Toward a comprehensive neurobiology of IGF-I.

Insulin-like growth factor I (IGF-I) belongs to an ancient family of hormones already present in early invertebrates. The insulin family is well characterized in mammals, although new members have been described recently. Since its characterization over 50 years ago, IGF-I has been considered a peptide mostly involved in the control of body growth and tissue remodeling. Currently, its most prominent recognized role is as a quasi-universal cytoprotectant. This role connects IGF-I with regulation of lifespan and with cancer, two areas of very active research in relation to this peptide. In the brain, IGF-I was formerly considered a neurotrophic factor involved in brain growth, as many other neurotrophic factors. Other aspects of the neurobiology of IGF-I are gradually emerging and suggest that this growth factor has a prominent role in brain function as a whole. During development IGF-I is abundantly expressed in many areas, whereas once the brain is formed its expression is restricted to a few regions and in very low quantities. However, the adult brain appears to have an external input from serum IGF-I, where this anabolic peptide is abundant. Thus, serum IGF-I has been proven to be an important modulator of brain activity, including higher functions such as cognition. Many of these functions can be ascribed to its tissue-remodeling activity as IGF-I modulates adult neurogenesis and angiogenesis. Other activities are cytoprotective; indeed, IGF-I can be considered a key neuroprotective peptide. Still others pertain to the functional characteristics of brain cells, such as cell excitability. Through modulation of membrane channels and neurotransmission, IGF-I impinges directly on neuronal plasticity, the cellular substrate of cognition. However, to fully understand the role of IGF-I in the brain, we have to sum the actions of locally produced IGF-I to those of serum IGF-I, and this is still pending. Thus, an integrated view of the role played by IGF-I in the brain is not yet possible. An operational approach to overcome this limitation would be to consider IGF-I as a signal coupling environmental influences on body metabolism with brain function. Or in a more colloquial way, we may say that IGF-I links body "fitness" with brain fitness, providing a mechanism to the roman saying "mens sana in corpore sano."