Suppression of IGF-I signals in neural stem cells enhances neurogenesis and olfactory function during aging

Zayna Chaker 1 Saba Aïd 1 Hugues Berry 2, 3, 4 Martin Holzenberger 1
4 BEAGLE - Artificial Evolution and Computational Biology
LIRIS - Laboratoire d'InfoRmatique en Image et Systèmes d'information, Inria Grenoble - Rhône-Alpes, LBBE - Laboratoire de Biométrie et Biologie Evolutive, CarMeN - Cardiovasculaire, métabolisme, diabétologie et nutrition
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 characteris- tics 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 alter- ations 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 stim- ulation 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 olfac- tory sensory function.
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Aging Cell, Wiley Open Access, 2015, pp.847-856. 〈10.1111/acel.12365〉
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Zayna Chaker, Saba Aïd, Hugues Berry, Martin Holzenberger. Suppression of IGF-I signals in neural stem cells enhances neurogenesis and olfactory function during aging. Aging Cell, Wiley Open Access, 2015, pp.847-856. 〈10.1111/acel.12365〉. 〈hal-01163564〉

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