Sirt1 通过调节 DMH 和 LH 中的 NK2 同源盒 1 延长了小鼠的寿命并延缓了衰老。
Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH.
机构信息
Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
出版信息
Cell Metab. 2013 Sep 3;18(3):416-30. doi: 10.1016/j.cmet.2013.07.013.
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.
哺乳动物 Sir2 同源物 Sirt1 在代谢调节中发挥重要作用。然而，Sirt1 在衰老和长寿调节中的作用仍存在争议。在这里，我们证明大脑特异性 Sirt1 过表达（BRASTO）转基因小鼠在雄性和雌性中均表现出显著的寿命延长，并且年老的 BRASTO 小鼠表现出与衰老延迟一致的表型。这些表型是通过增强神经活性介导的，特别是在背内侧和外侧下丘脑核（DMH 和 LH）中，通过增加食欲素 2 型受体（Ox2r）的表达。我们确定 Nk2 同源盒 1（Nkx2-1）是 Sirt1 的伴侣，它上调 Ox2r 的转录，并与 Sirt1 在 DMH 和 LH 中共定位。DMH/LH 特异性敲低 Sirt1、Nkx2-1 或 Ox2r 和 DMH 特异性 Sirt1 过表达进一步支持 Sirt1/Nkx2-1/Ox2r 介导的信号通路在与长寿相关的表型中的作用。我们的发现表明，DMH/LH 优势 Sirt1 活性在哺乳动物衰老和长寿调节中的重要性。
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