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

• Published in: Cell metabolism 2013-09, Vol.18 (3), p.416-430
• Main Authors: Satoh, Akiko, Brace, Cynthia S., Rensing, Nick, Cliften, Paul, Wozniak, David F., Herzog, Erik D., Yamada, Kelvin A., Imai, Shin-ichiro
• Format: Article
• Language: English
• Subjects: Aging; Animals; Body Temperature; Female; Hypothalamus - metabolism; Longevity; Male; Mice; Mice, Transgenic; Mitochondria - metabolism; Mitochondria - pathology; Motor Activity; Muscle, Skeletal - metabolism; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Orexin Receptor Antagonists; Orexin Receptors - genetics; Orexin Receptors - metabolism; Phenotype; Promoter Regions, Genetic; RNA Interference; RNA, Small Interfering - metabolism; Signal Transduction; Sirtuin 1 - antagonists & inhibitors; Sirtuin 1 - genetics; Sirtuin 1 - metabolism; Thyroid Nuclear Factor 1; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic; Up-Regulation
• ISSN: 1550-4131; 1932-7420
• 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. [Display omitted] •BRASTO mice show life span extension and phenotypes consistent with delay in aging•BRASTO mice exhibit enhanced neural activity and Ox2r expression in the DMH and LH•Sirt1, its partner Nkx2-1, and Ox2r in the DMH and LH mediate beneficial phenotypes•DMH/LH-predominant Sirt1 activity is crucial to delay aging and promote longevity