Anti-aging properties of melatonin in an in vitro murine senescence model: involvement of the sirtuin 1 pathway.
Sirtuin 1 is a member of the sirtuin family of protein deacetylases, which have attracted considerable attention as mediators of lifespan extension in several model organisms. Induction of sirtuin 1 expression also attenuates neuronal degeneration and death in animal models of Alzheimer's disease and Huntington's disease. In this study, an in vitro model of neuronal aging was used to test in several ways whether melatonin acts as a sirtuin 1 inducer and if this effect could be neuroprotective. It is shown that melatonin is able to increase the level of this deacetylase in young primary neurons, as well as in aged neurons. We also observed an increase in the deacetylation of several substrates of sirtuin 1, such as p53, PGC-1alpha, FoxO1, ADAM10 and NFkappaB. In addition, there was a reduction in its nuclear translocation and, subsequently, an improvement in transcriptional activity. Sirtinol, a sirtuin 1 inhibitor, was used to correlate these effects with sirtuin. It is shown that sirtinol reduces sirtuin 1 expression and impairs the beneficial action of melatonin on cell viability and apoptosis prevention. Moreover, some of the sirtuin 1 substrates studied also reversed the melatonin effect when sirtinol is added to the cells, mainly p53. Globally, these results add weight to the findings of previous reports, indicating a new role for melatonin in improving cell function gated to an increased neuroprotective role for the sirtuin 1 pathway.
Tajes
M
M
Unitat de Farmacologia i Farmacognòsia Facultat de Farmàcia, Institut de Biomedicina (IBUB), Centros de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Universitat de Barcelona, Nucli Universitari de Pedralbes, Barcelona, Spain.
Gutierrez-Cuesta
J
J
Ortuño-Sahagun
D
D
Camins
A
A
Pallàs
Mercè
M
D051722:ADAM Proteins / Q000378:metabolism; D000072197:ADAM10 Protein; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D015153:Blotting, Western; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D047468:Immunoprecipitation; D008550:Melatonin / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000071161:Forkhead Box Protein O1
D051722:ADAM Proteins; D000072197:ADAM10 Protein; D000975:Antioxidants; D051858:Forkhead Transcription Factors; D008550:Melatonin; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins; D056564:Sirtuin 1; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C501429:Ppargc1a protein, rat; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C542371:ADAM10 protein, rat