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Accelelration of stem cell aging and age-related disorder in premature aging model mouse

Planned Research

Project AreaEstablishing a new paradigm of the pathogenesis of diseases through the understanding of stem cell aging
Project/Area Number 26115004
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionFoundation for Biomedical Research and Innovation at Kobe

Principal Investigator

Nabeshima Yo-ichi  公益財団法人神戸医療産業都市推進機構, その他部局等, その他 (60108024)

Project Period (FY) 2014-07-10 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥127,530,000 (Direct Cost: ¥98,100,000、Indirect Cost: ¥29,430,000)
Fiscal Year 2018: ¥24,700,000 (Direct Cost: ¥19,000,000、Indirect Cost: ¥5,700,000)
Fiscal Year 2017: ¥24,570,000 (Direct Cost: ¥18,900,000、Indirect Cost: ¥5,670,000)
Fiscal Year 2016: ¥24,700,000 (Direct Cost: ¥19,000,000、Indirect Cost: ¥5,700,000)
Fiscal Year 2015: ¥24,570,000 (Direct Cost: ¥18,900,000、Indirect Cost: ¥5,670,000)
Fiscal Year 2014: ¥28,990,000 (Direct Cost: ¥22,300,000、Indirect Cost: ¥6,690,000)
Keywords老化 / ビタミンD / Calpain 1 / NAD代謝 / 幹細胞の枯渇 / 幹細胞老化 / 幹細胞 / クロトー / 免疫系細胞 / 個体老化 / Klotho / ケモカイン / 炎症性サイトカイン / 組織障害 / 炎症 / カルパイン / Rag2 / 海馬 / サーチュイン / 細胞障害 / 脂質代謝 / グルコース代謝 / eNampt
Outline of Final Research Achievements

Sever cell and tissue damages are observed in lung, kidney, skin, and blood vessels of a-klotho deficient mouse in association with the occurrence of multiple aging related disorders.
We found that increased stem cell growth and followed exhaustion of stem cells were induced to compensate sever cell and tissue damages. We next analyzed metabolic abnormalities and great activation of calpain-1 observed in a-klotho deficient mouse caused cell and tissue damages and followed compensatory responses of stem cells. In addition, we analyzed the abnormality of NAD metabolism in a-klotho deficient mouse and discovered the remarkable acceleration of secondary (usually minor) pathway of NAD metabolism.

Academic Significance and Societal Importance of the Research Achievements

老化個体における幹細胞の振る舞いについての情報、幹細胞の枯渇に関する情報はほとんどないことから、本研究成果は幹細胞老化に関する基本情報としての意義が高い。
老化に伴うNAD代謝の変化、NMNの低下は知られていただが、早期老化マウスにおいてNAD代謝の副次経路が顕著に亢進していることが初めて明らかになった意義は高い。

Report

(6 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • 2015 Annual Research Report
  • 2014 Annual Research Report
  • Research Products

    (47 results)

All 2019 2018 2017 2016 2015 2014 Other

All Int'l Joint Research (2 results) Journal Article (15 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 15 results,  Open Access: 12 results,  Acknowledgement Compliant: 6 results) Presentation (27 results) (of which Int'l Joint Research: 3 results,  Invited: 27 results) Book (2 results) Patent(Industrial Property Rights) (1 results)

  • [Int'l Joint Research] University of Illinois at Chicago(米国)

    • Related Report
      2015 Annual Research Report
  • [Int'l Joint Research] University of California, Los Angeles(米国)

    • Related Report
      2015 Annual Research Report
  • [Journal Article] Alzheimer Aβ Assemblies Accumulate in Excitatory Neurons upon Proteasome Inhibition and Kill Nearby NAKα3 Neurons by Secretion2019

    • Author(s)
      Komura Hitomi、Kakio Shota、Sasahara Tomoya、Arai Yoshie、Takino Naomi、Sato Michio、Satomura Kaori、Ohnishi Takayuki、Nabeshima Yo-ichi、Muramatsu Shin-ichi、Kii Isao、Hoshi Minako
    • Journal Title

      iScience

      Volume: 13 Pages: 452-477

    • DOI

      10.1016/j.isci.2019.01.018

    • NAID

      120006576457

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Caveolin-1 Promotes Early Neuronal Maturation via Caveolae-Independent Trafficking of N-Cadherin and L1.2018

    • Author(s)
      Shikanai M, Nishimura YV, Sakurai M, Nabeshima YI, Yuzaki M, Kawauchi T.
    • Journal Title

      iScience

      Volume: 7 Pages: 53-67

    • DOI

      10.1016/j.isci.2018.08.014

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Forebrain Ptf1a is required for sexual differentiation of the brain.2018

    • Author(s)
      Fujiyama T., Miyashita S., Tsuneoka Y., Nagaoka M., Kakizaki M., Kanno S., Ishikawa Y., Kawaguchi Y., Yanagawa Y., Magnuson MA., Nabeshima Y., Masashi Yanagisawa M., Funato H., Hoshino M.
    • Journal Title

      Cell Reports

      Volume: 24 Pages: 9-94

    • NAID

      120006491717

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Diagnostic and clinical significance of the titin fragment in urine of Duchenne muscular dystrophy patients.2018

    • Author(s)
      Awano H. Matsumoto M., Nagai M., Taku Shirakawa T., Maruyama N., Iijima K., Nabeshima Y., Matsuo M.
    • Journal Title

      Clinica Chimica Acta

      Volume: 476 Pages: 111-116

    • DOI

      10.1016/j.cca.2017.11.024

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Morphological and Molecular Basis of Cytoplasmic Dilation and Swelling in Cortical Migrating Neurons2017

    • Author(s)
      Nishimura Yoshiaki、Nabeshima Yo-ichi、Kawauchi Takeshi
    • Journal Title

      Brain Sciences

      Volume: 7 Issue: 7 Pages: 87-87

    • DOI

      10.3390/brainsci7070087

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mouse macrophages show different requirements for phosphatidylserine receptor Tim4 in efferocytosis2017

    • Author(s)
      Yanagihashi Yuichi、Segawa Katsumori、Maeda Ryota、Nabeshima Yo-ichi、Nagata Shigekazu
    • Journal Title

      Proc Natl Acad Sci U S A

      Volume: 114 Issue: 33 Pages: 8800-8805

    • DOI

      10.1073/pnas.1705365114

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Fgf21 regulates T-cell development in the neonatal and juvenile thymus.2017

    • Author(s)
      Nakayama Y, Masuda Y, Ohta H, Tanaka T, Washida M, Nabeshima YI, Miyake A, Itoh N, Konishi M
    • Journal Title

      Scientific Reports

      Volume: 23 Issue: 1 Pages: 330-330

    • DOI

      10.1038/s41598-017-00349-8

    • NAID

      120006305890

    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Establishment of a highly sensitive sandwich ELISA for the N-terminal fragment of titin in urine.2016

    • Author(s)
      Maruyama N., Asai T., Abe C, Inada A., Miyashita K, Maeda M., Matsuo M., Nabeshima Y.
    • Journal Title

      Sci Rep.

      Volume: 6 Issue: 1 Pages: 39375-39386

    • DOI

      10.1038/srep39375

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Effects of 17β-estradiol and androgen on glucose metabolism in skeletal muscle.2016

    • Author(s)
      Inada A., Fujii NL, Inada O., Higaki Y., Nabeshima Y.
    • Journal Title

      Endocrinology

      Volume: 157 Pages: 4691-4705

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Adjusting the 17β-Estradiol to Androgen Ratio Ameriorates Diabetic Nephropathy2016

    • Author(s)
      Inada A., Inada O., Nagafuchi S., Katsuta H., Yasunami Y., Fujii NL., Matsubara T., Arai H., Fukatsu A. Nabeshima Y.
    • Journal Title

      J. American Society of Nephrology

      Volume: 27 Issue: 2 Pages: 3035-3050

    • DOI

      10.1681/asn.2016121275

    • Related Report
      2016 Annual Research Report 2015 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Hepatocyte β-Klotho regulates lipid homeostasis but not body weight in mice.2016

    • Author(s)
      Kobayashi K., Tanaka T., Okada S., Morimoto Y., Matsumura S., InoueK., Kimura K., Yagi T., Saito Y., Fushiki T., Inoue H., Matsumoto M. Nabeshima Y.
    • Journal Title

      FASEB J.

      Volume: 30 Pages: 849-862

    • Related Report
      2016 Annual Research Report 2015 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Na,K-ATPaseα3 is a death target of alzheimer patient amyloid-β assembly.2015

    • Author(s)
      Ohnishi T, ..., Matsui K, ..., Hoshi M (計35名, 記載欄不足)
    • Journal Title

      Proc Natl Acad Sci U S A

      Volume: 112 Issue: 32 Pages: 4465-4474

    • DOI

      10.1073/pnas.1421182112

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Structural insight into an Alzheimer’s brain-derived spherical assembly of amyloid beta by solid-state NMR2015

    • Author(s)
      Parthasarathy, S. Inoue, M. Xiao, Y.Matsumura, Y. Nabeshima, Y. L. Hoshi, M. Ishii, Y.
    • Journal Title

      J. Am. Chem. Soc

      Volume: 137 Issue: 20 Pages: 6480-6483

    • DOI

      10.1021/jacs.5b03373

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Calpain 1 inhibitor BDA-410 ameliorates α-klotho-deficiency phenotypes resembling human aging-related syndromes.2014

    • Author(s)
      Nabeshima Y., Washida M., Tamura M., Maeno A., Ohnishi M., Shiroishi T., Imura A., Razzaque MS., Nabeshima Y.
    • Journal Title

      Sci Rep.

      Volume: 4 Issue: 1 Pages: 1-7

    • DOI

      10.1038/srep05847

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Reduced Renal α-Klotho Expression in CKD Patients and Its Effect on Renal Phosphate Handling and Vitamin D Metabolism.2014

    • Author(s)
      Sakan H, Nakatani K, Asai O, Imura A, Tanaka T, Yoshimoto S, Iwamoto N, Kurumatani N, Iwano M, Nabeshima Y, Konishi N, Saito Y.
    • Journal Title

      PLoS One.

      Volume: 9

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] KlothoとFGF23、FGF15による代謝の恒常性制御2018

    • Author(s)
      鍋島陽一
    • Organizer
      第91回日本内分泌学会学術総会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 健康長寿の実現を目指した老化研究の推進2018

    • Author(s)
      鍋島陽一
    • Organizer
      第65回日本実験動物学会総会学術集会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] a-Klothoの機能と病態における意義2018

    • Author(s)
      鍋島陽一
    • Organizer
      29回Forum in Dojin
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] クロトーの分子機能2017

    • Author(s)
      鍋島陽一
    • Organizer
      日本解剖学会シンポジウム
    • Place of Presentation
      長崎
    • Year and Date
      2017-03-28
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Klothoによって紡がれた生命の糸を解きほぐす2017

    • Author(s)
      鍋島陽一
    • Organizer
      先端モデル動物支援成果発表会
    • Place of Presentation
      大津
    • Year and Date
      2017-02-06
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] 健康長寿の実現を目指した老化研究の推進2017

    • Author(s)
      鍋島陽一
    • Organizer
      愛媛大学セミナー
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] alpha-Klotho in health and diseases2017

    • Author(s)
      Yo-ichi Nabeshima
    • Organizer
      2017 Tohoku Forum for Creativity Thematic Program “Aging Science: from Molecules to Society
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Klothoによって紡がれた生命の糸を解きほぐす2017

    • Author(s)
      鍋島陽一
    • Organizer
      高い教養を涵養する特論 千葉大学講演
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] Klothoによって紡がれた生命の糸を解きほぐす2017

    • Author(s)
      鍋島陽一
    • Organizer
      東大分生研セミナー
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] Klothoによって紡がれた生命の糸を解きほぐす。2017

    • Author(s)
      鍋島陽一
    • Organizer
      第7回Clinical & Basic Research Forum
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 老化モデルとしてのa-Klotho変異マウス2017

    • Author(s)
      鍋島陽一
    • Organizer
      第7回細胞再生医療研究会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] Klothoによって紡がれた生命の糸を解きほぐす。2017

    • Author(s)
      鍋島陽一
    • Organizer
      国立健康・栄養研究所の創立記念講演会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] Klothoの発見を端緒とする老化・認知症研究の進展2017

    • Author(s)
      鍋島陽一
    • Organizer
      基礎老化学会2017 秋のシンポジウム
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] Klothoによって紡がれた生命の糸を解きほぐす2017

    • Author(s)
      鍋島陽一
    • Organizer
      大阪大学微生物学研究所学術講演会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 健康長寿の実現を目指した老化研究の推進2016

    • Author(s)
      鍋島陽一
    • Organizer
      第8回抗加齢内分泌研究会
    • Place of Presentation
      東京
    • Year and Date
      2016-09-04
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Calpain 1 inhibitor BDA-410 ameliorates alpha-Klotho deficiency phenotypes resembling human aging syndromes2016

    • Author(s)
      Yo-ichi Nabeshima
    • Organizer
      FASEB Symposium on The Biology of Calpain in Health and Disease
    • Place of Presentation
      Big Sky, Montana
    • Year and Date
      2016-07-17
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] α-Klotho in Health and Disease2016

    • Author(s)
      Yo-ichi Nabeshima
    • Organizer
      CADM 2016 International Symposium of the Center for Animal Disese Model; Metabolic Disease and Aging
    • Place of Presentation
      Tokyo
    • Year and Date
      2016-07-16
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] α-Klotho in Health and Disease2016

    • Author(s)
      鍋島陽一
    • Organizer
      日本生化学会近畿支部集会
    • Place of Presentation
      神戸
    • Year and Date
      2016-05-21
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Klothoの分子機能解析―蛋白間相互作用における糖鎖の新たな機能―2016

    • Author(s)
      鍋島陽一
    • Organizer
      創薬薬理ファーラムだい60回談話会
    • Place of Presentation
      東京
    • Year and Date
      2016-05-20
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] 蛋白間相互作用における糖鎖の新たな機能2015

    • Author(s)
      鍋島陽一
    • Organizer
      第38回日本分子生物学会年会 ワークショップ
    • Place of Presentation
      神戸
    • Year and Date
      2015-12-01
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] Klothoの分子機能と老化関連疾患2015

    • Author(s)
      鍋島陽一
    • Organizer
      脳心血管抗加齢研究会2015
    • Place of Presentation
      大阪
    • Year and Date
      2015-11-28
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] クロトーの分子機能解析―蛋白間相互作用における糖鎖の新たな機能―2015

    • Author(s)
      鍋島陽一
    • Organizer
      第6回 Molecular Cardiovascular Conference II Keynote Lecture
    • Place of Presentation
      福岡
    • Year and Date
      2015-09-04
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] クロトーの分子機能と病態2015

    • Author(s)
      鍋島陽一
    • Organizer
      第一回日本筋学会学術集会
    • Place of Presentation
      東京
    • Year and Date
      2015-08-08
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] α-Klotho in health and diseases.2015

    • Author(s)
      Yo-ichi Nabeshima
    • Organizer
      The 6th Nagasaki-Hallym Joint Meeting on Neurobiology and Brain Aging.
    • Place of Presentation
      Nagasaki
    • Year and Date
      2015-03-16
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Klothoの構造機能連関――蛋白間相互作用における糖鎖の新たな機能――2014

    • Author(s)
      鍋島陽一
    • Organizer
      第37回東京成長ホルモン成長因子セミナー
    • Place of Presentation
      東京
    • Year and Date
      2014-11-07
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Klothoによって紡がれた生命の糸を解きほぐす2014

    • Author(s)
      鍋島陽一
    • Organizer
      第7回糖化ストレス研究会
    • Place of Presentation
      東京
    • Year and Date
      2014-10-18
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] α- and β-Klothos in health and diseases.2014

    • Author(s)
      Yo-ichi Nabeshim
    • Organizer
      Asian-Aging 2011 Japan-Korea joint conference on aging and neurodegeneration
    • Place of Presentation
      Jeju (Korea)
    • Year and Date
      2014-09-21 – 2014-09-23
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Book] Aging Mechanisms: Cells, Metabolism, Longevity, and Brain Agingα-Klotho in health and diseases2015

    • Author(s)
      Yo-ichi Nabeshima
    • Publisher
      Springer
    • Related Report
      2014 Annual Research Report
  • [Book] α-Klotho/FGF23システム:電解質代謝、老化関連疾患、腎不全を結ぶ新たな視点2014

    • Author(s)
      鍋島陽一
    • Total Pages
      7
    • Publisher
      CLINICAL CALCIUM
    • Related Report
      2014 Annual Research Report
  • [Patent(Industrial Property Rights)] 活性型 GcMAF の製造方法2017

    • Inventor(s)
      鍋島陽一、鍋島曜子、阿部千秋
    • Industrial Property Rights Holder
      鍋島陽一、鍋島曜子、阿部千秋
    • Industrial Property Rights Type
      特許
    • Filing Date
      2017
    • Related Report
      2017 Annual Research Report

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Published: 2014-11-20   Modified: 2022-01-28  

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