Igf-I signaling and effects on longevity.

Insulin and insulin-like signaling regulate survival and lifespan in a variety of animal species, from nematodes and flies to higher vertebrates and mammals. Recently, it was shown that brain IGF-I receptor and brain IRS2 control mammalian lifespan, and that this occurs through neuroendocrine mechanisms, control of energy metabolism and modified stress resistance. Furthermore, it was demonstrated that insulin receptor substrate molecules are implicated downstream of insulin and IGF receptors in the extension of lifespan. We showed recently that early postnatal diet plays a significant role in the development of the somatotropic axis, and that part of the neuroendocrine plasticity of growth hormone secretion depends on postnatal nutrition. We also showed that the prevalence of cardiovascular and metabolic pathologies varied with the development of somatotropic function. Neuroendocrine pathways are also prime targets for pharmacological treatments, and administration of rapamycin to adult mice has indeed recently been reported to prolong lifespan in mice. With respect to human aging, new studies identified several genes of the somatotropic axis as longevity determinants, and a recent study shows that variants of FOXO3A, downstream signaling molecule in the insulin/IGF pathway, are associated with extreme longevity in humans. Finally, several functional mutations of the human IGF-IR have been discovered in centenarians.