神经发生
生物
神经干细胞
嗅球
细胞生物学
神经科学
蛋白激酶B
嗅觉系统
干细胞
信号转导
中枢神经系统
作者
Zayna Chaker,Saba Aïd,Hugues Berry,Martin Holzenberger
出处
期刊:Aging Cell
[Wiley]
日期:2015-07-29
卷期号:14 (5): 847-856
被引量:75
摘要
Summary 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 NSC s 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 −/− NSC s 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 NSC s induced a gain‐of‐function phenotype during aging, marked by optimized management of cell renewal, and enhanced olfactory sensory function.
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