A substantial amount of data shows that mutations in genes that share similarities with the human genes involved in the insulin/IGF-I signal response pathway are responsible for an impairment of IGF-I/insulin signaling and for an extension of the Caenorhabditis elegans life span. In particular, the best characterized genes of this ancestral IGF-I/insulin response pathway are: DAF-2, ortholog to the human IGF-I/insulin receptor family; AGE-1, ortholog to human p110 catalytic subunit of phosphoinositide 3-kinase, which is involved in IGF-I/insulin signal transduction; and DAF-16, ortholog to the human FOXO family of Forkhead transcription factors, which regulates IGF-I/insulin-induced changes in gene transcription.

Further recent studies have shown that mutations in the Drosophila melanogaster INR gene (similar to the human insulin receptor) and in the CHICO gene, the ortholog to human insulin receptor substrate-1 (IRS-1), the protein associated with the IGF-I/insulin receptor, affect the life span, confirming the hypothesis that the insulin/IGF-I response pathway plays a role in the regulation of invertebrate longevity.

Intriguingly, mutations in the Saccaromyces cerevisiae SCH9 gene, which share similarities with insulin/IGF-I-regulated AKT1/AKT2 kinases, affect the life span of the yeast. On the basis of these data it has been predicted that genes involved in the insulin/IGF-I response pathway play a role in longevity throughout evolution.

A major role of IGF-I in mammalian longevity has been suggested by studies on dwarf mice carrying mutations in transcription factors PIT-1 and PROP-1, which are characterized by a long life span and reduced IGF-I plasma levels. Conversely, transgenic animals with elevated plasma IGF-I levels have a short life span. In humans there is evidence that long-lived subjects have decreased plasma IGF-I levels and preserved insulin action compared with aged subjects, thus indicating that an efficient insulin response has an impact on human longevity.

Scientists tested the hypothesis that polymorphic variants of IGF-I response pathway genes, namely IGF-IR (IGF-I receptor; G/A, codon 1013), PI3KCB (phosphoinositol 3-kinase; T/C, 359 bp; A/G, 303 bp), IRS-1 (insulin receptor substrate-1; G/A, codon 972), and FOXO1A (T/C, 97347 bp), play a role in systemic IGF-I regulation and human longevity. The major finding of this investigation was that subjects carrying at least an A allele at IGF-IR have low levels of free plasma IGF-I and are more represented among long-lived people. Moreover, genotype combinations at IGF-IR and PI3KCB genes affect free IGF-I plasma levels and longevity. These findings represent the first indication that free IGF-I plasma levels and human longevity are coregulated by an overlapping set of genes, contributing to the hypothesis that the impact of the IGF-I/insulin pathway on longevity is a property that has been evolutionarily conserved throughout the animal kingdom.