Abstract
Downregulation of insulin-like growth factor (IGF) pathways prolongs lifespan in various species, including mammals. Still, the cellular mechanisms by which IGF signaling controls the aging trajectory of individual organs are largely unknown. Here, we asked whether suppression of IGF-I receptor (IGF-1R) in adult stem cells preserves long-term cell replacement, and whether this may prevent age-related functional decline in a regenerating tissue. Using neurogenesis as a paradigm, we showed that conditional knockout of IGF-1R specifically in adult neural stem cells (NSC) maintained youthful characteristics of olfactory bulb neurogenesis within an aging brain. We found that blocking IGF-I signaling in neural precursors increased cumulative neuroblast production and enhanced neuronal integration into the olfactory bulb. This in turn resulted in neuro-anatomical changes that improved olfactory function. Interestingly, mutants also displayed long-term alterations in energy metabolism, possibly related to IGF-1R deletion in NSCs throughout lifespan. We explored Akt and ERK signaling cascades and revealed differential regulation downstream of IGF-1R, with Akt phosphorylation preferentially decreased in IGF-1R−/− NSCs within the niche, and ERK pathway downregulated in differentiated neurons of the OB. These challenging experimental results were sustained by data from mathematical modeling, predicting that diminished stimulation of growth is indeed optimal for tissue aging. Thus, inhibiting growth and longevity gene IGF-1R in adult NSCs induced a gain-of-function phenotype during aging, marked by optimized management of cell renewal, and enhanced olfactory sensory function.
Highlights
In higher organisms, adult tissues harbor stem cells that generate lifelong new differentiated cells, ensuring long-term repair and Accepted for publication 22 May 2015 individual longevity
We investigated short- and long-term effects of insulin-like growth factor (IGF)-I signaling on adult neural stem cells (NSC), showing how this important energysensing pathway regulates lifelong management of neuronal replacement
To target adult NSCs, we used a nestin-CreERT2 transgene (Lagace et al, 2007) expressing tamoxifen (Tam)-inducible Cre recombinase selectively in these cells and crossed it into mice that carry a floxed IGF-1R gene and a Cre-inducible tdTomato knock-in cell lineage marker. These nestin-CreERT2;CAG-tdTomato+/0;IGF-1Rflox/flox mice and their controls were injected with Tam at 3 months of age, inducing loss of IGF-1R and intense red label in all NSCs and their cell progeny born after Cre induction
Summary
Adult tissues harbor stem cells that generate lifelong new differentiated cells, ensuring long-term repair and Accepted for publication 22 May 2015 individual longevity. This process has been extensively studied in the adult mouse brain, since the discovery of neural stem and progenitor cells (neural stem cell – NSC) (Doetsch et al, 1999; Doetsch, 2003). Using a novel transgenic mouse model, we inactivated IGF-I signaling in adult NSCs, and traced knockout cell lineages from the subventricular zone (SVZ) to OB by monitoring a fluorescent reporter. This study concludes that lifelong exposure of NSCs to IGF-I accelerates the agerelated decline of adult neurogenesis in the olfactory system, entailing noticeable changes in sensory function and possibly in metabolic regulation
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