Regulation of cancer and aging by FoxO and investigation of compounds for regulation of FoxO

2018 Fiscal Year Final Research Report

• Project/Area Number: 15H04682
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Environmental physiology(including physical medicine and nutritional physiology)
• Research Institution: Nagasaki University
• Principal Investigator: SHIMOKAWA Isao 長崎大学, 医歯薬学総合研究科(医学系), 教授 (70187475)
• Co-Investigator(Kenkyū-buntansha): 森 亮一 長崎大学, 医歯薬学総合研究科(医学系), 准教授 (30509310) ; 朴 盛浚 長崎大学, 医歯薬学総合研究科(医学系), 助教 (60635853)
• Research Collaborator: KOMATSU Toshimitsu
• Project Period (FY): 2015-04-01 – 2019-03-31
• Keywords: 老化 / カロリー制限 / FoxO転写因子 / 癌

Outline of Final Research Achievements

To elucidate the differential roles of FoxO1 and 3 in inhibition of cancer and extension of lifespan by calorie restriction (CR), we focused on mitochondria functions and metabolism in Foxo1+/- and Foxo3+/- mice. Oxygen consumption rates in the state 3 of mitochondria isolated from liver tissues were greater in Foxo3+/- CR mice than in WT CR mice at 24 months of age (mo). The mitochondrial membrane potential was also elevated in Foxo3+/- CR mice. A hepatic metabolome revealed that some metabolites in the glycolysis were significantly affected in Foxo3+/- CR mice. These findings suggest necessity of FoxO3 for inhibition by CR of aging-related declines in mitochondrial functions and metabolism. A carcinogen-induced hepatocellular carcinoma model suggests that FoxO3 is required for development of the tumor. Conditional knock-out of Foxo3 gene in the white adipose tissue and in the brain indicated that these tissues are not essential for the life-extending effect of CR.

Free Research Field

基礎老化学

Academic Significance and Societal Importance of the Research Achievements

ヒトのFOXO3遺伝子多形と長寿の関連性が複数の集団で指摘されていた。CRによる寿命延伸に関わるFoxO3関連メカニズムを解明することは、ヒトの健康寿命の延伸メカニズムに迫ることができる点で、学術的、社会的意義は大きい。今後、アイソフォーム特異的活性化化合物を探索できれば、老化関連疾患の制御を目指す創薬に発展できる。