Elucidation of the regulatory mechanisms of cellular senescence using a novel mouse model to establish the molecular basis of aging

• Project/Area Number: 19H03431
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Kanazawa University (2022); The University of Tokyo (2019-2021)
• Principal Investigator: Johmura Yoshikazu 金沢大学, がん進展制御研究所, 教授 (40616322)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2022: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
• Keywords: 細胞老化 / 細胞周期 / 一細胞解析 / 慢性炎症 / 非アルコール性脂肪肝炎 / 個体老化 / 一細胞遺伝子発現解析 / 老化 / がん / 加齢性疾患 / 慢性腎不全 / 生活習慣病 / 炎症 / DNA損傷 / p53 / シングルセル解析 / バイオイメージング

Outline of Research at the Start

生体内における老化細胞の制御機構や、老化細胞が個体老化を引き起こす分子基盤は不明な点が多い。本研究では、一細胞レベルで老化細胞を同定・単離・トレース可能なマウス、および老化細胞特異的なノックアウトマウスといった新規マウスモデルを用いて、生体内における老化細胞の誘導・除去・蓄積の機構やその役割を明らかにすることにより、老化細胞が個体老化・加齢性疾病発症に及ぼす影響を統括的に解明する。

Outline of Final Research Achievements

Recently, molecular genetic analysis has shown that artificially removing senescent cells from old individuals significantly delays the onset of age-related diseases and even extends life span itself, indicating that the accumulation of senescent cells is one of the main causes of individual aging. However, the mechanisms of induction, removal, and accumulation of senescent cells in vivo and the molecular basis for senescent cell-induced individual aging remain unclear. In this study, we establishedand analhyzed mice in which senescent cells can be identified, isolated, and traced at the single-cell level, and genetically engineered mice specific for senescent cells, to clarify the mechanisms of induction, removal, and accumulation of senescent cells in vivo and their roles.

Academic Significance and Societal Importance of the Research Achievements

老化細胞を一細胞レベルで同定・検出できるマウスを用いた老化細胞の動態・性状解析により、生体内における老化細胞は多様性に富んでいることを見出すとともに、がん治療でも使用されている免疫チェックポイント阻害剤の老化病態治療への応用につながる知見を得ることができた。また、老化細胞の蓄積やそれを起点とした慢性炎症が個体老化や加齢関連疾患の病態の基盤であることも明らかにすることができた。本研究成果は、21世紀の先進医療において重要課題の一つである老化・老年病の予防法の開発につながるとことが期待される。

Research Products

• [Journal Article] Targeting cellular senescence as a therapeutic approach in non-alcoholic steatohepatitis (2023)
  • Author(s): Nakano Yasuhiro、Johmura Yoshikazu
  • Journal Title: Annals of Hepatology Volume: 28 Issue: 2 Pages: 100900-100900
  • DOI: 10.1016/j.aohep.2023.100900
  • Peer Reviewed / Open Access
• [Journal Article] Transcriptomic characterization of Lonrf1 at the single-cell level under pathophysiological conditions (2023)
  • Author(s): Li Dan、Wang Teh-Wei、Aratani Sae、Omori Satotaka、Tamatani Maho、Johmura Yoshikazu、Nakanishi Makoto
  • Journal Title: The Journal of Biochemistry Volume: - Issue: 6 Pages: 459-469
  • DOI: 10.1093/jb/mvad021
  • Peer Reviewed
• [Journal Article] Blocking PD-L1-PD-1 improves senescence surveillance and ageing phenotypes (2022)
  • Author(s): Wang, T. W., Y. Johmura, N. Suzuki, S. Omori, T. Migita, K. Yamaguchi, S. Hatakeyama, S. Yamazaki, E. Shimizu, S. Imoto, Y. Furukawa, A. Yoshimura, and M. Nakanishi
  • Journal Title: Nature Volume: 611 Issue: 7935 Pages: 358-364
  • DOI: 10.1038/s41586-022-05388-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sentinel p16INK4a+ cells in the basement membrane form a reparative niche in the lung (2022)
  • Author(s): Reyes Nabora S.、Krasilnikov Maria、Allen Nancy C.、Lee Jin Young、Hyams Ben、Zhou Minqi、Ravishankar Supriya、Cassandras Monica、Wang Chaoqun、Khan Imran、Matatia Peri、Johmura Yoshikazu、Molofsky Ari、Matthay Michael、Nakanishi Makoto、Sheppard Dean、Campisi Judith、Peng Tien
  • Journal Title: Science Volume: 378 Issue: 6616 Pages: 192-201
  • DOI: 10.1126/science.abf3326
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Alteration of Trop-2 expression in breast cancer cells by clinically used therapeutic agents and acquired tamoxifen resistance (2022)
  • Author(s): Zhu Jing、Wu Wenwen、Togashi Yukiko、Taira Nihira Naoe、Johmura Yoshikazu、Zhu Dajiang、Nakanishi Makoto、Miyoshi Yasuo、Ohta Tomohiko
  • Journal Title: Breast Cancer Volume: 29 Issue: 6 Pages: 1076-1087
  • DOI: 10.1007/s12282-022-01389-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TP53/p53-FBXO22-TFEB controls basal autophagy to govern hormesis (2021)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders (2021)
  • 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
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] リソソーム恒常性維持の破綻による 老化細胞形質の獲得メカニズム (2022)
  • Author(s): 城村由和
  • Organizer: 第95回日本生化学会大会
  • Invited
• [Presentation] Escape from senescence surveillance by PD-L1-PD-1 immune checkpoint and its blockade ameliorates various senescence-associated disorders (2022)
  • Author(s): Yoshikazu Johmura
  • Organizer: 2nd Chinese Oncology Young Elite Summit 2022
  • Int'l Joint Research / Invited
• [Presentation] Targeting immune escape mechanism in senescent cells ameliorates various senescence-associated disorders (2022)
  • Author(s): Yoshikazu Johmura
  • Organizer: 23rd Northeastern Asian Symposium on “Cellular Senescence: From Pathophysiology to Treatment
  • Int'l Joint Research / Invited
• [Presentation] 老化細胞の免疫監視機構の解明に よる新たな個体老化制御法の可能性 (2022)
  • Author(s): 城村由和
  • Organizer: 第32回日本サイトメトリー学会
  • Invited
• [Presentation] 老化細胞の生存維持に重要な代謝特性の理解と それを標的とした新たな個体老化制御法の開発 (2021)
  • Author(s): 城村由和
  • Organizer: 第63回日本老年医学会学術集会
  • Invited
• [Presentation] 一細胞解析を用いたがんにおける細胞老化の多様性と役割の解明 (2021)
  • Author(s): 城村由和
  • Organizer: 第80回日本癌学会学術総会
  • Invited
• [Presentation] 免疫チェックポイント阻害による老化細胞除去と個体老化制御 (2021)
  • Author(s): 王徳偉、城村由和、中西真
  • Organizer: 第94回日本生化学会大会
  • Invited
• [Presentation] Tissue and cell type-specific heterogeneity of p16high senescent cells revealed by single-cell transcriptomes (2020)
  • Author(s): 城村由和
  • Organizer: MBSJ2020
  • Int'l Joint Research / Invited
• [Presentation] Role of cellular senescence in aging and age-related disorder (2019)
  • Author(s): Yoshikazu Johmura
  • Organizer: 1st International Symposium on Inflammation Cellular Sociology
  • Int'l Joint Research / Invited
• [Book] 実験医学2022年2月号 (2022)
  • Author(s): 高橋 暁子
  • Total Pages: 139
  • Publisher: 羊土社
  • ISBN: 9784758125529
• [Book] 生物の寿命延長 (2022)
  • Author(s): 南野 徹
  • Total Pages: 460
  • Publisher: エヌ・ティー・エス
  • ISBN: 9784860437732
• [Remarks] 抗PD1抗体は老化細胞の免疫監視を強化し， 老年病・生活習慣病を改善する
  • URL: https://www.kanazawa-u.ac.jp/rd/112856