Research Paper Volume 11, Issue 16 pp 6336—6357
Inhibition of de novo ceramide biosynthesis affects aging phenotype in an in vitro model of neuronal senescence
- 1 Center of Excellence on Aging and Translational Medicine (CeSI-MeT), University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
- 2 Department of Neuroscience, Imaging, and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
- 3 Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
- 4 Department of Psychological, Health and Territorial Sciences, University G. d’Annunzio of Chieti-Pescara, Chieti, Italy
- 5 Department of Pharmacy, University G. d’Annunzio of Chieti-Pescara, Chieti, Italy
- 6 Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Temple University, Philadelphia, PA 19122, USA
- 7 National Institute for Nuclear Physics (INFN), Gran Sasso National Laboratory (LNGS), Assergi, Italy
- 8 Departments of Anatomy and Neurobiology, Biochemistry and Pharmacology, University of California Irvine, Irvine, CA 92697, USA
- 9 Departments of Neurology and Pharmacology, Institute for Mind Impairments and Neurological Disorders (iMIND), University of California Irvine, Irvine, CA 92697, USA
Received: May 24, 2019 Accepted: August 10, 2019 Published: August 29, 2019https://doi.org/10.18632/aging.102191
How to Cite
Copyright © 2019 Granzotto et al. This is an open-access article distributed under the terms of the Creative Commons Attribution (CC BY 3.0) License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Although aging is considered to be an unavoidable event, recent experimental evidence suggests that the process can be counteracted. Intracellular calcium (Ca2+i) 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 thede novoceramide biosynthesis, on the aging phenotype of cortical neurons cultured for 22 days, a setting employed as anin vitromodel of senescence. Our findings indicate that, compared to control cultures, ‘aged’ neurons display dysregulation of [Ca2+]ilevels, 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+]isignaling and reduction of mitochondrial dysfunction and ROS generation. The results suggest that thede novoceramide 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.