title: SIRT1 suppresses the senescence-associated secretory phenotype through epigenetic gene regulation.
abstract: Senescent cells develop a pro-inflammatory response termed the senescence-associated secretory phenotype (SASP). As many SASP components affect surrounding cells and alter their microenvironment, SASP may be a key phenomenon in linking cellular senesence with individual aging and age-related diseases. We herein demonstrated that the expression of Sirtuin1 (SIRT1) was decreased and the expression of SASP components was reciprocally increased during cellular senescence. The mRNAs and proteins of SASP components, such as IL-6 and IL-8, quickly accumulated in SIRT1-depleted cells, and the levels of these factors were also higher than those in control cells, indicating that SIRT1 negatively regulated the expression of SASP factors at the transcriptional level. SIRT1 bound to the promoter regions of IL-8 and IL-6, but dissociated from them during cellular senescence. The acetylation of Histone H3 (K9) and H4 (K16) of the IL-8 and IL-6 promoter regions gradually increased during cellular senescence. In SIRT1-depleted cells, the acetylation levels of these regions were already higher than those in control cells in the pre-senescent stage. Moreover, these acetylation levels in SIRT1-depleted cells were significantly higher than those in control cells during cellular senescence. These results suggest that SIRT1 repressed the expression of SASP factors through the deacetylation of histones in their promoter regions.
authors: Department of Cognitive Brain Science, Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan; Department of Aging Research, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors: Tomohisa
authors: T
authors: Hayakawa
authors: Department of Cognitive Brain Science, Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan.
authors: Mika
authors: M
authors: Iwai
authors: Department of Cognitive Brain Science, Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan; Department of Bioengineering, Nagaoka University of Technology, Nagaoka, Niigata, Japan.
authors: Satoshi
authors: S
authors: Aoki
authors: Department of Bioengineering, Nagaoka University of Technology, Nagaoka, Niigata, Japan.
authors: Koichi
authors: K
authors: Takimoto
authors: Department of Aging Research, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan; Department of Mechanism of Aging, Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan.
authors: Mitsuo
authors: M
authors: Maruyama
authors: Department of Cognitive Brain Science, Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan.
authors: Wakako
authors: W
authors: Maruyama
authors: Department of Cognitive Brain Science, Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan; Department of Aging Research, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors: Noboru
authors: N
authors: Motoyama
mesh_terms: D000107:Acetylation; D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics*; D044127:Epigenesis, Genetic; D055785:Gene Knockdown Techniques; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D056564:Sirtuin 1 / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D006657:Histones; D056564:Sirtuin 1
references: Mol Cell. 2009 Nov 13;36(3):365-78
references: 19917246
references: Nature. 2005 Aug 4;436(7051):720-4
references: 16079850
references: Nat Cell Biol. 2010 Jul;12(7):676-85
references: 20526329
references: J Cell Biol. 2011 Feb 21;192(4):547-56
references: 21321098
references: PLoS One. 2011;6(3):e17487
references: 21408175
references: Cell Metab. 2011 Apr 6;13(4):461-8
references: 21459330
references: Genes Dev. 2011 Jun 15;25(12):1245-61
references: 21646373
references: Blood. 2011 Sep 15;118(11):2941-50
references: 21734240
references: Nature. 2011 Sep 22;477(7365):482-5
references: 21938067
references: Cell Metab. 2011 Oct 5;14(4):528-36
references: 21982712
references: Genes Dev. 2011 Oct 15;25(20):2137-46
references: 21979374
references: Nature. 2005 Aug 4;436(7051):725-30
references: 16079851
references: Cell. 2008 Nov 28;135(5):907-18
references: 19041753
references: PLoS Biol. 2008 Dec 2;6(12):2853-68
references: 19053174
references: Nat Rev Cancer. 2009 Feb;9(2):81-94
references: 19132009
references: Mol Cell. 2009 Oct 9;36(1):2-14
references: 19818705
references: Genes Dev. 2011 Oct 15;25(20):2125-36
references: 21979375
references: Mol Cell. 2012 Jan 13;45(1):123-31
references: 22178396
references: Nat Rev Mol Cell Biol. 2012 Apr;13(4):225-38
references: 22395773
references: Aging (Albany NY). 2012 Dec;4(12):932-51
references: 23385065
references: Cell. 2013 Jul 18;154(2):430-41
references: 23870130
references: Nat Cell Biol. 2013 Aug;15(8):978-90
references: 23770676
references: Cell Metab. 2013 Sep 3;18(3):416-30
references: 24011076
references: Cell. 2013 Dec 19;155(7):1624-38
references: 24360282
references: Genes Dev. 2014 Jan 15;28(2):99-114
references: 24449267
references: Nature. 2014 Feb 20;506(7488):316-21
references: 24522534
references: Nat Cell Biol. 2014 Mar;16(3):201-7
references: 24576896
references: Nature. 2014 May 22;509(7501):439-46
references: 24848057
references: Trends Genet. 2014 Jul;30(7):271-86
references: 24877878
references: FEBS Lett. 2002 Jul 17;523(1-3):157-62
references: 12123824
references: Mol Cell Biol. 2002 Apr;22(7):2111-23
references: 11884599
references: Trends Cell Biol. 2014 Aug;24(8):464-71
references: 24786309
references: J Biol Chem. 2002 Oct 11;277(41):38540-9
references: 12140282
references: J Biol Chem. 2004 Jan 16;279(3):2030-7
references: 14570874
references: Cell. 2004 Feb 20;116(4):551-63
references: 14980222
references: EMBO J. 2006 May 17;25(10):2167-77
references: 16675955
references: J Biol Chem. 2006 Oct 6;281(40):29568-74
references: 16880208
references: Nature. 2006 Nov 30;444(7119):638-42
references: 17136094
references: Nature. 2007 Jun 7;447(7145):686-90
references: 17554302
references: Nature. 2007 Jun 7;447(7145):725-9
references: 17554309
references: Mol Biol Cell. 2008 Mar;19(3):1210-9
references: 18184747
references: Cell. 2008 Jun 13;133(6):1006-18
references: 18555777
references: Cell. 2008 Jun 13;133(6):1019-31
references: 18555778
references: Cell. 2008 Aug 22;134(4):657-67
references: 18724938
references: Gene Ther. 2000 Jun;7(12):1063-6
references: 10871756
references: Nature. 2001 Mar 8;410(6825):227-30
references: 11242085
references: Cell. 2001 Oct 19;107(2):149-59
references: 11672523
references: Science. 2004 Mar 26;303(5666):2011-5
references: 14976264
references: EMBO J. 2004 Jun 16;23(12):2369-80
references: 15152190
references: Genes Dev. 1999 Oct 1;13(19):2570-80
references: 10521401
references: Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):15998-6003
references: 15520384
references: Int J Mol Med. 2005 Aug;16(2):237-43
references: 16012755
references: Nature. 2005 Aug 4;436(7051):642
references: 16079833
references: Nature. 2005 Aug 4;436(7051):660-5
references: 16079837
references: Annu Rev Pathol. 2010;5:99-118
references: 20078217