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Investigative research on the extention of healthy lifespan that can be applied to humans based on mitochondrial unfolded protein response

Research Project

Project/Area Number 20KK0228
Research Category

Fund for the Promotion of Joint International Research (Fostering Joint International Research (B))

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 59:Sports sciences, physical education, health sciences, and related fields
Research InstitutionTokyo University of Science

Principal Investigator

Higami Yoshikazu  東京理科大学, 薬学部生命創薬科学科, 教授 (90253640)

Co-Investigator(Kenkyū-buntansha) 小林 正樹  東京理科大学, 薬学部生命創薬科学科, 講師 (30795612)
下川 功  長崎大学, 医歯薬学総合研究科(医学系), 客員研究員 (70187475)
田川 亮真  東京理科大学, 薬学部生命創薬科学科, 助教 (70844455)
Project Period (FY) 2020-10-27 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000)
Fiscal Year 2023: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2022: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2021: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywordsカロリー制限 / 食餌誘導性肥満 / 脂肪萎縮 / 老化 / 脂肪酸生合成 / ミトコンドリ生合成 / ミトコンドリアストレス応答 / GDF15 / レスベラトロール / サル / マウス / 白色脂肪組織 / RNA-seq / 脂肪組織 / ミトコンドリアUPR
Outline of Research at the Start

CRによる脂肪組織におけるミトコンドリアアンフールデッドプロテイン反応(mtUPR)を切り口として、肥満症の脂肪組織と比較することにより、その本体を明らかにする。また、マウスとサルにおけるCRによる共通する変化を明らかにするとともに、成長ホルモン/IGF-1シグナル抑制非依存性に制御されるメカニズムの中から、新たなヒトへも有効な分子メカニズムを明らかにする。加えて、本研究を、米国NIAのde Cabo博士の研究室と共同で実施することにより、若手研究者の国際化、本邦における老化生物学を専門とする次世代をリードする若手研究者の育成に貢献する。

Outline of Final Research Achievements

We compared the effects of caloric restriction (CR), which is beneficial to the organism, its counterpart, diet-induced obesity (DIO), fat-specific mitochondrial mitochondria proteostasis disorder by mitochondrial intermediate peptidase (MIPEP) deficiency, the mitochondria stress-induced mitokine Growth differentiation factor 15 (GDF15), and the CR-mimetic drug resveratrol (RS). The results showed that DIO and aMKO enhanced inflammation, increased mitochondria stress including GDF15 expression, and suppressed fatty acid synthesis and mitochondria biosynthesis. CR, on the other hand, showed conflicting results. The CR-mimetic effect of RS was limited. In addition, GDF15 was shown to play a defensive role against aging-associated stress in vivo.

Academic Significance and Societal Importance of the Research Achievements

CRは、代謝改善・抗老化・寿命延伸を誘導する。CRの有益な効果は、近年、サルにおいても観察されることが報告されている。それゆえ、CRはヒトの健康寿命延伸にも有効であると考えられ、CR模倣薬の開発が望まれている。レスベラトロル(RS)はCR模倣薬として注目されている。本研究により、サルの脂肪組織において、RSによるCR模倣効果は、脂肪酸生合成の亢進や炎症の抑制に関して、わずかに見られるものの、限定的であること、さらに、CR作用とは異なるものの、老化の制御にはGDF15シグナルの活性化が有益である可能性が示唆され、ヒトへ外挿する前にサルを用いた解析が必要と考えられた。

Report

(2 results)
  • 2023 Final Research Report ( PDF )
  • 2021 Research-status Report
  • Research Products

    (7 results)

All 2022 2021 2020 Other

All Int'l Joint Research (1 results) Journal Article (6 results) (of which Peer Reviewed: 6 results,  Open Access: 6 results)

  • [Int'l Joint Research] National Institute on Aging(米国)

    • Related Report
      2021 Research-status Report
  • [Journal Article] Individual evaluation of aging- and caloric restriction-related changes to distinct multimeric complexes of circulating adiponectin by immunoblotting2022

    • Author(s)
      Kobayashi Masaki、Nezu Yuichiro、Itoh Mayu、Uchida Rio、Arikawa Tomoya、Otsubo Minami、Nozaki Yuka、Tagawa Ryoma、Fujishima Yuya、Maeda Norikazu、Shimomura Iichiro、Higami Yoshikazu
    • Journal Title

      Experimental Gerontology

      Volume: 164 Pages: 111821-111821

    • DOI

      10.1016/j.exger.2022.111821

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Long-Term Dietary Taurine Lowers Plasma Levels of Cholesterol and Bile Acids2022

    • Author(s)
      Tagawa Ryoma、Kobayashi Masaki、Sakurai Misako、Yoshida Maho、Kaneko Hiroki、Mizunoe Yuhei、Nozaki Yuka、Okita Naoyuki、Sudo Yuka、Higami Yoshikazu
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 23 Issue: 3 Pages: 1793-1793

    • DOI

      10.3390/ijms23031793

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Prolonged caloric restriction ameliorates age-related atrophy in slow and fast muscle fibers of rat soleus muscle2021

    • Author(s)
      Yuhei Mizunoe, Masaki Kobayashi, Hiroki Saito, Akifumi Goto, Ryota Migitaka, Kumi Miura, Naoyuki Okita, Yuka Sudo, Ryoma Tagawa, Miki Yoshida, Ai Umemori, Yoshimi Nakagawa, Hitoshi Shimano, Yoshikazu Higami
    • Journal Title

      Experimental gerontology

      Volume: 154 Pages: 111519-111519

    • DOI

      10.1016/j.exger.2021.111519

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Contribution of PGC-1α to Obesity- and Caloric Restriction-Related Physiological Changes in White Adipose Tissue2021

    • Author(s)
      Kobayashi Masaki、Deguchi Yusuke、Nozaki Yuka、Higami Yoshikazu
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Issue: 11 Pages: 6025-6025

    • DOI

      10.3390/ijms22116025

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mitochondrial Unfolded Protein Responses in White Adipose Tissue: Lipoatrophy, Whole-Body Metabolism and Lifespan2021

    • Author(s)
      Kobayashi Masaki、Nezu Yuichiro、Tagawa Ryoma、Higami Yoshikazu
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Issue: 6 Pages: 2854-2854

    • DOI

      10.3390/ijms22062854

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Trehalose induces SQSTM1/p62 expression and enhances lysosomal activity and antioxidative capacity in adipocytes2020

    • Author(s)
      Kobayashi Masaki、Yasukawa Hiromine、Arikawa Tomoya、Deguchi Yusuke、Mizushima Natsumi、Sakurai Misako、Onishi Shoichi、Tagawa Ryoma、Sudo Yuka、Okita Naoyuki、Higashi Kyohei、Higami Yoshikazu
    • Journal Title

      FEBS Open Bio

      Volume: 11 Issue: 1 Pages: 185-194

    • DOI

      10.1002/2211-5463.13055

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access

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Published: 2020-10-29   Modified: 2025-01-30  

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