Functionally significant insulin-like growth factor I receptor mutations in centenarians.

Area of Science:

• Genetics
• Gerontology
• Molecular Biology

Background:

• Lifespan is actively modulated by the insulin/insulin-like growth factor I (IGFI) pathway in model organisms.
• Mutations in IGFI pathway genes extend lifespan in yeasts, worms, flies, and mice, suggesting conserved mechanisms.
• Evolutionary tradeoffs raise questions about the relevance of these findings to human populations.

Purpose of the Study:

• To investigate biochemical, phenotypic, and genetic variations in Ashkenazi Jewish centenarians and their families.
• To determine if alterations in the insulin/IGF1 pathway are associated with human longevity.
• To explore the role of the IGF1 receptor (IGF1R) gene in exceptional lifespan.

Main Methods:

• Studied a cohort of Ashkenazi Jewish centenarians, their offspring, and matched controls.
• Analyzed serum IGFI levels and anthropometric data (stature).
• Performed sequence analysis of IGF1 and IGF1R genes and measured IGF1R activity in lymphocytes.

Main Results:

• Observed a gender-specific increase in serum IGFI and smaller stature in female offspring of centenarians.
• Found an overrepresentation of heterozygous IGF1R mutations in female centenarians compared to controls.
• These mutations were associated with high serum IGFI levels and reduced IGF1R activity.

Conclusions:

• Genetic alterations in the human IGF1R gene are associated with increased susceptibility to longevity.
• The IGF1 signaling pathway plays a role in modulating human lifespan.
• Findings suggest a conserved role for the IGFI pathway in aging across species.