IGF-1 Receptors in Mammalian Longevity: Less is More

Abstract

Recent advances in research into ageing mechanisms have revealed that the cellular receptors InR and DAF-2 control the life span of fruit flies and roundworms, respectively. Comparative studies have identified these structurally and evolutionarily related tyrosine kinase receptors as orthologues of the mammalian insulin receptor (IR) and insulin-like growth factor receptor type 1 (IGF-1R). We investigated whether IGF-1R also regulates life span in mammals, by targeting the gene encoding this receptor in the mouse. Mice with a homozygous null mutation of this gene (IGF-1R−/−) were not viable because of severe growth retardation and developmental immaturity at birth. Heterozygous knockout mice (IGF-1R+/−) were, however, fully viable, and we studied life span and a number of age-related physiological parameters in this model (Holzenberger et al. 2003). Heterozygous knockout mice presented a 50% decrease in the number of IGF-1 receptors in all tissues but were healthy despite this defect. Life span analysis, comparing IGF-1R+/− mice with their wild-type littermates, showed that this mutation significantly increased longevity, by 26%, when both sexes were analysed together. Evaluated separately, IGF-1R+/− females lived 33% longer than wild-type females, whereas male mutants lived 16% longer than wild-type males. Growth and development were normal in long-lived IGF-1R+/− mice. They displayed no dwarfism, had normal energy metabolism and nutrient uptake, and physical activity identical to that of their wild-type control littermates. Moreover, no change was observed in male and female fertility and reproduction. IGF-1R+/− mutants displayed a high level of resistance in vivo to oxidative stress, a widely accepted key determinant of the ageing process. This finding was reproduced in vitro in experiments with mutant embryonic fibroblasts with hydrogen peroxide treatment used to generate oxidative stress. We tried to unravel the molecular mechanisms involved in life span control via IGF signalling by examining the major intracellular pathways involved. We found that levels of Akt and Erk1/2 MAP kinase activation were clearly diminished in cells derived from long-lived mutants. Moreover, the signal transduction molecule p66 Shc (one of the isoforms of Shc, and also a major substrate of IGF-1R), previously shown to control both the cellular response to oxidative stress and life span in mice, also showed a clear lack of activation in IGF-1R+/− cells. This finding provides the first mechanistic evidence for a link between IGF-1R activation and the regulation of stress resistance. Overall, our results strongly suggest a possible role for the IGF-1 receptor as a major regulator of mammalian longevity. There is also circumstantial evidence of a relationship between growth and longevity in humans, but further studies are required to formally identify the human genes determining life span. Recent studies in C. elegans have shown that life span is regulated in a non cell-autonomous fashion, and that the nervous system may play a central role in these processes. Together, these exciting findings open up new avenues of research, including the possibility of extending life span pharmacologically.