title: A dietary regimen of caloric restriction or pharmacological activation of SIRT1 to delay the onset of neurodegeneration.
abstract: 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.
authors.affiliation: Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Johannes
authors.initials: J
authors.lastname: Gräff
authors.forename: Martin
authors.initials: M
authors.lastname: Kahn
authors.forename: Alireza
authors.initials: A
authors.lastname: Samiei
authors.forename: Jun
authors.initials: J
authors.lastname: Gao
authors.forename: Kristie T
authors.initials: KT
authors.lastname: Ota
authors.forename: Damien
authors.initials: D
authors.lastname: Rei
authors.forename: Li-Huei
authors.initials: LH
authors.lastname: Tsai
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001284:Atrophy / Q000209:etiology / Q000517:prevention & control; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D031204:Caloric Restriction / Q000379:methods*; D016022:Case-Control Studies; D003072:Cognition Disorders / Q000209:etiology / Q000628:therapy*; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics; D004195:Disease Models, Animal; D004311:Double-Blind Method; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000235:genetics / Q000502:physiology; D008297:Male; D008569:Memory Disorders / Q000209:etiology / Q000517:prevention & control; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009419:Nerve Tissue Proteins / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000150:complications* / Q000473:pathology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D010770:Phosphotransferases; D010880:Piperidines / Q000627:therapeutic use; D016622:Silver Staining; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000473:pathology; D013844:Thiazoles / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014810:Vitamin E / Q000008:administration & dosage
chemical_list: C492236:Cdk5r1 protein, mouse; D009419:Nerve Tissue Proteins; D010880:Piperidines; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; C582726:tert-butyl 4-((2-(2-(6-(2-(tert-butoxycarbonyl(methyl)amino)ethylamino)-2-butylpyrimidine-4-carboxamido)phenyl)thiazolo(5,4-b)pyridin-6-yl)methoxy)piperidine-1-carboxylate; D014810:Vitamin E; D049452:Green Fluorescent Proteins; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D010751:Phosphopyruvate Hydratase