Section: New Results

IGF-I signalling in neural stem cells during neurogenesis and aging

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. Z. Chaker, in M. Holzenberg Lab (Centre de Recherche Saint-Antoine, Paris), 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 maintained youthful characteristics of olfactory bulb neurogenesis within an aging brain. This in turn resulted in neuro-anatomical changes that improved olfactory function. To help interpret these results, we developed a mathematical model of stem cell differentiation using ordinary differential equations with time-dependent growth, division and death rates (to account for aging) and optimizing at each time step the amount of IGF-IR to maximize an experimentally-derived tissue efficiency criterion. The model predicts that decreased stimulation of growth in adults is indeed optimal for tissue aging. Thus, inhibiting growth and longevity gene IGF-1R in adult stem cells induced a gain-of-function phenotype during aging, marked by optimized management of cell renewal, and enhanced olfactory sensory function.

This work has been published in the article [14] .