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      Sirt1 Extends Life Span and Delays Aging in Mice through the Regulation of Nk2 Homeobox 1 in the DMH and LH

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      Cell Metabolism

      Elsevier BV

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          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. Copyright © 2013 Elsevier Inc. All rights reserved.

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          Author and article information

          Journal
          Cell Metabolism
          Cell Metabolism
          Elsevier BV
          15504131
          September 2013
          September 2013
          : 18
          : 3
          : 416-430
          Article
          10.1016/j.cmet.2013.07.013
          3794712
          24011076
          © 2013

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