Scientists uncover rare gene variants that help people live past 100

By Hugo Francisco de SouzaReviewed by Susha Cheriyedath, M.Sc.Mar 26 2025

By pinpointing two ultra-rare mutations in a key growth-regulating gene, scientists reveal a surprising biological route to longer, healthier lives—without the usual signs of aging.

Study: Identification of functional rare coding variants in IGF-1 gene in humans with exceptional longevity. Image Credit: joingate / Shutterstock

In a recent study published in the journal Scientific Reports, researchers analyzed whole-exome genetic data from more than 2,000 Ashkenazi Jewish centenarians and their relatives to investigate functional gene modifications in the insulin-like growth factor-1 (IGF-1) gene that may contribute to their exceptional longevity.

They compared the functional coding variants of these individuals with those of their families and controls and discovered two extremely rare functional IGF-1 mutations (propeptide numbering: IGF-1:p.Ile91Leu and IGF-1:p.Ala118Thr; mature peptide residue numbering: Ile43Leu and Ala70Thr) potentially responsible for longevity outcomes. The IGF-1:p.Ala118Thr variant had previously been classified as a variant of uncertain significance (VUS) in ClinVar and was noted in individuals with IGF-1 deficiency.

They conducted molecular dynamics simulations on the Ile91Leu variant and found it contributed to less stable binding affinity with the IGF-1 receptor (IGF-1R), thereby diminishing receptor signaling and attenuating its activity. For the Ala118Thr variant, researchers observed significantly reduced circulating IGF-1 serum levels, which similarly reduced IGF-1R signaling.

Their findings suggest that, like findings hitherto exclusively observed in model organisms, the highly conserved IGF-1 axis is associated with human longevity and may be studied to help promote healthy aging in future populations.

Background

Insulin-like growth factor-1 (IGF-1) is a circulating hormone that regulates growth, metabolism, and development in humans and other organisms. It is produced by the liver in response to cues from growth hormone (GH) and is known to be remarkably well-conserved, with little to no genetic variation across species.

Previous studies have reported that attenuated signaling between the insulin/IGF-1 axis corresponds with increased lifespans in model (experimental) organisms such as mice and dogs. Still, similar studies in humans are minimal and, till now, remain inconclusive.

Recent whole-exome sequence data suggest the presence of two rare heterozygous IGF-1 variants in a small subset of Ashkenazi Jewish centenarians, indicating that further investigation into the gene and its molecular dynamics is warranted to enhance our understanding of IGF-1’s role in aging.

About the Study

The present study aims to identify IGF-1 gene variants that potentially contribute to enhanced longevity in Ashkenazi Jewish centenarians, their circulating (serum) IGF-1 levels, and the mechanisms underlying their observed outcomes (exceptional longevity).

Study data were obtained from two Albert Einstein College of Medicine-hosted longevity cohorts – the LonGenity study and the Longevity Genes Project (LGP). Both cohorts comprised individuals with ‘exceptional longevity’ (age ≥ 95 years), their offspring, and controls without familial longevity. For the present study, the analyses were restricted to whole-exome sequencing (WES) data from Ashkenazi Jews.

WES data were obtained from the Regeneron Genetics Center (RGC) and included datasets from 2,332 individuals. Poor-quality (low sequence coverage) datasets were excluded from the analyses (n = 224). Since the variants under investigation were known to be rare, variants with minor allele frequencies (MAF) of less than 1% were included in downstream analyses, as most genome-wide association studies (GWAS) and whole-exome sequencing (WES) typically do not consider rare genetic variants during analyses.

The combined annotation-dependent depletion (CADD) score method was used to predict the functional nature of IGF-1 variants, with all variants having a CADD score of 20 or higher considered ‘functional.’

The mechanisms potentially contributing to the exceptional longevity of the identified variants were evaluated using protein modeling in conjunction with molecular dynamics (MD) simulations. For these simulations, IGF-1 receptor (IGF-1R) three-dimensional (3D) structures were obtained from the Protein Data Bank (PDP ID: 6JK8). Subsequent docking experiments were carried out using Schrödinger Maestro 2023–2 software. All analyses were conducted for the Ile91Leu mutant and wild-type IGF-1, with their respective receptor binding energetics measured using the Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) method.

Study Findings

Of the 2,108 WES datasets analyzed, ten individuals revealed IGF-1 variants potentially contributing to exceptional longevity – two women carried the IGF-1:p.Ile91Leu variant, while two male centenarians, three offspring, and three control individuals carried the IGF-1:p.Ala118Thr variant.

Notably, both of these variants were estimated to have a MAF ≤ 0.01, which is much lower than the ~5.0% cutoff used in most GWAS and WES analyses. This is likely why these variants have been overlooked in previous human IGF-1 longevity studies. Remarkably, carriers of both mutant IGF-1 variants were found to be free from cardiovascular diseases (CVDs), diabetes mellitus, and cognitive decline, despite being over 100 years old.

MD simulations revealed that the Ile91Leu variant demonstrated substantially poorer binding affinity with IGF-1R than wild-type IGF-1. This suggests that the variant would signal the IGF-1 receptor to a much lower extent than its wild-type counterparts, thereby attenuating IGF-1R’s activation.

In contrast, Ala118Thr variants were found to correspond with significantly reduced circulating IGF-1 serum concentrations, thereby having similar end results – lower IGF-1R signaling and attenuated receptor activation. Notably, the Ala118Thr variant was not modeled in MD simulations, as its location outside the receptor-binding domain suggested a different mechanism. Surprisingly, in contrast to previously identified IGF-1 variants, which almost all contributed to stunted growth or developmental abnormalities, these novel variants demonstrated no observable growth defects.

Conclusions

Despite attenuating IGF-1R activation through different means (reduced binding efficacy in Ile91Leu variants versus reducing circulating/available IGF-1 serum concentrations in Ala118Thr variants), the findings of the present study suggest that reduced IGF-1R activity can contribute to exceptional lifespans and healthy aging of a rare subset of Ashkenazi Jewish centenarians and their relatives.