Whole body analysis of plasma membrane damage induced cellular senescence

• Project/Area Number: 19K21598
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Studies on the Super-Aging Society
• Research Institution: Okinawa Institute of Science and Technology Graduate University
• Principal Investigator: Moriyama Yohsuke 沖縄科学技術大学院大学, サイエンステクノロジーグループ, サイエンス・テクノロジーアソシエイト (00452532)
• Co-Investigator(Kenkyū-buntansha): 河野 恵子 沖縄科学技術大学院大学, 膜生物学ユニット, 准教授 (30632723)
• Project Period (FY): 2019-06-28 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2021: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2019: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 細胞膜損傷 / PDL / 細胞周期 / 細胞老化 / ホスファチジルセリン / ミトコンドリア / 膜修復 / 組織透明化

Outline of Research at the Start

健康寿命を延ばし老化を抑制することを最終的な目標として掲げ、細胞が代謝は行うが分裂・増殖を停止している「細胞老化」の新たな誘導機構である細胞膜損傷・修復について、細胞老化の遺伝子パスウェイが膜損傷により誘導される機序を培養細胞を用いて明らかにするとともに、「細胞老化のホットスポット」をマウスの全臓器/器官から探索する。さらに膜損傷に起因する細胞老化と全身の老化を臓器特異的な遺伝子改変マウスで促進/抑制して証明し、細胞老化と全身の老化をコントロールする手法を探索する。

Outline of Final Research Achievements

The prevention of aging is required to extend healthy life expectancy. Since "cellular senescence" causes suppression of cell division and functional decline of organs, research on elimination of senescent cells based on understanding of the mechanism of cellular senescence has been attracting attention around the world.
In general, senescent cells were thought to be induced by an enhanced DNA damage response, but we have found that plasma membrane damage and repair induces cellular senescence even without DNA damage. We have identified a transient increase in intracellular calcium as one of the factors involved in this process, the deepening of multiple stages of cellular senescence via organellar changes, and the identification of upstream genes that trigger cellular senescence independent of DNA damage.

Academic Significance and Societal Importance of the Research Achievements

老化の抑制は健康寿命および寿命の延長に寄与すると考えられている。そのための手段として老化細胞の除去が注目を集めているが、細胞の老化機構の理解に基づく細胞老化の抑制は侵襲性が低く健康に資すると考えられる。
本研究では新たに見出した細胞老化の引き金である細胞膜損傷に着目し、生体内で頻繁に生じる膜損傷がいかに細胞老化を引き起こすかを明らかにしつつある。細胞老化の最上流遺伝子を同定し、また膜損傷から細胞老化にかけての遺伝子発現と細胞内イベントの時系列変化の解析から重要な介入点を複数見出しており、今後の研究の発展により細胞膜損傷に起因する細胞老化を抑制する薬剤を選抜できるものと考えている。

Research Products

• [Journal Article] Time-resolved transcriptomic profiling of senescence-associated secretory phenotype (SASP) in multiple senescent cell subtypes (2022)
  • Author(s): Razali Nurhanani、Moriyama Yohsuke、Chiu Yatzu、Suda Kojiro、Kono Keiko
  • Journal Title: BioRxiv Volume: 0 Pages: 0-0
  • DOI: 10.1101/2022.06.27.497690
  • Open Access
• [Journal Article] Semi-in vitro detection of Mg2+-dependent DNase that specifically digest mitochondrial nucleoids in the zygote of Physarum polycephalum (2022)
  • Author(s): Urakawa, N., Nakamura, S., Kishimoto, M., Moriyama, Y., Kawano, S., Higashiyama, T. & Sasaki, N.
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 2995-2995
  • DOI: 10.1038/s41598-022-06920-2
  • Peer Reviewed / Open Access
• [Journal Article] Plasma membrane damage limits replicative lifespan in yeast and human fibroblasts (2021)
  • Author(s): Keiko Kono, Yoshikazu Johmura, Yohsuke Moriyama Yumiko Masukagami, Koutarou Nishimura, Hunter Barbee, Hiroshi Takase, Shinju Sugiyama, Yoshikatsu Sato, Tetsuya Higashiyama, Makoto Nakanishi
  • Journal Title: BioRxiv Volume: 2021 Pages: 0-0
  • DOI: 10.1101/2021.03.26.437120
  • Open Access
• [Presentation] Plasma membrane damage, immune response, and cellular senescence (2022)
  • Author(s): Moriyama Y and Kono K
  • Organizer: The 28th East Asia Joint Symposium on biomedical Research
  • Int'l Joint Research
• [Presentation] Plasma membrane damage-induced senescent cells accelerate wound healing via extracellular vesicles and soluble molecules (2022)
  • Author(s): Barbee H, Moriyama Y, and Kono K
  • Organizer: Cell Bio 2022
  • Int'l Joint Research
• [Presentation] Plasma membrane damage limits replicative lifespan in yeast and induces premature senescence in human fibroblasts (2022)
  • Author(s): Suda K, Moriyama Y, Razali N,Chiu Y, and Kono K
  • Organizer: EMBO Workshop 2022 The DNA damage response, immunity and aging
  • Int'l Joint Research
• [Presentation] Time-resolved transcriptomic profiling of senescence-associated secretory phenotype (SASP) in multiple senescent cell subtypes (2022)
  • Author(s): Razali N, Moriyama Y, Chiu Y, Suda K, Turkki T and Kono K
  • Organizer: EMBO Workshop 2022 The DNA damage response, immunity and aging
  • Int'l Joint Research
• [Presentation] Ca2+ accumulation in mitochondria mediates plasma membrane damage-dependent cellular senescence (2022)
  • Author(s): Suda K, Razali N, Moriyama Y, Kono K
  • Organizer: The 45th Annual Meeting of the Molecular Biology Society of Japan
• [Presentation] Plasma membrane damage induces wound-healing SASPs in normal human fibroblasts (2021)
  • Author(s): Nurhanani Razali, Yohsuke Moriyama, Yatzu Chiu and Keiko Kono
  • Organizer: The 6th International Cell Senescence Association Conference
  • Int'l Joint Research
• [Presentation] The miRNA Signature Associated with Plasma Membrane Damage-dependent Senescence (2021)
  • Author(s): Yatzu Chiu, Yohsuke Moriyama, Nurhanani Binti Razali and Keiko Kono
  • Organizer: The 6th International Cell Senescence Association Conference
  • Int'l Joint Research
• [Presentation] Fate determination by the cellular surface wound in the budding yeast (2019)
  • Author(s): Keiko Kono and Yohsuke Moriyama
  • Organizer: Japanese Society for Biotechnology annual meeting