title: Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH.
abstract: The mammalian Sir2 ortholog Sirt1 plays an important role in metabolic regulation. However, the role of Sirt1 in the regulation of aging and longevity is still controversial. Here we demonstrate that brain-specific Sirt1-overexpressing (BRASTO) transgenic mice show significant life span extension in both males and females, and aged BRASTO mice exhibit phenotypes consistent with a delay in aging. These phenotypes are mediated by enhanced neural activity specifically in the dorsomedial and lateral hypothalamic nuclei (DMH and LH, respectively), through increased orexin type 2 receptor (Ox2r) expression. We identified Nk2 homeobox 1 (Nkx2-1) as a partner of Sirt1 that upregulates Ox2r transcription and colocalizes with Sirt1 in the DMH and LH. DMH/LH-specific knockdown of Sirt1, Nkx2-1, or Ox2r and DMH-specific Sirt1 overexpression further support the role of Sirt1/Nkx2-1/Ox2r-mediated signaling for longevity-associated phenotypes. Our findings indicate the importance of DMH/LH-predominant Sirt1 activity in the regulation of aging and longevity in mammals.
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Akiko
authors.initials: A
authors.lastname: Satoh
authors.forename: Cynthia S
authors.initials: CS
authors.lastname: Brace
authors.forename: Nick
authors.initials: N
authors.lastname: Rensing
authors.forename: Paul
authors.initials: P
authors.lastname: Cliften
authors.forename: David F
authors.initials: DF
authors.lastname: Wozniak
authors.forename: Erik D
authors.initials: ED
authors.lastname: Herzog
authors.forename: Kelvin A
authors.initials: KA
authors.lastname: Yamada
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Imai
mesh_terms: D000375:Aging; D000818:Animals; D001831:Body Temperature; D005260:Female; D007031:Hypothalamus / Q000378:metabolism; D008136:Longevity; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009043:Motor Activity; D018482:Muscle, Skeletal / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: C501103:Cd200r1 protein, mouse; C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D034741:RNA, Small Interfering; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1