Elucidating the Mechanisms of Insulin Resistance Associated with Aging Using Samples from Patients with Progeria Werner Syndrome

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K17485
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Chiba University
• Principal Investigator: Kinoshita Daisuke 千葉大学, 大学院医学研究院, 特任助教 (50868635)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 遺伝性早老症Werner症候群 / 細胞老化 / SASP / 脂肪分化・萎縮 / インスリン抵抗性 / mTORシグナル伝達経路 / ラパマイシン / ウェルナー遺伝子ノックアウト線虫

Outline of Final Research Achievements

Subcutaneous fat loss correlates with insulin resistance in patients with Werner's syndrome, a hereditary premature aging disorder. Analysis of cells derived from the patient's subcutaneous fat (hereafter referred to as "patient cells") showed signs of premature cellular senescence. Comprehensive analysis of gene expression revealed that gene expression related to chromosome regulation and cell division was decreased in patient cells. We also confirmed suppression of adipogenic differentiation in patient cells, and decreased insulin signaling. Rapamycin, an inhibitor of the mTOR signaling pathway, which has been focused on in relation to aging, improved the aforementioned premature cellular senescence and decreased insulin signaling, and prolonged the life span of nematode models of premature aging.

Free Research Field

老年医学

Academic Significance and Societal Importance of the Research Achievements

本研究は、遺伝性早老症Werner症候群の皮下脂肪における早期老化を細胞レベルで初めて証明し、インスリン抵抗性に寄与することを示唆した。また、本疾患におけるmTORシグナル伝達経路を標的とした治療の有望性も提示した。遺伝性早老症Werner症候群は、ヒト老化のモデル疾患と言われ、老化に伴う耐糖能異常の新規治療戦略へ向けた基盤構築につながり得る。