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

Area of Science:

• Genetics
• Molecular Biology
• Gerontology

Background:

• Reduced signaling through the insulin/insulin-like growth factor-1 (IGF-1) axis is linked to longevity across species.
• The IGF-1 gene is highly conserved, and no coding variants have been previously identified in human longevity studies.

Purpose of the Study:

• To identify functional coding variants within the IGF-1 gene in a cohort of Ashkenazi Jewish centenarians, their offspring, and controls.
• To investigate the impact of identified variants on IGF-1 signaling and receptor binding.

Main Methods:

• Whole exome sequencing of 2,108 individuals from a longevity cohort.
• Identification and characterization of IGF-1 coding variants.
• All-atom molecular dynamics simulations to assess variant effects on IGF-1/IGF-1R interactions.

Main Results:

• Two likely functional coding variants, IGF-1:p.Ile91Leu and IGF-1:p.Ala118Thr, were identified in the longevity cohort.
• The novel IGF-1:p.Ile91Leu variant, found in a centenarian, showed reduced binding affinity and stability with the IGF-1 receptor.
• The IGF-1:p.Ala118Thr variant was associated with lower circulating IGF-1 levels.

Conclusions:

• The identified IGF-1 variants, IGF-1:p.Ile91Leu and IGF-1:p.Ala118Thr, attenuate IGF-1 receptor activity.
• Impaired IGF-1 binding and reduced circulating IGF-1 levels due to these variants may contribute to exceptional human longevity.
• This study provides genetic evidence linking reduced IGF-1 signaling to human lifespan.