title: SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging.
abstract: SIRT1 is a NAD(+)-dependent protein deacetylase that governs many physiological pathways, including circadian rhythm in peripheral tissues. Here, we show that SIRT1 in the brain governs central circadian control by activating the transcription of the two major circadian regulators, BMAL1 and CLOCK. This activation comprises an amplifying circadian loop involving SIRT1, PGC-1α, and Nampt. In aged wild-type mice, SIRT1 levels in the suprachiasmatic nucleus are decreased, as are those of BMAL1 and PER2, giving rise to a longer intrinsic period, a more disrupted activity pattern, and an inability to adapt to changes in the light entrainment schedule. Young mice lacking brain SIRT1 phenocopy these aging-dependent circadian changes, whereas mice that overexpress SIRT1 in the brain are protected from the effects of aging. Our findings indicate that SIRT1 activates the central pacemaker to maintain robust circadian control in young animals, and a decay in this activity may play an important role in aging.
authors.affiliation: Glenn Laboratory for the Science of Aging, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Hung-Chun
authors.initials: HC
authors.lastname: Chang
authors.forename: Leonard
authors.initials: L
authors.lastname: Guarente
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics; D000375:Aging; D000818:Animals; D001921:Brain / Q000378:metabolism; D057906:Circadian Clocks; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011401:Promoter Regions, Genetic; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013493:Suprachiasmatic Nucleus / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1