Ali Amanat, Zhang Zhengdong D, Gao Tina, Aleksic Sandra, Gavathiotis Evripidis, Barzilai Nir, Milman Sofiya
Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY, 10461, USA.
Institute for Aging Research and the Einstein-NSC, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY, 10461, USA.
Sci Rep. 2025 Mar 25;15(1):10199. doi: 10.1038/s41598-025-94094-y.
Diminished signaling via insulin/insulin-like growth factor-1 (IGF-1) axis is associated with longevity in different model organisms. IGF-1 gene is highly conserved across species, with only few evolutionary changes identified in it. Despite its potential role in regulating lifespan, no coding variants in IGF-1 have been reported in human longevity cohorts to date. This study investigated the whole exome sequencing data from 2,108 individuals in a cohort of Ashkenazi Jewish centenarians, their offspring, and controls without familial longevity to identify functional IGF-1 coding variants. We identified two likely functional coding variants IGF-1:p.Ile91Leu and IGF-1:p.Ala118Thr in our longevity cohort. Notably, a centenarian specific novel variant IGF-1:p.Ile91Leu was located at the binding interface of IGF-1-IGF-1R, whereas IGF-1:p.Ala118Thr was significantly associated with lower circulating levels of IGF-1. We performed extended all-atom molecular dynamics simulations to evaluate the impact of Ile91Leu on stability, binding dynamics and energetics of IGF-1 bound to IGF-1R. The IGF-1:p.Ile91Leu formed less stable interactions with IGF-1R's critical binding pocket residues and demonstrated lower binding affinity at the extracellular binding site compared to wild-type IGF-1. Our findings suggest that IGF-1:p.Ile91Leu and IGF-1:p.Ala118Thr variants attenuate IGF-1R activity by impairing IGF-1 binding and diminishing the circulatory levels of IGF-1, respectively. Consequently, diminished IGF-1 signaling resulting from these variants may contribute to exceptional longevity in humans.
胰岛素/胰岛素样生长因子-1（IGF-1）轴信号减弱与不同模式生物的长寿相关。IGF-1基因在物种间高度保守，其中仅发现少数进化变化。尽管其在调节寿命方面具有潜在作用，但迄今为止，在人类长寿队列中尚未报道IGF-1的编码变体。本研究调查了一组阿什肯纳兹犹太百岁老人、他们的后代以及无家族长寿史的对照人群中2108名个体的全外显子测序数据，以鉴定功能性IGF-1编码变体。我们在我们的长寿队列中鉴定出两个可能具有功能的编码变体IGF-1:p.Ile91Leu和IGF-1:p.Ala118Thr。值得注意的是，百岁老人特异性新变体IGF-1:p.Ile91Leu位于IGF-1-IGF-1R的结合界面，而IGF-1:p.Ala118Thr与较低的IGF-1循环水平显著相关。我们进行了扩展的全原子分子动力学模拟，以评估Ile91Leu对与IGF-1R结合的IGF-1的稳定性、结合动力学和能量学的影响。与野生型IGF-1相比，IGF-1:p.Ile91Leu与IGF-1R的关键结合口袋残基形成的相互作用不太稳定，并且在细胞外结合位点表现出较低的结合亲和力。我们的研究结果表明，IGF-1:p.Ile91Leu和IGF-1:p.Ala118Thr变体分别通过损害IGF-1结合和降低IGF-1的循环水平来减弱IGF-1R活性。因此，由这些变体导致的IGF-1信号减弱可能有助于人类的超长寿命。
