrial function in BAT and a blunted thermogenic (rectal temperature, BAT temperature, and whole-body oxygen consumption) response to acute cold exposure, prolonged fasting, and administration of β-adrenergic agonists (norepinephrine and CL-316243). In addition, the absence of NAMPT in WAT markedly reduced adrenergic-mediated lipolytic activity, likely through inactivation of the NAD(+)-SIRT1-caveolin-1 axis, which limits an important fuel source fatty acid for BAT thermogenesis. These metabolic abnormalities were rescued by treatment with nicotinamide mononucleotide (NMN), which bypasses the block in NAD(+) synthesis induced by NAMPT deficiency. Although BANKO mice, which lack NAMPT in BAT only, had BAT cellular alterations similar to the ANKO mice, BANKO mice had normal thermogenic and lipolytic responses. We also found NAMPT expression in supraclavicular adipose tissue (where human BAT is localized) obtained from human subjects increased during cold exposure, suggesting our finding in rodents could apply to people. These results demonstrate that adipose NAMPT-mediated NAD(+) biosynthesis is essential for regulating adaptive thermogenesis, lipolysis, and whole-body energy metabolism.

  • Access to Document (DOI)

• Intestinal Epithelial NAD+ Biosynthesis Regulates GLP-1 Production and Postprandial Glucose Metabolism in Mice

  Nagahisa, T., Yamaguchi, S., Kosugi, S., Homma, K., Miyashita, K., Irie, J., Yoshino, J. and Itoh, H.

  Endocrinology 163 ( 4 )  2022.02

  Corresponding author, Accepted,  ISSN  0013-7227

  　View Summary

  Obesity is associated with perturbations in incretin production and whole-body glucose metabolism, but the precise underlying mechanism remains unclear. Here, we tested the hypothesis that nicotinamide phosphoribosyltransferase (NAMPT), which mediates the biosynthesis of nicotinamide adenine dinucleotide (NAD+), a key regulator of cellular energy metabolism, plays a critical role in obesity-associated intestinal pathophysiology and systemic metabolic complications. To this end, we generated a novel mouse model, namely intestinal epithelial cell-specific Nampt knockout (INKO) mice. INKO mice displayed diminished glucagon-like peptide-1 (GLP-1) production, at least partly contributing to reduced early-phase insulin secretion and postprandial hyperglycemia. Mechanistically, loss of NAMPT attenuated the Wnt signaling pathway, resulting in insufficient GLP-1 production. We also found that diet-induced obese mice had compromised intestinal NAMPT-mediated NAD+ biosynthesis and Wnt signaling pathway, associated with impaired GLP-1 production and whole-body glucose metabolism, resembling the INKO mice. Finally, administration of a key NAD+ intermediate, nicotinamide mononucleotide (NMN), restored intestinal NAD+ levels and obesity-associated metabolic derangements, manifested by a decrease in ileal Proglucagon expression and GLP-1 production as well as postprandial hyperglycemia in INKO and diet-induced obese mice. Collectively, our study provides mechanistic and therapeutic insights into intestinal NAD+ biology related to obesity-associated dysregulation of GLP-1 production and postprandial hyperglycemia.

  • Access to Document (DOI)

• Diurnal variation in PDK4 expression is associated with plasma free fatty acid availability in people.

  Shintaro Yamaguchi, Anna C Moseley, Paloma Almeda-Valdes Kelly L Stromsdorfer, Michael P Franczyk, Adewole L Okunade,Bruce W Patterson, Samuel Klein, Jun Yoshino

  J Clin Endocrinol Metab. (Journal of Clinical Endocrinology and Metabolism)  103 ( 3 ) 1068 - 1076 2018.03

  Research paper (scientific journal), Joint Work, Lead author, Accepted,  ISSN  0021972X

  　View Summary

  CONTEXT: Many biological pathways involved in regulating substrate metabolism display rhythmic oscillation patterns. In rodents, clock genes regulate circadian rhythms of metabolic genes and substrate metabolism. However, the interrelationships among substrate metabolism, metabolic genes, and clock genes have not been fully explored in people. OBJECTIVE: We tested the hypothesis that the diurnal expression pattern of pyruvate dehydrogenase kinase 4 (PDK4), a key metabolic enzyme involved in fuel switching between glucose and free fatty acids (FFAs), is associated with plasma FFA concentration and clock genes. DESIGN AND METHODS: We analyzed peripheral blood mononuclear cells (PBMCs), subcutaneous adipose tissue, and plasma samples obtained serially during 24 hours from metabolically healthy women (n = 10) and evaluated the interrelationships among PDK4, plasma FFA, and clock genes. We also determined the potential mechanisms responsible for PDK4 transcriptional regulation by using primary human PBMCs and adipocytes. RESULTS: We found that PDK4 diurnal expression patterns were similar in PBMCs and adipose tissue (ρ = 0.84, P < 0.001). The diurnal variation in PBMC PDK4 expression correlated more strongly with plasma FFA and insulin (ρ = 0.86 and 0.63, respectively, both P < 0.001) concentrations than clock genes. Data obtained from primary culture experiments demonstrated that FFAs directly induced PDK4 gene expression, at least in part through activation of peroxisome proliferator-activated receptor α. CONCLUSIONS: Our results suggest that plasma FFA availability is an important regulator of diurnal expression patterns of PDK4, and we identify a novel interaction between plasma FFA and cellular diurnal rhythms in regulating substrate metabolism.

  • Access to Document (DOI)

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Papers, etc., Registered in KOARA 【 Display / hide 】

Papers, etc., Registered in KOARA 【 Display / hide 】

• Therapeutic potential of intestinal epithelial NAMPT-mediated NAD+ biosynthesis in insulin resistance

  Yamaguchi, Shintarō

  科学研究費補助金研究成果報告書 2020

• Generation of kidney tubular cells from human pluripotent stem cells

  Yamaguchi, Shintaro

  科学研究費補助金研究成果報告書 2016

• The use of human pluripotent stem-cell-derived renal/vascular precursors and organ decellularization for the generation of a kidney organoid

  Yamaguchi, Shintaro

  科学研究費補助金研究成果報告書 2015

• Clarification of new pathological mechanisms for chronic kidney disease using technology that induces endothelial cells from human ES/iPS cells

  Yamaguchi, Shintaro

  科学研究費補助金研究成果報告書 2012

Reviews, Commentaries, etc. 【 Display / hide 】

Reviews, Commentaries, etc. 【 Display / hide 】

• 糖尿病および合併症治療の展望～糖尿病患者の健康長寿への架け橋～　NAD+合成系賦活化に基づく2型糖尿病およびその合併症予防・治療の試み

  山口 慎太郎

  糖尿病合併症 ((一社)日本糖尿病合併症学会)  35 ( 2 ) 183 - 185 2021.08

• 超高齢社会日本におけるNAD+生物学トランスレーショナル研究の意義と可能性

  山口 慎太郎, 伊藤 裕, 吉野 純

  日本老年医学会雑誌 ((一社)日本老年医学会)  57 ( 3 ) 213 - 223 2020.07

  ISSN  0300-9173

  　View Summary

  老化・加齢は癌,糖尿病,アルツハイマー病などの種々の疾患の最も重要な危険因子として知られている.未曾有の超高齢社会にある我が国において,高齢者の健康寿命の延伸を図る新しい方法論の開発は喫緊の課題であると言える.Nicotinamide adenine dinucleotide NAD+は,約110年前に発見された古典的な補酵素として知られている.言わばルネッサンスを迎えた近年のNAD+生物学研究の爆発的な展開により,ヒトを含めた哺乳動物において,老化に伴うNicotinamide phosphoribosyltransferase(NAMPT)を含むNAD+生合成酵素活性の低下,あるいはCD38に代表されるNAD+分解酵素活性の亢進により,全身性に臓器NAD+量が減少することが明らかとなった.そして,遺伝子改変動物モデルを駆使した解析により,このNAD+量の減少が老化に伴う機能障害,老化関連疾患の病態形成に重要な役割を果たすことが解明されつつある.さらに,数々の疾患モデル動物,老化マウスを用いた検討により,nicotinamide mononucleotide(NMN),nicotinamide riboside(NR)に代表されるNAD+中間代謝産物が,健康増進作用,抗老化作用を発揮することも続々と報告されている.これらの結果は,NAD+生物学研究の臨床応用,社会実装への機運を高め,現在,ヒトにおけるNAD+中間代謝産物の安全性,効能を検討する臨床研究が世界的に展開されている.本総説では,目紛しいほどの進化を遂げるこれらNAD+生物学研究トランスレーショナル研究の進捗を最新の知見を交え紹介し,超高齢社会日本におけるその研究の意義,可能性を考察したいと思う.(著者抄録)

• 老化関連疾患における NAD⁺合成系・ミトコン ドリアサーチュン SIRT3 の生理学的重要性と治療標的としての可能性.

  山口慎太郎、吉野純

  日本臨床  2016

  Article, review, commentary, editorial, etc. (scientific journal), Joint Work

• 【糖尿病性腎症研究の最前線】SGLT2阻害薬の新たな知見　サーチュインの活性化を介した腎保護効果

  西岡 謙, 山口 慎太郎, 林 香

  腎と透析 ((株)東京医学社)  96 ( 2 ) 209 - 213 2024.02

  ISSN  0385-2156

  　View Summary

  ＜文献概要＞はじめに　ナトリウム(Na)・グルコース共役輸送体2(sodium glucose cotransporter 2:SGLT2)阻害薬は,2型糖尿病患者を対象としたCREDENCE試験,非糖尿病患者を対象に取り入れたDAPA-CKD試験,EMPA-KIDNEY試験により,糖尿病合併の有無によらない慢性腎臓病(chronic kidney disease:CKD)に対する腎保護作用が示された。包括的CKD臨床効果情報縦断データベースを活用した解析から,SGLT2阻害薬の腎保護作用は,血糖改善に依存せず,蛋白尿やレニン・アンジオテンシン系(renin-angiotensin system:RAS)阻害薬の有無にも影響されないことも判明している。本稿では,SGLT2阻害薬が腎保護効果をもたらす機序について,主に基礎研究の観点から概説する。

• 【SGLT2阻害薬から見えてくる新たな生体システムの姿】SGLT2阻害薬によるNAD+合成系-サーチュインの活性化を介した腎保護効果

  山口 慎太郎, 伊藤 裕

  細胞 ((株)ニュー・サイエンス社)  55 ( 4 ) 216 - 219 2023.04

  ISSN  1346-7557

  　View Summary

  SGLT2阻害薬の腎保護効果が複数の大規模臨床研究で明らかとなり,SGLT2阻害薬は,糖尿病・非糖尿病性腎臓病の進展抑制薬として実臨床で欠かせない薬剤となった。腎機能低下の危険因子である,糖尿病は,近位尿細管でNicotinamide Adenine Dinucleotide(NAD+)合成系を抑制し,NAD+依存性脱アセチル化酵素サーチュインの活性を減弱する。一方で,SGLT2阻害薬は,近位尿細管にカロリー制限環境を生み出し,NAD+合成系-サーチュインを活性化することで,尿細管機能を改善し,さらには尿細管と糸球体連関のメディエーターを回復することにより糸球体保護効果を発揮する。SGLT2阻害薬は,尿細管のカロリー制限により,尿細管・糸球体両者の保護作用を有する慢性腎臓病進展抑制薬としての立ち位置を超え,健康長寿を達成するkey drugとなる可能性が期待されている。(著者抄録)

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Research Projects of Competitive Funds, etc. 【 Display / hide 】

Research Projects of Competitive Funds, etc. 【 Display / hide 】

• 腎血管内皮および足細胞NAD合成系を標的とした老化に伴う腎硬化症発症予防法の開発

  2025.04

  -

  2030.03

  基盤研究(C), Principal investigator

• 脂肪組織血管新生能を標的とした血管内皮NAD賦活化による肥満2型糖尿病発症予防

  2021.04

  -

  2025.03

  MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Principal investigator

• 腸管NAMPT-NAD合成系を標的としたNMNによるインスリン抵抗性予防法の開発

  2018.04

  -

  2021.03

  MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Early-Career Scientists , Principal investigator

• ヒトES・iPS細胞由来腎臓・血管前駆細胞と脱細胞化技術の融合による新規腎臓再生

  2014.04

  -

  2016.03

  文部科学省・日本学術振興会, 科学研究費助成事業, 山口 慎太郎, 若手研究(B), 補助金, 研究代表者, No Setting

Courses Taught 【 Display / hide 】

Courses Taught 【 Display / hide 】

• INTRODUCTION TO CLINICAL CLERKSHIPS

  2026

• CBT (COMPUTER BASED TESTING)

  2026