title: Misregulation of an adaptive metabolic response contributes to the age-related disruption of lipid homeostasis in Drosophila.
abstract: Loss of metabolic homeostasis is a hallmark of aging and is commonly characterized by the deregulation of adaptive signaling interactions that coordinate energy metabolism with dietary changes. The mechanisms driving age-related changes in these adaptive responses remain unclear. Here, we characterize the deregulation of an adaptive metabolic response and the development of metabolic dysfunction in the aging intestine of Drosophila. We find that activation of the insulin-responsive transcription factor Foxo in intestinal enterocytes is required to inhibit the expression of evolutionarily conserved lipases as part of a metabolic response to dietary changes. This adaptive mechanism becomes chronically activated in the aging intestine, mediated by changes in Jun-N-terminal kinase (JNK) signaling. Age-related chronic JNK/Foxo activation in enterocytes is deleterious, leading to sustained repression of intestinal lipase expression and the disruption of lipid homeostasis. Changes in the regulation of Foxo-mediated adaptive responses thus contribute to the age-associated breakdown of metabolic homeostasis.
authors.affiliation: Department of Biology, University of Rochester, Rochester, NY 14627, USA; Buck Institute for Research on Aging, Novato, CA 94945, USA. Electronic address: jkarpac@buckinstitute.org.
authors.forename: Jason
authors.initials: J
authors.lastname: Karpac
authors.forename: Benoit
authors.initials: B
authors.lastname: Biteau
authors.forename: Heinrich
authors.initials: H
authors.lastname: Jasper
mesh_terms: D000367:Age Factors; D000818:Animals; D030801:Animals, Genetically Modified; D029721:Drosophila Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D007178:Inbreeding; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000201:enzymology; D050356:Lipid Metabolism / Q000502:physiology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; C477334:FOXO protein, Drosophila; D051858:Forkhead Transcription Factors; D014157:Transcription Factors; D048670:MAP Kinase Kinase 4
references.citation: Cell Metab. 2009 Dec;10(6):481-90
references.pmid: 19945405
references.citation: Aging Cell. 2009 Jun;8(3):288-95
references.pmid: 19627268
references.citation: Genes Dev. 2009 Oct 1;23(19):2333-44
references.pmid: 19797770
references.citation: Mol Syst Biol. 2011 Jun 21;7:502
references.pmid: 21694719
references.citation: Science. 1997 Nov 14;278(5341):1319-22
references.pmid: 9360933
references.citation: Nature. 1997 Oct 30;389(6654):994-9
references.pmid: 9353126
references.citation: PLoS Genet. 2010 Oct 14;6(10):e1001159
references.pmid: 20976250
references.citation: Science. 2002 May 10;296(5570):1118-20
references.pmid: 12004130
references.citation: Dev Cell. 2011 Jun 14;20(6):841-54
references.pmid: 21664581
references.citation: Cell. 2010 Nov 24;143(5):813-25
references.pmid: 21111239
references.citation: Aging Cell. 2011 Oct;10(5):735-48
references.pmid: 21443682
references.citation: PLoS Biol. 2007 Jan;5(1):e2
references.pmid: 17326724
references.citation: Annu Rev Physiol. 2003;65:313-32
references.pmid: 12471165
references.citation: J Biol Chem. 2009 May 15;284(20):13296-13300
references.pmid: 19297333
references.citation: Nature. 2001 Dec 13;414(6865):799-806
references.pmid: 11742412
references.citation: Cell Stem Cell. 2011 Nov 4;9(5):402-11
references.pmid: 22056138
references.citation: Nat Cell Biol. 2005 Mar;7(3):278-85
references.pmid: 15696159
references.citation: Cell. 2011 May 13;145(4):596-606
references.pmid: 21565616
references.citation: Cell Metab. 2009 Sep;10(3):199-207
references.pmid: 19723496
references.citation: Nat Rev Mol Cell Biol. 2013 Feb;14(2):83-97
references.pmid: 23325358
references.citation: Genes Dev. 2003 Aug 15;17(16):2006-20
references.pmid: 12893776
references.citation: Oncogene. 2008 Apr 7;27(16):2276-88
references.pmid: 18391970
references.citation: Cell. 2004 May 14;117(4):421-6
references.pmid: 15137936
references.citation: EMBO J. 2007 Jan 24;26(2):380-90
references.pmid: 17183370
references.citation: Genes Dev. 2013 Feb 15;27(4):429-40
references.pmid: 23392608
references.citation: J Endocrinol. 2006 Aug;190(2):191-202
references.pmid: 16899554
references.citation: Cell Metab. 2012 Jan 4;15(1):122-7
references.pmid: 22197324
references.citation: Mol Cell. 2000 Jul;6(1):77-86
references.pmid: 10949029
references.citation: Ageing Res Rev. 2013 Jan;12(1):436-44
references.pmid: 22706186
references.citation: Nature. 2006 Dec 21;444(7122):1038-43
references.pmid: 17183314
references.citation: Trends Endocrinol Metab. 2002 May-Jun;13(4):156-62
references.pmid: 11943559
references.citation: Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4494-9
references.pmid: 15767565
references.citation: J Biol Chem. 2012 Jun 8;287(24):20132-43
references.pmid: 22511764
references.citation: Cell Stem Cell. 2008 Oct 9;3(4):442-55
references.pmid: 18940735
references.citation: Annu Rev Physiol. 2008;70:191-212
references.pmid: 17988211
references.citation: Science. 2003 Jan 24;299(5606):572-4
references.pmid: 12543978
references.citation: J Biol Chem. 2000 Mar 24;275(12):9047-54
references.pmid: 10722755
references.citation: Aging Cell. 2008 Jun;7(3):318-34
references.pmid: 18284659
references.citation: Aging Cell. 2008 Aug;7(4):478-90
references.pmid: 18485125
references.citation: Annu Rev Nutr. 2010 Aug 21;30:291-314
references.pmid: 20420525
references.citation: Science. 2003 Feb 28;299(5611):1346-51
references.pmid: 12610294
references.citation: J Cell Biol. 2005 Jul 18;170(2):295-304
references.pmid: 16009721
references.citation: Science. 2004 Jul 16;305(5682):361
references.pmid: 15192154
references.citation: Trends Endocrinol Metab. 2009 Apr;20(3):100-6
references.pmid: 19251431
references.citation: Biochimie. 2000 Nov;82(11):997-1004
references.pmid: 11099796
references.citation: Science. 2013 Jan 11;339(6116):172-7
references.pmid: 23307735
references.citation: Diabetes. 2006 May;55(5):1270-5
references.pmid: 16644682
references.citation: Proc Natl Acad Sci U S A. 2012 Dec 26;109(52):21528-33
references.pmid: 23236133
references.citation: Science. 2008 Nov 7;322(5903):957-60
references.pmid: 18988854
references.citation: Diabetes. 2011 Jun;60(6):1734-42
references.pmid: 21498783
references.citation: Oncogene. 2003 Jan 30;22(4):602-14
references.pmid: 12555073
references.citation: Cell Metab. 2010 Dec 1;12(6):567-79
references.pmid: 21109190
references.citation: Nature. 2006 Jan 26;439(7075):470-4
references.pmid: 16340960
references.citation: Nature. 2006 Jan 26;439(7075):475-9
references.pmid: 16340959
references.citation: Cell. 2005 Apr 8;121(1):115-25
references.pmid: 15820683
references.citation: Exp Gerontol. 2011 May;46(5):349-54
references.pmid: 21111799
references.citation: Diabetes. 2012 Jun;61(6):1315-22
references.pmid: 22618766
references.citation: PLoS Genet. 2012 Jan;8(1):e1002478
references.pmid: 22275878
references.citation: Aging Cell. 2008 Oct;7(5):688-99
references.pmid: 18665908
references.citation: Physiol Rev. 2006 Apr;86(2):651-67
references.pmid: 16601270
references.citation: Nature. 2002 Nov 21;420(6913):333-6
references.pmid: 12447443
references.citation: Cell. 2011 May 13;145(4):607-21
references.pmid: 21565617
references.citation: EMBO J. 2004 Dec 8;23(24):4802-12
references.pmid: 15538382
references.citation: Cell. 2012 Mar 2;148(5):852-71
references.pmid: 22385956
references.citation: Nature. 2004 Jun 3;429(6991):562-6
references.pmid: 15175753
references.citation: Cell Metab. 2005 Apr;1(4):215-6
references.pmid: 16054064
references.citation: Mol Cell. 2000 Jul;6(1):87-97
references.pmid: 10949030
references.citation: Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12596-601
references.pmid: 11675495
references.citation: Trends Cell Biol. 2003 Feb;13(2):79-85
references.pmid: 12559758
references.citation: J Mol Biol. 2008 Mar 7;376(5):1215-23
references.pmid: 18234213
references.citation: PLoS One. 2009 Jun 26;4(6):e6063
references.pmid: 19557170
references.citation: Cell Metab. 2013 Jan 8;17(1):85-100
references.pmid: 23312285
references.citation: Cell. 2003 Nov 14;115(4):489-502
references.pmid: 14622602
references.citation: J Clin Invest. 2000 Jan;105(2):199-205
references.pmid: 10642598
references.citation: Biochem J. 2009 Dec 14;425(1):13-26
references.pmid: 20001959