Scientists discover rare gene variants that help people live past 100

Scientists discover rare gene variants that help people live past 100

By identifying two ultra-rare mutations in a key growth-regulating gene, scientists show a surprising biological path to a longer, healthier life - without the usual signs of aging.

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

The genetic homogeneity of the Ashkenazi Jewish population allowed researchers to detect rare variants more effectively because shared ancestry reduces “genetic noise” that often obscures subtle longevity mutations in different groups.

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.Ala118TH. The IGF-1: P.ALA118THR variant was previously classified as a variant of uncertain significance (VUS) in Clinvar and in individuals with IGF-1 deficiency detected.

They performed molecular dynamics simulations in the Ile91Leu variant and found that it contributed to a lower stable binding affinity with the IGF-1 receptor (IGF-1R), thereby reducing the receptor's 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 results suggest that the highly conserved IGF-1 axis is associated with human longevity, as previously observed exclusively in model organisms, and may be investigated to 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 growth hormone (GH) cues and is known to be remarkably well conserved, with little to no genetic variation between species.

Previous studies have reported that attenuated signaling between the insulin/IGF-1 axis corresponds to increased lifespan in model (experimental) organisms such as mice and dogs. Nevertheless, similar human studies are minimal and so far 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 study of the gene and its molecular dynamics is required to improve our understanding of the role of IGF-1 in the gene.

About the study

Carriers of the ILE91Leu variant showed normal blood levels of IGF-1, suggesting that their longevity stems entirely from impaired receptor signaling - not from hormone starvation - in contrast to the Ala118THR group, whose low IGF-1 levels mimicked calorie-restricted animals.

The present study aims to identify IGF-1 gene variants that may contribute to enhanced longevity of Ashkenazi Jewish Hundreds, their circulating (serum) IGF-1 levels, and the mechanisms underlying their observed results (extraordinary longevity).

Study data were obtained from two Albert Einstein College of Medicine-hosted longevity cohorts - the Langdenity Study and the Longevity Genes Project (LGP). Both cohorts included individuals with “exceptional longevity” (age ≥ 95 years), their offspring, and controls without familial longevity. For the present study, analyzes were limited to whole exome sequencing (WES) data from Ashkenazi Jews.

WES data were obtained from the Regeneron Genetics Center (RGC) and included records from 2,332 individuals. Poor quality (low sequence coverage) datasets were excluded from analyzes (n = 224). Because the variants studied were rarely known, variants with minor allele frequencies (MAF) 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) scoring 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 researchers marked both variants with a strict CADD score cutoff of ≥20, a computational tool that predicts the functional impact of DNA changes and has only been studied with high-confidence mutations.

The mechanisms that may contribute to the exceptional longevity of the identified variants were assessed using protein modeling coupled with molecular dynamics (MD) simulations. For these simulations, three-dimensional IGF-1 receptor (IGF-1R) structures were obtained from the protein database (PDP ID: 6JK8). Subsequent docking experiments were carried out using Schrödinger Maestro 2023–2 software. All analyzes were performed for the ILE91Leu mutant and wild-type IGF-1, measuring their respective receptor binding energetics using born surface molecular mechanics generalization (MM-GBSA).

Study results

Of the 2,108 WES datasets analyzed, ten individuals showed IGF-1 variants that potentially contributed to exceptional longevity - two females carried the IGF-1: P.Ile91Leu variant, while two males, three offspring and three controls carried the IGF-1: P.ala118Thr variant.

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

This is the first time that mutations in the IGF-1 gene itself - not just the receptor - have been linked to human longevity, making it a new focus for aging research.

MD simulations showed that the Ile91Leu variant exhibited significantly poorer binding affinity with IGF-1R than wild-type IGF-1. This suggests that the variant signals the IGF-1 receptor to a much lower extent than its wild-type counterparts, thereby attenuating IGF-1R activation.

In contrast, Ala118THR variants were found to correspond to significantly reduced circulating IGF-1 serum concentrations, showing similar end results - lower IGF-1R signaling and attenuated receptor activation. Notably, the Ala118THR variant was not modeled in MD simulations because its location outside the receptor binding domain suggested a different mechanism. Surprisingly, these novel variants showed no observable growth defects, unlike previously identified IGF-1 variants, almost all of which contributed to stunted growth or developmental defects.

Conclusions

Despite attenuated IGF-1R activation by different means (reduced binding efficacy in ILE91Leu variants versus reduction in circulating/available IGF-1 serum concentrations in ALA118THR variants), the results of the present study suggest that reduced IGF-1R activities contribute to exceptional lifespan and healthy functioning of a rare subset of rare subset of Ashkenazzenazzenazzensäden can contribute.

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