The therapeutic potential of senolysis targeting SAGP for age related disorders

• Project/Area Number: 18K08063
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Niigata University
• Principal Investigator: Suda Masayoshi 新潟大学, 医歯学総合病院, 専任助教 (70714509)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 細胞老化 / 老化 / 血管 / 生活習慣病

Outline of Final Research Achievements

We identified a novel protein, senescence-associated glycoprotein (SAGP), as a biomarker of cellular senescence. SAGP expression in aorta and adipose tissue were significantly increased in chronological aging mice, atherosclerosis mice and obese mice. We developed a cytotoxic vaccine targeting SAGP. Treatment with SAGP vaccine successfully eliminated SAGP positive senescent cells in the adipose tissue of the obese mice and improve glucose metabolism. Administration of SAGP vaccine to ApoE-KO mice significantly reduced atherogenesis with the improvement of inflammation. Furthermore, vaccine treatment extended the lifespan of progeroid mice. These data indicate that senolytic therapy targeting SAGP-positive cells could become a strategy for aging and age related diseases.

Academic Significance and Societal Importance of the Research Achievements

近年、老化細胞除去により加齢に伴う様々な疾患および個体老化を改善するという報告が出てきているが、老化細胞除去に用いる薬剤の多くは抗がん剤であり、新たな標的分子が必要であった。本研究ではSAGPを老化細胞除去の新しい標的分子として有用であることを示した。またSAGPを標的としたワクチン治療が糖尿病や動脈硬化、個体老化に有用である事を明らかにした。また、既存の老化細胞除去薬は投与後比較的早期に老化細胞が再度蓄積される事から、生活習慣病や老化といった慢性の病態において長期間作用の持続するワクチン療法は非常に有用であると考える。