Epigenetic regulation of caloric restriction in aging

BMC Medicine

Trygve O Tollefsbol²  Michael Daniel¹  Yuanyuan Li³ 

[1]Department of Biology, University of Alabama at Birmingham, 1300 University Boulevard, Birmingham, AL 35294, USA

[2]Diabetes Comprehensive Center, University of Alabama at Birmingham, 1825 University Boulevard, Birmingham, AL 35294, USA

[3]Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, 1802 6th Avenue South, AL 35294, USA

关键词: aging;    epigenetic;    caloric restriction;   

Others  :  1126714
DOI  :  10.1186/1741-7015-9-98

 received in 2011-05-06, accepted in 2011-08-25,  发布年份 2011

【 摘 要 】

The molecular mechanisms of aging are the subject of much research and have facilitated potential interventions to delay aging and aging-related degenerative diseases in humans. The aging process is frequently affected by environmental factors, and caloric restriction is by far the most effective and established environmental manipulation for extending lifespan in various animal models. However, the precise mechanisms by which caloric restriction affects lifespan are still not clear. Epigenetic mechanisms have recently been recognized as major contributors to nutrition-related longevity and aging control. Two primary epigenetic codes, DNA methylation and histone modification, are believed to dynamically influence chromatin structure, resulting in expression changes of relevant genes. In this review, we assess the current advances in epigenetic regulation in response to caloric restriction and how this affects cellular senescence, aging and potential extension of a healthy lifespan in humans. Enhanced understanding of the important role of epigenetics in the control of the aging process through caloric restriction may lead to clinical advances in the prevention and therapy of human aging-associated diseases.

【 授权许可】

   
2011 Li et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 2.

【 参考文献 】

• [1]Mitchell BD, Hsueh WC, King TM, Pollin TI, Sorkin J, Agarwala R, Schäffer AA, Shuldiner AR: Heritability of life span in the Old Order Amish. Am J Med Genet 2001, 102:346-352.
• [2]Mathers JC: Nutritional modulation of ageing: genomic and epigenetic approaches. Mech Ageing Dev 2006, 127:584-589.
• [3]Sharp ZD, Richardson A: Aging and cancer: can mTOR inhibitors kill two birds with one drug? Target Oncol 2011, 6:41-51.
• [4]Mill J, Dempster E, Caspi A, Williams B, Moffitt T, Craig I: Evidence of monozygotic twin (MZ) discordance in methylation level at two CpG sites in the promoter region of the catechol-O-methyltransferase (COMT) gene. Am J Med Genet B Neuropsychiatr Genet 2006, 141B:421-425.
• [5]Oates NA, van Vliet J, Duffy DL, Kroes HY, Martin NG, Boomsma DI, Campbell M, Coulthard MG, Whitelaw E, Chong S: Increased DNA methylation at the AXIN1 gene in monozygotic twin from a pair discordant for a caudal duplication anomaly. Am J Hum Genet 2006, 79:155-162.
• [6]Petronis A, Gottesman II, Kan P, Kennedy JL, Basile VS, Paterson AD, Popendikyte V: Monozygotic twins exhibit numerous epigenetic differences: clues to twin discordance? Schizophr Bull 2003, 29:169-178.
• [7]Poulsen P, Esteller M, Vaag A, Fraga MF: The epigenetic basis of twin discordance in age-related diseases. Pediatr Res 2007, 61:38R-42R.
• [8]Weindruch R, Walford RL: The Retardation of Aging and Disease by Dietary Restriction. Springfield, IL: Charles C Thomas; 1988:436.
• [9]Sinclair DA: Toward a theory of caloric restriction and longevity regulation. Mech Ageing Dev 2005, 126:987-1002.
• [10]McCay CM, Crowell MF, Maynard LA: The effect of retarded growth upon the length of life span and upon the ultimate body size. 1935. Nutrition 1989, 5:155-171.
• [11]Cooper TM, Mockett RJ, Sohal BH, Sohal RS, Orr WC: Effect of caloric restriction on life span of the housefly, Musca domestica. FASEB J 2004, 18:1591-1593.
• [12]Forster M, Morris P, Sohal R: Genotype of age influence the effect of caloric intake on mortality in mice. FASEB J 2003, 17:690-692.
• [13]Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, Allison DB, Cruzen C, Simmons HA, Kemnitz JW, Weindruch R: Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 2009, 325:201-204.
• [14]Koubova J, Guarente L: How does calorie restriction work? Genes Dev 2003, 17:313-321.
• [15]Richardson A: The effect of age and nutrition on protein synthesis by cells and tissues from mammals. In Handbook of Nutrition in the Aged. Edited by Watson RR. Boca Raton, FL: CRC Press; 1985:31-48.
• [16]Weindruch R, Walford RL, Fligiel S, Guthrie D: The retardation of aging in mice by dietary restriction: Longevity, cancer, immunity and lifetime energy intake. J Nutr 1986, 116:641-654.
• [17]Pugh TD, Oberley TD, Weindruch R: Dietary intervention at middle age: caloric restriction but not dehydroepiandrosterone sulfate increases lifespan and lifetime cancer incidence in mice. Cancer Res 1999, 59:1642-1648.
• [18]Hernandez-Valencia M, Patti ME: A thin phenotype is protective for impaired glucose tolerance and related to low birth weight in mice. Arch Med Res 2006, 37:813-817.
• [19]Ketonen J, Pilvi T, Mervaala E: Caloric restriction reverses high-fat diet-induced endothelial dysfunction and vascular superoxide production in C57Bl/6 mice. Heart Vessels 2010, 25:254-262.
• [20]Wu P, Shen Q, Dong S, Xu Z, Tsien JZ, Hu Y: Calorie restriction ameliorates neurodegenerative phenotypes in forebrain-specific presenilin-1 and presenilin-2 double knockout mice. Neurobiol Aging 2008, 29:1502-1511.
• [21]Sun D, Krishnan A, Su J, Lawrence R, Zaman K, Fernandes G: Regulation of immune function by calorie restriction and cyclophosphamide treatment in lupus-prone NZB/NZW F1 mice. Cell Immunol 2004, 228:54-65.
• [22]Cruzen C, Colman RJ: Effects of caloric restriction on cardiovascular aging in non-human primates and humans. Clin Geriatr Med 2009, 25:733-743.
• [23]Roth GS, Ingram DK, Lane MA: Caloric restriction in primates and relevance to humans. Ann N Y Acad Sci 2001, 928:305-315.
• [24]Holloszy JO, Fontana L: Caloric restriction in humans. Exp Gerontol 2007, 42:709-712.
• [25]Sohal R, Weindruch R: Oxidative stress, caloric restriction, and aging. Science 1996, 273:59-63.
• [26]Merry B: Molecular mechanisms linking calorie restriction and longevity. Int J Biochem Cell Biol 2002, 34:1340-1354.
• [27]Kouzarides T: Chromatin modifications and their function. Cell 2007, 128:693-705.
• [28]Li Y, Tollefsbol TO: Dietary effect on epigenetics during the aging process. In Epigenetics of Aging. Edited by Tollefsbol TO. New York: Springer-Verlag; 2009:407-416.
• [29]Egger G, Liang G, Aparicio A, Jones P: Epigenetics in human disease and prospects for epigenetic therapy. Nature 2004, 429:457-463.
• [30]Hass BS, Hart RW, Lu MH, Lyn-Cook BD: Effects of caloric restriction in animals on cellular function, oncogene expression, and DNA methylation in vitro. Mutat Res 1993, 295:281-289.
• [31]Li Y, Liu L, Tollefsbol T: Glucose restriction can extend normal cell lifespan and impair precancerous cell growth through epigenetic control of hTERT and p16 expression. FASEB J 2010, 24:1442-1453.
• [32]Lin SJ, Defossez PA, Guarente L: Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 2000, 289:2126-2128.
• [33]Guarente L, Picard F: Calorie restriction: the SIR2 connection. Cell 2005, 120:473-482.
• [34]Leibiger IB, Berggren PO: Sirt1: a metabolic master switch that modulates lifespan. Nat Med 2006, 12:34-36.
• [35]Bordone L, Cohen D, Robinson A, Motta MC, van Veen E, Czopik A, Steele AD, Crowe H, Marmor S, Luo J, Gu W, Guarente L: SIRT1 transgenic mice show phenotypes resembling calorie restriction. Aging Cell 2007, 6:759-767.
• [36]Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA: Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 2004, 305:390-392.
• [37]Razin A, Riggs AD: DNA methylation and gene function. Science 1980, 210:604-610.
• [38]Cross SH, Bird AP: CpG islands and genes. Curr Opin Genet Dev 1995, 5:309-314.
• [39]Callinan PA, Feinberg AP: The emerging science of epigenomics. Hum Mol Genet 2006, 15:R95-R101.
• [40]Li E, Beard C, Jaenisch R: Role for DNA methylation in genomic imprinting. Nature 1993, 366:362-365.
• [41]Li E, Beard C, Forster A, Bestor TH, Jaenisch R: DNA methylation, genomic imprinting, and mammalian development. Cold Spring Harb Symp Quant Biol 1993, 58:297-305.
• [42]Chan MF, Liang G, Jones PA: Relationship between transcription and DNA methylation. Curr Top Microbiol Immunol 2000, 249:75-86.
• [43]Goll MG, Bestor TH: Eukaryotic cytosine methyltransferases. Annu Rev Biochem 2005, 74:481-514.
• [44]Chen T, Tsujimoto N, Li E: The PWWP domain of Dnmt3a and Dnmt3b is required for directing DNA methylation to the major satellite repeats at pericentric heterochromatin. Mol Cell Biol 2004, 24:9048-9058.
• [45]Okano M, Bell DW, Haber DA, Li E: DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 1999, 99:247-257.
• [46]Okano M, Takebayashi S, Okumura K, Li E: Assignment of cytosine-5 DNA methyltransferases Dnmt3a and Dnmt3b to mouse chromosome bands 12A2-A3 and 2H1 by in situ hybridization. Cytogenet Cell Genet 1999, 86:333-334.
• [47]Okano M, Xie S, Li E: Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat Genet 1998, 19:219-220.
• [48]Knapowski J, Wieczorowska-Tobis K, Witowski J: Pathophysiology of ageing. J Physiol Pharmacol 2002, 53:135-146.
• [49]Issa JP, Ahuja N, Toyota M, Bronner MP, Brentnall TA: Accelerated age-related CpG island methylation in ulcerative colitis. Cancer Res 2001, 61:3573-3577.
• [50]Issa JP, Ottaviano YL, Celano P, Hamilton SR, Davidson NE, Baylin SB: Methylation of the oesterogen receptor CpG island links ageing and neoplasia in human colon. Nat Genet 1994, 7:536-540.
• [51]Issa JP, Vertino PM, Boehm CD, Newsham IF, Baylin SB: Switch from monoallelic to biallelic human IGF2 promoter methylation during aging and carcinogenesis. Proc Natl Acad Sci USA 1996, 93:11757-11762.
• [52]Singhal RP, Mays-Hoopes LL, Eichhorn GL: DNA methylation in aging of mice. Mech Ageing Dev 1987, 41:199-210.
• [53]Waki T, Tamura G, Sato M, Motoyama T: Age-related methylation of tumor suppressor and tumor-related genes: an analysis of autopsy samples. Oncogene 2003, 22:4128-4133.
• [54]Wilson VL, Smith RA, Ma S, Cutler RG: Genomic 5-methyldeoxycytidine decreases with age. J Biol Chem 1987, 262:9948-9951.
• [55]Kim TY, Lee HJ, Hwang KS, Lee M, Kim JW, Bang YJ, Kang GH: Methylation of RUNX3 in various types of human cancers and premalignant stages of gastric carcinoma. Lab Invest 2004, 84:476-484.
• [56]Vageuro A, Reinberg D: Calorie restriction and the exercise of chromatin. Genes Dev 2009, 23:1849-1869.
• [57]Muñoz-Najar U, Sedivy JM: Epigenetic control of aging. Antioxid Redox Signal 2011, 14:241-259.
• [58]Chouliaras L, van den Hove DL, Kenis G, Dela Cruz J, Lemmens MA, van Os J, Steinbusch HW, Schmitz C, Rutten BP: Caloric restriction attenuates age-related changes in DNA methyltransferases 3a in mouse hippocampus. Brain Behav Immun 2011, 25:616-623.
• [59]So AY, Jung JW, Lee S, Kim HS, Kang KS: DNA Methyltransferase controls stem cell aging by regulating BMI1 and EZH2 through microRNAs. PLoS One 2011, 6:e19503.
• [60]Gore SD: Combination therapy with DNA methyltransferase inhibitors in hematologic malignancies. Nat Clin Pract Oncol 2005, 2(Suppl 1):S30-S35.
• [61]Li Y, Tollefsbol TO: Impact on DNA methylation in cancer prevention and therapy by bioactive dietary compounds. Curr Med Chem 2010, 17:2141-2151.
• [62]Li Y, Yuan YY, Meeran SM, Tollefsbol TO: Synergistic epigenetic reactivation of estrogen receptor-α (ERα) by combined green tea polyphenol and histone deacetylase inhibitor in ERα-negative breast cancer cells. Mol Cancer 2010, 9:274. BioMed Central Full Text
• [63]Li Y, Liu L, Andrews LG, Tollefsbol TO: Genistein depletes telomerase activity through cross-talk between genetic and epigenetic mechanisms. Int J Cancer 2009, 125:286-296.
• [64]Ahima RS: Connecting obesity, aging and diabetes. Nat Med 2009, 15:996-997.
• [65]Larsen TM, Dalskov S, van Baak M, Jebb S, Kafatos A, Pfeiffer A, Martinez JA, Handjieva-Darlenska T, Kunesová M, Holst C, Saris WH, Astrup A: The Diet, Obesity and Genes (Diogenes) Dietary Study in eight European countries: a comprehensive design for long-term intervention. Obes Rev 2009, 11:76-91.
• [66]Milagro FI, Campión J, Cordero P, Goyenechea E, Gómez-Uriz AM, Abete I, Zulet MA, Martínez JA: A dual epigenetic approach for the search of obesity biomarkers: DNA methylation in relation to diet-induced weight loss. FASEB J 2011, 25:1378-1389.
• [67]Bouchard L, Rabasa-Lhoret R, Faraj M, Lovoie ME, Mill J, Pérusse L, Vohl MC: Differential epigenomic and transcriptomic responses in subcutaneous adipose tissue between low and high responders to caloric restriction. Am J Clin Nutr 2010, 91:309-320.
• [68]Campión J, Milagro FI, Goyenechea E, Martínez JA: TNF-α promoter methylation as a predictive biomarker for weight-loss response. Obesity (Silver Spring) 2009, 17:1293-1297.
• [69]Luger K, Mäder AW, Richmond RK, Sargent DF, Richmond TJ: Crystal structure of the nucleosome core particle at 2.8 Å resolution. Nature 1997, 389:251-260.
• [70]Clayton AL, Hazzalin CA, Mahadevan LC: Enhanced histone acetylation and transcription: a dynamic perspective. Mol Cell 2006, 23:289-296.
• [71]de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB: Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J 2003, 370:737-749.
• [72]Strahl BD, Allis CD: The language of covalent histone modifications. Nature 2000, 403:41-45.
• [73]Kadonaga JT: Eukaryotic transcription: an interlaced network of transcription factors and chromatin-modifying machines. Cell 1998, 92:307-313.
• [74]Meyerson M, Counter CM, Eaton EN, Ellisen LW, Steiner P, Caddle SD, Ziaugra L, Beijersbergen RL, Davidoff MJ, Liu Q, Bacchetti S, Haber DA, Weinberg RA: hEST2, the punitive human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell 1997, 90:785-795.
• [75]Kanaya T, Kyo S, Takakura M, Ito H, Namiki M, Inoue M: hTERT is a critical determinant of telomerase activity in renal-cell carcinoma. Int J Cancer 1998, 78:539-543.
• [76]Richon VM, Sandhoff TW, Rifkind RA, Marks PA: Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc Natl Acad Sci 2000, 97:10014-10019.
• [77]Sambucetti LC, Fischer DD, Zabludoff S, Kwon PO, Chamberlin H, Trogani N, Xu H, Cohen D: Histone deacetylase inhibition selectively alters the activity and expression of cell cycle proteins leading to specific chromatin acetylation and antiproliferative effects. J Biol Chem 1999, 274:34940-34947.
• [78]Richon VM, O'Brien JP: Histone deacetylase inhibitors: a new class of potential therapeutic agents for cancer treatment. Clin Cancer Res 2002, 8:662-664.
• [79]Ma X, Ezzeldin HH, Diasio RB: Histone deacetylase inhibitors: current status and overview of recent clinical trials. Drugs 2009, 69:1911-1934.
• [80]Meeran SM, Patel SN, Tollefsbol TO: Sulforaphane causes epigenetic repression of hTERT expression in human breast cancer cell lines. PLoS One 2010, 5:e11457.
• [81]Kanfi Y, Peshti V, Gozlan YM, Rathaus M, Gil R, Cohen HY: Regulation of SIRT1 protein levels by nutrient availability. FEBS Lett 2008, 582:2417-2423.
• [82]Crujeiras AB, Parra D, Goyenechea E, Martínez JA: Sirtuin gene expression in human mononuclear cells is modulated by caloric restriction. Eur J Clin Invest 2008, 38:672-678.
• [83]Wakeling LA, Ions LJ, Ford D: Could Sirt1-mediated epigenetic effects contribute to the longevity response to dietary restriction and be mimicked by other dietary interventions? Age (Dordr) 2009, 31:327-341.
• [84]Li Y, Tollefsbol TO: p16INK4a suppression by glucose restriction contributes to human cellular lifespan extension through Sirt1-mediated epigenetic and genetic mechanisms. PLoS One 2011, 6:e17421.
• [85]Haigis MC, Guarente LP: Mammalian sirtuins: emerging roles in physiology, aging, and calorie restriction. Genes Dev 2006, 20:2913-2921.
• [86]McBurney MW, Yang X, Jardine K, Hixon M, Boekelheide K, Webb JR, Lansdorp PM, Lemieux M: The mammalian SIR2α protein has a role in embryogenesis and gametogenesis. Mol Cell Biol 2003, 23:38-54.
• [87]Cheng HL, Mostoslavsky R, Saito S, Manis JP, Gu Y, Patel P, Bronson R, Appella E, Alt FW, Chua KF: Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc Natl Acad Sci USA 2003, 100:10794-10799.
• [88]Luo J, Nikolaev AY, Imai S, Chen D, Su F, Shiloh A, Guarente L, Gu W: Negative control of p53 by Sir2α promotes cell survival under stress. Cell 2001, 107:137-148.
• [89]Langley E, Pearson M, Faretta M, Bauer UM, Frye RA, Minucci S, Pelicci PG, Kouzarides T: Human sir2 deacetylases p53 and antagonizes PML/p53-induced cellular senescence. EMBO J 2002, 21:2383-2396.
• [90]Vaziri H, Dessain SK, Ng Eaton E, Imai SI, Frye RA, Pandita TK, Guarente L, Weinberg RA: hSIR2SIRT1 functions as a NAD-dependent p53 deacetylase. Cell 2001, 107:149-159.
• [91]Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, Tran H, Ross SE, Mostoslavsky R, Cohen HY, Hu LS, Cheng HL, Jedrychowski MP, Gygi SP, Sinclair DA, Alt FW, Greenberg ME: Stress-dependent regulation of FOXO transcription factors by the sirt1 deacetylase. Science 2004, 303:2011-2015.
• [92]Motta MC, Divecha N, Lemieux M, Kamel C, Chen D, Gu W, Bultsma Y, McBurney MW, Guarente L: Mammalian sirt1 represses forkhead transcription factors. Cell 2004, 116:551-563.
• [93]Schilling MM, Oeser JK, Boustead JN, Flemming BP, O'Brien RM: Gluconeogenesis: re-evaluating the FOXO1-PGC-1α connection. Nature 2006, 443:E10-E11.
• [94]Vega RB, Huss JM, Kelly DP: The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor α in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol Cell Biol 2000, 20:1868-1876.
• [95]Kennedy BK, Gotta M, Sinclair DA, Mills K, McNabbs DS, Murthy M, Park SM, Laroche T, Gasser SM, Guarente L: Redistribution of silencing proteins from telomeres to the nucleolus is associated with extension of lifespan in S. cerevisiae. Cell 1997, 89:381-391.
• [96]Vaquero A, Sternglanz R, Reinberg D: NAD+-dependent deacetylation of H4 lysine 16 by class III HDACs. Oncogene 2007, 26:5505-5520.
• [97]Oberdoerffer P, Michan S, McVay M, Mostoslavsky R, Vann J, Park SK, Hartlerode A, Stegmuller J, Hafner A, Loerch P, Wright SM, Mills KD, Bonni A, Yankner BA, Scully R, Prolla TA, Alt FW, Sinclair DA: Sirt1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 2008, 135:907-918.
• [98]Vaquero A, Scher M, Erdjument-Bromage H, Tempst P, Serrano L, Reinberg D: Sirt1 regulates the histone methyl-transferases SUV39H1 during heterochromatin formation. Nature 2007, 450:440-444.
• [99]Jeong J, Juhn K, Lee H, Kim SH, Min BH, Lee KM, Cho MH, Park GH, Lee KH: Sirt1 promotes DNA repair activity and deacetylation of Ku70. Exp Mol Med 2007, 39:8-13.
• [100]Cohen HY, Lavu S, Bitterman KJ, Hekking B, Imahiyerobo TA, Miller C, Frye R, Ploegh H, Kessler BM, Sinclair DA: Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis. Mol Cell 2004, 13:627-638.
• [101]Wong H, Riabowol K: Differential CDK-inhibitor gene expression in aging human diploid fibroblasts. Exp Gerontol 1996, 31:311-325.
• [102]Gil J, Peters G: Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all. Nat Rev Mol Cell Biol 2006, 7:667-677.
• [103]Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K, Su L, Sharpless NE: Ink4a/Arf expression is a biomarker of aging. J Clin Invest 2004, 114:1299-1307.
• [104]Alcorta DA, Xiong Y, Phelps D, Hannon G, Beach D, Barrett JC: Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Proc Natl Acad Sci USA 1996, 93:13742-13747.
• [105]Melk A, Schmidt BM, Takeuchi O, Sawitzki B, Rayner DC, Halloran PF: Expression of p16INK4a and other cell cycle regulator and senescence associated genes in aging human kidney. Kidney Int 2004, 65:510-520.
• [106]Fischle W, Wang Y, Allis CD: Histone and chromatin cross-talk. Curr Opin Cell Biol 2003, 15:172-183.
• [107]Kouzarides T: Histone methylation in transcriptional control. Curr Opin Genet Dev 2002, 12:198-209.
• [108]Bracken AP, Kleine-Kohlbrecher D, Dietrich N, Pasini D, Gargiulo G, Beekman C, Theilgaard-Mönch K, Minucci S, Porse BT, Marine JC, Hansen KH, Helin K: The polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev 2007, 21:525-530.
• [109]Jacobs JJ, Kieboom K, Marino S, DePinho RA, van Lohuizen M: The oncogene and polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 1999, 397:164-168.
• [110]Kia SK, Gorski MM, Giannakopoulos S, Verrijzer CP: SW1/SNF mediates polycomb eviction and epigenetic reprogramming of the INK4b-ARF-INK4a locus. Mol Cell Biol 2008, 28:3457-3464.
• [111]Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA: Small molecule activators of sirtuins extend Saccharomyces cerevisiae. Nature 2003, 425:191-196.
• [112]Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, Sinclair D: Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 2004, 430:686-689.
• [113]Bass TM, Weinkove D, Houthoofd K, Gems D, Partridge L: Effects of resveratrol on lifespan in Drosophila melanogaster and Caenorhabditis elegans. Mech Ageing Dev 2007, 128:546-552.
• [114]Barger JL, Kayo T, Vann JM, Arias EB, Wang J, Hacker TA, Wang Y, Raederstorff D, Morrow JD, Leeuwenburgh C, Allison DB, Saupe KW, Cartee GD, Weindruch R, Prolla TA: A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS One 2008, 3:e2264.
• [115]Agarwal B, Baur JA: Resveratrol and life extension. Ann N Y Acad Sci 2011, 1215:138-143.
• [116]Fischer-Posovszky P, Kukulus V, Tews D, Unterkircher T, Debatin KM, Fulda S, Wabitsch M: Resveratrol regulates human adipocyte number and function in a Sirt1-dependent manner. Am J Clin Nutr 2010, 92:5-15.
• [117]Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA: Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006, 444:337-342.
• [118]Patel KR, Scott E, Brown VA, Gescher AJ, Steward WP, Brown K: Clinical trials of resveratrol. Ann N Y Acad Sci 2011, 1215:161-169.
• [119]Subramanian L, Youssef S, Bhattacharya S, Kenealey J, Polans AS, van Ginkel PR: Resveratrol: challenges in translation to the clinic: a critical discussion. Clin Cancer Res 2010, 16:5942-5948.
• [120]Yoo CB, Jones PA: Epigenetic therapy of cancer: past, present and future. Nat Rev Drug Discov 2006, 5:37-50.
• [121]Meeran SM, Ahmed A, Tollefsbol TO: Epigenetic targets of bioactive dietary components for cancer prevention and therapy. Clin Epigenetics 2010, 1:101-116.
• [122]Taylor CK, Levy RM, Elliott JC, Burnett BP: The effect of genistein aglycone on cancer and cancer risk: a review of in vitro, preclinical, and clinical studies. Nutr Rev 2009, 67:398-415.
• [123]Jayagopal V, Albertazzi P, Kilpatrick ES, Howarth EM, Jennings PE, Hepburn DA, Atkin SL: Beneficial effects of soy phytoestrogen intake in postmenopausal women with type 2 diabetes. Diabetes Care 2002, 25:1709-1714.
• [124]Kao YH, Chang HH, Lee MJ, Chen CL: Tea, obesity, and diabetes. Mol Nutr Food Res 2006, 50:188-210.
• [125]Shanafelt TD, Call TG, Zent CS, LaPlant B, Bowen DA, Roos M, Secreto CR, Ghosh AK, Kabat BF, Lee MJ, Yang CS, Jelinek DF, Erlichman C, Kay NE: Phase I trial of daily oral Polyphenon E in patients with asymptomatic Rai stage 0 to II chronic lymphocytic leukemia. J Clin Oncol 2009, 27:3808-3814.
• [126]Dhahbi JM, Mote PL, Fahy GM, Spindler SR: Identification of potential caloric restriction mimetics by microarray profiling. Physiol Genomics 2005, 23:343-350.