Rare Gene Mutations Linked to Longevity in Ashkenazi Jews

A study in *Scientific Reports* identified two rare mutations in the insulin-like growth factor-1 (IGF-1) gene associated with exceptional longevity in Ashkenazi Jewish centenarians. Researchers analyzed whole-exome genetic data from over 2,000 individuals and found the IGF-1:p.Ile91Leu and IGF-1:p.Ala118Thr mutations. The genetic homogeneity of the Ashkenazi Jewish population facilitated the detection of these rare variants. Molecular dynamics simulations indicated that the Ile91Leu variant weakens the binding affinity with the IGF-1 receptor (IGF-1R), reducing receptor signaling. The Ala118Thr variant was linked to significantly reduced circulating IGF-1 serum levels, also diminishing IGF-1R signaling. Carriers of the Ile91Leu variant had normal IGF-1 blood levels, while the Ala118Thr group showed low IGF-1 levels, similar to effects seen in calorie-restricted animals. Notably, carriers of both mutations were free from cardiovascular diseases (CVDs), diabetes mellitus, and cognitive decline, despite being over 100 years old. These findings suggest that attenuated IGF-1R activity, achieved through different mechanisms, may contribute to increased lifespan and healthy aging.