Calorie Restriction and Cancer Prevention: Established and Emerging Mechanisms

  • Stephen D. HurstingEmail author
  • Nikki A. Ford
  • Sarah M. Dunlap
  • Marcie J. Hursting
  • Laura M. Lashinger
Part of the Energy Balance and Cancer book series (EBAC, volume 7)


Calorie restriction (CR) is one of the most potent, broadly acting dietary interventions for inducing weight loss and for inhibiting cancer in experimental models. Translation of the mechanistic lessons learned from research on CR to cancer prevention strategies in humans is important given the high prevalence of excess energy intake, obesity, and metabolic syndrome in many parts of the world and also given the established links between obesity-associated metabolic perturbations and increased risk and/or progression of many types of cancers. This chapter synthesizes findings on the biological mechanisms underlying many of the anticancer effects of CR, with emphasis on the role of inflammatory processes and growth factor signaling (well-established mechanisms) as well as vascular perturbations, autophagy, and sirtuins (emerging mechanisms). These CR-responsive pathways and processes represent targets for translating CR research into effective cancer prevention strategies in humans.


Vascular Endothelial Growth Factor Calorie Restriction Anticancer Effect mTOR Complex Visceral White Adipose Tissue 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Hursting SD, Smith SM, Lashinger LM, Harvey AE, Perkins SN (2010) Calories and carcinogenesis: lessons learned from 30 years of calorie restriction research. Carcinogenesis 31:83–89PubMedGoogle Scholar
  2. 2.
    Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, Allison DB, Cruzen C, Simmons HA, Kemnitz JW, Weindruch R (2009) Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325:201–204PubMedGoogle Scholar
  3. 3.
    Mattson JA, Roth GS, Beasley TM, Tilmon EM, Handy AM, Herbert RL, Longo DL, Allison DB, Young JE, Bryant M, Barnard D, Ward WF, Qi W, Ingram DK, deCabo R (2012) Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature 489(7415):318–321. doi: 10.1038/nature11432 Google Scholar
  4. 4.
    Harvie M, Howell A (2012) Energy restriction and the prevention of breast cancer. Proc Nutr Soc 71:263–275PubMedGoogle Scholar
  5. 5.
    Imayama I, Ulrich CM, Alfanao CM, Wang C, Xiao L, Wner MH, Campbell KL, Duggan C, Foster-Schubert KE, Kong A, Mason CE, Wnag CY, Blackburn GL, Bain CE, Thompson HJ, McTiernan A (2012) Effects of a caloric restriction weight loss diet and exercise on inflammatory biomarkers in overweight/obese postmenopausal women: a randomized controlled trial. Cancer Res 72:2314–2326PubMedGoogle Scholar
  6. 6.
    Campbell KL, Foster-Schubert KE, Alfano CM, Wang CC, Wang CY, Duggan CR, Mason C, Imayama I, Kong A, Bain CE, Blackburn GL, Stanczyj FZ, McTiernan A (2012) ­Reduced-calorie dietary weight loss, exercise and sex hormones in postmenopausal women: a randomized control trial. J Clin Oncol 30:2314–2326PubMedGoogle Scholar
  7. 7.
    Kagawa Y (1978) Impact of westernization on the nutrition of Japanese: changes in physique, cancer, longevity and centenarians. Prev Med 7:205–217PubMedGoogle Scholar
  8. 8.
    Michels KB, Ekbom A (2004) Caloric restriction and incidence of breast cancer. J Am Med Assoc 291:1226–1230Google Scholar
  9. 9.
    Tretli S, Gaard M (1996) Lifestyle changes during adolescence and risk of breast cancer: an ecologic study of the effect of World War II in Norway. Cancer Causes Control 7:507–512PubMedGoogle Scholar
  10. 10.
    Elias SG, Peeters PH, Grobbee DE, van Noord PA (2005) The 1944–1945 Dutch famine and subsequent overall cancer incidence. Cancer Epidemiol Biomarkers Prev 14:1981–1985PubMedGoogle Scholar
  11. 11.
    Keinan-Boker L, Vin-Raviv N, Lipshitz I, Linn S, Barchana M (2009) Cancer incidence in Israeli Jewish survivors of World War II. J Natl Cancer Inst 101:1489–1500PubMedGoogle Scholar
  12. 12.
    Koupil I, Plavinskaja S, Parfenova N, Shestov DB, Danziger PD, Vagero D (2009) Cancer mortality in women and men who survived the siege of Leningrad (1941–1944). Int J Cancer 124:1416–1421PubMedGoogle Scholar
  13. 13.
    Hursting SD, Forman MR (2009) Cancer risk from extreme stressors: lessons from European Jewish survivors of World War II. J Natl Cancer Inst 101:1436–1437PubMedGoogle Scholar
  14. 14.
    Heilbronn LK, de Jonge L, Frisard MI, DeLany JP, Larson-Meyer DE, Rood J, Nguyen T, Martin CK, Volaufova J, Most MM, Greenway FL, Smith SR, Deutsch WA, Williamson DA, Ravussin E (2009) Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial. JAMA 295:1539–1548Google Scholar
  15. 15.
    Redman LM, Heilbronn LK, Martin CK, de Jonge L, Williamson DA, Delany JP, Ravussin E (2009) Metabolic and behavioral compensations in response to caloric restriction: implications for the maintenance of weight loss. PLoS One 4:e4377PubMedGoogle Scholar
  16. 16.
    Colditz GA, Wollin KY, Gehlert S (2012) Applying what we know to accelerate cancer prevention. Sci Transl Med 127(4):1–9Google Scholar
  17. 17.
    Harvey AE, Lashinger LM, Hursting SD (2011) The growing challenge of obesity and cancer: an inflammatory subject. Ann N Y Acad Sci 1229:45–52PubMedGoogle Scholar
  18. 18.
    Subbaramaiah K, Howe LR, Bhardway P, Du B, Gravaghi C, Yantiss RK, Zhou XK, Blaho VA, Hia T, Yang P, Kopelovich L, Hudis CA, Dannenberg AJ (2011) Obesity is associated with inflammation and elevated aromatase expression in the mouse mammary gland. Cancer Prev Res 4:329–346Google Scholar
  19. 19.
    Olefsky JM, Glass CK (2010) Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 72:219–246PubMedGoogle Scholar
  20. 20.
    O’Rourke RW (2009) Inflammation in obesity-related diseases. Surgery 145:255–259PubMedGoogle Scholar
  21. 21.
    Renehan AG, Roberts DL, Dive C (2008) Obesity and cancer: pathophysiological and ­biological mechanisms. Arch Physiol Biochem 114:71–83PubMedGoogle Scholar
  22. 22.
    Karin M (2006) Nuclear factor-kappaB in cancer development and progression. Nature 441:431–436PubMedGoogle Scholar
  23. 23.
    Virchow R (1865) Aetiologie der neoplastischen Geschwulst/Pathogenie der neoplastischen Geschwulste [Etiology and pathology of cancerous tumors]. Die Krankhaften Geschwulste. Verlag von August Hirschwald, Berlin, p 57–101Google Scholar
  24. 24.
    Aggarwal BB, Gehlot P (2009) Inflammation and cancer: how friendly is the relationship for patients? Curr Opin Pharmacol 9:351–369PubMedGoogle Scholar
  25. 25.
    Ono M (2008) Molecular links between tumor angiogenesis and inflammation: inflammatory stimuli of macrophages and cancer cells as targets for therapeutic strategy. Cancer Sci 99:1501–1506PubMedGoogle Scholar
  26. 26.
    Del Prete A, Allavena P, Santoro G, Fumarulo R, Corsi MM, Mantovani A (2011) Molecular pathways in cancer-related inflammation. Biochem Med 21:264–275Google Scholar
  27. 27.
    Foltz CJ, Fox JG, Cahill R, Murphy JC, Yan L, Shames B, Schauer DB (1998) Spontaneous inflammatory bowel disease in multiple mutant mouse lines: association with colonization by Helicobacter hepaticus. Helicobacter 3:69–78PubMedGoogle Scholar
  28. 28.
    Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867PubMedGoogle Scholar
  29. 29.
    Allavena P, Sica A, Garlanda C, Mantovani A (2008) The Yin-Yang of tumor-associated macrophages in neoplastic progression and immune surveillance. Immunol Rev 222:155–161PubMedGoogle Scholar
  30. 30.
    Koki A, Khan NK, Woerner BM, Dannenberg AJ, Olson L, Seibert K, Edwards D, Hardy M, Isakson P, Masterrer JL (2002) Cyclooxygenase-2 in human pathological disease. Adv Exp Med Biol 507:177–184PubMedGoogle Scholar
  31. 31.
    Perkins SN, Hursting SD, Phang JM, Haines DC (1998) Calorie restriction reduces ulcerative dermatitis and infection-related mortality in p53-deficient and wild-type mice. J Invest Dermatol 111:292–296PubMedGoogle Scholar
  32. 32.
    Harvey A, Lashinger L, Otto G, Malone L, Hursting SD (2012) Decreased systemic insulin-like growth factor-1 in response to calorie restriction modulates tumor growth, NF-kB activation, and inflammation-related gene expression. Mol Carcinog. doi: 10.1002/mc.21940
  33. 33.
    Lashinger LM, Malone LM, Brown GW, Daniels EA, Goldberg JA, Otto G, Fischer SM, Hursting SD (2011) Rapamycin partially mimics the anticancer effects of calorie restriction in a murine model of pancreatic cancer. Cancer Prev Res 4:1041–1051Google Scholar
  34. 34.
    Sica A, Schioppa T, Mantovani A, Allavena P (2006) Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anticancer therapy. Eur J Cancer 42:717–727PubMedGoogle Scholar
  35. 35.
    Pollak M (2012) The insulin and insulin-like growth factor family in neoplasia: an update. Nat Rev Cancer 12:159–169PubMedGoogle Scholar
  36. 36.
    Hursting SD, Berger NA (2010) Energy balance, host-related factors, and cancer progression. J Clin Oncol 28:4058–4065PubMedGoogle Scholar
  37. 37.
    Gallagher EJ, Fierz Y, Ferguson RD, LeRoith D (2010) The pathway from diabetes and obesity to cancer, on the route to targeted therapy. Endocr Pract 16:864–873PubMedGoogle Scholar
  38. 38.
    Renehan AG, Zwahlen M, Minder C, O’Dwyer ST, Shalet SM, Egger M (2004) Insulin-like growth factor (IGF)-1, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet 363:1346–1353PubMedGoogle Scholar
  39. 39.
    Price AJ, Allen NE, Appleby PN, Crowe FL, Travis RC, Tipper SJ, Overvad K, Gronbæk H, Tjonneland A, Fons Johnsen N, Rinaldi S, Kaaks R, Lukanova A, Boeing H, Aleksandrova K, Trichopoulou A, Trichopoulos D, Andarakis G, Palli D, Krogh V, Tumino R, Sacerdote C, Bueno-de-Mesquita HB, Arguelles MV, Sanchez MJ, Chirlaque MD, Barricarte A, Larranaga N, Gonzalez CA, Stattin P, Johansson M, Khaw KT, Wareham NJ, Gunter MJ, Riboli E, Key TJ (2012) Insulin-like growth factor-1 concentration and risk of prostate cancer: results from the European Prospective Investigation into Cancer and Nutrition. Cancer Epidemiol Biomarkers Prev 21(9):1531–1541. doi: 10.1158/1055-9965.EPI-12-0481-T PubMedGoogle Scholar
  40. 40.
    Wong KK, Engelman JA, Cantley LC (2010) Targeting the PI3K signaling pathway in cancer. Curr Opin Genet Dev 20:87–90PubMedGoogle Scholar
  41. 41.
    Memmott RM, Dennis PA (2009) Akt-dependent and -independent mechanisms of mTOR regulation in cancer. Cell Signal 21:656–664PubMedGoogle Scholar
  42. 42.
    Moore T, Beltran LD, Carbajal S, Strom S, Traag J, Hursting SD, DiGiovanni J (2008) Dietary energy balance modulates signaling through the Akt/mammalian target of rapamycin pathway in multiple epithelial tissues. Cancer Prev Res 1:65–76Google Scholar
  43. 43.
    Lindsley JE, Rutter J (2004) Nutrient sensing and metabolic decisions. Comp Biochem Physiol B Biochem Mol Biol 139:543–559PubMedGoogle Scholar
  44. 44.
    De Angel RE, Conti CJ, Wheatley KE, Brenner AJ, deGraffenried LA, Hursting SD (2012) The enhancing effects of obesity on mammary tumor growth and Akt/mTOR pathway ­activation persist after weight loss and are reversed by Rad001. Mol Carcinog. doi: 10.1002/mc.21878
  45. 45.
    Nogueira LM, Dunlap SM, Ford NA, Hursting SD (2012) Calorie restriction and rapamycin inhibit MMTV-Wnt-1 mammary tumor growth in a mouse model of postmenopausal obesity. Endocr Relat Cancer 19:57–68PubMedGoogle Scholar
  46. 46.
    Vaiopoulos AG, Marinou K, Christodoulides C, Koutsilieris M (2012) The role of ­adiponectin in human vascular physiology. Int J Cardiol 155:188–193PubMedGoogle Scholar
  47. 47.
    Barb D, Williams CJ, Neuwirth AK, Mantzoros CS (2007) Adiponectin in relation to malignancies: a review of existing basic research and clinical evidence. Am J Clin Nutr 86:s858–s866PubMedGoogle Scholar
  48. 48.
    Stofkova A (2009) Leptin and adiponectin: from energy and metabolic dysbalance to inflammation and autoimmunity. Endocr Regul 43:157–168PubMedGoogle Scholar
  49. 49.
    Gautron L, Elmquist JK (2011) Sixteen years and counting: an update on leptin in energy balance. J Clin Invest 121:2087–2093PubMedGoogle Scholar
  50. 50.
    Villanueva EC, Myers MG (2008) Leptin receptor signaling and the regulation of mammalian physiology. Int J Obes 32(suppl 7):S8–S12Google Scholar
  51. 51.
    Rogozina OP, Bonorden MJ, Seppanen CN, Grande JP, Cleary MP (2011) Effect of chronic and intermittent calorie restriction on serum adiponectin and leptin and mammary tumorigenesis. Cancer Prev Res 4:568–581Google Scholar
  52. 52.
    Dalamaga M, Diakopoulos KN, Mantzoros CS (2012) The role of adiponectin in cancer: a review of current evidence. Endocr Rev 33:547–594PubMedGoogle Scholar
  53. 53.
    Grossmann ME, Nkhata KJ, Mizuno NK, Ray A, Cleary MP (2008) Effects of adiponectin on breast cancer cell growth and signaling. Br J Cancer 98:370–379PubMedGoogle Scholar
  54. 54.
    Rzepka-Gorska I, Bedner R, Cymbaluk-Ploska A, Chudecka-Glaz A (2008) Serum adiponectin in relation to endometrial cancer and endometrial hyperplasia with atypia in obese women. Eur J Gynaecol Oncol 29:594–597PubMedGoogle Scholar
  55. 55.
    Tian YF, Chu CH, Wh MH, Chang CL, Yang T, Chou YC, Hsu GC, Yu CP, Yu JC, Sun CA (2007) Anthropometric measures, plasma adiponectin, and breast cancer risk. Endocr Relat Cancer 14:669–677PubMedGoogle Scholar
  56. 56.
    Stattin P, Lukanova A, Biessy C, Soderberg S, Palmqvist R, Kaaks R, Olsson T, Jellum E (2004) Obesity and colon cancer: does leptin provide a link? Int J Cancer 109:149–152PubMedGoogle Scholar
  57. 57.
    Zheng Q, Dunlap SM, Zhu J, Downs-Kelly E, Rich JN, Hursting SD, Berger NA, Reizes O (2011) Leptin deficiency suppresses MMV-Wnt-1 mammary tumor growth in obese mice and abrogates tumor initiating cell survival. Endocr Relat Cancer 18:491–503PubMedGoogle Scholar
  58. 58.
    Fenton JI, Hord NG, Lavigne JA, Perkins SN, Hursting SD (2005) Leptin, insulin-like growth factor-1, and insulin-like growth factor-2 are mitogens in ApcMin/+ but not Apc+/+ colonic epithelial cells. Cancer Epidemiol Biomarkers Prev 14:1646–1652PubMedGoogle Scholar
  59. 59.
    Jung CH, Rhee EJ, Choi JH, Bae JC, Yoo SH, Kim WJ, Park CY, Mok JO, Kim CH, Lee WY, Oh KW, Park SW, Kim SW (2010) The relationship of adiponectin/leptin ratio with homeostasis model assessment insulin resistance index and metabolic syndrome in apparently healthy Korean male adults. Korean Diabetes J 34:237–243PubMedGoogle Scholar
  60. 60.
    Mirza S, Qu HQ, Li Q, Martinez PJ, Rentfro AR, McCormick JB, Fisher-Hoch SP (2011) Adiponectin/leptin ratio and metabolic syndrome in a Mexican American population. Clin Invest Med 34:E290PubMedGoogle Scholar
  61. 61.
    Labruna G, Pasanisi F, Nardelli C, Caso R, Vitale DF, Contaldo F, Sacchetti L (2011) High leptin/adiponectin ratio and serum triglycerides are associated with an “at-risk” phenotype in young severely obese patients. Obesity 19:1492–1496PubMedGoogle Scholar
  62. 62.
    Cleary MP, Ray A, Rogozina OP, Dogan S, Grossman ME (2009) Targeting the adiponectin:leptin ratio for postmenopausal breast cancer prevention. Front Biosci 1:329–357Google Scholar
  63. 63.
    Ashizawa N, Yahata T, Quan J, Adachi S, Yoshihara, Tanaka K (2010) Serum leptin-adiponectin ratio and endometrial cancer risk in postmenopausal female subjects. Gynecol Oncol 119:65–69PubMedGoogle Scholar
  64. 64.
    Chen DC, Chung YF, Yeh YT, Chaung HC, Kuo FC, Fu OY, Chen HY, Hou ME, Yuan SS (2006) Serum adiponectin and leptin levels in Taiwanese breast cancer patients. Cancer Lett 237:109–114PubMedGoogle Scholar
  65. 65.
    Iwaki T, Urano T, Umemura K (2012) PAI-1, progress in understanding the clinical problem and its etiology. Br J Haematol 157:291–298PubMedGoogle Scholar
  66. 66.
    Skurk T, Hauner H (2004) Obesity and impaired fibrinolysis: role of adipose production of plasminogen activator inhibitor-1. Int J Obes Relat Metab Disord 28:1357–1364PubMedGoogle Scholar
  67. 67.
    Carter JC, Church FC (2009) Obesity and breast cancer: the roles of peroxisome proliferator-activated receptor-gamma and plasminogen activator inhibitor-1. PPAR Res 2009:345320–345333PubMedGoogle Scholar
  68. 68.
    McMahon GA, Petitclerc E, Stefansson S, Smith E, Wong MK, Westwick RJ, Ginsburg D, Brooks PC, Lawrence DA (2001) Plasminogen activator inhibior-1 regulates tumor growth and angiogenesis. J Biol Chem 276:33964–33968PubMedGoogle Scholar
  69. 69.
    Byrne AM, Bouchier-Hayes DJ, Harmey JH (2005) Angiogenic and cell survival functions of vascular endothelial growth factor (VEGF). J Cell Mol Med 9:777–794PubMedGoogle Scholar
  70. 70.
    Saharinen P, Eklund L, Pulkki K, Bono P, Alitalo K (2011) VEGF and angiopoietin signaling in tumor angiogenesis and metastasis. Trends Mol Med 17:347–362PubMedGoogle Scholar
  71. 71.
    Cao Y (2007) Angiogenesis modulates adipogenesis and obesity. J Clin Invest 117:2362–2368PubMedGoogle Scholar
  72. 72.
    Liu Y, Tamimi RM, Collins LC, Schnitt SJ, Gilmore HL, Connolly JL, Colditz GA (2011) The association between vascular endothelial growth factor expression in invasive breast cancer and survival varies with intrinsic subtypes and use of adjuvant systemic therapy: results from the Nurses’ Health Study. Breast Cancer Res Treat 129:175–184PubMedGoogle Scholar
  73. 73.
    Powolny AA, Wang S, Carlton PS, Hoot DR, Clinton SK (2008) Interrelationships between dietary restriction, the IGF-1 axis, and expression of vascular endothelial growth factor by prostate adenocarcinoma in rats. Mol Carcinog 47:458–476PubMedGoogle Scholar
  74. 74.
    Lashinger LM, Malone LM, MacArthur MJ, Goldberg JA, Daniels EA, Pavone A, Colby JK, Smith NC, Perkins SN, Fischer SM, Hursting SD (2011) Genetic reduction of insulin-like growth factor-1 mimics the anticancer effects of calorie restriction on cyclooxygenase-2-driven pancreatic neoplasia. Cancer Prev Res 4:1030–1040Google Scholar
  75. 75.
    Blando J, Moore T, Hursting SD, Jiang G, Saha A, Beltran L, Shen J, Repass J, Strom S, DiGiovanni J (2011) Dietary energy balance modulates prostate cancer progression in Hi-Myc mice. Cancer Prev Res 4:2002–2014Google Scholar
  76. 76.
    Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y (2004) In vivo analysis of autophagy in response to nutrient starvation in mice expressing a fluorescent autophagosome marker. Mol Biol Cell 15:1101–1111PubMedGoogle Scholar
  77. 77.
    Ezaki J, Matsumoto N, Takeda-Ezaki M, Komatsu M, Takahashi K, Hiraoka Y, Taka H, Fujimura T, Takehana K, Yoshida M, Iwata J, tanida I, Furuya N, Zheng DM, Tada N, Tanaka K, Kominami E, Ueno T (2011) Liver autophagy contributes to the maintenance of blood glucose and amino acid levels. Autophagy 7:727–736PubMedGoogle Scholar
  78. 78.
    Kapahi P, Chen D, Rogers AN, Katewa SD, Li PW, Thomas EL, Kockel L (2010) With TOR, less is more: a key role for the conserved nutrient-sensing pathway in aging. Cell Metab 11:453–465PubMedGoogle Scholar
  79. 79.
    Chang YY, Juhasz G, Goraksha-Hicks P, Arsham AM, Mallin DR, Muller LK, Neufield TP (2009) Nutrient-dependent regulation of autophagy through the target of rapamycin pathway. Biochem Soc Trans 37:232–236PubMedGoogle Scholar
  80. 80.
    Kim J, Kundu M, Viollet B, Guan KL (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13:132–141PubMedGoogle Scholar
  81. 81.
    Madeo F, Tavermarakis N, Kroemer G (2010) Can autophagy promote longevity? Nat Cell Biol 12:842–846PubMedGoogle Scholar
  82. 82.
    Guo JY, Chen HY, Matthew R, Fan J, Strohecker AM, Karsli-Uzunbas G, Kamphorst JJ, Chen G, Lemons JM, Karantza V, Coller HA, Dipaola RS, Gelinas C, Rabinowitz JD, White E (2011) Activated ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev 25:460–470PubMedGoogle Scholar
  83. 83.
    Yang T, Fu M, Pestell R, Sauve AA (2006) SIRT1 and endocrine signaling. Trends Endocrinol Metab 17:186–191PubMedGoogle Scholar
  84. 84.
    Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA (2004) Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305:390–392PubMedGoogle Scholar
  85. 85.
    Metoyer CF, Pruitt K (2008) The role of sirtuin proteins in obesity. Pathophysiology 15:103–108PubMedGoogle Scholar
  86. 86.
    Lin SJ, Defossez PA, Guarente L (2000) Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289:2126–2128PubMedGoogle Scholar
  87. 87.
    Tissenbaum HA, Guarente L (2001) Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410:227–230PubMedGoogle Scholar
  88. 88.
    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 (2007) SIRT1 transgenic mice show phenotypes resembling calorie restriction. Aging Cell 6:759–767PubMedGoogle Scholar
  89. 89.
    Ramsey KM, Mills KF, Satoh A, Imai S (2008) Age-associated loss of Sirt1-mediated enhancement of glucose-stimulated insulin secretion in beta cell-specific Sirt1-overexpressing (BESTO) mice. Aging Cell 7:78–88PubMedGoogle Scholar
  90. 90.
    Nemoto S, Fergusson MM, Finkel T (2005) SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}. J Biol Chem 280:16456–16460PubMedGoogle Scholar
  91. 91.
    Lim CS (2006) SIRT1: tumor promoter or tumor suppressor? Med Hypotheses 67:341–344PubMedGoogle Scholar
  92. 92.
    Ford J, Jiang M, Milner J (2005) Cancer-specific functions of SIRT1 enable human epithelial cancer cell growth and survival. Cancer Res 65:10457–10463PubMedGoogle Scholar
  93. 93.
    Chen WY, Wang DH, Yen RC, Luo J, Gu W, Baylin SB (2005) Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. Cell 123:437–448PubMedGoogle Scholar
  94. 94.
    Zhao W, Kruse JP, Tang Y, Jung SY, Qin J, Gu W (2008) Negative regulation of the deacetylase SIRT1 by DBC1. Nature 451:587–590PubMedGoogle Scholar
  95. 95.
    Suzuki K, Hayashi R, Ichikawa T, Imanishi S, Yamada T, Inomata M, Miwa T, Matsui S, Usui I, Urakaze M, Matsuya Y, Ogawa H, Sakaurai H, Salki I, Tobe K (2012) SRT 1720, a SIRT1 activator, promotes tumor cell migration and lung tumor metastasis of breast cancer in mice. Oncol Rep 27:1726–1732PubMedGoogle Scholar
  96. 96.
    Firestein R, Blander G, Michan S, Oberdoerffer P, Ogino S, Campbell J, Bhimavarapu A, Luikenhuis S, de Cabo R, Fuchs C, Hahn WC, Guarente LP, Sinclair DA (2008) The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS One 3:e2020PubMedGoogle Scholar
  97. 97.
    Baur JA, Sinclair DA (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5:493–506PubMedGoogle Scholar
  98. 98.
    Herranz D, Iglesias G, Munoz-Maerin M, Serrano M (2011) Limited role of Sirt1 in cancer protection by dietary restriction. Cell Cycle 10:2215–2217PubMedGoogle Scholar
  99. 99.
    Lee CK, Klopp RG, Weindruch R, Prolla TA (1999) Gene expression profile of aging and its retardation by caloric restriction. Science 285:1390–1393PubMedGoogle Scholar
  100. 100.
    Cao SX, Dhahbi JM, Mote PL, Spindler SR (2001) Genomic profiling of short- and long-term caloric restriction effects in the liver of aging mice. Proc Natl Acad Sci U S A 98:10630–10635PubMedGoogle Scholar
  101. 101.
    Padovani M, Lavigne JA, Chandramouli GVR, Perkins SN, Barrett JC, Hursting SD, Bennett LM, Berrigan D (2009) Distinct effects of calorie restriction and exercise on mammary gland gene expression in C57BL/6 mice. Cancer Prev Res 2:1076–1087Google Scholar
  102. 102.
    Wheatley KE, Nogueira LM, Perkins SN, Hursting SD (2011) Differential effects of calorie restriction and exercise on the adipose transcriptome in diet-induced obese mice. J Obes 2011:265417PubMedGoogle Scholar
  103. 103.
    Nogueira LM, Lavigne JA, Perkins SN, Chandramoulli GVR, Lui H, Barrett JC, Hursting SD (2012) Dose-dependent effects of calorie restriction on metabolism, gene expression and mammary tumor burden are partially mediated by insulin-like growth factor-1. Cancer Med 1(2):275–288PubMedGoogle Scholar
  104. 104.
    Sachdev D, Yee D (2007) Disrupting insulin-like growth factor signaling as a potential cancer therapy. Mol Cancer Ther 6:1–12PubMedGoogle Scholar
  105. 105.
    McKinsey EL, Parrish JK, Irwin AE, Niemeyer BF, Kern HB, Birks DK, Jedlicka P (2011) A novel oncogenic mechanism in Ewing sarcoma involving IGF pathway targeting by EWS/Fli1-regulated microRNA’s. Oncogene 30:4910–4920PubMedGoogle Scholar
  106. 106.
    Gullett NP, Ruhul A, Bayraktar S, Pezzuto JM, Shin DM, Khuri FR, Aggarwal BB, Surh YJ, Kucuk O (2010) Cancer prevention with natural compounds. Semin Oncol 37:258–281PubMedGoogle Scholar
  107. 107.
    Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA (2009) Rapamycin fed late in life extends lifespan in genetically herterogeneous mice. Nature 460:392–395PubMedGoogle Scholar
  108. 108.
    Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, Davis JG, Salmon AB, Richardson A, Ahima RS, Guertin DA, Sabatini DM, Bauer JA (2012) Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335:1638–1643PubMedGoogle Scholar
  109. 109.
    Pollak MN (2012) Investigating metformin for cancer prevention and treatment: the end of the beginning. Cancer Discov 2(9):778–790PubMedGoogle Scholar
  110. 110.
    Dowling RJ, Niraula S, Stambolic V, Goodwin PJ (2012) Metformin in cancer: translational challenges. J Mol Endocrinol 48:R31–R43PubMedGoogle Scholar
  111. 111.
    Decensi A, Puntoni M, Goodwin P, Cazzaniga M, Gennari A, Bonammi B, Gandini S (2010) Metformin and cancer risk in diabetic patients: a systematic review and metaanalysis. Cancer Prev Res 3:1451–1461Google Scholar
  112. 112.
    Currie CJ, Poole CD, Gale EA (2009) The influence of glucose—lowering therapies on cancer risk in type 2 diabetics. Diabetologia 52:1766–1777PubMedGoogle Scholar
  113. 113.
    Goodwin PJ, Stambolic V, Lemieux J, Chen BE, Parulekar WR, Gelmon KA, Hershman DL, Hobday TJ, Ligibel JA, Mayer IA, Pritchard KI, Whelan TJ, Rastogi P, Shepherd LE (2011) Evaluation of metformin in early breast cancer: a modification of the traditional paradigm for clinical testing of antic-cancer agents. Breast Cancer Res Treat 126:215–220PubMedGoogle Scholar
  114. 114.
    Aljada A, Dong L, Mousa SA (2010) Sirtuin-targeting drugs: mechanisms of action and potential therapeutic applications. Curr Opin Investig Drugs 11:1158–1168PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Stephen D. Hursting
    • 1
    • 2
    Email author
  • Nikki A. Ford
    • 1
  • Sarah M. Dunlap
    • 1
  • Marcie J. Hursting
    • 3
  • Laura M. Lashinger
    • 1
  1. 1.Department of Nutritional SciencesThe University of Texas at AustinAustinUSA
  2. 2.Department of Molecular CarcinogenesisThe University of Texas-MD Anderson Cancer CenterSmithvilleUSA
  3. 3.Clinical Science ConsultingAustinUSA

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