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Origins of senescent cells that regulate aging in vivo

Research Project

Project/Area Number 20K21497
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 48:Biomedical structure and function and related fields
Research InstitutionThe University of Tokyo

Principal Investigator

Nakanishi Makoto  東京大学, 医科学研究所, 教授 (40217774)

Project Period (FY) 2020-07-30 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2021: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2020: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Keywords細胞老化 / p16 / シングルセル解析 / 老化細胞 / 個体老化
Outline of Research at the Start

本研究は、申請者らが樹立したp16陽性老化細胞を可視化マウスを用いて、臓器・組織からtdTomato陽性老化細胞を単離し、シングルセルトランスクリプトーム解析からそれぞれの臓器・組織における老化細胞の起源を決定する。決定された起源の細胞種特異的に個体内で細胞老化を誘導し、いかなる細胞の老化が個体・臓器・組織の加齢性変化や機能不全を引き起こすのかを明らかにする。個体老化の原因が特定の細胞老化によることが明らかとなれば、これを標的とした抗加齢療法や老年病予防法の確立、さらには健康寿命を延長することが可能となると期待できる。

Outline of Final Research Achievements

This study aims to identify senescent cells in individuals and analyze these cells at the single-cell level to determine the origin of senescent cells and their role in individual aging. Mice were generated in which p16-positive cells could be fluorescently stained with tdTomato in the presence of tamoxifen by insertion of CreERT2 into Exon1 at the p16Ink4a locus, currently the most reliable senescent cell marker.At the same time, DTR was also inserted to generate mice capable of selectively removing p16-positive cells in a diphtheria toxin (DT)-dependent manner. Using these mice, tdTomato-positive cells were isolated from various organs and tissues and subjected to single-cell transcriptome analysis. The results showed that senescent cells originated from various cell types and had diverse properties. Furthermore, their removal by DT improved the pathologies associated with various aging and lifestyle-related diseases.

Academic Significance and Societal Importance of the Research Achievements

細胞老化が様々な加齢性変化や生活習慣病に関わっていることが報告されているが、細胞老化研究は試験管内の解析が主であり、個体内のいつ、どこで、どのような性質を持っているのか全く分かっていなかった。このことから、個体老化や生活習慣病病態がどの様に老化細胞により制御されているのか全く不明であった。本研究により、世界で初めて一細胞レベルで老化細胞を解析可能なマウスが作製され、その解析から老化細胞の起源は多様であり、又それらの性質も起源となる細胞依存的に非常に不均一であることが分かった。これらの成果は、今後老化細胞により個体老化がどの様に制御されるのかを理解する上で非常に重要な知見を与えるものとなった。

Report

(2 results)
  • 2021 Final Research Report ( PDF )
  • 2020 Research-status Report
  • Research Products

    (13 results)

All 2021 2020

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

  • [Journal Article] A 3D tissue model-on-a-chip for studying the effects of human senescent fibroblasts on blood vessels2021

    • Author(s)
      Pauty Joris、Nakano Shizuka、Usuba Ryo、Nakajima Tadaaki、Johmura Yoshikazu、Omori Satotaka、Sakamoto Naoya、Kikuchi Akihiko、Nakanishi Makoto、Matsunaga Yukiko T.
    • Journal Title

      Biomaterials Science

      Volume: 9 Issue: 1 Pages: 199-211

    • DOI

      10.1039/d0bm01297a

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders2021

    • Author(s)
      Johmura Yoshikazu、Yamanaka Takehiro、Omori Satotaka、Wang Teh-Wei、Sugiura Yuki、Matsumoto Masaki、Suzuki Narumi、Kumamoto Soichiro、Yamaguchi Kiyoshi、Hatakeyama Seira、Takami Tomoyo、Yamaguchi Rui、Shimizu Eigo、Ikeda Kazutaka、Okahashi Nobuyuki、Mikawa Ryuta、Suematsu Makoto、Arita Makoto、Sugimoto Masataka et al
    • Journal Title

      Science

      Volume: 371 Issue: 6526 Pages: 265-270

    • DOI

      10.1126/science.abb5916

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] TP53/p53-FBXO22-TFEB controls basal autophagy to govern hormesis2021

    • Author(s)
      Suzuki Narumi、Johmura Yoshikazu、Wang Teh-Wei、Migita Toshiro、Wu Wenwen、Noguchi Rei、Yamaguchi Kiyoshi、Furukawa Yoichi、Nakamura Shuhei、Miyoshi Ichiro、Yoshimori Tamotsu、Ohta Tomohiko、Nakanishi Makoto
    • Journal Title

      Autophagy

      Volume: 11 Issue: 11 Pages: 1-18

    • DOI

      10.1080/15548627.2021.1897961

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Synthetic hyperacetylation of nucleosomal histones2020

    • Author(s)
      Kajino Hidetoshi、Nagatani Tomomi、Oi Miku、Kujirai Tomoya、Kurumizaka Hitoshi、Nishiyama Atsuya、Nakanishi Makoto、Yamatsugu Kenzo、Kawashima Shigehiro A.、Kanai Motomu
    • Journal Title

      RSC Chemical Biology

      Volume: 1 Issue: 2 Pages: 56-59

    • DOI

      10.1039/d0cb00029a

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] FBXO22, an epigenetic multiplayer coordinating senescence, hormone signaling, and metastasis2020

    • Author(s)
      Johmura Yoshikazu、Harris Alexander S.、Ohta Tomohiko、Nakanishi Makoto
    • Journal Title

      Cancer Science

      Volume: 111 Issue: 8 Pages: 2718-2725

    • DOI

      10.1111/cas.14534

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Two mouse models carrying truncating mutations in Magel2 show distinct phenotypes2020

    • Author(s)
      Ieda Daisuke、Negishi Yutaka、Miyamoto Tomomi、Johmura Yoshikazu、Kumamoto Natsuko、Kato Kohji、Miyoshi Ichiro、Nakanishi Makoto、Ugawa Shinya、Oishi Hisashi、Saitoh Shinji
    • Journal Title

      PLOS ONE

      Volume: 15 Issue: 8 Pages: e0237814-e0237814

    • DOI

      10.1371/journal.pone.0237814

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Generation of a p16 Reporter Mouse and Its Use to Characterize and Target p16high Cells In Vivo.2020

    • Author(s)
      Omori S, Wang TW, Johmura Y, ..., Sakamoto T (15番目), ..., Nakanishi M.
    • Journal Title

      Cell Metab

      Volume: 32 Issue: 5 Pages: 814-828

    • DOI

      10.1016/j.cmet.2020.09.006

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Recent evolution of a TET-controlled and DPPA3/STELLA-driven pathway of passive DNA demethylation in mammals2020

    • Author(s)
      Mulholland Christopher B.、Nishiyama Atsuya、(19名) Nakanishi Makoto、Bultmann Sebastian、Leonhardt Heinrich
    • Journal Title

      Nature Communications

      Volume: 11 Issue: 1

    • DOI

      10.1038/s41467-020-19603-1

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 老化を制御する2021

    • Author(s)
      中西 真
    • Organizer
      第34回神戸臨床腫瘍研究会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] 老化細胞での細胞死誘導2021

    • Author(s)
      中西 真
    • Organizer
      千里ライフサイエンスセミナー「細胞死研究の新展開」
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] 老化を制御する2021

    • Author(s)
      中西 真
    • Organizer
      第39回サイトプロテクション研究会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] UHRF1-dependent LIG1 recruitment on Lagging strand regulates Okazaki fragment joining2020

    • Author(s)
      Makoto Nakanishi
    • Organizer
      EPIGENETICS & CHROMATIN
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] 老化を制御する2020

    • Author(s)
      中西 真
    • Organizer
      福島県立医科大学医学部泌尿器科学講座リサーチセミナー
    • Related Report
      2020 Research-status Report
    • Invited

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Published: 2020-08-03   Modified: 2023-01-30  

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