Untangling IGF-I signaling in the aging brain

Decades ago, the insulin family of proteins, highly conserved along phylogeny, was established as genetic determinants of aging [1], an observation that, at that time, profoundly impacted theories of aging, and was accommodated into the former concept of antagonistic pleiotropy in aging and subsequent refinements [2]. The detrimental action on aging of insulin-like peptides (ILPs) signaling observed in invertebrate models, particularly the worm C. elegans and the fly D melanogaster, was later replicated in mammalian models, mostly in the mouse, and even included human observations [1]. While the constraints of these translational attempts from invertebrate models to mammals have been already discussed [3], mainstream thinking poses ILPs (in particular insulin and insulin-like growth factor I, or IGF-I) as detrimental in the aging process in all species, even though aging is now considered a multi-factorial and context-dependent process [2]. The latter may explain the large diversity of findings describing changes in ILP activity in the aging mammalian brain, where increased, reduced, or even unaltered ILP receptor activity have been reported in numerous publications, probably reflecting cell and context-dependent activity of ILPs. On top of these variety of observations, to the best of our knowledge, the majority of IGF-I effects documented in the aging brain are beneficial, while the opposite seems true with the IGF-I receptor (IGF-IR). To reconcile these apparently opposing observations we postulated that aging is associated to IGF-I resistance leading to defective IGF-I functioning. We will elaborate this notion further.