IGF signaling and aging
Insulin-like growth factor (IGF) and insulin signaling regulates lifespan and aging in animals. This has been shown in several species ranging from yeast to mammals, and thus appears to be evolutionary conserved. The lifespan-extending potential of IGF/insulin signaling has been discovered just over a decade ago by screening the genome of the nematode Caenorhabditis elegans for longevity genes. Since then, many of the initial findings from C. elegans were confirmed by mutagenesis studies in the fruitfly Drosophila. In mammals, similar roles for IGF/insulin signaling in aging have been demonstrated recently using homologous recombination targeting of orthologous genes. In all cases, reduction of IGF/insulin signaling activity is associated with increased longevity. Investigations on natural mouse mutants extended these findings by showing that developmental defects in pituitary cell lineages, leading to defects that include a decreased somatotropic function and lack of IGF, also significantly increase lifespan. Moreover, a solid molecular link has been found between IGF/insulin signaling and cellular as well as organismal resistance to oxidative stress, a key determinant of the aging process. Genome-wide expression studies in C. elegans corroborated this interesting mechanism. Transposing these findings to human biology is presently a major endeavor. First results from controlled genetic studies in humans have implicated the insulin-like growth factor receptor and one of its signal transducers, PI3-K, in human longevity. Similarly, a combined genetic and functional evaluation of the somatotropic axis in aging human populations identified a connection between IGF and aging. On the background of the above, most recent experimental data from mice and man will be presented.