Mutations in genes involved in the insulin/IGF-1 signaling pathway (IIS) improve longevity in animal models, but there is minimal evidence that mutations in human homologues of genes in this pathway are associated with a long-lived phenotype.

In order to find such evidence, one could take a traditional forward genetics approach and study populations of centenarians. A recent paper in PNAS by Willcox et al. looked at a population of long-lived Japanese men. DNA samples were taken from men enrolled in the Honolulu Heart Program/Honolulu Asia Aging Study (HHP/HAAS). These men enrolled in the study throughout 1991-1993, and had a mean age of 77.9. From this population of volunteers, “long-lived” participants were defined as those who survived to 95 years old or older (n= 213) and “average-lived” controls as those who died before 81 years (n=402).  

The researchers then used a candidate approach to select the genes to analyze as potential “longevity genes” from the insulin/IGF-1 pathway. They selected this pathway to focus their candidate search because insulin signaling is conserved through evolution; furthermore, from mutation analysis and knockout models in many model organisms, we know that decreasing insulin/IGF-1 signaling increases lifespan.  These phenotypes occur through regulation of FOXO transcription factors and their homologues. The authors hypothesized that single nucleotide polymorphisms (SNPs) in FOXO related genes could be responsible for the differing longevity phenotypes between the long-lived and average-lived cohorts. Five genes, ADIPOQ, FOXO1A, FOXO3A, SIRT1, and COQ7 were selected as candidates, and three SNPs were analyzed per gene. Despite the small number of genes and SNPs analyzed, the researchers identified FOXO3A as being significantly associated with the long-lived phenotype. Genotype analysis revealed that long-lived study participants had one or more copies of the “G” allele in the FOXO3A gene. The authors state that this finding is especially exciting because the FOXO family of proteins are closely related to the C. elegans protein, DAF-16, which has been shown to protect cells from oxidative stress, which could be a “plausible mechanism of action for modification of human aging.”

Additionally, these long-lived men also had significantly lower plasma insulin, low cancer incidence, cardiovascular disease, had good self reported health, and had high physical and cognitive function at the time of their enrollment regardless of their genotype. The decreased incidence of cardiovascular disease and cancer was also associated with the presence of the “G” allele. It is possible that remaining healthy phenotypes could be regulated by alternative genes not analyzed in this study.

As the authors address in their introduction, many previously published searches for longevity genes do not show reproducibility across populations (“with the exception of APOE”), so it will be intriguing to determine if this FOXO3A “G” allele will transcend various populations of centenarians.