酵母Sirtuins在细胞寿命中的作用
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摘要
酿酒酵母(以下简略为酵母)作为寿命分析模型广泛应用于寿命研究领域。酵母寿命分析方法有两种,分别是复制型酵母寿命分析法和时序型酵母寿命分析法。目前,通过酵母寿命分析模型已识别出包括SIR2在内的多个寿命调节基因。SIR2是目前较好的被确立起来的寿命调节基因,具有NAD依赖型脱乙酰化酶的活性,从原核生物到真核生物都有良好的保守性。Sirtuins (Sir2蛋白家族的总称)在细胞内具有功能上的多样性,其中包括对于压力耐受的调节、基因转录的调节、代谢通路的调节以及寿命调节作用等。Sir2是Sirtuins家族最早发现的成员,其功能是参与异染色质结构域转录的沉默调节,同时还参与复制型酵母寿命的调节。已证明,SIR2的缺失会缩短酵母的寿命,基因表达的增高会延长寿命。Sir2的高等真核生物的同源蛋白也被证实参与衰老相关疾病的调节。本文中,我们将阐述Sir2以及Sir2的酵母同源蛋白Hst1-Hst4的功能,以及由它们调节的酵母寿命。
Saccharomyces cerevisiae is a commonly used aging model. Aging in yeast is assayed primarily by measuring replicative lifespan(RLS) or chronological lifespan(CLS). Several longevity factors have been identified through RLS and CLS studies, including Sirtuins(Sir2 protein family members). Sirtuins are well-known aging factors and a class of NAD dependent protein deacetylases that are evolutionarily conserved from prokaryotes to higher eukaryotes. Sirtuins exhibit multiple intracellular functions, including stress response, gene transcription, cellular metabolism, and longevity. The Sir2 protein is the founding sirtuin family member that functions in transcriptional silencing of heterochromatin domains and as a pro longevity factor for replicative lifespan. Deleting SIR2 shortens replicative lifespan, while increased gene dosage causes extension. Furthermore,Sir2 homologs in higher eukaryotes have been implicated in mediating age related diseases as well. In this review,we summarize the role of Sir2 and its yeast homologs, Hst1 through Hst4, in replicative aging and chronological aging.
Saccharomyces cerevisiae is a commonly used aging model. Aging in yeast is assayed primarily by measuring replicative lifespan(RLS) or chronological lifespan(CLS). Several longevity factors have been identified through RLS and CLS studies, including Sirtuins(Sir2 protein family members). Sirtuins are well-known aging factors and a class of NAD dependent protein deacetylases that are evolutionarily conserved from prokaryotes to higher eukaryotes. Sirtuins exhibit multiple intracellular functions, including stress response, gene transcription, cellular metabolism, and longevity. The Sir2 protein is the founding sirtuin family member that functions in transcriptional silencing of heterochromatin domains and as a pro longevity factor for replicative lifespan. Deleting SIR2 shortens replicative lifespan, while increased gene dosage causes extension. Furthermore,Sir2 homologs in higher eukaryotes have been implicated in mediating age related diseases as well. In this review,we summarize the role of Sir2 and its yeast homologs, Hst1 through Hst4, in replicative aging and chronological aging.
引文
[1]Sauve AA,Celic I,Avalos J,Deng HT,Boeke JD,Schramm VL.Chemistry of gene silencing:the mechanism of NAD+-dependent deacetylation reactions.Biochemistry,2001,40(51):15456-15463.
[2]Rine J,Herskowitz I.Four genes responsible for a position effect on expression from HML and HMR in Saccharomyces cerevisiae.Genetics,1987,116(1):9-22.
[3]Brachmann CB,Sherman JM,Devine SE,Cameron EE,Pillus L,Boeke JD.The SIR2 gene family,conserved from bacteria to humans,functions in silencing,cell cycle progression,and chromosome stability.Genes&Developmment,1995,9(23):2888-2902.
[4]Xie JX,Pierce M,Gailus-Durner V,Wagner M,Winter E,Vershon AK.Sum1 and Hst1 repress middle sporulation-specific gene expression during mitosis in Saccharomyces cerevisiae.The EMBO Journal,1999,18(22):6448-6454.
[5]Bedalov A,Hirao M,Posakony J,Nelson M,Simon JA.NAD+-dependent deacetylase Hst1p controls biosynthesis and cellular NAD+levels in Saccharomyces cerevisiae.Molecular and Cellular Biology,2003,23(19):7044-7054.
[6]Li MG,Petteys BJ,McClure JM,Valsakumar V,Bekiranov S,Frank EL,Smith JS.Thiamine biosynthesis in Saccharomyces cerevisiae is regulated by the NAD+-dependent histone deacetylase Hst1.Molecular and Cellular Biology,2010,30(13):3329-3341.
[7]Smith JS,Brachmann CB,Celic I,Kenna MA,Muhammad S,Starai VJ,Avalos JL,Escalante-Semerena JC,Grubmeyer C,Wolberger C,Boeke JD.A phylogenetically conserved NAD+-dependent protein deacetylase activity in the Sir2protein family.Proceedings of the National Academy of Sciences of the United States of America,2000,97(12):6658-6663.
[8]Halme A,Bumgarner S,Styles C,Fink GR.Genetic and epigenetic regulation of the FLO gene family generates cell-surface variation in yeast.Cell,2004,116(3):405-415.
[9]Lamming DW,Latorre-Esteves M,Medvedik O,Wong SN,Tsang FA,Wang C,Lin SJ,Sinclair DA.HST2 mediates SIR2-independent life-span extension by calorie restriction.Science,2005,309(5742):1861-1864.
[10]Perrod S,Cockell MM,Laroche T,Renauld H,Ducrest AL,Bonnard C,Gasser SM.A cytosolic NAD-dependent deacetylase,Hst2p,can modulate nucleolar and telomeric silencing in yeast.The EMBO Journal,2001,20(1-2):197-209.
[11]Wilson JM,Le VQ,Zimmerman C,Marmorstein R,Pillus L.Nuclear export modulates the cytoplasmic Sir2 homologue Hst2.EMBO Reports,2006,7(12):1247-1251.
[12]Celic I,Masumoto H,Griffith WP,Meluh P,Cotter RJ,Boeke JD,Verreault A.The sirtuins Hst3 and Hst4p preserve genome integrity by controlling histone H3 lysine56 deacetylation.Current Biology,2006,16(13):1280-1289.
[13]Tasselli L,Zheng W,Chua KF.SIRT6:novel mechanisms and links to aging and disease.Trends in Endocrinology&Metabolism,2017,28(3):168-185.
[14]Zhong L,Mostoslavsky R.SIRT6:a master epigenetic gatekeeper of glucose metabolism.Transcription,2010,1(1):17-21.
[15]Li MG,Valsakumar V,Poorey K,Bekiranov S,Smith JS.Genome-wide analysis of functional sirtuin chromatin targets in yeast.Genome Biology,2013,14(5):R48.
[16]Simmons GE Jr,Pruitt WM,Pruitt K.Diverse roles of SIRT1 in cancer biology and lipid metabolism.International Journal of Molecular Sciences,2015,16(1):950-965.
[17]Zhang DY,Zhang CF,Fu BC,Sun L,Wang XQ,Chen W,Liu W,Liu KY,Du GQ,Ma CY,Jiang SL,Li RK,Tian H.Sirtuin3 protects aged human mesenchymal stem cells against oxidative stress and enhances efficacy of cell therapy for ischaemic heart diseases.Journal of Cellular and Molecular Medicine,2018,22(11):5504-5517.
[18]Liu H,Li SY,Liu XH,Chen YL,Deng HT.SIRT3overexpression inhibits growth of kidney tumor cells and enhances mitochondrial biogenesis.Journal of Proteome Research,2018,17(9):3143-3152.
[19]Vazquez BN,Thackray JK,Serrano L.Sirtuins and DNAdamage repair:SIRT7 comes to play.Nucleus,2017,8(2):107-115.
[20]Sutphin GL,Delaney JR,Kaeberlein M.Replicative lifespan analysis in budding yeast//Smith JS,Burke DJ.Yeast Genetics:Methods and Protocols.New York,NY:Humana Press,2014:341-357.
[21]Postnikoff SDL,Harkness TAA.Replicative and chronological life-span assays//Xiao W.Yeast Protocols.New York,NY:Humana Press,2014:223-227.
[22]Moretti P,Freeman K,Coodly L,Shore D.Evidence that a complex of SIR proteins interacts with the silencer and telomere-binding protein RAP1.Genes&Development,1994,8(19):2257-2269.
[23]Ghidelli S,Donze D,Dhillon N,Kamakaka RT.Sir2p exists in two nucleosome-binding complexes with distinct deacetylase activities.The EMBO Journal,2001,20(16):4522-4535.
[24]Wierman MB,Smith JS.Yeast sirtuins and the regulation of aging.FEMS Yeast Research,2014,14(1):73-88.
[25]Gallo CM,Smith DL Jr,Smith JS.Nicotinamide clearance by Pnc1 directly regulates Sir2-mediated silencing and longevity.Molecular and Cellular Biology,2004,24(3):1301-1312.
[26]Dodson AE,Rine J.Heritable capture of heterochromatin dynamics in Saccharomyces cerevisiae.eLife,2015,4:e05007.
[27]Rusche LN,Kirchmaier AL,Rine J.The establishment,inheritance,and function of silenced chromatin in Saccharomyces cerevisiae.Annual Review of Biochemistry,2003,72:481-516.
[28]Hoppe GJ,Tanny JC,Rudner AD,Gerber SA,Danaie S,Gygi SP,Moazed D.Steps in assembly of silent chromatin in yeast:Sir3-independent binding of a Sir2/Sir4 complex to silencers and role for Sir2-dependent deacetylation.Molecular and Cellular Biology,2002,22(12):4167-4180.
[29]RuschéLN,Kirchmaier AL,Rine J.Ordered nucleation and spreading of silenced chromatin in Saccharomyces cerevisiae.Molecular Biology of the Cell,2002,13(7):2207-2222.
[30]Suka N,Suka Y,Carmen AA,Wu JS,Grunstein M.Highly specific antibodies determine histone acetylation site usage in yeast heterochromatin and euchromatin.Molecular Cell,2001,8(2):473-479.
[31]Gartenberg MR,Smith JS.The nuts and bolts of transcriptionally silent chromatin in Saccharomyces cerevisiae.Genetics,2016,203(4):1563-1599.
[32]Kennedy BK,Austriaco NR Jr,Zhang JS,Guarente L.Mutation in the silencing gene S/R4 can delay aging in S.cerevisiae.Cell,1995,80(3):485-496.
[33]Kennedy BK,Gotta M,Sinclair DA,Mills K,McNabb DS,Murthy M,Pak SM,Laroche T,Gasser SM,Guarente L.Redistribution of silencing proteins from telomeres to the nucleolus is associated with extension of life span in S.cerevisiae.Cell,1997,89(3):381-391.
[34]Sinclair DA,Guarente L.Extrachromosomal rDNAcircles-a cause of aging in yeast.Cell,1997,91(7):1033-1042.
[35]Ganley ARD,Ide S,Saka K,Kobayashi T.The effect of replication initiation on gene amplification in the rDNA and its relationship to aging.Molecular Cell,2009,35(5):683-693.
[36]Fabrizio P,Gattazzo C,Battistella L,Wei M,Cheng C,McGrew K,Longo VD.Sir2 blocks extreme life-span extension.Cell,2005,123(4):655-667.
[37]Smith DL Jr,McClure JM,Matecic M,Smith JS.Calorie restriction extends the chronological lifespan of Saccharomyces cerevisiae independently of the Sirtuins.Aging Cell,2007,6(5):649-662.
[38]Wu ZY,Song LX,Liu SQ,Huang DJ.A high throughput screening assay for determination of chronological lifespan of yeast.Experimental Gerontology,2011,46(11):915-922.
[39]McCord R,Pierce M,Xie JX,Wonkatal S,Mickel C,Vershon AK.Rfm1,a novel tethering factor required to recruit the Hst1 histone deacetylase for repression of middle sporulation genes.Molcular and Cellular Biology,2003,23(6):2009-2016.
[40]Kang WK,Devare M,Kim JY.HST1 increases replicative lifespan of a sir2Δmutant in the absence of PDE2 in Saccharomyces cerevisiae.Journal of Microbiology,2017,55(2):123-129.
[41]Maas NL,Miller KM,DeFazio LG,Toczyski DP.Cell cycle and checkpoint regulation of histone H3 K56 acetylation by Hst3 and Hst4.Molecular Cell,2006,23(1):109-119.
[42]Tsuchiya M,Dang N,Kerr EO,Hu D,Steffen KK,Oakes JA,Kennedy BK,Kaeberlein M.Sirtuin-independent effects of nicotinamide on lifespan extension from calorie restriction in yeast.Aging Cell,2006,5(6):505-514.
[43]Dahlin JL,Chen XY,Walters MA,Zhang ZG.Histone-modifying enzymes,histone modifications and histone chaperones in nucleosome assembly:lessons learned from Rtt109 histone acetyltransferases.Critical Reviews in Biochemistry and Molecular Biology,2015,50(1):31-53.
[44]Ide S,Saka K,Kobayashi T.Rtt109 prevents hyper-amplification of ribosomal RNA genes through histone modification in budding yeast.PLoS Genetics,2013,9(4):e1003410.
[45]Hachinohe M,Yamane M,Akazawa D,Ohsawa K,Ohno M,Terashita Y,Masumoto H.A reduction in age-enhanced gluconeogenesis extends lifespan.PLoS One,2013,8(1):e54011.
[46]Tissenbaum HA,Guarente L.Increased dosage of a sir-2gene extends lifespan in Caenorhabditis elegans.Nature,2001,410(6825):227-230.
[47]Berdichevsky A,Viswanathan M,Horvitz HR,Guarente L.C.elegans SIR-2.1 interacts with 14-3-3 proteins to activate DAF-16 and extend life span.Cell,2006,125(6):1165-1177.
[48]Rogina B,Helfand SL.Sir2 mediates longevity in the fly through a pathway related to calorie restriction.Proceedings of the National Academy of Sciences of the United States of America,2004,101(45):15998-16003.
[49]Whitaker R,Faulkner S,Miyokawa R,Burhenn L,Henriksen M,Wood JG,Helfand SL.Increased expression of Drosophila Sir2 extends life span in a dose-dependent manner.Aging(Albany NY),2013,5(9):682-691.
[50]Matecic M,Stuart S,Holmes SG.SIR2-induced inviability is suppressed by histone H4 overexpression.Genetics,2002,162(2):973-976.
[2]Rine J,Herskowitz I.Four genes responsible for a position effect on expression from HML and HMR in Saccharomyces cerevisiae.Genetics,1987,116(1):9-22.
[3]Brachmann CB,Sherman JM,Devine SE,Cameron EE,Pillus L,Boeke JD.The SIR2 gene family,conserved from bacteria to humans,functions in silencing,cell cycle progression,and chromosome stability.Genes&Developmment,1995,9(23):2888-2902.
[4]Xie JX,Pierce M,Gailus-Durner V,Wagner M,Winter E,Vershon AK.Sum1 and Hst1 repress middle sporulation-specific gene expression during mitosis in Saccharomyces cerevisiae.The EMBO Journal,1999,18(22):6448-6454.
[5]Bedalov A,Hirao M,Posakony J,Nelson M,Simon JA.NAD+-dependent deacetylase Hst1p controls biosynthesis and cellular NAD+levels in Saccharomyces cerevisiae.Molecular and Cellular Biology,2003,23(19):7044-7054.
[6]Li MG,Petteys BJ,McClure JM,Valsakumar V,Bekiranov S,Frank EL,Smith JS.Thiamine biosynthesis in Saccharomyces cerevisiae is regulated by the NAD+-dependent histone deacetylase Hst1.Molecular and Cellular Biology,2010,30(13):3329-3341.
[7]Smith JS,Brachmann CB,Celic I,Kenna MA,Muhammad S,Starai VJ,Avalos JL,Escalante-Semerena JC,Grubmeyer C,Wolberger C,Boeke JD.A phylogenetically conserved NAD+-dependent protein deacetylase activity in the Sir2protein family.Proceedings of the National Academy of Sciences of the United States of America,2000,97(12):6658-6663.
[8]Halme A,Bumgarner S,Styles C,Fink GR.Genetic and epigenetic regulation of the FLO gene family generates cell-surface variation in yeast.Cell,2004,116(3):405-415.
[9]Lamming DW,Latorre-Esteves M,Medvedik O,Wong SN,Tsang FA,Wang C,Lin SJ,Sinclair DA.HST2 mediates SIR2-independent life-span extension by calorie restriction.Science,2005,309(5742):1861-1864.
[10]Perrod S,Cockell MM,Laroche T,Renauld H,Ducrest AL,Bonnard C,Gasser SM.A cytosolic NAD-dependent deacetylase,Hst2p,can modulate nucleolar and telomeric silencing in yeast.The EMBO Journal,2001,20(1-2):197-209.
[11]Wilson JM,Le VQ,Zimmerman C,Marmorstein R,Pillus L.Nuclear export modulates the cytoplasmic Sir2 homologue Hst2.EMBO Reports,2006,7(12):1247-1251.
[12]Celic I,Masumoto H,Griffith WP,Meluh P,Cotter RJ,Boeke JD,Verreault A.The sirtuins Hst3 and Hst4p preserve genome integrity by controlling histone H3 lysine56 deacetylation.Current Biology,2006,16(13):1280-1289.
[13]Tasselli L,Zheng W,Chua KF.SIRT6:novel mechanisms and links to aging and disease.Trends in Endocrinology&Metabolism,2017,28(3):168-185.
[14]Zhong L,Mostoslavsky R.SIRT6:a master epigenetic gatekeeper of glucose metabolism.Transcription,2010,1(1):17-21.
[15]Li MG,Valsakumar V,Poorey K,Bekiranov S,Smith JS.Genome-wide analysis of functional sirtuin chromatin targets in yeast.Genome Biology,2013,14(5):R48.
[16]Simmons GE Jr,Pruitt WM,Pruitt K.Diverse roles of SIRT1 in cancer biology and lipid metabolism.International Journal of Molecular Sciences,2015,16(1):950-965.
[17]Zhang DY,Zhang CF,Fu BC,Sun L,Wang XQ,Chen W,Liu W,Liu KY,Du GQ,Ma CY,Jiang SL,Li RK,Tian H.Sirtuin3 protects aged human mesenchymal stem cells against oxidative stress and enhances efficacy of cell therapy for ischaemic heart diseases.Journal of Cellular and Molecular Medicine,2018,22(11):5504-5517.
[18]Liu H,Li SY,Liu XH,Chen YL,Deng HT.SIRT3overexpression inhibits growth of kidney tumor cells and enhances mitochondrial biogenesis.Journal of Proteome Research,2018,17(9):3143-3152.
[19]Vazquez BN,Thackray JK,Serrano L.Sirtuins and DNAdamage repair:SIRT7 comes to play.Nucleus,2017,8(2):107-115.
[20]Sutphin GL,Delaney JR,Kaeberlein M.Replicative lifespan analysis in budding yeast//Smith JS,Burke DJ.Yeast Genetics:Methods and Protocols.New York,NY:Humana Press,2014:341-357.
[21]Postnikoff SDL,Harkness TAA.Replicative and chronological life-span assays//Xiao W.Yeast Protocols.New York,NY:Humana Press,2014:223-227.
[22]Moretti P,Freeman K,Coodly L,Shore D.Evidence that a complex of SIR proteins interacts with the silencer and telomere-binding protein RAP1.Genes&Development,1994,8(19):2257-2269.
[23]Ghidelli S,Donze D,Dhillon N,Kamakaka RT.Sir2p exists in two nucleosome-binding complexes with distinct deacetylase activities.The EMBO Journal,2001,20(16):4522-4535.
[24]Wierman MB,Smith JS.Yeast sirtuins and the regulation of aging.FEMS Yeast Research,2014,14(1):73-88.
[25]Gallo CM,Smith DL Jr,Smith JS.Nicotinamide clearance by Pnc1 directly regulates Sir2-mediated silencing and longevity.Molecular and Cellular Biology,2004,24(3):1301-1312.
[26]Dodson AE,Rine J.Heritable capture of heterochromatin dynamics in Saccharomyces cerevisiae.eLife,2015,4:e05007.
[27]Rusche LN,Kirchmaier AL,Rine J.The establishment,inheritance,and function of silenced chromatin in Saccharomyces cerevisiae.Annual Review of Biochemistry,2003,72:481-516.
[28]Hoppe GJ,Tanny JC,Rudner AD,Gerber SA,Danaie S,Gygi SP,Moazed D.Steps in assembly of silent chromatin in yeast:Sir3-independent binding of a Sir2/Sir4 complex to silencers and role for Sir2-dependent deacetylation.Molecular and Cellular Biology,2002,22(12):4167-4180.
[29]RuschéLN,Kirchmaier AL,Rine J.Ordered nucleation and spreading of silenced chromatin in Saccharomyces cerevisiae.Molecular Biology of the Cell,2002,13(7):2207-2222.
[30]Suka N,Suka Y,Carmen AA,Wu JS,Grunstein M.Highly specific antibodies determine histone acetylation site usage in yeast heterochromatin and euchromatin.Molecular Cell,2001,8(2):473-479.
[31]Gartenberg MR,Smith JS.The nuts and bolts of transcriptionally silent chromatin in Saccharomyces cerevisiae.Genetics,2016,203(4):1563-1599.
[32]Kennedy BK,Austriaco NR Jr,Zhang JS,Guarente L.Mutation in the silencing gene S/R4 can delay aging in S.cerevisiae.Cell,1995,80(3):485-496.
[33]Kennedy BK,Gotta M,Sinclair DA,Mills K,McNabb DS,Murthy M,Pak SM,Laroche T,Gasser SM,Guarente L.Redistribution of silencing proteins from telomeres to the nucleolus is associated with extension of life span in S.cerevisiae.Cell,1997,89(3):381-391.
[34]Sinclair DA,Guarente L.Extrachromosomal rDNAcircles-a cause of aging in yeast.Cell,1997,91(7):1033-1042.
[35]Ganley ARD,Ide S,Saka K,Kobayashi T.The effect of replication initiation on gene amplification in the rDNA and its relationship to aging.Molecular Cell,2009,35(5):683-693.
[36]Fabrizio P,Gattazzo C,Battistella L,Wei M,Cheng C,McGrew K,Longo VD.Sir2 blocks extreme life-span extension.Cell,2005,123(4):655-667.
[37]Smith DL Jr,McClure JM,Matecic M,Smith JS.Calorie restriction extends the chronological lifespan of Saccharomyces cerevisiae independently of the Sirtuins.Aging Cell,2007,6(5):649-662.
[38]Wu ZY,Song LX,Liu SQ,Huang DJ.A high throughput screening assay for determination of chronological lifespan of yeast.Experimental Gerontology,2011,46(11):915-922.
[39]McCord R,Pierce M,Xie JX,Wonkatal S,Mickel C,Vershon AK.Rfm1,a novel tethering factor required to recruit the Hst1 histone deacetylase for repression of middle sporulation genes.Molcular and Cellular Biology,2003,23(6):2009-2016.
[40]Kang WK,Devare M,Kim JY.HST1 increases replicative lifespan of a sir2Δmutant in the absence of PDE2 in Saccharomyces cerevisiae.Journal of Microbiology,2017,55(2):123-129.
[41]Maas NL,Miller KM,DeFazio LG,Toczyski DP.Cell cycle and checkpoint regulation of histone H3 K56 acetylation by Hst3 and Hst4.Molecular Cell,2006,23(1):109-119.
[42]Tsuchiya M,Dang N,Kerr EO,Hu D,Steffen KK,Oakes JA,Kennedy BK,Kaeberlein M.Sirtuin-independent effects of nicotinamide on lifespan extension from calorie restriction in yeast.Aging Cell,2006,5(6):505-514.
[43]Dahlin JL,Chen XY,Walters MA,Zhang ZG.Histone-modifying enzymes,histone modifications and histone chaperones in nucleosome assembly:lessons learned from Rtt109 histone acetyltransferases.Critical Reviews in Biochemistry and Molecular Biology,2015,50(1):31-53.
[44]Ide S,Saka K,Kobayashi T.Rtt109 prevents hyper-amplification of ribosomal RNA genes through histone modification in budding yeast.PLoS Genetics,2013,9(4):e1003410.
[45]Hachinohe M,Yamane M,Akazawa D,Ohsawa K,Ohno M,Terashita Y,Masumoto H.A reduction in age-enhanced gluconeogenesis extends lifespan.PLoS One,2013,8(1):e54011.
[46]Tissenbaum HA,Guarente L.Increased dosage of a sir-2gene extends lifespan in Caenorhabditis elegans.Nature,2001,410(6825):227-230.
[47]Berdichevsky A,Viswanathan M,Horvitz HR,Guarente L.C.elegans SIR-2.1 interacts with 14-3-3 proteins to activate DAF-16 and extend life span.Cell,2006,125(6):1165-1177.
[48]Rogina B,Helfand SL.Sir2 mediates longevity in the fly through a pathway related to calorie restriction.Proceedings of the National Academy of Sciences of the United States of America,2004,101(45):15998-16003.
[49]Whitaker R,Faulkner S,Miyokawa R,Burhenn L,Henriksen M,Wood JG,Helfand SL.Increased expression of Drosophila Sir2 extends life span in a dose-dependent manner.Aging(Albany NY),2013,5(9):682-691.
[50]Matecic M,Stuart S,Holmes SG.SIR2-induced inviability is suppressed by histone H4 overexpression.Genetics,2002,162(2):973-976.