title: Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH.
abstract: Ageing is a result of gradual and overall functional deteriorations across the body; however, it is unknown whether an individual tissue primarily works to mediate the ageing progress and control lifespan. Here we show that the hypothalamus is important for the development of whole-body ageing in mice, and that the underlying basis involves hypothalamic immunity mediated by IκB kinase-β (IKK-β), nuclear factor κB (NF-κB) and related microglia-neuron immune crosstalk. Several interventional models were developed showing that ageing retardation and lifespan extension are achieved in mice by preventing ageing-related hypothalamic or brain IKK-β and NF-κB activation. Mechanistic studies further revealed that IKK-β and NF-κB inhibit gonadotropin-releasing hormone (GnRH) to mediate ageing-related hypothalamic GnRH decline, and GnRH treatment amends ageing-impaired neurogenesis and decelerates ageing. In conclusion, the hypothalamus has a programmatic role in ageing development via immune-neuroendocrine integration, and immune inhibition or GnRH restoration in the hypothalamus/brain represent two potential strategies for optimizing lifespan and combating ageing-related health problems.
authors: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors: Guo
authors: G
authors: Zhang
authors: Juxue
authors: J
authors: Li
authors: Sudarshana
authors: S
authors: Purkayastha
authors: Yizhe
authors: Y
authors: Tang
authors: Hai
authors: H
authors: Zhang
authors: Ye
authors: Y
authors: Yin
authors: Bo
authors: B
authors: Li
authors: Gang
authors: G
authors: Liu
authors: Dongsheng
authors: D
authors: Cai
mesh_terms: D000375:Aging / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology; D003071:Cognition / Q000187:drug effects; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D007031:Hypothalamus / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D051550:I-kappa B Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008136:Longevity / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000201:enzymology / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism*; D055495:Neurogenesis; D012098:Reproduction / Q000502:physiology
chemical_list: D016328:NF-kappa B; D007987:Gonadotropin-Releasing Hormone; D051550:I-kappa B Kinase
references: Neuron. 2004 Jan 8;41(1):45-55
references: 14715134
references: Cell Metab. 2005 Feb;1(2):145-52
references: 16054055
references: Trends Neurosci. 2011 May;34(5):269-81
references: 21419501
references: J Neurosci Res. 2002 Nov 1;70(3):258-63
references: 12391584
references: Neuron. 2009 Oct 15;64(1):110-22
references: 19840553
references: J Neurosci Methods. 2003 Mar 15;123(2):189-200
references: 12606067
references: Nat Cell Biol. 2012 Oct;14(10):999-1012
references: 22940906
references: J Biol Chem. 2011 Sep 16;286(37):32324-32
references: 21784844
references: Science. 2000 Oct 6;290(5489):147-50
references: 11021802
references: Mech Ageing Dev. 2005 Sep;126(9):913-22
references: 15885745
references: Neuron. 2007 Feb 1;53(3):337-51
references: 17270732
references: Nature. 2009 Nov 5;462(7269):104-7
references: 19847165
references: Mech Ageing Dev. 2004 Sep;125(9):629-32
references: 15491681
references: Cell. 2009 Apr 3;137(1):47-59
references: 19345186
references: Methods Mol Biol. 2000;99:205-16
references: 10909087
references: Cell. 2010 Mar 19;140(6):918-34
references: 20303880
references: Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9328-32
references: 7568127
references: Nature. 2009 Jul 16;460(7253):392-5
references: 19587680
references: Mol Cell Biol. 2006 Apr;26(8):2936-46
references: 16581769
references: Science. 2007 Jul 20;317(5836):369-72
references: 17641201
references: Proc Natl Acad Sci U S A. 2011 Feb 15;108(7):2939-44
references: 21282643
references: Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6736-41
references: 11371619
references: Cell. 2009 Jan 9;136(1):62-74
references: 19135889
references: Cell. 2011 May 13;145(4):584-95
references: 21565615
references: Proc Natl Acad Sci U S A. 2010 Aug 24;107(34):15193-8
references: 20696914
references: Genes Dev. 2007 Dec 15;21(24):3244-57
references: 18055696
references: Neuron. 2008 Aug 28;59(4):527-9
references: 18760689
references: Am J Pathol. 2008 Apr;172(4):868-81
references: 18349124
references: Brain. 2011 Sep;134(Pt 9):2722-35
references: 21908876
references: Nature. 2008 Mar 27;452(7186):492-6
references: 18337721
references: Adv Gerontol. 2002;10:35-9
references: 12577689
references: Cell. 2008 Oct 3;135(1):61-73
references: 18854155
references: Aging Cell. 2009 Dec;8(6):761-4
references: 19732045
references: J Gerontol A Biol Sci Med Sci. 2012 May;67(5):495-502
references: 22459617
references: Nature. 2007 May 31;447(7144):545-9
references: 17538612
references: Nat Med. 2011 Jun 05;17(7):883-7
references: 21642978
references: Proc Natl Acad Sci U S A. 2010 Dec 21;107(51):22272-7
references: 21135231
references: Nature. 2011 Aug 31;477(7362):90-4
references: 21886162
references: Nat Rev Immunol. 2011 Oct 25;11(11):775-87
references: 22025055
references: Mol Cell. 2009 Jul 10;35(1):48-57
references: 19595715
references: Mol Cell Biol. 2006 Oct;26(19):7283-98
references: 16980629
references: Nat Med. 1996 Jul;2(7):788-94
references: 8673925
references: Nature. 2004 Aug 5;430(7000):631-9
references: 15295589
references: Nat Neurosci. 2003 Oct;6(10):1072-8
references: 12947408