SIRT1, neuronal cell survival and the insulin/IGF-1 aging paradox.

Signaling through the insulin/IGF-1 pro-survival pathway is widely recognized to be neuroprotective as well as important for neuronal growth and physiology. In mammals, age-associated decline in circulating IGF-1 levels has been associated with neuronal aging and symptoms of neurodegeneration. Defects in IGF-1 receptor associated signaling has, however, been shown to significantly extend lifespan in models ranging from invertebrates to mouse. At least in C. elegans, restoring such defects in neurons alone reduces lifespan to wild-type levels. As we seek to delay brain aging and age-associated neuronal degeneration via nutritional and endocrinal supplements, an understanding of the mechanistic basis of this apparent paradox is important. Recent elucidation of the role of the protein deacetylase SIRT1 in cell survival and data associating IGF-1 with the regulation of SIRT1 expression may provide a direction towards resolving this issue.