在人类IGF-1基因中识别功能罕见的编码变异,具有异常长寿
Amanat Ali1,2, Zhengdong D Zhang3,4, Tina Gao5,4
1Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY, 10461, USA. amanat.ali@einsteinmed.edu.
Scientific reports
|March 26, 2025
概括
在百岁以上的人群中发现了胰岛素样生长因子-1 (IGF-1) 基因的两种新型遗传变异,可能通过减少IGF-1信号来解释他们的长寿. 这些IGF-1变体可能会影响IGF-1受体结合和循环IGF-1水平,从而促进寿命延长.
科学领域:
- 遗传学 遗传学 是一个
- 分子生物学分子生物学
- 老年学是一门学科.
背景情况:
- 通过胰岛素/胰岛素类生长因子-1 (IGF-1) 轴减少信号传递与物种间的寿命有关.
- IGF-1基因高度保守,在人类寿命研究中以前没有发现编码变异.
研究的目的:
- 确定IGF-1基因中的功能编码变体,在阿什肯纳兹犹太百岁老人,他们的后代和对照组中.
- 调查已识别的变异对IGF-1信号传递和受体结合的影响.
主要方法:
- 从长寿队列中对2,108个人的整体外基因组测序.
- 鉴定和描述IGF-1编码变体.
- 全原子分子动力学模拟以评估IGF-1/IGF-1R相互作用的变异效应.
主要成果:
- 在长寿队列中发现了两种可能的功能编码变体,即IGF-1:p.Ile91Leu和IGF-1:p.Ala118Thr.
- 在一个百岁老人身上发现的新型IGF-1:p.Ile91Leu变体,与IGF-1受体的结合亲和力和稳定性降低.
- IGF-1:p.Ala118Thr变异与循环IGF-1水平较低有关.
结论:
- 已识别的IGF-1变体IGF-1:p.Ile91Leu和IGF-1:p.Ala118Thr减弱了IGF-1受体的活性.
- 由于这些变异,IGF-1结合功能受损和循环IGF-1水平降低可能导致人类异常长寿.
- 这项研究提供了遗传证据,将降低的IGF-1信号与人类寿命联系起来.
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