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J Neurosci DOI:10.1523/JNEUROSCI.5657-12.2013

A dietary regimen of caloric restriction or pharmacological activation of SIRT1 to delay the onset of neurodegeneration.

Publication TypeJournal Article
Year of Publication2013
AuthorsGräff, J, Kahn, M, Samiei, A, Gao, J, Ota, KT, Rei, D, Tsai, L-H
JournalJ Neurosci
Date Published2013 May 22
KeywordsAnalysis of Variance, Animals, Atrophy, Brain, Caloric Restriction, Case-Control Studies, Cognition Disorders, Cyclin-Dependent Kinase 5, Disease Models, Animal, Double-Blind Method, Excitatory Postsynaptic Potentials, Female, Green Fluorescent Proteins, Immunoprecipitation, In Vitro Techniques, Long-Term Potentiation, Male, Memory Disorders, Mice, Mice, Transgenic, Microscopy, Electron, Transmission, Nerve Tissue Proteins, Neurodegenerative Diseases, Phosphopyruvate Hydratase, Phosphotransferases, Piperidines, Silver Staining, Sirtuin 1, Synapses, Thiazoles, Tumor Suppressor Protein p53, Vitamin E

Caloric restriction (CR) is a dietary regimen known to promote lifespan by slowing down the occurrence of age-dependent diseases. The greatest risk factor for neurodegeneration in the brain is age, from which follows that CR might also attenuate the progressive loss of neurons that is often associated with impaired cognitive capacities. In this study, we used a transgenic mouse model that allows for a temporally and spatially controlled onset of neurodegeneration to test the potentially beneficial effects of CR. We found that in this model, CR significantly delayed the onset of neurodegeneration and synaptic loss and dysfunction, and thereby preserved cognitive capacities. Mechanistically, CR induced the expression of the known lifespan-regulating protein SIRT1, prompting us to test whether a pharmacological activation of SIRT1 might recapitulate CR. We found that oral administration of a SIRT1-activating compound essentially replicated the beneficial effects of CR. Thus, SIRT1-activating compounds might provide a pharmacological alternative to the regimen of CR against neurodegeneration and its associated ailments.


Alternate JournalJ. Neurosci.
PubMed ID23699506
PubMed Central IDPMC3775567
Grant ListP01 AG027916 / AG / NIA NIH HHS / United States
P01AG027916 / AG / NIA NIH HHS / United States
/ / Howard Hughes Medical Institute / United States