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bioRxiv · 10.1101/2024.10.11.617885

Identification of functional rare coding variants in IGF-1 gene in humans with exceptional longevity

Ali, A.·Zhang, Z.·Gao, T.·Aleksic, S.·Gavathiotis, E.·Barzilai, N.·Milman, S.
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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 life span, no coding variants in IGF-1 have been reported in human longevity cohorts to date. This study investigated the whole exome sequencing data from 2,487 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-1Rs 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.

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Ali, A., Zhang, Z., Gao, T., Aleksic, S., Gavathiotis, E., Barzilai, N., Milman, S.. 2024-10-13. Identification of functional rare coding variants in IGF-1 gene in humans with exceptional longevity. https://doi.org/10.1101/2024.10.11.617885

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