Identification of functional rare coding variants in IGF-1 gene in humans with exceptional longevity
Abstract 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 cod...
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Nature Portfolio
2025-03-01
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| Online Access: | https://doi.org/10.1038/s41598-025-94094-y |
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| author | Amanat Ali Zhengdong D. Zhang Tina Gao Sandra Aleksic Evripidis Gavathiotis Nir Barzilai Sofiya Milman |
| author_facet | Amanat Ali Zhengdong D. Zhang Tina Gao Sandra Aleksic Evripidis Gavathiotis Nir Barzilai Sofiya Milman |
| author_sort | Amanat Ali |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
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| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-3e0eb3b35ac74d44a89b7b56d0981fc82025-08-20T02:49:32ZengNature PortfolioScientific Reports2045-23222025-03-0115111210.1038/s41598-025-94094-yIdentification of functional rare coding variants in IGF-1 gene in humans with exceptional longevityAmanat Ali0Zhengdong D. Zhang1Tina Gao2Sandra Aleksic3Evripidis Gavathiotis4Nir Barzilai5Sofiya Milman6Department of Medicine, Albert Einstein College of MedicineDepartment of Genetics, Albert Einstein College of MedicineDepartment of Medicine, Albert Einstein College of MedicineDepartment of Medicine, Albert Einstein College of MedicineDepartment of Medicine, Albert Einstein College of MedicineDepartment of Medicine, Albert Einstein College of MedicineDepartment of Medicine, Albert Einstein College of MedicineAbstract 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.https://doi.org/10.1038/s41598-025-94094-yIGF-1IGF-1RGenetic variantsAgingMolecular dynamics |
| spellingShingle | Amanat Ali Zhengdong D. Zhang Tina Gao Sandra Aleksic Evripidis Gavathiotis Nir Barzilai Sofiya Milman Identification of functional rare coding variants in IGF-1 gene in humans with exceptional longevity Scientific Reports IGF-1 IGF-1R Genetic variants Aging Molecular dynamics |
| title | Identification of functional rare coding variants in IGF-1 gene in humans with exceptional longevity |
| title_full | Identification of functional rare coding variants in IGF-1 gene in humans with exceptional longevity |
| title_fullStr | Identification of functional rare coding variants in IGF-1 gene in humans with exceptional longevity |
| title_full_unstemmed | Identification of functional rare coding variants in IGF-1 gene in humans with exceptional longevity |
| title_short | Identification of functional rare coding variants in IGF-1 gene in humans with exceptional longevity |
| title_sort | identification of functional rare coding variants in igf 1 gene in humans with exceptional longevity |
| topic | IGF-1 IGF-1R Genetic variants Aging Molecular dynamics |
| url | https://doi.org/10.1038/s41598-025-94094-y |
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