Revolutionizing Aging Research: The Key to Healthier Longevity Lies Within Our DNA

As populations age globally, understanding the genetic underpinnings of exceptional longevity has become paramount. Recent advancements in genomics provide compelling evidence linking specific rare mutations to extended lifespans, paving the way for innovative therapies targeting healthy aging.

Exploring the Genetic Landscape of Longevity

Through meticulous analysis of whole-exome genetic data from over 2,000 Ashkenazi Jewish centenarians and their relatives, researchers uncovered critical insights into functional gene modifications within the insulin-like growth factor-1 (IGF-1) gene. The unique genetic homogeneity of this population allowed scientists to detect rare variants more effectively, minimizing "genetic noise" that often complicates studies involving diverse groups.

This research focused on comparing the functional coding variants of these individuals with those of their families and controls, revealing two extremely rare IGF-1 mutations—propeptide numbering: IGF-1:p.Ile91Leu and IGF-1:p.Ala118Thr; mature peptide residue numbering: Ile43Leu and Ala70Thr—that may significantly contribute to longevity outcomes. Notably, the IGF-1:p.Ala118Thr variant was previously categorized as a variant of uncertain significance (VUS) in ClinVar and associated with IGF-1 deficiency.

Decoding the Mechanisms Behind Enhanced Longevity

Molecular dynamics simulations conducted on the Ile91Leu variant demonstrated its impact on reducing binding affinity with the IGF-1 receptor (IGF-1R), thereby diminishing receptor signaling and activity. In contrast, carriers of the Ala118Thr variant exhibited significantly lower circulating IGF-1 serum levels, which similarly reduced IGF-1R signaling. These findings suggest that attenuated signaling along the highly conserved IGF-1 axis correlates with increased lifespans, echoing results observed in model organisms like mice and dogs.

Further exploration revealed that carriers of the Ile91Leu variant maintained normal IGF-1 blood levels, indicating that their longevity stemmed purely from disrupted receptor signaling rather than hormone scarcity. Conversely, the Ala118Thr group's low IGF-1 levels mirrored effects seen in calorie-restricted animals, underscoring the complexity of these mechanisms and their potential implications for future interventions promoting healthy aging.

Advancing Aging Research Through Innovative Methodologies

Data for this study were sourced from two Albert Einstein College of Medicine-hosted longevity cohorts—the LonGenity study and the Longevity Genes Project (LGP). These cohorts included individuals with 'exceptional longevity' (age ≥ 95 years), their offspring, and controls without familial longevity. Whole-exome sequencing (WES) data from Ashkenazi Jews were analyzed, ensuring high-quality datasets by excluding poor-quality (low sequence coverage) samples.

Researchers utilized the combined annotation-dependent depletion (CADD) score method to predict the functional nature of IGF-1 variants, considering only those with a CADD score of 20 or higher as 'functional.' By employing protein modeling alongside molecular dynamics (MD) simulations, they evaluated the mechanisms potentially contributing to the exceptional longevity of the identified variants. Three-dimensional (3D) structures of the IGF-1 receptor (IGF-1R) were obtained from the Protein Data Bank (PDP ID: 6JK8), facilitating subsequent docking experiments using Schrödinger Maestro 2023–2 software.

Implications for Future Research and Therapeutic Development

Of the 2,108 WES datasets analyzed, ten individuals exhibited IGF-1 variants potentially linked to exceptional longevity. Remarkably, carriers of both mutant IGF-1 variants remained free from cardiovascular diseases (CVDs), diabetes mellitus, and cognitive decline despite surpassing 100 years of age. This discovery represents the first time coding mutations in the IGF-1 gene itself—not just the receptor—have been connected to human longevity, positioning it as a new focal point for aging research.

Molecular dynamics simulations indicated that the Ile91Leu variant displayed substantially poorer binding affinity with IGF-1R compared to wild-type IGF-1, suggesting reduced signaling efficacy. Meanwhile, the Ala118Thr variant corresponded with significantly diminished circulating IGF-1 serum concentrations, achieving similar outcomes through alternative mechanisms. Unlike previously identified IGF-1 variants, which typically caused stunted growth or developmental abnormalities, these novel mutations demonstrated no observable growth defects, offering promising avenues for therapeutic development.