Fig. 3.

A strongly simplified representation of the evolutionarily conserved insulin/insulin-like growth factor signaling (IIS) and target of rapamycin (TOR) network which regulates lifespan in distinct organisms, from invertebrates to humans. In response to environmental inputs (e.g., nutrients) the IIS and/or TOR branches of the network become activated; reduced input (inhibition) of the signaling network leads to the activation of downstream transcription factors (such as the forkhead box O transcription factor FOXO) that regulate the expression of hundreds of target genes, many of which are involved in longevity assurance (but which also affect other life-history traits, including growth, size, and reproduction). Many of the genetically homologous components of this network have been experimentally shown to affect lifespan in C. elegans, Drosophila, and mouse; evidence from GWAS shows that genetic polymorphisms in some of these components are also associated with exceptional longevity in humans. The homologs of IIS/TOR components have different names in different species: for example, in C. elegans, the insulin-like receptor (INR) is called DAF-2, PI3K is called AGE-1, and FOXO is called DAF-16; in humans, the FOXO homolog associated with longevity is called FOXO3A. Note that humans, in contrast to invertebrates, not only have an insulin receptor but also an insulin-like growth factor 1 receptor (IGF-1); it is thought that the different physiological functions of the insulin receptor versus the IGF-1 receptor in humans are being subsumed by a single insulin receptor in invertebrates