Although aging is considered to be an unavoidable event, recent experimental evidence suggests that the process can be counteracted. Intracellular calcium (Cai2+) dyshomeostasis, mitochondrial dysfunction, oxidative stress, and lipid dysregulation are critical factors that contribute to senescence-related processes. Ceramides, a pleiotropic class of sphingolipids, are important mediators of cellular senescence, but their role in neuronal aging is still largely unexplored. In this study, we investigated the effects of L-cycloserine (L-CS), an inhibitor of the de novo ceramide biosynthesis, on the aging phenotype of cortical neurons cultured for 22 days, a setting employed as an in vitro model of senescence. Our findings indicate that, compared to control cultures, 'aged' neurons display dysregulation of [Ca2+]i levels, mitochondrial dysfunction, increased generation of reactive oxygen species (ROS), altered synaptic activity as well as the activation of neuronal death-related molecules. Treatment with L-CS positively affected the senescent phenotype, a result associated with recovery of neuronal [Ca2+]i signaling and reduction of mitochondrial dysfunction and ROS generation. The results suggest that the de novo ceramide biosynthesis represents a critical intermediate in the molecular and functional cascade leading to neuronal senescence and identify ceramide biosynthesis inhibitors as promising pharmacological tools to decrease age-related neuronal dysfunctions.

Inhibition of de novo ceramide biosynthesis affects aging phenotype in an in vitro model of neuronal senescence

Castelli V.;Cimini A.;
2019-01-01

Abstract

Although aging is considered to be an unavoidable event, recent experimental evidence suggests that the process can be counteracted. Intracellular calcium (Cai2+) dyshomeostasis, mitochondrial dysfunction, oxidative stress, and lipid dysregulation are critical factors that contribute to senescence-related processes. Ceramides, a pleiotropic class of sphingolipids, are important mediators of cellular senescence, but their role in neuronal aging is still largely unexplored. In this study, we investigated the effects of L-cycloserine (L-CS), an inhibitor of the de novo ceramide biosynthesis, on the aging phenotype of cortical neurons cultured for 22 days, a setting employed as an in vitro model of senescence. Our findings indicate that, compared to control cultures, 'aged' neurons display dysregulation of [Ca2+]i levels, mitochondrial dysfunction, increased generation of reactive oxygen species (ROS), altered synaptic activity as well as the activation of neuronal death-related molecules. Treatment with L-CS positively affected the senescent phenotype, a result associated with recovery of neuronal [Ca2+]i signaling and reduction of mitochondrial dysfunction and ROS generation. The results suggest that the de novo ceramide biosynthesis represents a critical intermediate in the molecular and functional cascade leading to neuronal senescence and identify ceramide biosynthesis inhibitors as promising pharmacological tools to decrease age-related neuronal dysfunctions.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11697/140014
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