SIRTain regulators of premature senescence and accelerated aging

Abstract

The sirtuin proteins constitute class III histone deacetylases (HDACs). These evolutionarily conserved NAD⁺-dependent enzymes form an important component in a variety of cellular and biological processes with highly divergent as well as convergent roles in maintaining metabolic homeostasis, safeguarding genomic integrity, regulating cancer metabolism and also inflammatory responses. Amongst the seven known mammalian sirtuin proteins, SIRT1 has gained much attention due to its widely acknowledged roles in promoting longevity and ameliorating age-associated pathologies. The contributions of other sirtuins in the field of aging are also gradually emerging. Here, we summarize some of the recent discoveries in sirtuins biology which clearly implicate the functions of sirtuin proteins in the regulation of premature cellular senescence and accelerated aging. The roles of sirtuins in various cellular processes have been extrapolated to draw inter-linkage with anti-aging mechanisms. Also, the latest findings on sirtuins which might have potential effects in the process of aging have been reviewed.

Keywords

sirtuins / senescence / premature aging / longevity

References

[1] Abdelmohsen K, Pullmann R Jr, Lal A, Kim HH, Galban S, Yang X, Blethrow JD, Walker M, Shubert J, Gillespie DA (2007) Phosphorylation of HuR by Chk2 regulates SIRT1 expression. Mol cell25: 543-557

[2] Bauer I, Grozio A, Lasigliè D, Basile G, Sturla L, Magnone M, Sociali G, Soncini D, Caffa I, Poggi A (2012) The NAD+-dependent histone deacetylase SIRT6 promotes cytokine production and migration in pancreatic cancer cells by regulating Ca2+ responses. J BiolChem287: 40924-40937

[3] Brown K, Xie S, Qiu X, Mohrin M, Shin J, Liu Y, Zhang D, Scadden DT, Chen D (2013) SIRT3 reverses aging-associated degeneration. Cell reports3: 319-327

[4] Burnett C, Valentini S, Cabreiro F, Goss M, Somogyvári M, Piper MD, Hoddinot M, Sutphin GL, Leko V, Mcelwee JJ (2011) Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature477: 482-485

[5] Cai Y, Sheng ZY, Liang SX (2014) Radiosensitization Effect of Overexpression of Adenovirus-mediated SIRT6 on A549 Nonsmall Cell Lung Cancer Cells. Asian Pacific Journal of Cancer Prevention15: 7297-7301

[6] Chang HC, Guarente L (2014) SIRT1 and other sirtuins in metabolism. Trends in Endocrinology & Metabolism25: 138-145

[7] Chen D, Guarente L (2007) SIR2: a potential target for calorie restriction mimetics. Trends in molecular medicine13: 64-71

[8] Chen J, Xavier S, Moskowitz-Kassai E, Chen R, Lu CY, Sanduski K, Spes A, Turk B, Goligorsky MS (2012) Cathepsin cleavage of sirtuin 1 in endothelial progenitor cells mediates stress-induced premature senescence. The American journal of pathology180: 973-983

[9] Cheng HL, Mostoslavsky R, Saito SI, Manis JP, Gu Y, Patel P, Bronson R, Appella E, Alt FW, Chua KF (2003) Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)- deficient mice. ProcNatlAcadSci100: 10794-10799

[10] Choi JE, Mostoslavsky R (2014) Sirtuins, metabolism, and DNA repair. Current Opinion In Genetics & Development26: 24-32

[11] Chua KF, Mostoslavsky R, Lombard DB, Pang WW, Saito SI, Franco S, Kaushal D, Cheng HL, Fischer MR, Stokes N (2005) Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress. Cell Metab2: 67-76

[12] de Oliveira RM, Sarkander J, Kazantsev AG, Outeiro TF (2012) SIRT2 as a therapeutic target for age-related disorders. Frontiers in pharmacology3: 82

[13] Dobbin MM, Madabhushi R, Pan L, Chen Y, Kim D, Gao J, Ahanonu B, Pao PH, Qiu Y, Zhao Y (2013) SIRT1 collaborates with ATM and HDAC1 to maintain genomic stability in neurons. Nature neuroscience16: 1008-1015

[14] Dominy JE Jr, Lee Y, Jedrychowski MP, Chim H, Jurczak MJ, Camporez JP, Ruan HB, Feldman J, Pierce K, Mostoslavsky R (2012) The deacetylase Sirt6 activates the acetyltransferase GCN5 and suppresses hepatic gluconeogenesis. Mol cell48: 900-913

[15] Donmez G, Arun A, Chung CY, McLean PJ, Lindquist S, Guarente L (2012) SIRT1 protects against α-synuclein aggregation by activating molecular chaperones. The Journal of Neuroscience32: 124-132

[16] Elhanati S, Kanfi Y, Varvak A, Roichman A, Carmel-Gross I, Barth S, Gibor G, Cohen HY (2013) Multiple regulatory layers of SREBP1/2 by SIRT6. Cell reports4: 905-912

[17] Fu J, Jin J, Cichewicz RH, Hageman SA, Ellis TK, Xiang L, Peng Q, Jiang M, Arbez N, Hotaling K (2012) trans-(-)-ϵ-Viniferin increases mitochondrial sirtuin 3 (SIRT3), activates AMP-activated protein kinase (AMPK), and protects cells in models of Huntington Disease. J BiolChem287: 24460-24472

[18] Ghosh S, Zhou Z (2014) Genetics of aging, progeria and lamin disorders. Current opinion in genetics & development26: 41-46

[19] Giblin W, Skinner ME, Lombard DB (2014) Sirtuins: guardians of mammalian healthspan. Trends in Genetics30: 271-286

[20] Glorioso C, Oh S, Douillard GG, Sibille E (2011) Brain molecular aging, promotion of neurological disease and modulation by Sirtuin5 longevity gene polymorphism. Neurobiology of disease41: 279-290

[21] Gorenne I, Kumar S, Gray K, Figg N, Yu H, Mercer J, Bennett M(2013) Vascular smooth muscle cell sirtuin 1 protects against DNA damage and inhibits atherosclerosis. Circulation127: 386-396

[22] Gorospe M, de Cabo R (2008) AsSIRTing the DNA damage response. Trends in cell biology18: 77-83

[23] Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, Christodoulou DC, Murphy AJ, Valenzuela DM, Yancopoulos GD, Karow M, Blander G (2006) SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic β cells. Cell126: 941-954

[24] Herranz D, Muñoz-Martin M, Cañamero M, Mulero F, Martinez-Pastor B, Fernandez-Capetillo O, Serrano M (2010) Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat Comm1: 3

[25] Hirschey MD, Shimazu T, Jing E, Grueter CA, Collins AM, Aouizerat B, Stancakova A, Goetzmanz E, Lam MM, Schwer B (2011) SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Mol Cell44: 177-190

[26] Ho L, Titus AS, Banerjee KK, George S, Lin W, Deota S, Saha AK, Nakamura K, Gut P, Verdin E (2013) SIRT4 regulates ATP homeostasis and mediates a retrograde signaling via AMPK. Aging (Albany NY)5: 835

[27] Hubbard BP, Sinclair DA (2014) Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Trends in pharmacological sciences35: 146-154

[28] Jeong J, Juhn K, Lee H, Kim S, Min B, Lee K, Cho MH, Park GH, Lee K (2007) SIRT1 promotes DNA repair activity and deacetylation of Ku70. Experimental and Molecular Medicine39: 8

[29] Jing E, Emanuelli B, Hirschey MD, Boucher J, Lee KY, Lombard D, Verdin EM, Kahn CR (2011) Sirtuin-3 (Sirt3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production. Proc Natl Acad Sci108: 14608-14613

[30] Kaeberlein M, McVey M, Guarente L (1999) The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes & Dev13: 2570-2580

[31] Kaidi A, Weinert BT, Choudhary C, Jackson SP (2010) Human SIRT6 promotes DNA end resection through CtIPdeacetylation. Science329: 1348-1353

[32] Kamel C, Abrol M, Jardine K, He X, McBurney MW (2006) Sirt1 fails to affect p53-mediated biological functions. Aging cell5: 81-88

[33] Kanfi Y, Naiman S, Amir G, Peshti V, Zinman G, Nahum L, Bar- Joseph Z, Cohen HY (2012) The sirtuin SIRT6 regulates lifespan in male mice. Nature483: 218-221

[34] Kawahara TL, Michishita E, Adler AS, Damian M, Berber E, Lin M, McCord RA, Onqaiui KC, Boxer LD, Chang HY (2009) SIRT6 links histone H3 lysine 9 deacetylation to NF-κB-dependent gene expression and organismal life span. Cell136: 62-74

[35] Kim W, Kim JE (2013) SIRT7 an emerging sirtuin: deciphering newer rolES. JPP64: 531-534

[36] Kim HS, Xiao C, Wang RH, Lahusen T, Xu X, Vassilopoulos A, Vazqzuez-Ortiz G, Jeong WI, Park O, Ki SH (2010) Hepaticspecific disruption of SIRT6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis. Cell Metab12: 224-236

[37] Kim MY, Kang EL, Ham SA, Hwang JS, Yoo TS, Lee H, Paek KS, Park C, Lee HT, Kim JH (2012) The PPARδ-mediated inhibition of angiotensin II-induced premature senescence in human endothelial cells is SIRT1-dependent. Biochemical pharmacology84: 1627-1634

[38] Kim JK, Noh JH, Jung KH, Eun JW, Bae HJ, Kim MG, Chang YG, Shen Q, Park WS, Lee JY (2013) Sirtuin7 oncogenic potential in human hepatocellular carcinoma and its regulation by the tumor suppressors MiR-125a-5p and MiR-125b. Hepatology57: 1055-1067

[39] Kincaid B, Bossy-Wetzel E (2013) Forever young: SIRT3 a shield against mitochondrial meltdown, aging, and neurodegeneration. Frontiers in aging neuroscience5: 48

[40] Kugel S, Mostoslavsky R (2012) Chromatin and beyond: the multitasking roles for SIRT6. Trends in biochemical sciences39: 72-81

[41] Kulkarni SS, Cantó C (2014) The molecular targets of Resveratrol. Biochimicaet Biophysica Acta (BBA)-Molecular Basis of Disease14(8): 557-562

[42] Langley E, Pearson M, Faretta M, Bauer UM, Frye RA, Minucci S, Pelicci PG, Kouzarides T (2002) Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. The EMBO journal21: 2383-2396

[43] Lappas M (2012) Anti-inflammatory properties of sirtuin 6 in human umbilical vein endothelial cells. Mediators of Inflammation2012: 597514

[44] Laurent G, de Boer VC, Finley LW, Sweeney M, Lu H, Schug TT, Cen Y, Jeong SM, Li X, Sauve AA (2013) SIRT4 represses peroxisome proliferator-activated receptor α activity to suppress hepatic fat oxidation. Mol Cell Biol33: 4552-4561

[45] Lee HS, Ka SO, Lee SM, Lee SI, Park JW, Park BH (2013) Overexpression of Sirtuin 6 Suppresses Inflammatory Responses and Bone Destruction in Mice With Collagen-Induced Arthritis. Arthritis & Rheumatism65: 1776-1785

[46] Lee N, Kim DK, Kim ES, Park SJ, Kwon JH, Shin J, Park SM, Moon YH, Wang HJ, Gho YS (2014) Comparative interactomes of SIRT6 and SIRT7: Implication of functional links to aging. Proteomics14: 1610-1622

[47] Li K, Casta A, Wang R, Lozada E, Fan W, Kane S, Ge Q, Gu W, Orren D, Luo J (2008) Regulation of WRN protein cellular localization and enzymatic activities by SIRT1-mediated deacetylation. J BiolChem283: 7590-7598

[48] Li Y, Dai D, Lu Q, Fei M, Li M, Wu X (2013) Sirt2 suppresses glioma cell growth through targeting NF-ĸB-miR-21 axis. BiochemBiophys Res Commun441: 661-667

[49] Liu B, Wang J, Chan KM, Tjia WM, Deng W, Guan X, Huang JD, Li KM, Chau PY, Chen DJ (2005) Genomic instability in laminopathy-based premature aging. Nat Med11: 780-785

[50] Liu B, Ghosh S, Yang X, Zheng H, Liu X, Wang Z, Jin G, Zheng B, Kennedy BK, Suh Y (2012) Resveratrol rescues SIRT1- dependent adult stem cell decline and alleviates progeroid features in laminopathy-based progeria. Cell Metab16: 738-750

[51] Luna A, Aladjem MI, Kohn KW (2013) SIRT1/PARP1 crosstalk: connecting DNA damage and metabolism. Genome integrity4: 6

[52] Mao Z, Hine C, Tian X, Van Meter M, Au M, Vaidya A, Seluanov A, Gorbunova V (2011) SIRT6 promotes DNA repair under stress by activating PARP1. Science332: 1443-1446

[53] Mao Z, Tian X, Van Meter M, Ke Z, Gorbunova V, Seluanov A (2012) Sirtuin 6 (SIRT6) rescues the decline of homologous recombination repair during replicative senescence. Proc Natl Acad Sci USA109: 11800-11805

[54] McCord RA, Michishita E, Hong T, Berber E, Boxer LD, Kusumoto R, Guan S, Shi X, Gozani O, Burlingame AL (2009) SIRT6 stabilizes DNA-dependent protein kinase at chromatin for DNA double-strand break repair. Aging (Albany NY)1: 109

[55] Mellini P, Valente S, Mai A (2014) Sirtuin modulators: an updated patent review (2012-2014). Expert Opinion on Therapeutic Patents (0), 1-11

[56] Menghini R, Casagrande V, Cardellini M, Martelli E, Terrinoni A, Amati F, Vasa-Nicotera M, Ippoliti A, Novelli G, Melino G (2009) MicroRNA 217 modulates endothelial cell senescence via silent information regulator 1. Circulation120: 1524-1532

[57] Michishita E, Park JY, Burneskis JM, Barrett JC, Horikawa I (2005) Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol Biol Cell16: 4623-4635

[58] Michishita E, McCord RA, Berber E, Kioi M, Padilla-Nash H, Damian M, Cheung P, Kusumoto R, Kawahara TL, Barrett JC (2008) SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature452: 492-496

[59] Michishita E, McCord RA, Boxer LD, Barber MF, Hong T, Gozani O, Chua KF (2009) Cell cycle-dependent deacetylation of telomeric histone H3 lysine K56 by human SIRT6. Cell Cycle8: 2664-2666

[60] Min SW, Cho SH, Zhou Y, Schroeder S, Haroutunian V, Seeley WW, Huang EJ, Shen Y, Masliah E, Mukherjee C (2010) Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron67: 953-966

[61] Ming M, Han W, Zhao B, Sundaresan NR, Deng CX, Gupta MP, He YY (2014) SIRT6 promotes COX-2 expression and acts as an oncogene in skin cancer. Cancer research74: 5925-5933

[62] Mohamed JS, Wilson JC, Myers MJ, Sisson KJ, Alway SE (2014) Dysregulation of SIRT-1 in aging mice increases skeletal muscle fatigue by a PARP-1-dependent mechanism. Aging6: 820-834

[63] Mortuza R, Chen S, Feng B, Sen S, Chakrabarti S (2013) High glucose induced alteration of SIRTs in endothelial cells causes rapid aging in a p300 and FOXO regulated pathway. PloS one8: e54514

[64] Mostoslavsky R, Chua KF, Lombard DB, Pang WW, Fischer MR, Gellon L, Liu P, Mostoslavsky G, Franco S, Murphy MM (2006) Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell124: 315-329

[65] Nakagawa T, Guarente L (2009) Urea cycle regulation by mitochondrial sirtuin, SIRT5. Aging1: 578-581

[66] Navarro CL, De Sandre-Giovannoli A, Bernard R, Boccaccio I, Boyer A, Geneviève D, Hadj-Rabia S, Gaudy-Marqueste C, Smitt HS, Vabres P (2004) Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal laminopathy. Human molecular genetics13: 2493-2503

[67] Nguyen P, Lee S, Lorang-Lenis D, Trepel J, Smart DK (2014) SIRT2 interacts with β-catenin to inhibit Wnt signaling output in response to radiation-induced stress. Mol Cancer Res12: 1244-1253

[68] North BJ, Rosenberg MA, Jeganathan KB, Hafner AV, Michan S, Dai J, Baker DJ, Cen Y, Wu LE, Sauve AA (2014) SIRT2 induces the checkpoint kinase BubR1 to increase lifespan. The EMBO journal33: 1438-1453

[69] Ota H, Akishita M, Eto M, Iijima K, Kaneki M, Ouchi Y (2007) Sirt1 modulates premature senescence-like phenotype in human endothelial cells. Journal of Molecular and Cellular Cardiology43: 571-579

[70] Ota H, Eto M, Kano MR, Ogawa S, Iijima K, Akishita M, Ouchi Y (2008) Cilostazol inhibits oxidative stress-induced premature senescence via upregulation of Sirt1 in human endothelial cells. Arteriosclerosis, thrombosis, and vascular biology 28: 1634-1639

[71] Paredes S, Villanova L, Chua KF (2014) Molecular Pathways: Emerging Roles of Mammalian Sirtuin SIRT7 in Cancer. Clinical Cancer Research20: 1741-1746

[72] Rajamohan SB, Pillai VB, Gupta M, Sundaresan NR, Birukov KG, Samant S, Hottiger MO, Gupta MP (2009) SIRT1 promotes cell survival under stress by deacetylation-dependent deactivation of poly (ADP-ribose) polymerase 1. Mol Cell Biol29: 4116-4129

[73] Rardin MJ, He W, Nishida Y, Newman JC, Carrico C, Danielson SR, Guo A, Gut P, Sahu AK, Li B (2013) SIRT5 regulates the mitochondrial lysine succinylome and metabolic networks. Cell Metab18: 920-933

[74] Rehan L, Laszki-Szcząchor K, Sobieszczańska M, Polak-Jonkisz D (2014) SIRT1 and NAD as regulators of ageing. Life sciences105: 1-6

[75] Rimmelé P, Bigarella CL, Liang R, Izac B, Dieguez-Gonzalez R, Barbet G, Donovan M, Brugnara C, Blander JM, Sinclair DA (2014) Aging-like Phenotype and Defective Lineage Specification in SIRT1-Deleted Hematopoietic Stem and Progenitor Cells. Stem Cell Reports3: 44-59

[76] Salvioli S, Capri M, Bucci L, Lanni C, Racchi M, Uberti D, Memo M, Mari D, Govoni S, Franceschi C (2009) Why do centenarians escape or postpone cancer? The role of IGF-1, inflammation and p53. Cancer immunology, immunotherapy58: 1909-1917

[77] Satoh A, Brace CS, Rensing N, Cliften P, Wozniak DF, Herzog ED, Yamada KA, Imai SI (2013) Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH. Cell Metab18: 416-430

[78] Saunders LR, Verdin E (2007) Sirtuins: critical regulators at the crossroads between cancer and aging. Oncogene26: 5489-5504

[79] Saunders LR, Sharma AD, Tawney J, Nakagawa M, Okita K, Yamanaka S, Willenbring H, Verdin E (2010) miRNAs regulate SIRT1 expression during mouse embryonic stem cell differentiation and in adult mouse tissues. Aging (Albany NY)2(7): 415-431

[80] Scheibye-Knudsen M, Mitchell SJ, Fang EF, Iyama T, Ward T, Wang J, Dunn CA, Singh N, Veith S, Hasan-olive MM (2014) A high-fat diet and NAD⁺ activate Sirt1 to rescue premature aging in cockayne syndrome. Cell Metab20: 840-855

[81] Schmeisser K, Mansfeld J, Kuhlow D, Weimer S, Priebe S, Heiland I, Birringer M, Groth M, Segref A, Kanfi Y (2013) Role of sirtuins in lifespan regulation is linked to methylation of nicotinamide. NatChemBiol9: 693-700

[82] Schreiber KH, Kennedy BK (2013) When lamins go bad: nuclear structure and disease. Cell152: 1365-1375

[83] Sebastián C, Zwaans BM, Silberman DM, Gymrek M, Goren A, Zhong L, Ram O, Truelove J, Guimaraes AR, Toiber D (2012) The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell151: 1185-1199

[84] Shih J, Donmez G (2013) Mitochondrial sirtuins as therapeutic targets for age-related disorders. Genes & cancer4: 91-96

[85] Shin J, He M, Liu Y, Paredes S, Villanova L, Brown K, Qiu X, Nabavi N, Mohrin M, Wojnoonski K (2013) SIRT7 represses Myc activity to suppress ER stress and prevent fatty liver disease. Cell reports5: 654-665

[86] Shumaker DK, Dechat T, Kohlmaier A, Adam SA, Bozovsky MR, Erdos MR, Eriksson M, Goldman AE, Khuon S, Collins FS (2006) Mutant nuclear laminA leads to progressive alterations of epigenetic control in premature aging. PNAS103: 8703-8708

[87] Sundaresan NR, Vasudevan P, Zhong L, Kim G, Samant S, Parekh V, Pillai VB, Ravindra PV, Gupta M, Jeevanandam V (2012) The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun. Nat Med18: 1643-1650

[88] Thirumurthi U, Shen J, Xia W, LaBaff AM, Wei Y, Li CW, Chang WC, Chen CH, Lin HK, Yu D (2014) MDM2-mediated degradation of SIRT6 phosphorylated by AKT1 promotes tumorigenesis and trastuzumab resistance in breast cancer. Science Signaling7: ra71

[89] Toiber D, Erdel F, Bouazoune K, Silberman DM, Zhong L, Mulligan P, Sebastian C, Cosentino C, Martinez-Pastor B, Giacosa S (2013) SIRT6 recruits SNF2H to DNA break sites, preventing genomic instability through chromatin remodeling. Mol Cell51: 454-468

[90] Tran D, Bergholz J, Zhang H, He H, Wang Y, Zhang Y, Li Q, Kirkland JL, Xiao ZX (2014) Insulin-like growth factor-1 regulates the SIRT1-p53 pathway in cellular senescence. Aging Cell13: 669-678

[91] Uhl M, Csernok A, Aydin S, Kreienberg R, Wiesmüller L, Gatz SA (2010) Role of SIRT1 in homologous recombination. DNA repair9: 383-393

[92] Vakhrusheva O, Smolka C, Gajawada P, Kostin S, Boettger T, Kubin T, Brawn T, Bober E (2008a) Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice. Circulation Research102: 703-710

[93] Vakhrusheva O, Braeuer D, Liu Z, Braun T, Bober E (2008b) Sirt7- dependent inhibition of cell growth and proliferation might be instrumental to mediate tissue integrity during aging. J PhysiolPharmacol59: 201-212

[94] Van Meter M, Mao Z, Gorbunova V, Seluanov A (2011) SIRT6 overexpression induces massive apoptosis in cancer cells but not in normal cells. Cell cycle10: 3153-3158

[95] Vaquero A, Scher M, Lee D, Erdjument-Bromage H, Tempst P, Reinberg D (2004) Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin. Mol Cell16: 93-105

[96] Vassallo PF, Simoncini S, Ligi I, Chateau AL, Bachelier R, Robert S, Morere J, Fernandez S, Guillet B, Marcelli M (2014) Accelerated senescence of cord blood endothelial progenitor cells in premature neonates is driven by SIRT1 decreased expression. Blood123: 2116-2126

[97] Wang F, Tong Q (2009) SIRT2 suppresses adipocyte differentiation by deacetylating FOXO1 and enhancing FOXO1’s repressive interaction with PPARγ. MolBiolCell20: 801-808

[98] Wang F, Nguyen M, Qin F, Tong Q (2007) SIRT2 deacetylates FOXO3a in response to oxidative stress and caloric restriction. Aging cell6: 505-514

[99] Xiao C, Wang RH, Lahusen TJ, Park O, Bertola A, Maruyama T, Reynolds D, Chen Q, Xu X, Young HA (2012) Progression of chronic liver inflammation and fibrosis driven by activation of c-JUN signaling in Sirt6 mutant mice. J BiolChem287: 41903-41913

[100] Xu Z, Zhang L, Fei X, Yi X, Li W, Wang Q (2014) The miR-29b–Sirt1 axis regulates self-renewal of mouse embryonic stem cells in response to reactive oxygen species. Cellular signalling26: 1500-1505

[101] Yamagata K, Kitabayashi I (2009) Sirt1 physically interacts with Tip60 and negatively regulates Tip60-mediated acetylation of H2AX. Biochemical and biophysical research communications390: 1355-1360

[102] Yao H, Chung S, Hwang JW, Rajendrasozhan S, Sundar IK, Dean DA, McBurney MW, Guarente L, Gu W, Ronty M (2012) SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice. J Clin Invest122: 2032-2045

[103] Yoshizawa T, Karim MF, Sato Y, Senokuchi T, Miyata K, Fukuda T, Go S, Tasaki M, Uchimura K, Kadomatsu T (2014) SIRT7 Controls Hepatic Lipid Metabolism by Regulating the Ubiquitin-Proteasome Pathway. Cell metabolism19(4): 712-721

[104] Yuan HF, Zhai C, Yan XL, Zhao DD, Wang JX, Zeng Q, Chen L, Nan X, He LJ, Li ST (2012) SIRT1 is required for long-term growth of human mesenchymal stem cells. Journal of molecular medicine90: 389-400

[105] Yuan H, Su L, Chen WY (2013) The emerging and diverse roles of sirtuins in cancer: a clinical perspective. OncoTargets and therapy6: 1399

[106] Zhong L, D’Urso A, Toiber D, Sebastian C, Henry RE, Vadysirisack DD, Guimaraes A, Marinelli B, Wikstrom JD, Nir T (2010) The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1α. Cell140: 280-293

[107] Zhu H, Zhao L, Wang E, Dimova N, Liu G, Feng Y, Cambi F (2012) The QKI-PLP pathway controls SIRT2 abundance in CNS myelin. Glia60: 69-82

[108] Zhu Y, Yan Y, Principe DR, Zou X, Vassilopoulos A, Gius D (2014) SIRT3 and SIRT4 are mitochondrial tumor suppressor proteins that connect mitochondrial metabolism and carcinogenesis. Cancer & Metabolism2: 1-11

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