Understanding the interrelationship between senescent cells and age-related diseases and the elucidation of the mechanisms for the killing of senescent cells by senolytic drugs

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K16156
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Osaka University
• Principal Investigator: Wakita Masahiro 大阪大学, 免疫学フロンティア研究センター, 特任助教(常勤) (70794668)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: 細胞老化 / セノリティックドラッグ

Outline of Final Research Achievements

Cellular senescence is a stable cell cycle arrest that act as a defense mechanism against tumor development. However, the accumulation of senescent cells in the age process provokes inflammation, leading to the increase of risk of age-related diseases including dementia, arthritis, and cancer. The depletion of senescent cells, termed senotherapy, might be anticipated to alleviates and prevents the progression of age-related diseases. I found that ARV825, which was identified as a specific killing agent for senescent cells, could increase the efficiency of chemotherapy for xenograft tumor development, concomitant with the depletion of senescent cells. As I analyze the mechanism of ARV825-induced cell death, damaged mitochondria were accumulated due to the impaired autophagy flux, leading to the cell death mediated by the increase of ROS production. This mechanism is a common pathway in the cell death process of senescent cells induced by several previously reported senolytic drugs.

Free Research Field

がん、細胞老化

Academic Significance and Societal Importance of the Research Achievements

細胞老化は修復困難なDNA障害を受けた細胞が過増殖することを防ぐため、不可逆的に細胞周期が停止する機構であるが、この細胞は実は炎症性物質をはじめとする様々な液性因子を分泌することで加齢性の疾患を悪化させることが明らかになってきた。本研究では老化細胞を除去する効果を有する既報のセノリティックドラッグをがんの化学療法と併用することでがん治療に対する効果を高めることを見出した。さらに、セノリティックドラッグが共通の分子メカニズムを通じて老化細胞を死滅させていることを見出した。今後は本知見を元に、副作用が少なく老化細胞に対する選択性および高い有効性を示す薬剤開発へと発展することが期待される。