Molecular mechanisms governing lifespan extension via mitochondrial stress responses

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K10998
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 59040:Nutrition science and health science-related
• Research Institution: Osaka City University
• Principal Investigator: Eriko Kage-Nakadai (鹿毛枝里子) 大阪市立大学, 大学院生活科学研究科, 教授 (40453790)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: ミトコンドリアストレス応答 / 長寿 / 線虫

Outline of Final Research Achievements

Accumulating studies have argued that the mitochondrial unfolded protein response (UPRmt) is a mitochondrial stress response that promotes longevity in model organisms. In the present study, we screened an off-patent drug library to identify compounds that activate UPRmt using a mitochondrial chaperone hsp-6::GFP reporter system in Caenorhabditis elegans. Metolazone, a diuretic primarily used to treat congestive heart failure and high blood pressure, was identified as a prominent hit as it upregulated hsp-6::GFP and not the endoplasmic reticulum chaperone hsp-4::GFP. Furthermore, metolazone specifically induced the expression of mitochondrial chaperones in the HeLa cell line. Metolazone also extended the lifespan of worms in a atfs-1 and ubl-5-dependent manner. Notably, metolazone failed to increase lifespan in worms with knocked-down nkcc-1. These results suggested that metolazone activates the UPRmt across species and prolongs the lifespan of C. elegans.

Free Research Field

生物系薬学

Academic Significance and Societal Importance of the Research Achievements

ヒト抗老化の標的として「ミトコンドリアストレス応答」を制御する介入が有効である可能性が考えられるが、これまでに当該作用を期待でき、かつヒトが長期服用した場合の安全性が確認されている化合物は同定されていなかった。本研究では、線虫を用いて、高血圧治療に使われる利尿降圧剤メトラゾンの寿命延伸効果を発見した。本知見は、メトラゾンという薬の新たな薬効を示唆するとともに、ミトコンドリアストレス応答という抗老化のターゲット、抗老化薬という新たなコンセプトの提示につながる可能性がある。