DOI: 10.1126/science.1168112 , 1293 (2009); 324Science et al.Samuel Bowles,Affect the Evolution of Human Social Behaviors?Did Warfare Among Ancestral Hunter-GatherersThis copy is for your personal, non-commercial use only.. clicking herecolleagues, clients, or customers by , you can order high-quality copies for yourIf you wish to distribute this article to others. herefollowing the guidelines can be obtained byPermission to republish or repurpose articles or portions of articles (this information is current as of May 4, 2010 ):The following resources related to this article are available online at www.sciencemag.org http://www.sciencemag.org/cgi/content/full/324/5932/1293version of this article at: including high-resolution figures, can be found in the onlineUpdated information and services, http://www.sciencemag.org/cgi/content/full/324/5932/1293/DC1 can be found at: Supporting Online Materialfound at: can berelated to this articleA list of selected additional articles on the Science Web sites http://www.sciencemag.org/cgi/content/full/324/5932/1293#related-content http://www.sciencemag.org/cgi/content/full/324/5932/1293#otherarticles, 5 of which can be accessed for free: cites 29 articlesThis article 2 article(s) on the ISI Web of Science. cited byThis article has been http://www.sciencemag.org/cgi/content/full/324/5932/1293#otherarticles 2 articles hosted by HighWire Press; see: cited byThis article has been http://www.sciencemag.org/cgi/collection/psychologyPsychology : subject collectionsThis article appears in the following registered trademark of AAAS. is aScience2009 by the American Association for the Advancement of Science; all rights reserved. The title CopyrightAmerican Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by theScience on May 4, 2010 www.sciencemag.orgDownloaded fromblunts ectopic HIF-2a–induced increases in hepaticEpo gene expression, whereas concomitant Sirt1 andHIF-2a overexpression further augments hepaticEpo gene expression in normoxic mice comparedwith ectopic HIF-2a overexpression alone.Although Sirt1 overexpression augmentsHIF-2a–induced Epo expression, increased Sirt1activity alone is not sufficient to induce hepaticEpo gene expression in mice. Interestingly, HIFsignaling and Sirt1 activity in the liver are inverse-ly regulated during caloric restriction. Whereascaloric restriction of aged rats results in reducedHIF-1 signaling and blunted expression of HIFtarget genes in the liver, including Epo (38),caloric restriction is associated with increased he-patic Sirt1 activity (39), which indicates that Sirt1or HIF-2a signaling pathways can be controlledindependent of each other in a stress-dependentmanner. In addition to repressing HIF-1a sig-naling, caloric restriction may directly repressHIF signaling induced by HIF-2a. Alternatively,caloric restriction may induce expression of arepressor of Epo gene expression that suppressesSirt1/HIF-2a signaling in a dominant fashion.Our data integrate Sirt1-HIF-2a signalingwith other stress-responsive, prosurvival signaltransduction pathways that are modulated bySirt1 in mammals. HIF-2a is only present in ver-tebrates and regulates expression of prosurvivalfactors under hypoxia and other adverse en vi-ronmental conditions (2). HIF-2 signaling, regu-lated in part by hypoxia-induced acetylation, andSirt1 augmentation of HIF-2 signaling, conferredthrough Sirt1/HIF-2a complex formation as wellas by Sirt1-mediated deacetylation of acetylatedHIF-2a, likely have a specialized role in highermetazoans. Signaling from Sirt1 to HIF-2a couldbe induced by other environmental stresses be-sides hypoxia that alter pyridine nucleotide ho-meostasis and activate HIF-2a signaling. Identifyingthe relevant environmental stressors that induceSirt1/HIF-2a signaling and defining the role ofSirt1/HIF-2a signaling in the regulation of pro-tective cellular mechanisms in mammals mayprovide novel therapeutic opportunities for hu-man disease states.References and Notes1. G. L. Semenza, Biochem. Pharmacol. 59, 47 (2000).2. H. Tian, S. L. McKnight, D. W. Russell, Genes Dev. 11,72(1997).3. G. L. Wang, B. H. Jiang, E. A. Rue, G. L. Semenza, Proc.Natl. Acad. Sci. U.S.A. 92, 5510 (1995).4. M. Scortegagna et al., Nat. Genet. 35, 331 (2003).5. 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