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Molecular mechanisms governing lifespan extension via mitochondrial stress responses

Research Project

Project/Area Number 18K10998
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 59040:Nutrition science and health science-related
Research InstitutionOsaka City University

Principal Investigator

Eriko Kage-Nakadai  大阪市立大学, 大学院生活科学研究科, 教授 (40453790)

Project Period (FY) 2018-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywordsミトコンドリアストレス応答 / 長寿 / 線虫 / 寿命 / 老化 / ドラッグリパーパシング / 医薬品化合物 / ミトコンドリアストレス
Outline of Final Research Achievements

Accumulating studies have argued that the mitochondrial unfolded protein response (UPRmt) is a mitochondrial stress response that promotes longevity in model organisms. In the present study, we screened an off-patent drug library to identify compounds that activate UPRmt using a mitochondrial chaperone hsp-6::GFP reporter system in Caenorhabditis elegans. Metolazone, a diuretic primarily used to treat congestive heart failure and high blood pressure, was identified as a prominent hit as it upregulated hsp-6::GFP and not the endoplasmic reticulum chaperone hsp-4::GFP. Furthermore, metolazone specifically induced the expression of mitochondrial chaperones in the HeLa cell line. Metolazone also extended the lifespan of worms in a atfs-1 and ubl-5-dependent manner. Notably, metolazone failed to increase lifespan in worms with knocked-down nkcc-1. These results suggested that metolazone activates the UPRmt across species and prolongs the lifespan of C. elegans.

Academic Significance and Societal Importance of the Research Achievements

ヒト抗老化の標的として「ミトコンドリアストレス応答」を制御する介入が有効である可能性が考えられるが、これまでに当該作用を期待でき、かつヒトが長期服用した場合の安全性が確認されている化合物は同定されていなかった。本研究では、線虫を用いて、高血圧治療に使われる利尿降圧剤メトラゾンの寿命延伸効果を発見した。本知見は、メトラゾンという薬の新たな薬効を示唆するとともに、ミトコンドリアストレス応答という抗老化のターゲット、抗老化薬という新たなコンセプトの提示につながる可能性がある。

Report

(5 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (9 results)

All 2020 2019 2018

All Journal Article (8 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 8 results,  Open Access: 5 results) Presentation (1 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Metolazone upregulates mitochondrial chaperones and extends lifespan in Caenorhabditis elegans2020

    • Author(s)
      Ito Ai、Zhao Quichi、Tanaka Yoichiro、Yasui Masumi、Katayama Rina、Sun Simo、Tanimoto Yoshihiko、Nishikawa Yoshikazu、Kage-Nakadai Eriko
    • Journal Title

      Biogerontology

      Volume: 22 Issue: 1 Pages: 119-131

    • DOI

      10.1007/s10522-020-09907-6

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Toll-like receptor homolog TOL-1 regulates <i>Bifidobacterium infantis</i>-elicited longevity and behavior in <i>Caenorhabditis elegans</i>2019

    • Author(s)
      SUN Simo、MIZUNO Yasuko、KOMURA Tomomi、NISHIKAWA Yoshikazu、KAGE-NAKADAI Eriko
    • Journal Title

      Bioscience of Microbiota, Food and Health

      Volume: 38 Issue: 3 Pages: 105-110

    • DOI

      10.12938/bmfh.18-031

    • NAID

      130007684207

    • ISSN
      2186-3342
    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] daf-16/FOXO isoform b in AIY neurons is involved in low preference for Bifidobacterium infantis in Caenorhabditis elegans.2019

    • Author(s)
      Sun S, Ohta A, Kuhara A, Nishikawa Y, Kage-Nakadai E.
    • Journal Title

      Neurosci Res.

      Volume: Feb 4 Pages: 8-16

    • DOI

      10.1016/j.neures.2019.01.011

    • Related Report
      2019 Research-status Report 2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Host range-associated clustering based on multi-locus variable-number tandem-repeat analysis, phylotypes, and virulence genes of atypical enteropathogenic Escherichia coli strains2019

    • Author(s)
      Parvej MS, Nakamura H, Alam MA, Wang L, Zhang S, Emura K, Kage-Nakadai E, Wada T, Hara-Kudo Y, Nishikawa Y.
    • Journal Title

      Appl Environ Microbiol.

      Volume: 85 Issue: 6 Pages: e02796-18

    • DOI

      10.1128/aem.02796-18

    • NAID

      120006727806

    • URL

      https://ocu-omu.repo.nii.ac.jp/records/2019617

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Clostridium butyricum MIYAIRI 588 Increases the Lifespan and Multiple-Stress Resistance of Caenorhabditis elegans.2018

    • Author(s)
      Kato M, Hamazaki Y, Sun S, Nishikawa Y, Kage-Nakadai E.
    • Journal Title

      Nutrients

      Volume: 10 Issue: 12 Pages: 1921-1921

    • DOI

      10.3390/nu10121921

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Diffusely adherent Escherichia coli strains isolated from healthy carriers suppress cytokine secretions of epithelial cells stimulated by inflammatory substances2018

    • Author(s)
      Tanimoto Yoshihiko、Tamai Sayaka、Matsuzaki Takehiro、Takeuchi Narumi、Noju Takumi、Yanagida Saki、Kage-Nakadai Eriko、Yamaguchi Yoshihiro、Kodama Toshio、Nakamura Shota、Motooka Daisuke、Iida Tetsuya、Nishikawa Yoshikazu
    • Journal Title

      Infection and Immunity

      Volume: 87 Issue: 1 Pages: e00683-18

    • DOI

      10.1128/iai.00683-18

    • NAID

      120006548613

    • URL

      https://ocu-omu.repo.nii.ac.jp/records/2019889

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Imbalanced Expression of Tau and Tubulin Induces Neuronal Dysfunction in C. elegans Models of Tauopathy.2018

    • Author(s)
      Miyasaka T, Shinzaki Y, Yoshimura S, Yoshina S, Kage-Nakadai E, Mitani S, Ihara Y.
    • Journal Title

      Front Neurosci.

      Volume: 12 Pages: 415-415

    • DOI

      10.3389/fnins.2018.00415

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The small GTPase ARF-1.2 is a regulator of unicellular tube formation in Caenorhabditis elegans2018

    • Author(s)
      Kage-Nakadai E, Sun S, Iwata S, Yoshina ,S Nishikawa Y and Mitani S
    • Journal Title

      Journal of Physiological Sciences

      Volume: in press Issue: 1 Pages: 47-56

    • DOI

      10.1007/s12576-018-0617-5

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Neural and molecular basis involved in low preference to Bifidobacterium infantis in Caenorhabditis elegans2018

    • Author(s)
      Simo Sun, Yoshikazu Nishikawa, Eriko Kage-Nakadai
    • Organizer
      The 2018 C. elegans “Topics” Meeting, covering Aging, Metabolism, Pathogenesis, Stress, and Small RNAs
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research

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Published: 2018-04-23   Modified: 2023-01-30  

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